Conditions: Tuberculosis, Pulmonary Tuberculosis, Multidrug-Resistant Tuberculosis, MDR Tuberculosis Extensively Drug-Resistant Tuberculosis Pre-XDR-TB XDR-TB
Keywords: Tuberculosis Multi Drug-Resistant Tuberculosis Extensively Drug-Resistant Tuberculosis Drug-Resistant Tuberculosis Pretomanid PA-824 Bedaquiline Linezolid NC-007 TB Alliance pre-XDR-TB Sirturo Zyvox ZeNix
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 181
Healthy volunteers: no

Brief summary:
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB.

Detailed description:
A phase 3, multi-center, partially-blinded, randomized clinical trial in 4 parallel treatment groups. Bedaquiline and pretomanid treatment will not be blinded. Linezolid treatment dose and duration will be double-blinded.

Participants will have a screening period of up to 14 days and will be randomized to receive one of the 4 active treatment arms. Participants will be randomized to one of the 4 regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will utilize a randomization system using stratification with a random element to allocate participants evenly across the arms by HIV status and type of TB.

Each participant will receive 26 weeks of treatment. If participant's week 16 sputum sample is culture positive between the week 16 and week 26 treatment visits and their clinical condition suggests they may have an ongoing TB infection, Investigator may consider extending current treatment to 39 weeks. If the culture results between week 16 and week 26 are contaminated, missing or considered an isolated positive without clinical significance, available culture results should be used to make this decision. All decisions regarding treatment extension should be discussed with and approved by, in consultation with the Sponsor Medical Monitor before implementation. The treatment may also require modification due to toxicities. All dose modifications should be discussed with the Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required urgently for safety concerns.

Participants will be followed for 78 weeks after end of treatment.

Arms:
arm 1: 2 linezolid 600 mg active tablets once daily for 26 weeks plus 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks arm 2: 2 linezolid 600 mg active tablets once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks arm 3: 1 linezolid 600 mg active tablet once daily for 26 weeks, 1 placebo linezolid 600 mg tablet once daily for 26 weeks, 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks arm 4: 1 linezolid 600 mg active tablets once daily for 8 weeks, 1 placebo linezolid 600 mg half tablet once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks

Interventions: intervention 1: Pretomanid intervention 2: Linezolid intervention 3: Bedaquiline intervention 4: Placebo Linezolid
Intervention descriptions: intervention 1: 200mg tablets intervention 2: Scored 600mg tablets intervention 3: 100mg tablets intervention 4: Scored 600 mg tablets

Protocol document:
ICF_002.pdf: 
Global Alliance for TB Drug Development 
Clinical Trial Report 
NC-007-(B-Pa-L) 
ZeNix 
CONFIDENTIAL 
 
16.1.3 
List of Institutional Review Boards and Sample Informed Consent Form 
16.1.3.1 
List of Institutional Review Boards 
IRB (name/address) 
Country/ Agency 
Type 
Site Number 
University of Witwatersrand 
Johannesburg - Human Research 
Ethics Committee: (Medical) 
Suite 189, Private Bag x2600, 
Houghton 2041, South Africa 
South Africa/ Central 
1001 
1003 
1004 
1011 
IEC of National Center for 
Tuberculosis and Lung Disease 
8, Adzharskaya str., Tbilisi, 0101, 
Georgia 
Georgia/ Local 
1105 
Local Ethics Committee at Central 
Research Institute of Tuberculosis 
107564, Russia, Moscow, 2, 
Yauzskaya lane 
Russia/ Local 
1206 
National Medical Research Centre 
of Phthisiopulmonology and 
Infectious Diseases 
620039, Russia, Yekaterinburg , 
22nd Partsesd Str, Bld 50 
Russia/ Local 
1207 
Ethics Committee at FSBI “St.-
Petersburg Research Institute of 
Phthisiopulmonology” 
194064, Russia, Saint Petersburg, 32 
Politekhicheskaya St. 
Russia/ Local 
1208 
Ethics Committee at Ural Scientific 
Research Institution of 
Phthiziopulmonology 
620039, Russia, Yekaterinburg , 
22nd Partsesd Str, Bld 50 
Russia/ Local 
1209 
Moscow City Independent Ethics 
Committee 
125458, Russia, Moscow, 
Leningradskiy Prospekt, 51 
Russia/ Local 
1210 
The RF MoH, Department of State 
Regulation of Circulation of 
Medicines, Ethics Council 
125458, Russia, Moscow, 
Leningradskiy Prospekt, 51 
Russia/ Central 
1210 
The National Committee for Ethical 
Review of Clinical Trials 
MD 2009, Chisinau Mun., 3 A. 
Cosmescu str. 
Moldova/ Central 
2201 
16.1.3.2 
Sample Consent Form 
NC-007, Version 1.0, Addendum PIIC, 13JUN2018 
1 of 124


Global Alliance for TB Drug Development 
 
Clinical Trial Report 
NC-007-(B-Pa-L) 
 
ZeNix 
CONFIDENTIAL 
 
 
NC-007, Version 1.0, Master Addendum Parent, 13JUN2018 
NC-007, Version 1.0, Master Addendum Paeds, 13JUN2018 
NC-007, Version 2.0, Master HIV PIIC, 13JUN2018 
NC-007, Version 2.0, Master Main Paeds, 13JUN2018 
NC-007, Version 2.0, Master Main PIIC, 13JUN2018 
NC-007, Version 2.0, Master Parent PIIC, 13JUN2018 
NC-007, Version 2.0, HIV Paeds, 13JUN2018 
NC-007, Version 2.0, HIV Parent, 13JUN2018 
 
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Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date V X dd-mmm-yyyy                             M aster Addendum Version 1.0 Date13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-F V1.0  
 
Confidential | Page 1 of 6 
 
ADDENDUM TO THE 
PARTICIPANT INFORMATION AND INFORMED CONSENT FORM 
 
Protocol Number:  NC-007 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-
resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive 
multi-drug resistant tuberculosis (MDR-TB). 
 
Participant Initials:  
 
 
 
Participant Number: 
 
 
 
 
Introduction 
 
We previously invited you to take part in a study with a new combination of medicines. 
The names of the medicines are bedaquiline, linezolid, and pretomanid. 
 
You have signed the main informed consent form before you agreed to take part in 
this study.  It is important that you continue to read and understand the main informed 
consent form, at the same time as reading this new information. 
 
The sponsor has made some changes to the study. This form will tell you what these 
changes are and will provide information to help explain the study better.   
 
1. How will the study work? 
1 
 
The screening period, which is the time your study doctor is checking if you meet the 
requirements and if it is safe for you to be part of the study, is extended from 9 days 
to 14 days.  
 
The study doctor may decide to pause all your medications at any time during the 
treatment period. The study doctor may also decide that your linezolid medicine 
dose needs to be reduced, paused, or just your linezolid medicine needs to be 
stopped. If your dose of linezolid is reduced any time during the study, the study 
doctor may increase your linezolid dosage at a later visit, but not higher than the 
dose you started on.     
 
 
2. What will happen to me in the study? 
2 
 
In addition to the procedures listed in the previous main informed consent you 
signed, an additional eye exam will be performed on week 23 of your treatment 
period if you haven’t already reached week 23 when you sign this consent. 
3 of 124


Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date V X dd-mmm-yyyy                             M aster Addendum Version 1.0 Date13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-F V1.0  
 
Confidential | Page 2 of 6 
 
We will record when you are discharged from the hospital.  
 
If we collect sputum or TB bacteria from tests done before you are screened, it may 
be used to check the type of TB and what medication will work on that type of TB 
bacteria.  
 
Early Withdrawal  
 
There are different visits and procedures done depending on whether you 
withdrawal while you are still taking study medication or if you withdrawal during the 
follow-up after you complete the treatment.  The main informed consent only listed 
what was done if you withdrew while you were getting treatment. What will be done 
in each situation is detailed below: 
 
 
 
Early Withdrawal During Treatment Period  
Procedures 
 
Early Withdrawal 
Visit During 
Treatment 
Follow-up  
Week 12 
Follow-up  
Week 26 
Follow-up 
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count  
X 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
4 of 124


Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date V X dd-mmm-yyyy                             M aster Addendum Version 1.0 Date13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-F V1.0  
 
Confidential | Page 3 of 6 
 
If you haven’t had all your follow-up visits when you are withdrawn from the study, 
we may request that you to come back for 1 more visit at the clinic so we can 
monitor your health as well.  
 
Early Withdrawal During Follow-up Period 
Procedures 
 
Early Withdrawal 
Visit During Follow-
up  
Follow-up  
Week 12 (If 
applicable) 
Follow-up  
Week 26 (if 
applicable) 
Follow-up  
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count 
 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
 
 
3. Are there things that I cannot do while I’m in the study? 
3 
 
Male participants and your female sex partners need to use at least 1 method of 
birth control for as long as you are taking the study medicine and for up to 12 weeks 
(instead of 6 months as noted in the main consent) after you have taken the last 
dose of study medicine. Methods of birth control for female partners are different 
from the main consent and from female participants.  For female partners of male 
participants, hormone based contraceptives or IUDS can be used alone (at least 
one barrier method must be used with those methods for female participants). 
 
 
5 of 124


Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date V X dd-mmm-yyyy                             M aster Addendum Version 1.0 Date13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-F V1.0  
 
Confidential | Page 4 of 6 
 
Please note that it is your own responsibility to get the correct birth control for you 
from your family planning or birth control clinic.  Please speak with your study doctor 
if you are unsure of where to get the correct birth control.  
 
4. Whom can I contact if something worries me? 
4 
 
You can call the study doctor or another authorised person at any time 
of the day or night (24 hours) on Tel: <<add>> or <<add>>. 
 
  
Please refer to the main informed consent form for more information on whom to 
contact if you have complaints about this study. 
 
5. How do I agree to continue to be in this study? 
5 
 
If you want to continue to take part in this study, please read the consent statement 
and sign on the next page. 
 
 
6 of 124


Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date V X dd-mmm-yyyy                             M aster Addendum Version 1.0 Date13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-F V1.0  
 
Confidential | Page 5 of 6 
 
PARTICIPANT INFORMED CONSENT FORM 
 
By signing below, I agree that: 
 
• 
I have read, or someone has read the information sheet and consent form for this 
study to me, and I understand it. 
• 
I have had the chance to ask questions and I am happy with the answers. 
• 
I have had time to discuss the information with others and to decide if I want to 
take part. 
• 
I will get a signed and dated copy of this consent form on the day that I sign it. 
• 
I agree of my own free will to take part in this study. I know I have the right to stop 
taking part at any time, without giving any reason. If I stop taking part, it will not 
change my medical care or legal rights. 
• 
Site staff, representatives from the sponsor, including auditors, regulatory 
authorities and ethics committees can have direct access to my medical 
records. They will treat my information as confidential. 
• 
Add information about data collected being used up to the point of withdrawal.  
• 
<<Females only: “Follow up information on the outcome of my pregnancy can 
be collected, if needed.”>> 
• 
<<EU: “I consent to the processing/storing of my data and the transfer thereof to 
countries outside the EU.”>> 
• 
<<USA: I understand that I would additionally have to sign a HIPAA research data 
protection form.”>> 
 
 
 
Printed Name of Participant<</Legal 
Representative>> 
 
 
 
Signature/mark/thumb print of Participant<</Legal 
Representative>> 
 
Date 
 
 
(Participant/witness must write 
date) 
 
 
*Printed Name of Person Conducting Consent 
(If other than investigator<</delegate>>) 
 
 
 
*Signature of Person Conducting Consent 
 
Date 
7 of 124


Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date V X dd-mmm-yyyy                             M aster Addendum Version 1.0 Date13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-F V1.0  
 
Confidential | Page 6 of 6 
 
(If other than investigator<</delegate>>) 
 
 
(Person conducting consent must 
write date) 
 
I,   
(Insert name of investigator) 
hereby confirm that the above participant has been fully informed about the nature, 
conduct and risks of the above study. 
 
 
 
Signature of Investigator 
 
Date 
 
 
(Inv estigator must write date) 
 
By signing below, I verify that the above participant gave verbal informed consent. 
The participant has been informed about the risks and the benefits of the study, 
understands such risks and benefits and is able to agree to participation, without 
coercion, undue influence or inappropriate incentives. 
 
 
 
*Printed Name of Witness 
 
 
 
*Signature of Witness 
 
Date 
 
 
(Witness must write date) 
* Where applicable 
 
 
8 of 124


Addendum to the Parent or Legal Guardian Information and Informed Consent Form  
Prot ocol Version and Dat e: V X dd-mmm-yyyy       M aster Addendum Parent/Guardian Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy   
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 1 of 6 
 
ADDENDUM TO THE 
PARENT OR LEGAL GUARDIAN INFORMATION AND INFORMED 
CONSENT FORM 
 
Protocol Number:  NC-007 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-
resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive 
multi-drug resistant tuberculosis (MDR-TB). 
 
Participant Initials:  
 
 
 
Participant Number: 
 
 
 
 
Introduction 
 
We previously invited your child to take part in a study with a new combination of 
medicines. The names of the medicines are bedaquiline, linezolid, and pretomanid. 
 
You have signed the parent or legal guardian informed consent form before you 
agreed for your child to take part in this study.  It is important that you continue to 
read and understand the parent or legal guardian informed consent form, at the 
same time as reading this new information. 
 
The sponsor has made some changes to the study. This form will tell you what these 
changes are and will provide information to help explain the study better.   
 
1. How will the study work? 
1 
 
The screening period, which is the time your study doctor is checking if your child 
meets the requirements and if it is safe for him/her to be part of the study, is 
extended from 9 days to 14 days.  
 
The study doctor may decide to pause all your medications for your child at any 
time during the treatment period. The study doctor may also decide that your child’s 
linezolid medicine dose needs to be reduced, paused, or just your child’s linezolid 
medicine needs to be stopped. If your child’s dose of linezolid is reduced any time 
during the study, the study doctor may increase your child’s linezolid dosage at a 
later visit, but not higher than the starting dose.     
 
 
2. What will happen to my child in the study? 
2 
 
9 of 124


Addendum to the Parent or Legal Guardian Information and Informed Consent Form  
Prot ocol Version and Dat e: V X dd-mmm-yyyy       M aster Addendum Parent/Guardian Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy   
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 2 of 6 
 
In addition to the procedures listed in the previous parent or legal guardian informed 
consent you signed, an additional eye exam will be performed on week 23 of the 
treatment period if your child hasn’t already reached week 23 when this consent is 
signed 
. 
We will record when your child is discharged from the hospital.  
 
If we collect sputum or TB bacteria from tests done before your child is screened, it 
may be used to check the type of TB and what medication will work on that type of 
TB bacteria.  
 
Early Withdrawal  
 
There are different visits and procedures done depending on whether your child 
withdrawals while he/she is still taking study medication or if your child withdrawals 
during the follow-up after he/she completes the treatment.  The parent or legal 
guardian consent only listed what was done if your child withdrew while he/she was 
getting treatment. What will be done in each situation is detailed below: 
 
 
 
Early Withdrawal During Treatment Period  
Procedures 
 
Early Withdrawal 
Visit During 
Treatment 
Follow-up  
Week 12 
Follow-up  
Week 26 
Follow-up 
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count  
X 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
10 of 124


Addendum to the Parent or Legal Guardian Information and Informed Consent Form  
Prot ocol Version and Dat e: V X dd-mmm-yyyy       M aster Addendum Parent/Guardian Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy   
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 3 of 6 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
If your child hasn’t had all of their follow-up visits when they are withdrawn from the 
study, we may request that your child come back for 1 more visit at the clinic so we 
can monitor their health as well.  
 
Early Withdrawal During Follow-up Period 
Procedures 
 
Early Withdrawal 
Visit During Follow-
up  
Follow-up  
Week 12 (If 
applicable) 
Follow-up  
Week 26 (if 
applicable) 
Follow-up  
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count 
 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
 
 
3. Are there things that my child cannot do while I’m in the study? 
3 
 
Male participants and your female sex partners need to use at least 1 method of 
birth control for as long as you are taking the study medicine and for up to 12 weeks 
(instead of 6 months as noted in the main consent) after you have taken the last 
dose of study medicine. Methods of birth control for female partners are different 
from the main consent and from female participants.  For female partners of male 
participants, hormone based contraceptives or IUDS can be used alone (at least 
one barrier method must be used with those methods for female participants). 
11 of 124


Addendum to the Parent or Legal Guardian Information and Informed Consent Form  
Prot ocol Version and Dat e: V X dd-mmm-yyyy       M aster Addendum Parent/Guardian Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy   
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 4 of 6 
 
 
 
Please note that it is your own responsibility to get the correct birth control for you 
from your family planning or birth control clinic.  Please speak with your study doctor 
if you are unsure of where to get the correct birth control.  
 
4. Whom can I contact if something worries me or my child? 
4 
 
You can call the study doctor or another authorised person at the study 
site at any time of the day or night (24 hours) on Tel: <<add>> or 
<<add>>. 
 
  
Please refer to the parent or legal guardian informed consent form for more 
information on whom to contact if you have complaints about this study. 
 
5. How do I agree for my child  to continue to be in this study? 
5 
 
If you want your child to continue to take part in this study, please read the consent 
statement and sign on the next page. 
 
 
12 of 124


Addendum to the Parent or Legal Guardian Information and Informed Consent Form  
Prot ocol Version and Dat e: V X dd-mmm-yyyy       M aster Addendum Parent/Guardian Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy   
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 5 of 6 
 
PARTICIPANT INFORMED CONSENT FORM 
 
By signing below, I agree that: 
 
• 
I have read, or someone has read the information sheet and consent form for this 
study to me, and I understand it. 
• 
I have had the chance to ask questions and I am happy with the answers. 
• 
I have had time to discuss the information with others and to decide if I want my 
child to take part. 
• 
I will get a signed and dated copy of this consent form on the day that I sign it. 
• 
I agree of my own free will to let my child take part in this study. I know my child 
has the right to stop taking part at any time, without giving any reason. If my 
child stops taking part, it will not change his/her medical care or legal rights. 
• 
Site staff, representatives from the sponsor, including auditors, regulatory 
authorities and ethics committees can have direct access to my child’s medical 
records. They will treat my child’s information as confidential. 
• 
If my child withdraws from the study, study data collected about him/her up to 
the point of his/her withdrawal can still be used to carry out this study.   
• 
Girls only: “if my child becomes pregnant while on the study, follow-up 
information on the outcome of my child’s pregnancy can be collected, if 
needed.” 
<<EU: “I consent to the processing/storing of my data and the transfer thereof to 
countries outside the EU.”>> 
 
 
 
 
Printed Name of Parent/Legal Guardian 
 
 
 
Signature/mark/thumb print of Parent/Legal 
Guardian 
 
Date 
 
 
(Parent or Legal Guardian/witness 
must write date) 
 
 
*Printed Name of Person Conducting Consent 
(If other than investigator/delegate) 
 
 
 
13 of 124


Addendum to the Parent or Legal Guardian Information and Informed Consent Form  
Prot ocol Version and Dat e: V X dd-mmm-yyyy       M aster Addendum Parent/Guardian Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy   
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 6 of 6 
 
*Signature of Person Conducting Consent 
(If other than investigator/delegate) 
 
Date 
 
 
(Person conducting consent must 
write date) 
 
I,   
(Insert name of investigator) 
hereby confirm that the above Parent or Legal Guardian has been fully informed about the 
nature, conduct and risks of the above study. 
 
 
 
Signature of Investigator 
 
Date 
 
 
(Inv estigator must write date) 
 
By signing below, I verify that the above Parent or Legal Guardian gave verbal 
informed consent. The Parent or Legal Guardian has been informed about the risks 
and the benefits of the study, understands such risks and benefits and is able to 
agree to participation, without coercion, undue influence or inappropriate 
incentives. 
 
 
 
*Printed Name of Witness 
 
 
 
*Signature of Witness 
 
Date 
 
 
(Witness must write date) 
* Where applicable 
 
 
14 of 124


Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date: V X dd-mmm-yyyy                 M aster Addendum Paedeatric Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 1 of 6 
 
ADDENDUM TO THE 
PAEDIATRIC INFORMATION AND ASSENT FORM (14-17 YEARS AGE) 
 
 
Protocol Number:  NC-007 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-
resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive 
multi-drug resistant tuberculosis (MDR-TB). 
 
Participant Initials:  
 
 
 
Participant Number: 
 
 
 
 
Introduction 
 
We previously asked you to take part in a study with a new medicines. The names of 
the medicines are bedaquiline, linezolid, and pretomanid. 
 
You have signed the paediatric informed assent form before you agreed to take part 
in this study.  It is important that you continue to read and understand the paediatric 
informed assent form, at the same time as reading this new information. 
 
The sponsor has made some changes to the study. This form will tell you what these 
changes are and will provide information to help explain the study better.   
 
1. How will the study work? 
1 
 
The screening period, which is the time your study doctor will check if you qualify  
meet the requirements and if it is safe for you to be part of the study, has been 
changed from 9 days to 14 days.  
 
Your study doctor may decide to pause, reduce (lessen), or stop your linezolid. Your 
study doctor will tell you if you dose is changed. If your dose of linezolid is reduced 
anytime during the study, the study doctor may increase your linezolid dosage at a 
later visit- but not higher than the dose you started on.  
 
Your study doctor may pause or stop all the study medicines. 
 
 
2. What will happen to me in the study? 
2 
 
In addition to the procedures that you already know will happen from paediatric 
informed assent form you signed, another eye exam will be performed on week 23 
of your treatment period if you haven’t already reached week 23 when you sign this. 
15 of 124


Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date: V X dd-mmm-yyyy                 M aster Addendum Paedeatric Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 2 of 6 
 
 
We will record when you are discharged from the hospital.  
 
If we collect sputum or TB bacteria from tests done before you are screened, it may 
be used to check the type of TB and what medication will work on that type of TB 
bacteria.  
 
Early Withdrawal  
 
There are different visits and procedures done depending on whether you 
withdrawal while you are still taking study medication or if you withdrawal after you 
complete the treatment.  The paediatric informed assent form only listed what was 
done if you withdrew while you were getting treatment. What will be done in each 
situation is below: 
 
 
 
Early Withdrawal During Treatment Period  
Procedures 
 
Early Withdrawal 
Visit During 
Treatment 
Follow-up  
Week 12 
Follow-up  
Week 26 
Follow-up 
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count  
X 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
16 of 124


Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date: V X dd-mmm-yyyy                 M aster Addendum Paedeatric Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 3 of 6 
 
If you haven’t had all your follow-up visits when you are withdrawn from the study, 
we may request that you to come back for 1 more visit at the clinic so we can 
monitor your health as well.  
 
Early Withdrawal During Follow-up Period 
Procedures 
 
Early Withdrawal 
Visit During Follow-
up  
Follow-up  
Week 12 (If 
applicable) 
Follow-up  
Week 26 (if 
applicable) 
Follow-up  
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count 
 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
 
 
3. Are there things that I cannot do while I’m in the study? 
3 
 
We updated the assent Boys and now boys cannot take part in this study if you are 
planning to make someone pregnant during the treatment period or 12 weeks 
(instead of 6 months) after the last dose of study medicine 
 
If you are a boy and you sometimes have sex, you and your girlfriend must either use 
2 methods of birth control as we discussed above for the girls or use one form that 
your study doctor says you can use such as the birth control pill or an IUD.   
 
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Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date: V X dd-mmm-yyyy                 M aster Addendum Paedeatric Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 4 of 6 
 
Please talk to your study doctor if you are unsure of where to get the correct birth 
control. You are responsible for getting the correct birth control from your family 
planning or birth control clinic. 
 
4. Whom can I contact if something worries me? 
4 
 
You can call the study doctor or another authorised person at the study 
site any time of the day or night (24 hours) on Tel: <<add>> or <<add>>. 
 
  
Please refer to the paediatric informed assent form for more information on who to 
contact if you have complaints about this study. 
 
5. How do I agree to continue to be in this study? 
5 
 
If you want to continue to take part in this study, please read the statement and sign 
on the next page. 
 
 
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Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date: V X dd-mmm-yyyy                 M aster Addendum Paedeatric Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 5 of 6 
 
PARTICIPANT INFORMED CONSENT FORM 
 
By signing below, I agree that: 
 
• 
I have read the information sheet and consent form for this study, or someone 
has read it to me, and I understand it. 
• 
I have had the chance to ask questions and I am happy with the answers. 
• 
I have had time to discuss the information with others and to decide if I want to 
take part. 
• 
I will get a signed and dated copy of this consent form on the day that I sign it. 
• 
I agree of my own free will to take part in this study. I know I have the right to stop 
taking part at any time, without giving any reason. If I stop taking part, it will not 
change my medical care or legal rights. 
• 
Site staff, representatives from the sponsor, including auditors, regulatory 
authorities and ethics committees can have direct access to my medical 
records. They will treat my information as confidential. 
• 
If I withdraw from the study, study data collected about me up to the point of my 
withdrawal can still be used to carry out this study.   
• 
Girls only: “If I become pregnant on the study, follow-up information on the 
outcome of my pregnancy can be collected, if needed.” 
<<EU: “I consent to the processing/storing of my data and the transfer thereof to 
countries outside the EU.”>> 
 
 
 
Printed Name of Participant<</Legal 
Representative>> 
 
 
 
Signature/mark/thumb print of Participant<</Legal 
Representative>> 
 
Date 
 
 
(Participant/witness must write 
date) 
 
 
*Printed Name of Person Conducting Consent 
(If other than investigator<</delegate>>) 
 
 
 
*Signature of Person Conducting Consent 
(If other than investigator<</delegate>>) 
 
Date 
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Addendum to the Participant Information and Informed Consent Form  
Protocol Version and Date: V X dd-mmm-yyyy                 M aster Addendum Paedeatric Version 1 Dated13-Jun-2018 
Master Country/Site Version X Date dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 6 of 6 
 
 
 
(Person conducting consent must 
write date) 
 
I,   
(Insert name of investigator) 
hereby confirm that the above participant has been fully informed about the nature, 
conduct and risks of the above study. 
 
 
 
Signature of Investigator 
 
Date 
 
 
(Inv estigator must write date) 
 
By signing below, I verify that the above participant gave verbal informed consent. 
The participant has been informed about the risks and the benefits of the study, 
understands such risks and benefits and is able to agree to participation, without 
coercion, undue influence or inappropriate incentives. 
 
 
 
*Printed Name of Witness 
 
 
 
*Signature of Witness 
 
Date 
 
 
(Witness must write date) 
* Where applicable 
 
 
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Testing for HIV Participant Information and Informed Consent 
Protocol Version and Date V X dd-mmm-yyyy                  Master Study HIV PI/IC Version 2.0 Date 13-Jun-2018  
 
Mast er Country/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-C V2.0 
 
Confidential | Page 1 of 8 
 
PARTICIPANT INFORMATION AND INFORMED CONSENT FORM  
TESTING FOR HIV  
 
Protocol Name/Number:  ZeNix/NC-007-(B-Pa-L) 
Protocol Title:  
 
 
A Phase 3 partially-blinded, randomized trial assessing the  
safety and efficacy of various doses and treatment durations of linezolid plus  
bedaquiline and pretomanid in participants with pulmonary infection of either  
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or  
non-responsive multi-drug resistant tuberculosis (MDR-TB). 
 
Participant Initials:  
 
 
  Participant Number: 
 
 
 
 
Introduction  
 
This information sheet contains only information about testing for HIV in the study. 
Please read the main consent form that you have already signed for information 
about the main clinical study. 
 
Please read this information sheet before you agree to have the HIV test done as part 
of the main study. This document will answer the following questions: 
 
1. What is HIV? 
1 
 
2. Why are you testing me for HIV? 
2 
 
3. How will you do the HIV test? 
3 
 
4. What can go wrong with the HIV test? 
4 
 
5. How can the HIV test help me? 
5 
 
6. What happens if I am injured during the HIV test? 
6 
 
7. Will you keep my HIV test private? 
7 
 
8. Will you pay me to do the HIV test? 
8 
 
9. Will I have to pay for the HIV test? 
9 
 
10. Whom can I contact if something worries me? 
10 
 
11. How do I agree to have the HIV test? 
11 
 
If you have any other questions that are not answered in this document, please ask 
someone from the study staff for more information. We explained some difficult 
medical terms in the Glossary on page <<XX>>. 
 
 
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Testing for HIV Participant Information and Informed Consent 
Protocol Version and Date V X dd-mmm-yyyy                  Master Study HIV PI/IC Version 2.0 Date 13-Jun-2018  
 
Mast er Country/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-C V2.0 
 
Confidential | Page 2 of 8 
 
It is very important that you understand this information sheet before you agree to 
have your HIV test done. We would like you to ask as many questions as you need. 
If there is anything that you do not understand, please discuss this with the study 
doctor, the study staff, your own doctor, or with your family. 
 
Participant Notes 
 
 
 
 
 
 
1. What is HIV? 
1 
 
The human immunodeficiency virus (HIV) is a virus that causes acquired 
immunodeficiency syndrome (AIDS).  This is a condition in humans where the system 
that protects the body against diseases (immune system), begins to fail.  This leads to 
other infections, which the body would normally be able to fight, being able to grow 
and thrive. These infections can be life-threatening and are known as opportunistic 
infections*.  
How is HIV spread? 
Infection with HIV occurs by the transfer of blood, semen or other similar fluid, 
vaginal fluid, or breastmilk in which HIV is present.  The three major ways of getting 
HIV are: 
• 
having sex without a condom,  
• 
sharing needles, and  
• 
a mother with HIV gives birth, or if she breastfeeds her baby.  
How does HIV affect my body? 
HIV mainly infects cells in the immune system*, called CD4 cells, and causes the 
number of CD4 cells to drop.  When the number of CD4 cells drop below a certain 
amount, the body can no longer fight infection, and opportunistic infections may 
increase.  
How is HIV treated? 
If left untreated, most people who are HIV positive will get AIDS and die. However, 
about 1 in 10 people remain healthy for many years, with no obvious symptoms. 
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Testing for HIV Participant Information and Informed Consent 
Protocol Version and Date V X dd-mmm-yyyy                  Master Study HIV PI/IC Version 2.0 Date 13-Jun-2018  
 
Mast er Country/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-C V2.0 
 
Confidential | Page 3 of 8 
 
People with HIV are treated with anti-retrovirals (i.e. the medications used to fight 
the HIV virus). Using anti-retroviral medicine may help people to live longer.  
 
2. Why are you testing me for HIV? 
2 
 
This study has nothing to with HIV/AIDS or its treatment.  However, we need to test 
you for HIV as part of the study, and it may be unsafe for you to take part in the 
study if: 
• 
your CD4 count is lower than a certain number (<100 cells/µL) 
• 
you have had an existing TB and HIV diagnosis, you are taking HIV medicine and 
your viral load ("viral load" is a term that people living with HIV use to talk about 
how much of the virus is in their body) is higher than a certain number (>1000 
copies/mL) 
• 
you are diagnosed with tuberculosis and HIV and your study doctor recommends 
that the start of your HIV medicine should not be postponed until you have 
received at least 2 weeks of  an anti-tuberculosis regimen. and/or 
• 
you are currently receiving HIV medicine which cannot safely be taken with the 
study medicine and your study doctor decides it is not best for you to change 
your HIV medicine. 
 
You can take part in the study if you meet the other criteria for the study and if you 
test positive for HIV, and 
• 
your CD4 count is equal to or more than a certain number (≥ 100 cells/µL) 
• 
if you have previously been diagnosed with TB and your viral load is <1000 
copies/mL 
• 
you have a new TB and HIV diagnosis  
• 
you are diagnosed with tuberculosis and HIV and your study doctor agrees that 
the start of your HIV medicine may be postponed until you have received at 
least 2 weeks of an anti-tuberculosis regimen 
• 
HIV medicine that you will take during the study is safe to be taken with the study 
medicine; 
OR if you are HIV negative.  
 
3. How will you do the HIV test? 
3 
23 of 124


Testing for HIV Participant Information and Informed Consent 
Protocol Version and Date V X dd-mmm-yyyy                  Master Study HIV PI/IC Version 2.0 Date 13-Jun-2018  
 
Mast er Country/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-C V2.0 
 
Confidential | Page 4 of 8 
 
 
We will take an extra blood sample of 5 mL(about 1 teaspoon) in the main study. This 
extra blood sample will be taken at the same time as the routine blood samples in 
the clinical part of the study. It will not be necessary to prick you with a needle 
again. 
 
4. What can go wrong with the HIV test? 
4 
 
The risk when we take a blood sample includes discomfort where we prick you with 
the needle or you may have a bruise, bleed, and only rarely, get an infection, or 
faint. 
 
The following negative things may happen if you have an HIV test (especially if the 
result is that you are HIV positive): 
 
• 
friends, family and colleagues may possibly reject you and discriminate 
against you; 
• 
 you may have emotional problems, feel more stressed and feel uncertain 
about the future. 
 
5. How can the HIV test help me? 
5 
 
If you test negative, you may feel less worried after knowing your HIV status, and 
take steps to prevent yourself from getting HIV.   If you know you are HIV positive, it 
may reduce the stress that comes with the uncertainty of not knowing.  You can 
take advantage of treating your HIV early, monitoring your health, eating well and 
healthily.  You will also know if you can infect others, and what to do to stop this from 
happening.   
 
Women and their partners thinking about getting pregnant can take advantage of 
treatments that can help prevent their baby from getting HIV.   You can also possibly 
plan for future care of your children. 
 
6. What happens if I am injured during the HIV test? 
6 
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Testing for HIV Participant Information and Informed Consent 
Protocol Version and Date V X dd-mmm-yyyy                  Master Study HIV PI/IC Version 2.0 Date 13-Jun-2018  
 
Mast er Country/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-C V2.0 
 
Confidential | Page 5 of 8 
 
 
The insurance that the TB Alliance has taken out as required by the laws and 
regulations of your country covers the extra blood samples. For more details, see the 
information sheet describing the main clinical study. 
 
7. Will you keep my HIV test private? 
7 
 
We will respect your confidentiality* and only the study doctor and research team 
will know the results of the test.  Selected people working for TB Alliance, as well as 
representatives of government regulatory authorities and ethics committees will also 
have access to the results. These persons know that they must keep your information 
private.  You are giving permission for those people to see your medical records 
when you sign this document. 
 
8. Will you pay me to do the HIV test? 
8 
 
No, we will not pay you for giving the blood sample to do the HIV test.  
The TB Alliance or the study site will not be responsible for paying any costs related to 
your HIV treatment if you test positive. We will refer you to an HIV clinic for further 
testing and advice. 
 
9. Will I have to pay for the HIV test? 
9 
 
No, the HIV test will not cost you anything, 
<<If applicable add “You will receive HIV counseling before and after HIV test. The 
TB Alliance will pay for the test and the counseling.” 
 
 
 
 
10. Whom can I contact if something worries me? 
10 
 
You can call the study doctor or another authorised person at any time 
of the day or night (24 hours) on Tel: <<add>> or <<add>>. 
 
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Testing for HIV Participant Information and Informed Consent 
Protocol Version and Date V X dd-mmm-yyyy                  Master Study HIV PI/IC Version 2.0 Date 13-Jun-2018  
 
Mast er Country/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-C V2.0 
 
Confidential | Page 6 of 8 
 
  
Please refer to the main informed consent form for more information on whom to 
contact if you have complaints about this study. 
 
11. How do I agree to have the HIV test? 
11 
 
If you want to agree to do the HIV test, please read the statement on the following 
page and sign the form. 
 
Participant Notes 
 
 
 
 
 
 
Glossary 
Technical term 
Explanation 
HIV 
Human immunodeficiency virus 
AIDS 
Acquired immune deficiency syndrome 
opportunistic infections 
an infection that occurs when the immune system 
is weak 
immune system 
the system in your body that fights infections 
pulmonary 
of the lungs 
confidentiality 
a set of rules to keep information private 
 
 
 
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Testing for HIV Participant Information and Informed Consent 
Protocol Version and Date V X dd-mmm-yyyy                  Master Study HIV PI/IC Version 2.0 Date 13-Jun-2018  
 
Mast er Country/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-C V2.0 
 
Confidential | Page 7 of 8 
 
PARTICIPANT INFORMED CONSENT FORM FOR HIV TESTING 
 
By signing below, I agree that: 
 
• 
I have read, or someone has read the information sheet and consent form for this 
HIV testing to me, and I understand it. 
• 
I have had the chance to ask questions and I am happy with the answers. 
• 
I have had time to discuss the information with others and to decide if I want to 
do the test. 
• 
I will get a signed and dated copy of this consent form on the day that I sign it. 
• 
I voluntarily agree for HIV testing to be done. 
• 
Site staff, representatives from the sponsor, regulatory authorities and ethics 
committees can have direct access to my medical records. They will treat my 
information as confidential. 
• 
I hereby give up all rights to the test findings and I am not entitled to be paid 
anything because of the test findings. 
• 
<<EU: “I consent to the processing/storing of my data and the transfer thereof to 
countries outside the EU.”>> 
 
 
 
Printed Name of Participant  
 
 
 
Signature/mark/thumb print of Participant 
 
Date 
 
 
(Participant/witness must write 
date) 
 
 
*Printed Name of Person Conducting Consent 
(If other than investigator /delegate) 
 
 
 
*Signature of Person Conducting Consent 
(If other than investigator /delegate) 
 
Date 
 
 
(Person conducting consent must 
write date) 
 
I,   
(Insert name of investigator) 
hereby confirm that the above participant has been fully informed about the nature, 
conduct and risks of the HIV test. 
 
 
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Testing for HIV Participant Information and Informed Consent 
Protocol Version and Date V X dd-mmm-yyyy                  Master Study HIV PI/IC Version 2.0 Date 13-Jun-2018  
 
Mast er Country/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
TMP03-C V2.0 
 
Confidential | Page 8 of 8 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
(Inv estigator must write date) 
 
By signing below, I verify that the above participant gave verbal informed consent. 
The Participant has been informed about the risks and the benefits of the HIV test, 
understands such risks and benefits and is able to agree to have the HIV test, without 
coercion, undue influence or inappropriate incentives. 
 
 
 
*Printed Name of Witness 
 
 
 
*Signature of Witness 
 
Date 
 
 
(Witness must write date) 
* Where applicable 
 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 1 of 24 
PAEDIATRIC INFORMATION AND ASSENT FORM (14-17 YEARS AGE) 
 
Protocol Name/Number:  ZeNix/NC-007-(B-Pa-L) 
Protocol Title:   
 
 
A Phase 3 partially-blinded, randomized trial assessing the 
safety and efficacy of various doses and treatment durations of linezolid plus  
bedaquiline and pretomanid in participants with pulmonary infection of either  
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or  
non-responsive multi-drug resistant tuberculosis (MDR-TB). 
 
Participant Initials:  
 
     Participant Number: 
 
 
 
 
Introduction 
 
My name is ____________________________________ and I do research studies to help 
us find out more about diseases or sicknesses and to help find better ways of 
helping, or treating children and adults who are sick.  
 
I am going to give you information and invite you to be part of a study. You can 
choose whether or not you want to take part. We have discussed this research with 
your parent(s) / legal guardian and they know that we are also asking you for your 
agreement. If you are going to participate in the research, your parent(s) / legal 
guardian have to agree as well. If you do not want to take part in the research, you 
do not have to, even if your parents have agreed that you can.  
 
There may be some words that you don’t understand, or things that you want 
explained in more detail, because you are interested in it or worried about it. Please 
ask me to stop at any time and I will explain them to you.  
 
This assent form has two parts: 
• An information sheet that provides information about the study and 
• A statement (this is where you sign if you agree to take part) 
 
Write your notes or questions here: 
 
 
 
 
 
 
 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 2 of 24 
You will be given a copy of the full assent form. This document will answer the 
following questions: 
 
1. Is the study safe? 
1 
 
2. Do I have to take part? 
2 
 
3. Why are you doing the study? 
3 
 
4. How will the study work? 
4 
 
5. What will happen to me in the study? 
5 
 
6. What can go wrong in the study? 
6 
 
7. Are there things that I cannot do while I am in the study? 
7 
 
8. How can the study help me? 
8 
 
9. What other treatments can I choose? 
9 
 
10. What will happen if I get hurt in the study? 
10 
 
11. What will happen to my personal information? 
11 
 
12. Will I be paid to take part in this study? 
12 
 
13. Will it cost me anything to be in the study? 
13 
 
14. Who is in charge of the study? 
14 
 
15. What happens if I do not want to or cannot be in the study any more? 
15 
 
16. Whom can I contact if something worries me? 
16 
 
17. How do I agree to be in this study? 
17 
 
If you have any other questions that are not answered in this document, please ask 
someone from the study staff for more information. Difficult medical terms are 
marked with an (*) and are explained in the Glossary on page <<XX>>. 
 
It is very important that you understand this information sheet before you agree to 
take part in this study. We would like you to ask as many questions as you need. If 
there is anything that you do not understand, please discuss this with your 
parent(s) / legal guardian, the study doctor, the study staff, your own doctor or 
with your family. You do not have to decide immediately. 
 
1. Is the study safe? 
1 
 
The <<name of Ethics Committee as applicable>> and <<name of Regulatory 
Authority as applicable>> have checked this study and approved it because it 
complies with medical and ethical standards.   
 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 3 of 24 
In addition, the study will be done according to the Declaration of Helsinki 2013, 
International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) 
<<and list any other appropriate guidelines e.g. South African GCP Guidelines>>.   
 
One of the purposes of these regulations is to make sure that the rights of people 
taking part in studies are protected.  If you would like to read any of these guidelines 
and regulations, please ask your study doctor to give you a copy. 
 
2. Do I have to take part? 
2 
 
Your participation in this study is totally out of free will. You may choose not to be in 
the study or leave the study at any time by telling your parent(s)/legal guardian and 
the study doctor.  
 
If you decide not to be in the study or to leave the study, you will not lose any 
benefits that you would have had. The study doctor will give you a letter so that you 
can go to a place where they will give you the normal TB treatment. 
 
3. Why are you doing the study? 
3 
 
Tuberculosis (TB) is a contagious* disease caused by bacteria. The bacteria can 
travel through the air and spread from one person to the next.  
 
We are asking you to be in this study because the doctors found that you have a 
kind of TB [called extensively drug resistant pulmonary (i.e. in your lungs) TB (XDR-TB), 
pre-extensively drug resistant TB (pre-XDR-TB), or Multidrug Resistant TB (MDR-TB)]*, 
that is very hard to treat. The medicines used for this kind of TB must be taken for up 
to two years or more. New medicines are urgently needed to make the TB treatment 
time shorter and to treat the TB.  
 
A previous study called the Nix-TB study has shown that three medicines called 
bedaquiline, linezolid and pretomanid taken together may treat your type of TB.  
These medicines have been tested in the laboratory, on animals, on healthy human 
volunteers, and on over 70 humans who have TB and they may be effective against 
XDR-TB and MDR-TB. We want to do this study to see what dose and length of 
treatment of linezolid is the most effective in treating your type of TB while causing 
the least amount of side effects. The safety and effectiveness of the following three 
drugs together: bedaquiline, linezolid and pretomanid will also be tested.   
 
4. How will the study work? 
4 
 
About 180 people (called participants) will take part in this study. All the participants 
will be open to male and female<<14 (update for specific age for each 
Country/site)>> years old and older. The study will be done at approximately 12 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 4 of 24 
study centers around the world, including South Africa, Eastern Europe and Asia. We 
expect that you will be in this study for about 2 years. The study is split into 3 parts: 
 
Part 
Name 
Length 
Reason 
1 
Screening 
Up to 14 
days 
During this time, the study doctor will check if you 
qualify to be in the study and if it is safe for you to 
be part of the study.  
2 
Treatment 
26 weeks 
or  
39 weeks 
We will give you the study medicine for a total of 26 
weeks (about 6 months), depending on how you 
respond to the medicines. You will visit the 
hospital/clinic at least 17 times. Some of these visits 
may be while you are a patient in the hospital.  
If your TB has not been cured after 26 weeks of 
treatment, your study doctor may decide to extend 
your treatment to a total of 39 weeks.   
3 
Follow Up 
78 weeks 
After you finish taking the study medicine, your 
study doctor will check on your health for the next 
78 weeks (about one and a half years).  During this 
time, you will not take any study medicine but you 
will visit the hospital/clinic at least 8 times. 
 
If your study doctor decides that you may be in this study, and if you and your 
parent(s) / legal guardian agree by signing the necessary forms, the following will 
happen: 
 
You will be assigned by chance (like flipping a coin) to be given 1 of 4 possible doses 
of linezolid and, at the same time, you will also be given bedaquiline and 
pretomanid.  
 
Your study doctor may decide to pause, reduce (lessen), or stop your linezolid. Your 
study doctor will tell you if you dose is changed. If your dose of linezolid is reduced 
anytime during the study, the study doctor may increase your linezolid dosage at a 
later visit- but not higher than the dose you started on. If there is an emergency and 
the study doctor needs to know what linezolid treatment you are receiving, he/she 
can quickly and easily find this out.  
 
Your study doctor may pause or stop all the study medicines. 
 
We will give you the study medicines at each visit during the first part of the study and 
we will ask you to bring back all empty packets and unused medicines to your next 
visit.  
 
5. What will happen to me in the study? 
5 
 
For this study to be successful and for your own safety, it is important that you do 
exactly what the study doctor tells you to do throughout your time in the study.   
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 5 of 24 
Below are lists of the visits and what will happen at each visit during the study. The 
meanings of each of the procedures are explained in the next pages. There may be 
some small changes if your study doctor finds that it is necessary. This is a list of all the 
study visits and what will happen at each visit: 
 
 
 
 
 
 
 
Screeni
ng 
Visits 
Treatment 
Visits 
 
Post-Treatment 
Follow-up 
Visits 
 
Procedures 
 
Up to 14 days before 
Treatment 
Day 1 (Baseline) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7  
Week 8 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 20 
Week 23 
End of Treatment 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
smoking 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum 
collection 
X 
X X X X X 
 
X 
 
X X X 
 
X 
 
X X X X X X 
X X X X X 
Pregnancy 
Test 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
HIV, CD4 
Count and 
Viral Load 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood tests 
X 
X X X X X X X X X X X X X X X X X X 
 
 
 
 
 
 
 
ECG 
X 
X X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest X-Ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB 
Questionnair
e/s 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Vital Signs 
X 
X X X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X X X X X 
Physical 
Exam 
X 
X X X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X X X 
 
 
X X X X X 
X 
Pharmacokin
etic (PK) test  
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Eye Exam 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X X X X 
 
X 
 
 
 
 
 
Study 
Medicine 
check 
 
X X X X X X X X X X X X X X X X X 
 
 
 
 
 
 
 
 
Other 
medicines 
X 
X X X X X X X X X X X X X X X X X X X X 
X X X X X 
Adverse 
Events 
X 
X X X X X X X X X X X X X X X X X X X X 
X X X X X 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 6 of 24 
To help you understand what will happen at each visit, we have described these 
procedures below:  
Demography 
→ This is personal information about your date of 
birth, gender and race. 
Medical and smoking 
history 
→ You will be asked questions about your health 
history and whether you have ever smoked. 
Eligibility assessment 
→ 
This is a process of checking that you meet the 
study requirements to make sure it is safe for you 
to take part. 
Sputum collection 
→ 
You will be asked to cough up sputum (phlegm) 
into a small cup at different times in the study. 
The sputum is used to check whether you have 
TB, the type of TB you have, how many TB 
bacteria you have and what medicines will work 
on the TB bacteria. 
<<Add as required per country: If you have a 
stored sputum (or TB from your sputum) sample 
(which was collected before this visit) that could 
be used to allow you into this study or check the 
type of TB and what medication will work on that 
type of TB bacteria. If you and your 
parent/guardian both agree to it, this may be 
collected from the applicable laboratory and 
used if you check “yes” at the end of this 
consent>> 
The TB germs that have been taken out of your 
sputum will also be sent to laboratories in the 
United Kingdom (UK) every few months to test 
how they respond to the study medicines. 
HIV, CD4 count test and 
Viral load 
→ 
This is a test to see if you have HIV and, if you 
have, we will measure your CD4 count (a kind of 
cell that fights infection). You will be counselled 
on HIV before the blood tests are taken and 
again once the results are given to you, and you 
may be asked to sign a separate assent form 
give us permission to do this. 
Blood tests  
→ 
We will take some blood (about 20 millilitres or 4 
teaspoons) from you by inserting a small needle 
into a vein in your arm. We will test the blood to 
check if you are healthy.   
Urine tests 
→ 
You will be asked to give a sample of your urine 
in a small cup when you are at the clinic.  We will 
test the urine to check if you are healthy and to 
see if you have taken any drugs.   
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 7 of 24 
Pregnancy test 
→ 
If you are a girl, we will test your urine to see if you 
are pregnant, whether you sometimes have sex 
or not. 
ECG 
→ 
This is a test that we do by placing 12 sensors (like 
stickers) to your skin for a short time to check how 
your heart is working.  
Chest X-Ray 
→ This is a photograph of your lungs. 
TB and health 
questionnaire/s 
→ 
We will ask you to tell your study doctor about 
your TB symptoms and general health to check 
how you are feeling. 
Physical exam  
→ This is checking your body for signs of disease. 
Vital signs 
→ We will measure your blood pressure, heart rate, 
breathing, body temperature, height and weight. 
Pharmacokinetic (PK) test 
→ 
At some visits we will take some blood to check 
what happens to the medicines once you 
swallow them. We will take blood (about 20 
millilitres or 4 teaspoons) from you by inserting a 
small needle into a vein in your arm.  
Eye exam 
→ 
We will check how well you can see by asking 
you to read the letters or symbols off a chart, and 
to read numbers or symbols off cards with 
coloured patterns on them. We will also look at 
the lens of your eyes by using a machine that 
shines a small beam of light into your eye while 
the eye doctor looks into it with a type of 
magnifying glass.   
 
To test your lens, the eye doctor will need to put 
a couple of drops of medicine in your eyes that 
will make your pupil (the black part in the middle 
of your eye) get bigger for a short time. This 
allows the eye doctor to see into your eyes easily. 
This is the same as what happens to your eyes in 
the dark. 
Study medicine check 
→ 
We will ask you how much study medicine you 
have taken or not taken since the last time you 
were at the clinic. 
Hospital admission 
→ You may need to stay in the hospital if your study 
doctor thinks it will be safer for you. 
Hospital check-out 
→ 
Your study doctor will tell you when it is safe for 
you to not be in hospital all the time. We will 
record when you are checked-out of the 
hospital. 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 8 of 24 
 
After you have stopped or completed the study medicines, the study doctor will 
decide if you need more TB treatment. If you do, your study doctor will give you a 
letter to go to another place where they can treat your TB. It is very important that 
you go there as soon as possible and get more anti-TB treatment if your doctor 
recommends that. 
 
Treatment Extension 
 
If the study doctor decides that your treatment should be extended, either due to 
treatment pause of all of your study treatment, or if your TB is not cured after 26 
weeks of treatment, the following procedures will be performed at additional 
treatment visits.  
 
 
Optional Treatment Extension Visits 
Procedures 
 Every 3 weeks, for up to a total of 26 or 39 weeks of treatment 
Demography 
 
Medical and smoking history 
 
Eligibility assessment 
 
Sputum collection 
X 
Pregnancy Test 
 
HIV, CD4 Count and Viral Load 
 
Blood tests 
X 
ECG 
 
Chest X-Ray 
 
TB Questionnaire/s 
 
Vital Signs 
X 
Physical Exam 
X 
Pharmacokinetic (PK) test  
 
Eye Exam 
X 
Nerve Exam 
X 
Study Medicine check 
X 
Other medicines 
X 
Adverse Events 
X 
 
 
Early Withdrawal 
 
If you decide of your own free will, or your study doctor decides you should stop 
treatment or withdraw from the study before you have finished the above visits, the 
procedures listed below may be performed at an Early Withdrawal Visit.  If you have 
received more than 15 doses of the study medication and haven’t had your 12 
week follow-up visit when you are withdrawn from the study, we will request you to 
come back for 1 more visit at the clinic so we can monitor your health, and you will 
be contacted 2 more times for a visit that can take place at the clinic, your home or 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 9 of 24 
on the phone with your study doctor where the following procedures may be 
performed.   
 
Early Withdrawal During Treatment Period 
Procedures 
 
Early Withdrawal 
Visit 
Follow-up  
Week 12 
Follow-up  
Week 26 
F ll
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count  
X 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
  
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X
Survival/TB outcome 
 
 
X 
X
 
If you haven’t had all your follow-up visits when you are withdrawn from the study, 
we may request that you to come back for 1 more visit at the clinic so we can 
monitor your health as well.  
 
Early Withdrawal During Follow-up Period 
Procedures 
 
Early Withdrawal 
Visit During Follow-
up  
Follow-up  
Week 12 (If 
applicable) 
Follow-up  
Week 26 (if 
applicable) 
 Follow-up 
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count 
 
 
 
 
Blood tests 
X 
 
 
 
37 of 124


M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 10 of 24 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
 
If the study doctor feels it is necessary, you may be asked to come in for extra 
(unscheduled) visits that do not appear on the above charts. 
 
6. What can go wrong in the study? 
6 
 
There are some possible risks and inconveniences of being in the study. 
Tuberculosis is a serious disease that can kill you.   
 
You should not drink alcohol while you are taking study medicine or 
other TB medicines because alcohol may damage your liver. 
 
 
Details of the risks of taking the medicines in this study are noted below: 
 
Liver problems 
→ 
May be associated with symptoms such as 
nausea or vomiting, stomach pain, fever, 
weakness, itching, unusual tiredness, loss 
of appetite, light coloured bowel 
movements, dark coloured urine, 
yellowing of your skin or the white of your 
eyes.   
Liver problems may also be suggested by 
blood tests that show abnormalities in 
measures of your liver enzymes and other 
measures of how your liver is working. In 
rare cases liver problems may be serious 
and even lead to death. 
 
Pretomanid, 
Linezolid, 
Bedaquiline,  
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 11 of 24 
Headache 
→ pain in any part of the head 
Pretomanid, 
Linezolid, 
Bedaquiline,  
Stomach 
problems 
→ 
Tenderness or pain of the stomach area  
Feeling like you want to throw up, or 
actually throwing up. Also not feeling 
hungry, having diarrhoea (loose bowel 
movements) or having an upset stomach. 
Linezolid, 
Pretomanid, 
Bedaquiline     
Dizziness 
→ 
A feeling of being ‘drunk’ or ‘light 
headed’, especially when you stand up or 
sit down quickly. 
 
Linezolid, 
Bedaquiline  
 
The following are a list and description of side effects that are unique to each of the 
medicines: 
 
Pretomanid 
Besides the side effects mentioned above, the other side effects include: 
 
Reproductive 
organ 
changes  
 
→ 
Results from animal studies have shown that rats given 
pretomanid showed signs of damage to the male rats’ 
reproductive organs.  Recent studies in people have shown 
that there is no evidence that pretomanid damages the 
male reproductive organs. The potential for pretomanid to 
have an effect on the male reproductive organs will remain 
under evaluation. 
Cataracts 
(clouding of 
the lens in the 
eye) 
→ 
Other results from animal studies show that rats given 
Pretomanid developed cataracts at high doses over a 6-
month period of taking the medicine.  
It is not known if the effect found in rats indicates any risk for 
human beings. 
Fits 
(convulsions or 
seizures) 
→ 
were seen in some animal studies and in 1 patient treated 
with Pretomanid 
Skin problems 
→  
Inflamed areas on your skin, which may be red, itchy and/or 
painful. 
39 of 124


M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 12 of 24 
 
 
Linezolid 
Besides the side effects mentioned above, the other most common side effects seen 
in patients who took linezolid are: 
Changes in taste 
→ 
certain food or drinks may taste different to you 
Tongue 
discolouration 
→ 
the colour of your tongue changes 
Fungal infections 
→ 
when a fungus causes the infection 
Vaginal moniliasis → 
a fungal infection in the vagina 
Oral moniliasis 
→ 
a fungal infection in the mouth 
Fever 
→ 
When your body temperature goes higher than 38 °C or 
100.4 °F. 
Signs of nerve 
disturbances 
→ 
This is sometimes called ‘peripheral neuropathy’, which 
may be experienced as a painful burning, or stinging, 
tingling, sensation of pins and needles or numbness in your 
arms and legs. In some cases this can be permanent. 
 
Convulsions or 
seizures 
→ 
These are also commonly known as ‘fits’.   
A convulsion is when the body muscles contract and relax 
quickly and repeatedly / uncontrolled shaking of the 
body. 
A seizure is when there is a change in the normal electrical 
activity of the brain. 
 
 
 
Other side effects seen in patients who took linezolid include, but are not limited to: 
 
Myelo-
suppression 
→ 
a lack of certain cells in your blood that your body needs to 
function.  
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 13 of 24 
can make you feel tired and make your body being unable 
to fight off other illnesses or heal an injury. This could also 
make you bleed or bruise easily. 
Lactic acidosis 
→ 
a build-up of waste products in your blood that can cause 
constant nausea and vomiting. 
Serotonin 
syndrome 
→ 
this rare but serious condition may occur when linezolid is 
given with certain types of medications that affect a 
chemical in the brain called serotonin. Some of these 
medications include antidepressants.  Be sure to tell your 
study doctor about all prescription and non-prescription 
medications you are taking. 
It can cause many different symptoms, for example: 
confusion, restlessness, tremors, blushing, sweating and 
fever. 
Interactions with 
other medicines 
→ 
causing a rise in blood pressure 
Optic neuropathy 
→ 
A type of damage to the nerves in your eye that can lead 
to blindness if it is not treated.  This can be permanent. 
Low blood sugar 
→ 
This is often seen in patients with diabetes who have to take 
insulin or other medicines 
 
 
Bedaquiline 
From studies in 380 patients with TB who received Bedaquiline (312 of whom 
received Bedaquiline for as long as 6 months), we continued to see that Bedaquiline 
is generally safe and well tolerated.   Besides the side effects mentioned above, the 
other most common side effects seen in patients who took bedaquiline are: 
 
Serious side 
effects 
→ 
9 out of 79 patients (11%) taking bedaquiline with other 
TB medicines died, versus 2 out of 81 (3%) taking just the 
other TB medicines and no bedaquiline. 
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M ain Paediatric Information and Assent Form 
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PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 14 of 24 
It is not known why more patients in the bedaquiline 
group died. 
QTc interval 
increase 
→ 
An increase in the measure of the heart’s electrical 
activity. 
This was seen on the electrocardiogram in patients 
taking bedaquiline and in those taking other TB drugs. 
This may increase the risk that the heart does not beat 
in its normal, regular rhythm, which in rare cases cause 
death.  
However, no clinical side effects relating to heart 
rhythm problems were seen. 
Effects on the 
pancreas 
 
Studies in mice and dogs showed that bedaquiline 
caused damage to the pancreas.  It is not known if the 
effect found in mice and dogs indicates any risk for 
humans. 
Joint pain 
→ 
One type of joint pain that may be caused or worsened 
by some medicines is called gout.  Gout is caused by too 
much of a normal chemical in your body called uric 
acid. Uric acid is a chemical that is created when the 
body breaks down substances called purines. 
Purines are found in some foods (like seafood) and drinks 
(like beer). 
 
Accumulation in 
the body 
→ 
Bedaquiline leaves your body slowly after the last tablet 
is taken.  It takes about a year for all the drug to be 
removed from your body. 
 
In addition to the listed side effects your study doctor has information on side effects 
that may occur less often and your study doctor could discuss these with you. 
 
These are possible risks and side effects of procedures that we will perform: 
 
• 
Drawing blood is a normal part of routine medical care. There is a slight risk of 
discomfort. Drawing blood does not often cause fainting, inflammation of the 
vein, pain, bruising or bleeding at the place where the needle goes in. There 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 15 of 24 
is also a small chance of infection. But experienced staff will draw your blood 
under germ-free conditions.  
• 
When an ECG is done, the sensors, or stickers, may cause slight discomfort 
when they are removed from your skin. 
• 
An x-ray is a common test that exposes you to a small amount of radiation. 
Radiation adds up over your lifetime, but small doses like the one we use to 
take a picture of your chest will probably not be a risk to your health. 
• 
The eye tests are common. The drops we put into your eyes will make your 
eyes see blurry and be sensitive to light for a few hours after the examination, 
and during that time you should not drive. Very seldom eye tests can cause 
higher pressure in your eyes which can make you feel nauseous and can 
make your eyes hurt. If this happens, you should call the study doctor right 
away. 
 
It is important that you must do exactly what your study doctor and/or study nurse 
says.  
 
You must tell your study doctor immediately if: 
 
• 
you take any local or herbal medicines, medicine that a doctor prescribed or 
that you can buy at a chemist, 
• 
your medical condition changes, 
• 
you have seen any other healthcare providers, 
• 
you have any side effects*,  
• 
you have any complications*, or 
• 
you get hurt in any way while taking the study medicine. 
 
Your study doctor and/or nurse will ask you at every visit about any other medicine 
you may have taken and how you are feeling.  
 
 
Your condition may stay the same or get worse while you are in this study. However, 
the study doctor will watch you closely and if he/she feels that taking part in the 
study is not good for your health, he/she will immediately take you out of the study. 
 
Using the study medicine may have risks that we do not yet know about. If we find 
out about any of these risks, we will tell you about any new important information 
that may make you want to change your mind about staying in the study. 
 
 
 
 
 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 16 of 24 
7. Are there things that I cannot do while I am in the study? 
7 
Pregnancy  
Boys: You cannot take part in this study if you are planning to make someone 
pregnant during the treatment period or 12 weeks after the last dose of study 
medicine 
Girls:  You cannot take part in this study if you think you may be pregnant, are 
pregnant, are breast feeding or are trying to get pregnant during the treatment 
period or 6 months after the last dose of study medicine 
 
This is because there may be risks to a mother and her baby that we may not yet 
know about. 
 
We need to know about anything unusual that happens to you. You must feel free 
to call us anytime about anything that you are worried about or questions that you 
have.  
 
If you get sick or are worried about anything or have questions between visits to the 
clinic, you should tell your study doctor. You do not have to wait for your next visit. 
 
If you are a girl and can have babies (started your period) you must not fall 
pregnant or breastfeed while taking part in this research. You will have to take a 
pregnancy test. If you sometimes have sex, you must use effective birth control while 
you are taking part in the research. Effective birth control is using 2 methods of birth 
control while you are taking the study medicine and for 6 months after you have 
taken the last dose of study medicine. 
 
When you are taking the study medicine, birth control such as the pill and the 
contraceptive injection may not work as well as usual. Because of this, you must be 
willing not to have sex, or you will have to use 2 methods of birth control. Talk to your 
study doctor to explain the methods to you. If you can’t get birth control, you must 
also speak to your study doctor. The study doctor may be able to tell you about the 
correct birth control.   
If you become pregnant while you are taking part in the study, it is very important 
that you tell the study doctor immediately. If this happens, the study doctor will 
discuss with you what to do. Because there might be risks to an unborn child that we 
do not know about yet, you will be asked to stop taking part in the study. We may 
want to ask you some questions about your pregnancy and the baby and we may 
ask you to visit the study doctor at certain times while you are pregnant and after 
you have had your baby so that we can check how healthy you are and collect 
information about what happened to the baby.  
 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 17 of 24 
If you are a boy and you sometimes have sex, you and your girlfriend must either use 
2 methods of birth control as we discussed above for the girls or use one form that 
your study doctor says you can use such as the birth control pill or an IUD.   
 
 
You must tell your study doctor if you (if you are a girl) become pregnant during the 
study or within 6 months after the last time you took the study medicine. 
 
Please talk to your study doctor if you are unsure of where to get the correct birth 
control. You are responsible for getting the correct birth control from your family 
planning or birth control clinic. 
 
 
Foods and drinks that you cannot eat or drink 
• 
While you are taking your study medicine, you should not eat a lot of some 
foods or drinks that contain a lot of a protein called tyramine. Foods that 
contain a lot of tyramine include foods that may have had protein changes 
because they have been allowed to age, ferment, because they were 
pickled or smoked to improve their flavor. Examples are: aged cheeses, 
fermented or air-dried meats (cold cuts and biltong), sauerkraut, soy sauce, 
tap beers and red wines.   
 
Other medicines that you cannot use 
• 
You cannot use certain medicines for depression while you are using the study 
medicine.   
• 
There are some HIV medicines you should not use if you are HIV positive. Your 
study doctor can tell you which HIV medicines you can use during this study.   
• 
You should tell your doctor if you are taking any illegal drugs, because some 
illegal drugs can affect your safety or your ability to follow through with all the 
study procedures. 
 
8. How can the study help me? 
8 
 
Your TB could get better because you are in this study, but we cannot be sure about 
this. If the study medicine does not work well, it will not help you. However, the 
information that we get from the study can help us to make treatments for TB in the 
future, and in it can help other TB patients later on. 
 
The medical attention you will get because you are taking part in the study can help 
you to learn useful information about your health.   
 
9. What other treatments can I choose? 
9 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 18 of 24 
 
You do not have to take part in this study. If you decide not to take part, you will not 
be punished and you will still get care and treatment for your TB at <<TB clinic or 
specialized unit in a hospitalist location>> for at least <<add time period>>, per your 
country’s National TB Treatment Guidelines. 
 
If you do not take part in the study, your doctor will make sure that you are sent to 
another place to get treatment. 
 
10. What will happen if I get hurt in the study? 
10 
 
<< For ABPI Countries:  
 
The sponsor has taken out insurance in case you get hurt in this study.  
The sponsor will pay you for all reasonable medical expenses that you may have 
because you got hurt in this study according to the guidelines of the Association of 
the British Pharmaceutical Industry (ABPI guidelines). These guidelines say that the 
sponsor of the study should pay you if you get hurt because you took the study 
medicine or because of other procedures that were carried out according to the 
protocol for this study. You will not have to prove that it was the sponsor’s fault that 
you got hurt. Your study doctor has a copy of the ABPI guidelines if you would like to 
see them. 
The APBI guidelines say that the sponsor does not have to pay you if: 
• 
you got hurt because you took medicine or had a procedure that the study 
does not need or if you did not stick to the rules of the study;   
• 
the injury was not a serious injury that will last a long time and disable you. 
The ABPI guidelines say that the sponsor may pay you less, or may not have to pay 
you at all depending on the following reasons: 
• 
how serious the disease is that you are being treated for, how likely it is that 
something unpleasant will happen to you if you take the medication and any 
warnings that were given to you; 
• 
the risks and benefits of normal or standard treatments compared to the risks 
and benefits that we know the study medicine have or think that it may have; 
• 
if somebody who is not in the study did something wrong, or if the study 
doctor does not give you the right help if you have a bad reaction; 
• 
if you have been careless.  
Any money that the sponsor pays to you because of the ABPI guidelines does not 
mean that the sponsor is legally responsible for your injury. You will not lose any of the 
legal rights you have if you are hurt just because the sponsor has agreed to follow 
the ABPI guidelines. Please ask if you want more information about this.>> 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 19 of 24 
 
<<Country regulatory authorities that DO NOT require compliance to the ABPI clinical 
trial insurance guidelines,  
Text will be provided on an ‘as needed’ basis in consultation with TB Alliance 
Legal.>> 
11. What will happen to my personal information? 
11 
 
We won’t tell other people that you are taking part in this research, and we won’t 
give information about you to anyone who does not work in the study.  
 
We will keep information about you that we collected during the research in a safe 
place and no-one except the researchers will be able to see it. Any information 
about you will have a number on it, and not your name. Only the researchers will 
know what your number is, and we will keep that information in a locked cupboard. 
We won’t give it to anyone, except the research sponsor, your study doctor and the 
people that look at the information on behalf of the sponsor. 
 
12. Will I be paid to take part in this study? 
12 
 
You will not be paid to take part in this study.  However, the sponsor will pay your 
parent(s) / legal guardian back for expenses such as for transport to and from the 
study site and other costs that you may have because of taking part in the study.   
 
 
 
 
13. Do I need to pay anything to be in this study? 
13 
 
The sponsor will pay all costs related to the study such as the study medicine, 
treatment, tests, examinations, and procedures specified in the protocol (study 
plan).   
 
Not you, your parents/legal guardian, nor your <<medical insurance/aid,>> 
healthcare provider will have to pay for these expenses.  In other words, you will not 
have to pay for anything that is needed for your participation in this study. 
 
14. Who is in charge of the study? 
14 
 
The study is sponsored by the Global Alliance for TB Drug Development (TB Alliance), 
a not-for-profit organization based in New York in the United States.  
 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 20 of 24 
15. What happens if I do not want to or cannot be in the study anymore? 
15 
 
You may stop participating in the study for the following reasons: 
 
• 
Testing comes back that shows your TB won’t respond to the study medicines. 
• 
You do not do what the study doctor tells you to do. 
• 
You do not take the study medicine as the doctor tells you to. 
• 
Testing comes back that shows your TB won’t respond to the study drugs. 
• 
The study doctor decides that it is best for you. 
• 
If you ask to stop (you don’t have to explain why). 
• 
If the TB Alliance asks you to stop. 
• 
If the TB Alliance stops the study or closes the study site. 
• 
If you become pregnant (girls who can get pregnant). 
 
If you decide to leave the study, please tell us immediately.  
 
If you leave the study, the doctor would like to ask you some questions and check 
your health to make sure that you are safe and any possible side effects from the 
study medicine are treated.  Your study doctor/site staff may need to perform 
certain procedures previously mentioned in the “5. What will happen to me in the 
study?” section.  
 
16. Whom can I contact if something worries me? 
16 
 
You can call the study doctor or another authorised person at the study 
site any time of the day or night (24 hours) on Tel: <<add>> or <<add>>. 
 
  
 
For questions about your rights as a participant in a study: 
 
If you want any information about your rights as a study participant, or if you have 
complaints about this study, you may contact the <<add name of Ethics 
Committee>>, which is an independent committee established to help protect the 
rights of research participants. Their contact details are as follows: 
 
<<Add name, address and contact telephone/fax numbers>> 
For complaints, if you think that the study doctor or ethics committee did not help 
you: 
 
<<include per country as appropriate>> 
 
 
 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 21 of 24 
17. How do I agree to be in this study? 
17 
 
If you want to take part in this study, please read the statement and sign on page 
<<XX>>. 
 
Personal doctor / specialist notification option: 
 
Please mark below, by writing your initials in the correct block, if you want me to tell 
your personal doctor or your specialist that you are taking part in this study: 
 
   YES, I want my study doctor to tell my personal doctor / specialist that I am 
taking part in this study. 
  NO, I do not want my study doctor to tell my personal doctor / specialist that I 
am taking part in this study. 
  I do not have a personal doctor / specialist. 
 
Collection of Pre-screening Stored Sputum (or TB from your sputum) Sample 
agreement: 
 
Please mark below, by writing your initials in the correct block, if you agree for your 
stored sputum sample or TB from your sputum (taken before this visit/reading and 
signing this form) to be collected from the storing laboratory: 
 
 
YES, I agree if available, for my stored sputum sample or TB from your sputum 
to be collected from the laboratory and used for this study. 
 
NO, I do not want my stored sputum sample or TB from your sputum to be 
collected from the laboratory and used for this study. 
 
Participant Notes 
 
 
 
 
 
 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 22 of 24 
 
 
 
 
 
 
Glossary 
Technical term 
Explanation 
complications 
another disease or condition that makes your TB 
worse 
contagious 
can be spread to other people 
adverse events 
unwanted events 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 23 of 24 
PAEDIATRIC INFORMED ASSENT FORM 
 
By signing below, I agree that: 
 
• 
I have read the information sheet and consent form for this study, or someone 
has read it to me, and I understand it. 
• 
I have had the chance to ask questions and I am happy with the answers. 
• 
I have had time to discuss the information with others and to decide if I want to 
take part. 
• 
I will get a signed and dated copy of this consent form on the day that I sign it. 
• 
I agree of my own free will to take part in this study. I know I have the right to stop 
taking part at any time, without giving any reason. If I stop taking part, it will not 
change my medical care or legal rights. 
• 
Site staff, representatives from the sponsor, including auditors, regulatory 
authorities and ethics committees can have direct access to my medical 
records. They will treat my information as confidential. 
• 
If I withdraw from the study, study data collected about me up to the point of my 
withdrawal can still be used to carry out this study.   
• 
Girls only: “If I become pregnant on the study, follow-up information on the 
outcome of my pregnancy can be collected, if needed.” 
<<EU: “I consent to the processing/storing of my data and the transfer thereof to 
countries outside the EU.”>> 
 
 
 
Printed Name of Participant 
 
 
 
Signature/mark/thumb print of Participant 
 
Date 
 
 
(Participant/witness must write 
date) 
 
 
*Printed Name of Person Conducting Consent 
(If other than study doctor/delegate) 
 
 
 
*Signature of Person Conducting Consent 
(If other than study doctor/delegate) 
 
Date 
 
 
(Person conducting consent must 
write date) 
 
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M ain Paediatric Information and Assent Form 
Prot ocol Version and Dat e: V X dd-mmm-yyyy               M aster Paediatric Assent Version 2.0 Date 13-Jun-2018                     
Country/Site Version: V X dd-mmm-yyyy 
 
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 24 of 24 
I,   
(Insert name of investigator) 
hereby confirm that the above participant has been fully informed about the nature, 
conduct and risks of the above study. 
 
 
 
Signature of Investigator (study doctor) 
 
Date 
 
 
(Inv estigator must write date) 
 
By signing below, I verify that the above participant gave verbal informed consent. 
The participant has been informed about the risks and the benefits of the study, 
understands such risks and benefits and is able to agree to participation, without 
coercion, undue influence or inappropriate incentives. 
 
 
 
*Printed Name of Witness 
 
 
 
*Signature of Witness 
 
Date 
 
 
(Witness must write date) 
* Where applicable 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 1 of 28 
PARTICIPANT INFORMATION AND INFORMED CONSENT FORM 
 
Protocol Name/Number:  ZeNix/NC-007-(B-Pa-L) 
Protocol Title:  
 
 
A Phase 3 partially-blinded, randomized trial assessing the 
safety and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or 
non-responsive multi-drug resistant tuberculosis (MDR-TB). 
 
Participant Initials:  
 
 
Participant Number: 
_____ 
 
Introduction 
 
We invite you to take part in a study with a new combination of medicines. The names 
of the medicines are bedaquiline, linezolid, and pretomanid.  
 
Please read this information sheet before you agree to take part. This document will 
answer the following questions: 
 
1. Is the study safe? 
1 
 
2. Do I have to take part? 
2 
 
3. Why are you doing the study? 
3 
 
4. How will the study work? 
4 
 
5. What will happen to me in the study? 
5 
 
6. What can go wrong in the study? 
6 
 
7. Are there things that I cannot do while I am in the study? 
7 
 
8. How can the study help me? 
8 
 
9. What are my other choices for treatment? 
9 
 
10. What will happen if I get hurt in the study? 
10 
 
11. What will happen to my personal information? 
11 
 
12. Will I be paid to take part in this study? 
12 
` 
13. Will it cost me anything to be in the study? 
13 
 
14. Who is in charge of the study? 
14 
 
15. What happens if I do not want to or cannot be in the study 
anymore? 
15 
 
16. Whom can I contact if something worries me? 
16 
 
17. How do I agree to be in this study? 
17 
 
If you have any other questions that are not answered in this document, please ask 
someone from the study staff for more information. Difficult medical terms are marked 
with an (*) and are explained in the Glossary on page <x>. 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 2 of 28 
It is very important that you understand this information sheet before you 
agree to take part in this study. We would like you to ask as many questions 
as you need. If there is anything that you do not understand, please discuss 
this with the study doctor, the study staff, your own doctor or with your 
family. 
 
Participant Notes 
 
 
 
 
 
 
 
 
 
 
1. Is the study safe? 
1 
 
The <<name of Ethics Committee as applicable>> and <<name of Regulatory 
Authority as applicable>>have checked and approved this study because it 
complies with medical and ethical standards.   
 
In addition, the study will be done according to the Declaration of Helsinki 2013, 
International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) 
<<and list any other appropriate guidelines e.g. South African GCP Guidelines>>.   
 
One of the purposes of these regulations is to make sure that the rights of people 
taking part in research studies are protected.  If you would like to read any of these 
guidelines and regulations, please ask your study doctor to give you a copy. 
 
2. Do I have to take part? 
2 
 
Your participation in this study is totally voluntary (out of free will).  You may choose 
not to be in the study or leave the study (withdraw your consent) at any time by 
telling the study doctor.  
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 3 of 28 
If you decide not to be in the study or if you withdraw your consent, you will not lose 
any benefits that you otherwise would have had. If you withdraw before you 
complete treatment, the study doctor will give you a referral letter to an MDR or 
XDR-TB unit, TB clinic, or hospital where they will give you the standard TB treatment 
as to all TB patients, according to your country’s National TB Treatment Guidelines. 
 
3. Why are you doing the study? 
3 
 
You have been diagnosed with extensively drug resistant pulmonary (i.e. in your 
lungs) TB (XDR-TB), pre-extensively drug resistant TB (pre-XDR-TB), or Multidrug 
Resistant TB (MDR-TB). This means that these forms of TB bacteria, or germs, are 
present in your lungs and they do not respond to treatment or require treatment that 
you can’t tolerate. These forms of TB can be very hard to treat and medicines must 
be taken for up to two years or even longer.   
 
It is possible that because people do not take the medicines correctly, TB resistance 
to these medicines is becoming more common.  These forms of resistant TB can be 
very difficult to treat.  New medicines are urgently needed to make the TB treatment 
time shorter and to treat resistant TB.   
 
A previous study called the Nix-TB study has shown that three medicines called 
bedaquiline, linezolid and pretomanid taken together may treat your type of TB.  To 
date, these medicines have been tested in the laboratory, on animals ,on healthy 
human volunteers, and on over 70 TB participants and have been shown to be 
possibly effective against XDR-TB and MDR-TB.  We want to do this study to see what 
dose and length of treatment of linezolid is the most effective in treating your type of 
TB while causing the least amount of side effects. The safety and effectiveness of the 
following three drugs together: bedaquiline, linezolid and pretomanid will also be 
tested.   
 
4. How will the study work? 
4 
 
About 180 people (called participants) will be taking part in this study. All the 
participants will be men and women <<14 (update for specific age for each 
Country/site)>> years old and older.  The trial will be conducted globally and it is 
planned that participants will be from approximately 12 research centers around the 
world, including but not limited to <<Country specific to ICF>> and additional 
centers in South Africa <<delete South Africa if noted previously in Country 
specific>>, Eastern Europe and Asia. <<When required by EC, list known targeted 
countries within the regions>>.  We expect that you will be in this study for about 2 
years. The study is split into 3 parts: 
 
Part 
Name 
Length 
Reason 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 4 of 28 
1 
Screening 
Up to 14 
days 
During this time, the study doctor is checking if you 
meet the requirements and if it is safe for you to be 
part of the study. This may be several visits and take 
up to 14 days. If you don’t meet all of the 
requirements when you are screened, you may 
have the opportunity to be screened at a later time 
if the doctor thinks you would be able to meet the 
requirements then.  
2 
Treatment 
26 weeks 
or  
39 weeks 
You will receive study medicine for a total of 26 
weeks, depending on how you respond to the 
medicines. You will visit the hospital/clinic at least 17 
times.  Some of these visits may be while you are a 
patient in the hospital.  
If the study doctor determines that you need to 
pause your treatment for any reason, then your 
treatment may extend longer than 26 weeks.  If 
your TB has not been cured after 26 weeks of 
treatment, your study doctor may decide to extend 
your treatment to a total of 39 weeks.   
3 
Follow Up 
78 weeks 
After you finish taking the study medicine, your 
study doctor will check on your health for the next 
78 weeks. During this time, you won’t be on the 
study medicine but you will visit the hospital/clinic at 
least 8 times during this part. 
 
If your study doctor decides that you qualify to be in this study, and if you agree to 
be in this study by signing this consent form, the following will happen: 
 
You will be randomly assigned (purely by chance, like flipping a coin) to receive one 
of the 4 possible linezolid doses below.  This study is partially blinded, which means 
neither you nor your study doctor will know what dose you will receive or how long 
you will receive linezolid. This is done by giving everyone the same number of tablets, 
some participants receive tablets that look like the linezolid medication, but do not 
contain linezolid, these are called placebo. We can only tell you at the end of the 
study (i.e. when the treatment blind has been broken) to which of the treatments 
you were assigned. If there is an emergency and the study doctor needs to know 
what linezolid treatment you are receiving, he/she can quickly and easily find this 
out. 
 
• 
Linezolid 1200 milligrams (mg) daily for 26 weeks plus linezolid placebo or; 
• 
Linezolid 600 mg daily for 26 weeks plus linezolid placebo or; 
• 
Linezolid 1200 mg daily for 9 weeks plus linezolid placebo, then linezolid 
placebo for 17 weeks or; 
• 
Linezolid 600 mg daily for 9 weeks plus linezolid placebo then linezolid 
placebo for 17 weeks. 
In addition to linezolid and linezolid placebo, all participants will receive the 
following: 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 5 of 28 
• 
bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 
weeks plus;  
• 
pretomanid 200 mg once daily for 26 weeks 
 
You and your study doctor will know how much bedaquiline and pretomanid you are 
receiving.  
 
Pretomanid is a new medicine that has not been approved for the treatment of TB by 
any Government Regulatory Authority. Bedaquiline has been approved for treatment 
of MDR-TB in the United States of America and in Europe<<and has been approved 
by “specific regulatory authority when relevant” for treatment of MDR-TB in 
“Country”>>.  Linezolid has been approved around the world to treat many kinds of 
infections caused by germs.  Linezolid is not approved for TB treatment, though it is 
sometimes used to treat TB patients if other approved medicines do not work. 
 
You will take 5 whole tablets and one half tablet a day for the first 8 weeks of study 
treatment.  You will then take 4 whole tablets and one half tablet a day for the 
remaining 18 weeks of study treatment.   
 
The study doctor may decide to pause all your medications. The study doctor may 
also decide that your linezolid medicine dose needs to be reduced, paused, or just 
your linezolid medicine needs to be stopped. You will know if the study doctor 
decides to reduce, pause, or stop the linezolid.  If your dose is reduced, neither you 
nor your doctor will know your current dose or the dose your linezolid medicine is 
reduced to. If your dose of linezolid is reduced anytime during the study, the study 
doctor may increase your linezolid dosage at a later visit, but not higher than the 
dose you started on.   You will continue to receive the same number of tablets and 
half tablets, some or all the tablets with medicine will be replaced with placebos.  
 
You will be given study medicines at each visit during the Treatment Period and asked 
to bring back all empty packets/bottles and unused medicines to your next visit.  
 
5. What will happen to me in the study? 
5 
 
You must be willing to follow all study procedures and requirements. For this study to 
be successful and for your own safety, it is important that you co-operate fully with 
the study doctor and follow his/her instructions precisely throughout your time in the 
study.   
 
 
 
 
 
 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 6 of 28 
Depending on your response to the medicine and study procedures, there may be 
some slight changes to the treatment visits and procedures, and how long you stay 
in the study.  This is a list of all the study visits and what will happen at each visit: 
 
 
Screenin
g 
Visits 
Treatment 
Visits 
 
Post-Treatment 
Follow-up 
Visits 
 
Procedures 
 
Up to 14 days before 
Treatment  
Day 1 (Baseline) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7  
Week 8 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 20 
Week 23 
End of Treatment 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum 
collection 
X 
X X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X X 
X 
X 
X X 
X 
X 
X X 
X 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
HIV, CD4 Count 
and Viral Load 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Blood tests 
X 
X X 
X 
X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
 
 
 
 
 
 
 
 
ECG 
X 
X X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest X-Ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
TB 
Questionnaire/s 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Vital Signs 
X 
X X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X X 
X 
Physical Exam 
X 
X X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X X 
X 
Pharmacokineti
c (PK) test  
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Eye Exam 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X X 
X 
X 
 
X 
 
 
 
 
 
Nerve Exam 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X X 
X 
 
 
X 
X 
 
X 
 
X 
Study Medicine 
check 
 
X X 
X 
X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
 
 
 
 
 
 
 
 
Other 
medicines 
X 
X X 
X 
X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
Adverse Events 
X 
X X 
X 
X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
 
 
 
 
 
 
 
 
 
 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 7 of 28 
 
To help understand what will happen at each visit, we have described these below: 
 
 
Demography 
→ 
This is personal information about your date of 
birth, gender and race that you will be asked 
about. 
Medical and smoking 
history 
→ 
You will be asked about your medical (including 
alcohol and drug use) and smoking history and 
all other medicines, including prescription, herbal 
and traditional you may have taken in the last 30 
days, or are currently still taking. 
Eligibility assessment 
→ 
This is a process of checking that you meet the 
study requirements to make sure it is safe for you 
to take part. 
Sputum collection 
→ 
You will be asked to cough up sputum (phlegm) 
into a small cup at different times in the study. 
The sputum is used to check that you have TB, 
the type of TB you have, how many TB bacteria 
you have and what medicines will work on the TB 
bacteria. 
<<Add as required per country: If you have a 
stored sputum (or TB from your sputum) sample 
(which was collected before this visit) that could 
be used to allow you into this study or check the 
type of TB and what medication will work on that 
type of TB bacteria. If you agree to it, this may be 
collected from the applicable laboratory and 
used if you check “yes” at the end of this 
consent>> 
  
The TB germs that have been taken out of your 
sputum will also be sent to laboratories in the 
United Kingdom (UK) every few months to test 
how they respond to the study medicines. They 
may also be used to research new testing 
methods for TB and/or study medicines. These 
germs will not contain any material from your 
body; only the TB germs. You will not receive the 
results from these tests or get any more benefit 
from these tests being done. The testing could be 
done for as long as five years after you take part. 
HIV, viral load and CD4 
count test  
→ This is a test to see if you have been infected with 
HIV and, if you have, we will measure your CD4 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 8 of 28 
count (a kind of cell that fights infection) and the 
amount of HIV virus in your blood.  You will be 
counselled on HIV before the blood tests are 
taken and again once the results are given to 
you, and you may be asked to sign a separate 
informed consent form. 
Blood tests  
→ 
Blood will be taken from you by inserting a small 
needle into a vein in your arm. The blood will be 
tested to check if you are healthy.  A total of 
about 360 millilitres (72 teaspoons) of blood will 
be collected over the whole study, or about 
20mL (4 teaspoons) at each study visit. 
Urine tests 
→ 
You will be asked to provide a sample of your 
urine in a small cup when you are at the clinic.  
The urine will be tested to check if you are 
healthy.   
Your urine will be tested to see if you have taken 
any drugs like cannabis, cocaine, 
amphetamines, opiates, benzodiazepines and 
barbiturates. 
Pregnancy test 
→ 
If you are a woman who is able to have children, 
your urine will be tested to see if you are 
pregnant, whether or not you are sexually active. 
ECG 
→ 
A test that is done by placing 12 sensors (like 
stickers) to your skin for a short time to check how 
your heart is working.   
Chest X-Ray 
→ This is a photograph of your lungs. 
TB and health 
questionnaire/s 
→ 
You will be asked to tell your study doctor about 
your TB symptoms and general health to check 
how you are feeling. 
Physical exam  
→ This is an assessment of your body to check for 
signs of disease. 
Vital signs 
→ 
A measurement of your blood pressure, heart 
rate, breathing rate, body temperature, height 
and weight. 
Pharmacokinetic (PK) test 
→ 
Blood will be taken at some visits to check what 
happens to the medicines once you swallow 
them. Blood will be taken from you by inserting a 
small needle into a vein in your arm. About 20 
milliliters (4 teaspoons) of blood will be taken from 
you for this test. 
Eye exam 
→ 
This is a check of your vision by asking you to 
read the letters or symbols off a chart, and to 
read numbers or symbols off of cards with 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 9 of 28 
coloured patterns on them. There will also be an 
exam to look at the lens of your eyes using a 
machine that shines a thin beam of light into the 
eye while the eye doctor looks into it with a type 
of magnifying glass.   
To test your lens he/she will need to put a couple 
of drops of medicine in your eyes that will enlarge 
your pupil for a short time. This allows the eye 
doctor to see easily into your eyes. This is the 
same as what happens to your eyes in the dark. 
Nerve Exam 
 
You will be asked to answer some questions 
about whether you experience any feelings such 
as a painful burning, or stinging, tingling, 
sensation of pins and needles or numbness in 
your arms and legs. The doctor will test your legs 
to see what your reflexes are like and if you feel 
vibrations. 
Study medicine check 
→ 
You will be asked how much study medicine you 
have taken or not taken, since the last time you 
were at the clinic. 
Hospital admission 
→ You may need to stay in the hospital if your study 
doctor considers it safer for you. 
Hospital check-out 
→ 
Your study doctor will tell you when it is safe for 
you to not be in hospital all the time. We will 
record when you are checked out from the 
hospital. 
 
If you are admitted to the hospital, but allowed to go home for the weekend, or if 
you are discharged from the hospital during the treatment period, used medicine 
containers/unused medicine should be returned when you return to the hospital.  
 
After you have stopped or completed the study medicines, the study doctor will 
decide if you need more TB treatment.  If you do, your study doctor will give you a 
referral letter to an MDR or XDR-TB unit or hospital.  It is very important that you go to 
the hospital as soon as possible and continue anti-TB treatment if your doctor 
recommends that. 
 
 
 
 
 
 
 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 10 of 28 
 
 
Treatment Extension 
 
If the study doctor decides that your treatment should be extended, either due to a 
pause of all of your study treatment, or if your TB is not cured after 26 weeks of 
treatment, the following procedures will be performed at additional treatment visits.  
 
 
Optional Treatment Extension Visits 
Procedures 
 Every 3 weeks, for up to a total of 26 or 39 weeks of treatment 
Demography 
 
Medical and smoking history 
 
Eligibility assessment 
 
Sputum collection 
X 
Pregnancy Test 
 
HIV, CD4 Count and Viral Load 
 
Blood tests 
X 
ECG 
 
Chest X-Ray 
 
TB Questionnaire/s 
 
Vital Signs 
X 
Physical Exam 
X 
Pharmacokinetic (PK) test  
 
Eye Exam 
X 
Nerve Exam 
X 
Study Medicine check 
X 
Other medicines 
X 
Adverse Events 
X 
 
Early Withdrawal  
 
If you decide of your own free will, or your study doctor decides you should stop 
treatment or withdraw from the study before you have finished the above visits, the 
procedures listed below may be performed at an Early Withdrawal Visit.  If you have 
received more than 15 doses of the study medication and haven’t had your 12 
week follow-up visit when you are withdrawn from the study, we will request you to 
come back for 1 more visit at the clinic so we can monitor your health, and you will 
be contacted 2 more times for a visit that can take place at the clinic, your home or 
on the phone with your study doctor where the following procedures may be 
performed.   
 
 
 
 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 11 of 28 
 
 
Early Withdrawal During Treatment Period  
Procedures 
 
Early Withdrawal 
Visit During 
Treatment 
Follow-up  
Week 12 
Follow-up  
Week 26 
Follow-up 
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count  
X 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
If you haven’t had all your follow-up visits when you are withdrawn from the study, 
we may request that you to come back for 1 more visit at the clinic so we can 
monitor your health as well.  
 
Early Withdrawal During Follow-up Period 
Procedures 
 
Early Withdrawal 
Visit During Follow-
up  
Follow-up  
Week 12 (If 
applicable) 
Follow-up  
Week 26 (if 
applicable) 
Follow-up  
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count 
 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 12 of 28 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
If the study doctor feels it is necessary, you may be asked to come in for extra 
(unscheduled) visits that do not appear on the above charts. 
 
6. What can go wrong in the study? 
6 
 
There are some possible risks and inconveniences of being in the study. 
 
Tuberculosis is a serious disease that can be fatal; all combinations of drugs used 
together in regimens to treat tuberculosis have rarely been associated with serious 
side effects, including death.   
 
You should not drink alcohol while you are taking study medication or 
other TB drugs as alcohol may damage your liver. 
You should tell your doctor if you have heart problems, including a slow 
heart rate, or if you have low thyroid hormone levels.  
You will have ECGs from time to time to monitor the electrical activity of 
your heart, including the QT interval. 
 
 
Details of the risks of taking the medicines in this study are noted below: 
 
Liver problems 
→ 
May be associated with symptoms such as 
nausea or vomiting, stomach pain, fever, 
weakness, itching, unusual tiredness, loss 
of appetite, light coloured bowel 
movements, dark coloured urine, 
yellowing of your skin or the white of your 
eyes.   
Liver problems may also be suggested by 
blood tests that show abnormalities in 
measures of your liver enzymes and other 
measures of how your liver is working. In 
Pretomanid, 
Linezolid, 
Bedaquiline,  
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 13 of 28 
rare cases liver problems may be serious 
and even lead to death. 
 
Headache 
→ pain in any part of the head 
Pretomanid, 
Linezolid, 
Bedaquiline,  
Stomach 
problems 
→ 
Tenderness or pain of the stomach area  
Feeling like you want to throw up, or 
actually throwing up. Also not feeling 
hungry, having diarrhoea (loose bowel 
movements) or having an upset stomach. 
Linezolid, 
Pretomanid, 
Bedaquiline     
Dizziness 
→ 
A feeling of being ‘drunk’ or ‘light 
headed’, especially when you stand up or 
sit down quickly. 
 
Linezolid, 
Bedaquiline  
 
The following are a list and description of side effects that are unique to each of the 
medicines: 
 
Pretomanid 
Besides the side effects mentioned above, the other side effects include: 
 
Reproductive 
organ 
changes  
 
→ 
Results from animal studies have shown that rats given 
pretomanid showed signs of damage to the male rats’ 
reproductive organs.  Recent studies in people have shown 
that there is no evidence that pretomanid damages the 
male reproductive organs. The potential for pretomanid to 
have an effect on the male reproductive organs will remain 
under evaluation. 
Cataracts 
(clouding of 
the lens in the 
eye) 
→ 
Other results from animal studies show that rats given 
Pretomanid developed cataracts at high doses over a 6-
month period of taking the medicine.  
It is not known if the effect found in rats indicates any risk for 
human beings. 
Fits 
(convulsions or 
seizures) 
→ 
were seen in some animal studies and in 1 patient treated 
with Pretomanid 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 14 of 28 
Skin problems 
→  
Inflamed areas on your skin, which may be red, itchy and/or 
painful. 
 
 
Linezolid 
Besides the side effects mentioned above, the other most common side effects seen 
in patients who took linezolid are: 
Changes in taste 
→ 
certain food or drinks may taste different to you 
Tongue 
discolouration 
→ 
the colour of your tongue changes 
Fungal infections 
→ 
when a fungus causes the infection 
Vaginal moniliasis → 
a fungal infection in the vagina 
Oral moniliasis 
→ 
a fungal infection in the mouth 
Fever 
→ 
When your body temperature goes higher than 38 °C or 
100.4 °F. 
Signs of nerve 
disturbances 
→ 
This is sometimes called ‘peripheral neuropathy’, which 
may be experienced as a painful burning, or stinging, 
tingling, sensation of pins and needles or numbness in your 
arms and legs. In some cases this can be permanent. 
 
Convulsions or 
seizures 
→ 
These are also commonly known as ‘fits’.   
A convulsion is when the body muscles contract and relax 
quickly and repeatedly / uncontrolled shaking of the 
body. 
A seizure is when there is a change in the normal electrical 
activity of the brain. 
 
 
 
Other side effects seen in patients who took linezolid include, but are not limited to: 
 
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Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 15 of 28 
Myelo-
suppression 
→ 
a lack of certain cells in your blood that your body needs to 
function.  
can make you feel tired and make your body being unable 
to fight off other illnesses or heal an injury. This could also 
make you bleed or bruise easily. 
Lactic acidosis 
→ 
a build-up of waste products in your blood that can cause 
constant nausea and vomiting. 
Serotonin 
syndrome 
→ 
this rare but serious condition may occur when linezolid is 
given with certain types of medications that affect a 
chemical in the brain called serotonin. Some of these 
medications include antidepressants.  Be sure to tell your 
study doctor about all prescription and non-prescription 
medications you are taking. 
It can cause many different symptoms, for example: 
confusion, restlessness, tremors, blushing, sweating and 
fever. 
Interactions with 
other medicines 
→ 
causing a rise in blood pressure 
Optic neuropathy 
→ 
A type of damage to the nerves in your eye that can lead 
to blindness if it is not treated.  This can be permanent. 
Low blood sugar 
→ 
This is often seen in patients with diabetes who have to take 
insulin or other medicines 
 
 
Bedaquiline 
From studies in 380 patients with TB who received Bedaquiline (312 of whom 
received Bedaquiline for as long as 6 months), we continued to see that Bedaquiline 
is generally safe and well tolerated.   Besides the side effects mentioned above, the 
other most common side effects seen in patients who took bedaquiline are: 
 
Serious side 
effects 
→ 
9 out of 79 patients (11%) taking bedaquiline with other 
TB medicines died, versus 2 out of 81 (3%) taking just the 
other TB medicines and no bedaquiline. 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 16 of 28 
It is not known why more patients in the bedaquiline 
group died. 
QTc interval 
increase 
→ 
An increase in the measure of the heart’s electrical 
activity. 
This was seen on the electrocardiogram in patients 
taking bedaquiline and in those taking other TB drugs. 
This may increase the risk that the heart does not beat 
in its normal, regular rhythm, which in rare cases cause 
death.  
However, no clinical side effects relating to heart 
rhythm problems were seen. 
Effects on the 
pancreas 
 
Studies in mice and dogs showed that bedaquiline 
caused damage to the pancreas.  It is not known if the 
effect found in mice and dogs indicates any risk for 
humans. 
Joint pain 
→ 
One type of joint pain that may be caused or worsened 
by some medicines is called gout.  Gout is caused by too 
much of a normal chemical in your body called uric 
acid. Uric acid is a chemical that is created when the 
body breaks down substances called purines. 
Purines are found in some foods (like seafood) and drinks 
(like beer). 
 
Accumulation in 
the body 
→ 
Bedaquiline leaves your body slowly after the last tablet 
is taken.  It takes about a year for all the drug to be 
removed from your body. 
 
 
In addition to the listed side effects your study doctor has information on side effects 
that may occur less often and your study doctor could discuss these with you. 
 
Possible risks and side effects of procedures to be performed: 
 
• 
Drawing blood is normally done as part of routine medical care. There is a slight 
risk of discomfort.  Drawing blood may rarely cause fainting, inflammation of 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 17 of 28 
the vein, pain, bruising or bleeding at the site where the needle goes in.  There 
is also a slight risk of infection.  Your protection is that experienced staff will draw 
your blood under germ free conditions.  
• 
When an ECG is done, the sensors, or stickers, may cause slight discomfort 
when they are removed from your skin. 
• 
An x-ray is a common test exposing you to a small amount of radiation.  The 
effect of radiation adds up over your lifetime, but small doses like the one used 
to take a picture of your chest is not likely to be a risk to your health. 
• 
The eye tests are common. The drops put into your eyes will cause your vision 
to be blurred and sensitive to light for a few hours after the examination, during 
which time you should not drive. In very rare cases they can cause increased 
pressure in the eye with nausea and pain. If this happens, call the study doctor 
right away. 
 
It is important that you follow your study doctor’s and/or study nurses’ instructions 
exactly. 
 
You must inform your study doctor immediately if: 
 
• 
you take any local or herbal remedies, prescribed or non-prescribed (over the 
counter) medicines, 
• 
your medical condition changes, 
• 
you have seen any other healthcare providers, 
• 
you have any side effects, 
• 
you have any complications*, or 
• 
you have any injuries while taking the study medicine. 
 
Your study doctor and/or nurse will ask you at every visit about any other medication 
you may have taken and how you are feeling.  
 
It is possible that your condition will stay the same or get worse while you are in this 
study. However, the study doctor will watch you closely and if he/she feels that 
participating in the study is not good for your health, he/she will immediately take 
you off the study. 
 
There may be risks with the use of the study medicine that we do not yet know of.  If 
we become aware of these, we will tell you of any new important findings that may 
affect your willingness to stay in the study. 
 
 
 
 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 18 of 28 
7. Are there things that I cannot do while I am in the study? 
7 
 
You cannot take part in this study if you are breastfeeding,                 
pregnant or trying to get pregnant. 
 
This is because there may be risks to becoming pregnant and to an unborn child 
that we may not yet know of. If you can get pregnant, we will test you before you 
take the study medicine and during the study to see if you are pregnant. 
 
Women participants who CAN become pregnant: 
 
You must use 2 methods of birth control. You need to use birth control for as long as 
you are taking the study medicine and for up to 6 months after you have taken the 
last dose of study medicine. 
 
When taking the study medicine, birth control that are based on hormones only, 
such as the contraceptive pill or injection, may not work as well as usual. Because of 
this, either you must be willing not to have sex, or you must use 2 methods of birth 
control, for example: 
 
a) Double (2 different types) barrier methods, which may include a male 
condom, diaphragm, cervical cap, or female condom; OR 
b) 1 barrier method described above used together with a hormone-based birth 
control (tablet or injection), or an intra-uterine device  
 
If you are a female participant and become pregnant while you are in the study, it is 
very important for you to tell the study doctor immediately.  If this happens, the study 
doctor will discuss with you what to do.   
 
Since there might be unknown risks to an unborn child, we will ask you to stop taking 
part in the study.  We may have questions about your pregnancy and the baby and 
we may ask you to visit the study doctor at certain times during and after your 
pregnancy to check your health status and collect information on the outcome of 
your pregnancy.  
 
Male participants’ female sex partner who CAN become pregnant:  
 
You and your female partner need to use at least 1 method of birth control for as 
long as you are taking the study medicine and for up to 12 weeks after you have 
taken the last dose of study medicine. Examples of methods of birth control are as 
follows: 
 
Double barrier method, which can include a male condom, diaphragm, cervical 
cap, or female condom; OR 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 19 of 28 
Hormone-based contraceptives or an intra-uterine device for your female partner. 
 
Please note that it is your own responsibility to get the correct birth control for you 
from your family planning or birth control clinic.  Please speak with your study doctor 
if you are unsure of where to get the correct birth control. 
 
 
Women participants, and male participants’ female sex partner, who CANNOT 
become pregnant:  
 
You do not need to use birth control if you are: 
 
a) Not an active heterosexual male or female participant, or you do not 
practice sex; OR 
b) A female participant or male participants’ female sex partner, and have had 
an operation to remove both ovaries, or both ovarian tubes have been tied 
or cut and or the uterus has been removed, or you have not had a period for 
at least 12 months in a row; OR 
c) A male participant or female participants’ male sex partner, who has had 
both testes tubes tied or cut, or have had both testes removed at least 3 
months before the study. 
 
Foods and drinks that you cannot eat or drink 
• 
Large quantities of foods or beverages that contain a lot of a protein called 
tyramine should be avoided while taking your study medicine.  Foods high in 
tyramine include those that may have had protein changes by aging, 
fermentation, pickling, or smoking to improve flavor, such as aged cheeses, 
fermented or air-dried meats, sauerkraut, soy sauce, tap beers and red wines.  
You should talk to your study doctor if you have questions about how you can 
avoid large quantities of tyramine.  
• 
You should not drink alcohol while you are taking study medication as alcohol 
may damage your liver. 
 
Other medicines that you cannot use 
• 
You cannot use certain medications to treat depression while you are on the 
study medication.  
• 
There are other medications that you cannot use while you are on the study 
drug because they may increase the risk of abnormal heart rhythms, or 
because they may affect what your body does to the study medication after 
you take them.  Your study doctor can tell you which medications these are.   
• 
If you are HIV positive, certain HIV medications should not be used.  Your 
study doctor can tell you which HIV medications can be used during this 
study.   
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M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 20 of 28 
• 
You should inform your doctor if you are taking any illegal drugs, because 
some illegal drugs can affect your safety or your ability to follow through with 
all the study procedures. 
 
8. How can the study help me? 
8 
 
There is a chance that your TB may get better because you are in this study, but we 
cannot guarantee this.  If the study medicine does not work well you will not get any 
benefit from being in the study.  However, the information that we get from the 
study can help in making future treatments for TB, and in the long run it will likely help 
other TB patients. 
 
The close medical attention you will get by taking part in the study may help you to 
learn useful information about your health status.   
 
9. What are my other choices for treatment? 
9 
 
You do not have to take part in this study. If you decide not to take part, you will not 
be disadvantaged and you will still receive care and treatment for your TB at <<TB 
clinic or specialized unit in a hospitalist location>> for at least <<add time period>>, 
per your country’s National TB Treatment Guidelines. 
 
If you do not take part in the study, your doctor will make sure you remain in or are 
sent to an MDR-TB unit or XDR-TB unit or hospital for treatment. 
 
10. What will happen if I am injured in the study? 
10 
 
<< For ABPI Countries:  
 
The sponsor has taken out insurance in case you get injured in this study.  
The sponsor will pay you for all reasonable medical expenses you may have 
because you are injured in this study, according to the guidelines of the Association 
of the British Pharmaceutical Industry (ABPI guidelines). These guidelines recommend 
that the sponsor of the study, without any legal commitment, should pay you, 
without you having to prove that it is at fault, for any injury resulting from giving the 
study medicine or other procedures carried out in accordance with the protocol for 
this study. Your study doctor has a copy of the ABPI guidelines if you would like to 
see them. 
The APBI guidelines do not require the sponsor to pay you if the injury: 
• 
resulted from a medicine or procedure that is not required by the study or if 
you did not stick to the rules of the study;   
• 
was not a serious injury that will last a long time and disable you. 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 21 of 28 
Because of the following reasons, you may be paid less or the sponsor may not have 
to pay you at all under the ABPI Guidelines: 
• 
how serious the disease is that is being treated, how likely you are to have 
adverse reactions and any warnings that were given to you; 
• 
the risks and benefits of normal or standard treatments compared to the risks 
and benefits that we know the study medicine have or think that it may have; 
• 
a wrongful act of someone outside the study, or if the study doctor does not 
properly deal with an adverse reaction; 
• 
if you have been negligent.  
Any payment that the sponsor makes to you because of the ABPI guidelines does 
not mean that the sponsor is legally responsible for your injury. You will not lose any of 
the legal rights you have if you are injured just because the sponsor has agreed to 
follow the ABPI guidelines. Please ask if you want more information on this.>> 
<<Country regulatory authorities that DO NOT require compliance to the ABPI clinical 
trial insurance guidelines,  
Text will be provided on an ‘as needed’ basis in consultation with TB Alliance 
Legal.>> 
 
11. What will happen to my personal information? 
11 
 
All records with information that can identify you will be kept confidential and, as far 
as the applicable laws and regulations allow, will not be made publicly available.   
 
The study doctor and research team will use personal information about you to carry 
out this study.  This may include your name, address, medical history and information 
from your study visits. However, this personal information will stay at the study site and 
will not be included in the study data that we will send to the sponsor or 
representatives of the sponsor. You will only be identified by a coded number in 
reports or publications that are produced from this study (study data). 
 
To confirm that the study data collected about you is correct and related to you, 
selected people working for the sponsor including auditors, as well as 
representatives of government regulatory authorities and ethics committees will 
have access to your personal information at the study site.  These persons know that 
they must keep your information confidential.  By signing this document, you are 
agreeing to let them have access to your information. 
 
The sponsor may send your coded study data that were collected from your country 
to other countries.  <<EU: “Your data might be transferred to countries outside the 
EU”.>>However, they will obey all local and international laws and regulations on 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 22 of 28 
data privacy to protect your personal and other information, even in countries 
where data privacy laws are less strict. 
 
The sponsor or representatives may use this study data for the following purposes: 
 
• 
To see if the study medicine works and is safe. 
• 
To compare the study medicine to other medicines. 
• 
For other activities related to the study medicine. 
 
You have the right to ask the study doctor about the data we are collecting about 
you. You can ask the study doctor to allow you to see your personal information and 
you can ask him/her to make any corrections, if needed. 
 
The results of the study will only be available once all participants have completed 
the study, the information has been collected and checked, and the results have 
been analyzed (looked at and a decision made about them).  If you want to know 
the results of the study you may contact your study doctor and he/she will tell you 
the results if they are ready. 
 
The results of this study will be made available to national and international 
medicine regulatory agencies to help them decide if the new treatments are 
helping to treat TB.  In addition, the results may be published in international medical 
journals so that doctors and other health workers might learn from this work. You will 
not be named in any reports/publications. 
 
A description of this clinical trial will be available on www.clinicaltrials.gov, as 
required by United States law<< and other countries as required, e.g.  
www.sanctr.gov.za, as required by South African law>>. This <these>> website<
> 
will not show information that can identify you. At most, the website<
> will include 
a summary of the results. You can search this<<these>> website<
> at any time. 
 
12. Will I be paid to take part in this study? 
12 
 
You will not be paid to take part in this study.  However, the sponsor will pay you 
back for out-of-pocket expenses such as for transport to and from the study site and 
other various costs that you may have because of your study participation.   
 
You will get, depending on your out of pocket expenses, an amount of -<<specify 
amount and frequency e.g. x per visit and add any pro-rata payments if 
applicable>>.  If your study related costs are more than the specified amount and 
you have proof of such costs, please discuss it with your study doctor. 
 
 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 23 of 28 
13. Do I need to pay anything to be in this study? 
13 
 
The sponsor will pay all costs related to the study such as the study medicine, 
treatment, tests, examinations and procedures specified in the protocol.  Not you, 
nor your <<medical insurance / aid,>> healthcare provider will have to pay for these 
expenses.  In other words, you will not have to pay for anything that is needed for 
your participation in this study. 
 
Should you need to visit any doctor, besides your study doctor, or you are 
hospitalized for any illness, including to treat your TB, then you will need to visit the 
doctor or hospital as allowed by your healthcare provider <<or medical insurance / 
aid>>.  These medical visits, that are not part of the clinical study, are not paid for by 
the study. 
 
14. Who is in charge of the study? 
14 
 
The study is sponsored by the Global Alliance for TB Drug Development (TB Alliance), 
a not-for-profit organization based in New York in the United States.  
 
The TB Alliance will pay the study staff for doing this study. The study doctor will not 
benefit unduly if you are included in the study. 
 
15. What happens if I do not want to or cannot be in the study anymore? 
15 
 
Your participation in the study may be stopped for the following reasons: 
 
• 
Testing comes back that shows your TB won’t respond to the study medicines 
• 
You do not follow the study doctor’s instructions. 
• 
You do not take the study medicine as prescribed. 
• 
Testing comes back that shows your TB will respond to medicines that treat drug 
sensitive TB 
• 
The study doctor decides that it is in your best interest (e.g. you experience 
certain adverse events* during the study). 
• 
If you ask to stop (you don’t have to explain why). 
• 
If the TB Alliance asks you to stop. 
• 
If the TB Alliance stops the study or closes the study site. 
• 
If you become pregnant (women who can get pregnant). 
 
If you decide to withdraw from the study, please tell us immediately. If you withdraw 
from the study, it will not change your access to other medical care or the quality of 
the care.   
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 24 of 28 
If you leave the study, the doctor would like to ask you some questions and check 
your health to make sure that you are safe and any possible side effects from the 
study medicine are treated.  If your study treatment is stopped, based on you and 
your study doctor’s choice, you will be asked to continue to come to some of the 
study visits or be contacted in another way, unless you decide to withdraw from the 
study completely. If your treatment is stopped or you withdraw from the study 
completely, your study doctor/site staff may need to perform certain procedures 
previously mentioned in the “What will happen to me in the study” section. 
 
We may ask you to come to the hospital/study site to complete these procedures. 
 
Once you have left the study, the study doctor will give you a referral letter to an 
MDR or XDR-TB unit or hospital for further treatment of your TB or to another physician 
for routine medical care if your TB infection is cured.  
 
16. Whom can I contact if something worries me? 
16 
 
You can call the study doctor or another person at the study site 
at any time of the day or night (24 hours) on Tel: <<add>> or 
<<add>>. 
 
 
For questions about your rights as a participant in a study: 
 
If you want any information about your rights as a study participant, or if you have 
complaints about this study, you may contact the <<add name of Ethics 
Committee>>, which is an independent committee established to help protect the 
rights of research participants. Their contact details are as follows: 
 
<<Add name, address and contact telephone/fax numbers>> 
 
For complaints, if you think that the study doctor or ethics committee did not help 
you: 
 
<<include per country as appropriate>> 
 
 
17. How do I agree to be in this study? 
17 
 
If you want to take part in this study, please read the consent statement and sign on 
page <<XX>>. 
 
 
Personal doctor / specialist notification option: 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 25 of 28 
Please mark below, by writing your initials in the correct block, if you want me to tell 
your personal doctor or your specialist that you are taking part in this study: 
 
 
YES, I want my study doctor to tell my personal doctor / specialist that I am 
taking part in this study. 
 
NO, I do not want my study doctor to tell my personal doctor / specialist that I 
am taking part in this study. 
 
I do not have a personal doctor / specialist. 
 
 
Collection of Pre-screening Stored Sputum (or TB from your sputum) Sample 
agreement: 
 
Please mark below, by writing your initials in the correct block, if you agree for your 
stored sputum sample or TB from your sputum (taken before this visit/reading and 
signing this form) to be collected from the storing laboratory: 
 
 
YES, I agree if available, for my stored sputum sample or TB from your sputum 
to be collected from the laboratory and used for this study. 
 
NO, I do not want my stored sputum sample or TB from your sputum to be 
collected from the laboratory and used for this study. 
 
 
Participant Notes 
 
 
 
 
 
 
 
 
 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 26 of 28 
 
 
Glossary 
Technical term 
Explanation 
complications 
another disease or condition that makes your TB 
worse 
diaphragm 
A soft latex or silicone dome with a spring in the 
rim. The spring creates a seal against the wall of 
the vagina. 
adverse events 
unwanted events 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 27 of 28 
PARTICIPANT INFORMED CONSENT FORM 
 
By signing below, I agree that: 
 
• 
I have read, or someone has read the information sheet and consent form for this 
study to me, and I understand it. 
• 
I have had the chance to ask questions and I am happy with the answers. 
• 
I have had time to discuss the information with others and to decide if I want to 
take part. 
• 
I will get a signed and dated copy of this consent form on the day that I sign it. 
• 
I agree of my own free will to take part in this study. I know I have the right to stop 
taking part at any time, without giving any reason. If I stop taking part, it will not 
change my medical care or legal rights. 
• 
Site staff, representatives from the sponsor, including auditors, regulatory 
authorities and ethics committees can have direct access to my medical 
records. They will treat my information as confidential. 
• 
If I withdraw from the study, study data collected about me up to the point of my 
withdrawal can still be used to carry out this study.   
• 
Female participantsonly: “If I become pregnant while on the study, follow up 
information on the outcome of my pregnancy can be collected, if needed.” 
• 
<<EU: “I consent to the processing/storing of my data and the transfer thereof to 
countries outside the EU.”>> 
 
 
 
Printed Name of Participant/Legal 
Representative 
 
 
 
Signature/mark/thumbprint of 
Participant/Legal Representative 
 
Date 
 
 
(Participant/witness must write 
date) 
 
 
 
*Printed Name of Person Conducting Consent 
(If other than investigator/delegate) 
 
 
 
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M ain Participant Information and Informed Consent Form 
Protocol Version and Date: V X dd-mmm-yyyy 
  
M aster PI/IC Version 2.0 Date 13 June 2018 
Master Country / Site Version X Dat e dd-mmm-yyyy  
 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
TMP03-A V3.0  
 
Confidential | Page 28 of 28 
 
 
*Signature of Person Conducting Consent 
(If other than investigator/delegate) 
 
Date 
 
 
(Person conducting consent must 
write date) 
 
I,   
(Insert name of investigator) 
hereby confirm that the above participant has been fully informed about the 
nature, conduct and risks of the above study. 
 
 
 
Signature of Investigator 
 
Date 
 
 
(Inv estigator must write date) 
 
By signing below, I verify that the above participant gave verbal informed consent. 
The participant has been informed about the risks and the benefits of the study, 
understands such risks and benefits and is able to agree to participation, without 
coercion, undue influence or inappropriate incentives. 
 
 
 
*Printed Name of Witness 
 
 
 
*Signature of Witness 
 
Date 
 
 
(Witness must write date) 
* Where applicable 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 1 of 28 
PARENT OR LEGAL GUARDIAN INFORMATION AND INFORMED 
CONSENT FORM 
 
Protocol Name/Number:  ZeNix/NC-007-(B-Pa-L) 
Protocol Title:  
 
 
A Phase 3 partially-blinded, randomized trial assessing the  
safety and efficacy of various doses and treatment durations of linezolid plus  
bedaquiline and pretomanid in participants with pulmonary infection of either  
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or  
non-responsive multi-drug resistant tuberculosis (MDR-TB). 
 
Participant Initials:  
 
     Participant Number: 
 
 
 
 
Introduction 
 
We invite your child to take part in a study with a new combination of medicines. The 
names of the medicines are bedaquiline, linezolid and pretomanid.  
  
Please read this information sheet before you agree for your child to take part. This 
document will answer the following questions: 
 
1. Is the study safe? 
1 
 
2. Does my child have to take part? 
2 
 
3. Why are you doing the study? 
3 
 
4. How will the study work? 
4 
 
5. What will happen to my child in the study? 
5 
 
6. What can go wrong in the study? 
6 
 
7. Are there things that my child cannot do while he/she is in the study? 
7 
 
8. How can the study help my child? 
8 
 
9. What are my child’s other choices for treatment? 
9 
 
10. What will happen if my child gets hurt in the study? 
10 
 
11. What will happen to my child’s personal information? 
11 
 
12. Will my child be paid to take part in this study? 
12 
 
13. Will it cost me anything for my child to be in the study? 
13 
 
14. Who is in charge of the study? 
14 
 
15. What happens if my child does not want to or cannot be in the study any 
more? 
15 
 
16. Whom can I contact if something worries me or my child? 
16 
 
17. How do I agree for my child to be in this study? 
17 
 
If you have any other questions that are not answered in this document, please ask 
someone from the study staff for more information. Difficult medical terms are marked 
with an (*) and are explained in the Glossary on page <<XX>>. 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 2 of 28 
It is very important that you understand this information sheet before you agree for 
your child to take part in this study. We would like you to ask as many questions as 
you need. If there is anything that you do not understand, please discuss this with 
the study doctor, the study staff, your own doctor or with your family. 
 
Parent or Legal Guardian Notes 
 
 
 
 
 
 
 
 
 
 
1. Is the study safe? 
1 
 
The <<name of Ethics Committee as applicable>> and <<name of Regulatory 
Authority as applicable>> have checked this study and have approved it because it 
complies with medical and ethical standards.   
 
In addition, the study will be done according to the Declaration of Helsinki 2013, 
International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) 
<<and list any other appropriate guidelines e.g. South African GCP Guidelines>>.   
 
One of the purposes of these regulations is to make sure that the rights of people 
taking part in research studies are protected. If you or your child would like to read 
any of these guidelines and regulations, please ask your child’s study doctor to give 
you a copy. 
 
2. Does my child have to take part? 
2 
 
Your child’s participation in this study is totally voluntary (out of free will). Your child 
may choose not to be in the study or leave the study (withdraw his/her consent) at 
any time by telling the study doctor.  
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 3 of 28 
If you decide not to have your child take part in the study or if your child no longer 
wants to take part, he/she will not lose any benefits that he/she otherwise would 
have had. The study doctor will give you a referral letter to take your child to an MDR 
or XDR-TB unit, TB clinic, or hospital where they will give him/her the standard TB 
treatment according to your country’s National TB Treatment Guidelines. 
 
3. Why is your child doing the study? 
3 
 
Your child has been diagnosed with extensively drug resistant pulmonary (i.e. in the 
lungs) TB (XDR-TB), pre-extensively drug resistant TB (pre-XDR-TB), or Multidrug 
Resistant TB (MDR-TB). This means that these forms of TB bacteria, or germs, are 
present in your child’s lungs and that these bacteria do not respond to treatment or 
requires treatment that he/she can’t tolerate. These forms of TB can be very hard to 
treat and medicines must be taken for up to two years or even longer.  
 
It is possible that because people do not take the medicines correctly, TB resistance 
to these medicines is becoming more common.  These forms of resistant TB can be 
very difficult to treat. New medicines are urgently needed to make the TB treatment 
time shorter and to treat resistant TB.   
 
A previous study called the Nix-TB study has shown that three medicines called 
bedaquiline, linezolid and pretomanid taken together may treat your child’s type of 
TB. To date, these medicines have been tested in the laboratory, on animals, on 
healthy human volunteers, and on over 70 TB participants and have been shown to 
be possibly effective against XDR-TB and MDR-TB. We want to do this study is to see 
what dose and length of treatment of linezolid is the most effective in treating your 
child’s type of TB while causing the least amount of side effects. The safety and 
effectiveness of the following three drugs together: bedaquiline, linezolid and 
pretomanid will also be tested.   
 
4. How will the study work? 
4 
 
About 180 people (called participants) will be taking part in this study. All the 
participants will be male and female <<14 (update for specific age for each 
Country/site)>> years old and older. The trial will be conducted globally and it is 
planned that they will be from approximately 12 research centers around the world, 
including but not limited to <<Country specific to ICF>> and additional centers in 
South Africa <<delete South Africa if noted previously in Country specific>>, Eastern 
Europe and Asia. <<When required by EC, list known targeted countries within the 
regions>>. We expect that your child will be in this study for about 2 years. The study 
is split into 3 parts: 
 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 4 of 28 
Part 
Name 
Length 
Reason 
1 
Screening 
Up to 14 
days 
During this time, the study doctor checks if your 
child meets the requirements and if it is safe for 
him/her to be part of the study. This may be over 
several visits and take up to 14 days. If your child 
doesn’t meet all of the requirements when he/she is 
screened, your child may have the opportunity to 
be screened at a later time if the doctor thinks 
he/she would be able to meet the requirements 
then.  
2 
Treatment 
26 weeks 
or  
39 weeks 
Your child will receive study medicine for a total of 
26 weeks, depending on how he/she responds to 
the medicines. Your child will visit the hospital/clinic 
at least 17 times. Some of these visits may be while 
he/she is a patient in the hospital.  
If the study doctor determines that your child needs 
to pause his/her treatment for any reason, then 
his/her treatment may last longer than 26 weeks. If 
your child’s TB has not been cured after 26 weeks of 
treatment, the study doctor may decide to extend 
your child’s treatment to a total of 39 weeks.   
3 
Follow-up 
78 weeks 
After your child has finished taking the study 
medicine, the study doctor will check on your 
child’s health for the next 78 weeks. During this time, 
your child won’t be on the study medicine but 
he/she will visit the hospital/clinic at least 8 times 
during this part. 
 
If your child’s study doctor decides that he/she qualifies to be in this study, and if you 
and your child agree for him/her to be in this study by signing the consent and 
assent forms, the following will happen: 
 
Your child will be randomly assigned (purely by chance, like flipping a coin) to 
receive one of the 4 possible linezolid doses below. This study is partially blinded, 
which means neither your child nor your child’s study doctor will know what dose 
he/she will receive or how long he/she will receive linezolid. This is done by giving 
everyone the same number of tablets, some participants receive tablets that look 
like the linezolid medicine, but do not contain linezolid. These are called placebo. 
We can only tell you at the end of the study (i.e. when the treatment blind has been 
broken) to which of the treatments your child was assigned. If there is an emergency 
and the study doctor needs to know what linezolid treatment your child is receiving, 
he/she can quickly and easily find this out. 
 
• 
Linezolid 1200 milligrams (mg) daily for 26 weeks plus linezolid placebo; or 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 5 of 28 
• 
Linezolid 600 mg daily for 26 weeks plus linezolid placebo; or 
• 
Linezolid 1200 mg daily for 9 weeks plus linezolid placebo, then linezolid 
placebo for 17 weeks; or 
• 
Linezolid 600 mg daily for 9 weeks plus linezolid placebo then linezolid 
placebo for 17 weeks.  
In addition to linezolid and linezolid placebo, all participants will receive the 
following: 
• 
bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 
weeks plus;  
• 
pretomanid 200 mg once daily for 26 weeks. 
Your child and the study doctor will know how much bedaquiline and pretomanid 
he/she is receiving.  
 
Pretomanid is a new medicine that has not been approved for the treatment of TB 
by any Government Regulatory Authority. Bedaquiline has been approved for 
treatment of MDR-TB in the United States of America and in Europe <<and has been 
approved by “specific regulatory authority when relevant” for treatment of MDR-TB 
in “Country”>>. Linezolid has been approved around the world to treat many kinds 
of infections caused by germs. Linezolid is not approved for TB treatment, but it is 
sometimes used to treat TB patients if other approved medicines do not work. 
Your child will take 5 whole tablets and one half tablet a day for the first 8 weeks of 
study treatment. Your child will then take 4 whole tablets and one half tablet a day 
for the remaining 18 weeks of study treatment.   
 
The study doctor may decide to pause all medication for your child. The study 
doctor may also decide that your child’s linezolid medicine dose needs to be 
reduced, paused, or just your child’s linezolid medicine needs to be stopped. You 
will know if the study doctor decides to reduce, pause or stop the linezolid.  If your 
child’s dose is reduced, neither you nor your child’s doctor will know your child’s 
current dose or the dose your child’s linezolid medicine is reduced to. If your child’s 
dose of linezolid is reduced anytime during the study, the study doctor may increase 
your child’s linezolid dosage at a later visit, but not higher than the starting dose. 
Your child will continue to receive the same number of tablets and half tablets, 
some or all of the tablets with medicine will be replaced with placebos. 
 
Your child will be given study medicines at each visit in the Treatment Period and 
asked to bring back all empty packets/bottles and unused medicines to his/her next 
visit.  
 
If for any reason the study doctor decides that all of the study medicine needs to be 
interrupted, then your child’s treatment period may be longer. If your child’s TB has 
not been cured after 26 weeks of treatment, the study doctor may decide to extend 
your child’s treatment to 39 weeks. 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 6 of 28 
5. What will happen to my child in the study? 
5 
 
Your child must be willing to follow all study procedures and requirements. For this 
study to be successful and for his/her own safety, it is important that your child works 
together fully with the study doctor and follow his/her instructions precisely 
throughout your child’s time in the study.   
 
Depending on your child’s reaction to the medicine and study procedures, there 
may be some slight changes to the treatment visits and procedures, and  
how long your child will have to stay in the study. This is a list of all the study visits and 
what will happen at each visit: 
 
 
Screenin
g 
Visits 
Treatment 
Visits 
 
Post-Treatment 
Follow-up 
Visits 
 
Procedures 
 
Up to 14 days before 
Treatment 
Day 1 (Baseline) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7  
Week 8 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 20 
Week 23 
End of Treatment 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum 
collection 
X 
X X 
X X X 
 
X 
 
X X 
X 
 
X 
 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
HIV, CD4 Count 
and Viral Load 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood tests 
X 
X X 
X X X X 
X X X X 
X X X X 
X X X 
X 
 
 
 
 
 
 
 
ECG 
X 
X X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest X-Ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB 
Questionnaire/
s 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Vital Signs 
X 
X X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X X X 
 
 
X X X 
X X 
X 
Pharmacokinet
ic (PK) test  
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Eye Exam 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X X X 
X 
 
X 
 
 
 
 
 
Study Medicine 
check 
 
X X 
X X X X 
X X X X 
X X X X 
X X X 
 
 
 
 
 
 
 
 
Other 
medicines 
X 
X X 
X X X X 
X X X X 
X X X X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X X 
X X X X 
X X X X 
X X X X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
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Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 7 of 28 
To help understand what will happen at each of your child’s visits, we have 
described these below: 
 
Demography 
→ 
This is personal information about your child’s 
date of birth, gender and race that you will be 
asked about. 
Medical and smoking 
history 
→ 
You and your child will be asked about your 
child’s medical and smoking history and all other 
medicines, including over-the-counter, 
prescription, herbal and traditional medicines 
your child may have taken in the last 30 days, or 
are currently still taking. 
Eligibility assessment 
→ 
This is a process of checking that your child meets 
the study requirements to make sure it is safe for 
him/her to take part. 
Sputum collection 
→ 
Your child will be asked to cough up sputum 
(phlegm) into a small cup at different times in the 
study. The sputum is used to check if your child 
has TB, the type of TB your child has, how many 
TB bacteria your child has and what medicines 
will work on the TB bacteria. 
 
<<Add as required per country: If your child has a 
stored sputum (or TB from his/her sputum) sample 
(which was collected before this visit) that could 
be used to allow him/her into this study or check 
the type of TB and what medication will work on 
that type of TB bacteria. If you and your child 
both agree to it, this may be collected from the 
applicable laboratory and used if you check 
“yes” at the end of this consent>> 
 
The TB germs that have been taken out of your 
child’s sputum will also be sent to laboratories in 
the United Kingdom (UK) every few months to test 
how they respond to the study medicines. They 
may also be used to research new testing 
methods for TB and/or study medicines. These 
germs will not contain any material from your 
child’s body; only the TB germs. You/your child 
will not receive the results from these tests or get 
any more benefit from these tests being done. 
The testing could be done for as long as five 
years after your child take part. 
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Parent or Legal Guardian Information and Informed Consent Form 
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HIV, CD4 count test and 
Viral load 
→ 
This is a test to see if your child has been infected 
with HIV and, if he/she has, we will measure your 
child’s CD4 count (a kind of cell that fights 
infection). You and your child will be counselled 
on HIV before the blood tests are taken and 
again once the results are given to you, and you 
and your child may be asked to sign separate 
informed consent and assent forms. 
Blood tests  
→ 
Blood will be taken from your child by inserting a 
small needle into a vein in his/her arm. The blood 
will be tested to check if your child is healthy. 
Each blood draw is about 20 millilitres (4 
teaspoons). 
Urine tests 
→ 
Your child will be asked to provide a sample of 
his/her urine in a small cup when he/she is at the 
clinic. The urine will be tested to check if your 
child is healthy.   
Your child’s urine will be tested to see if he/she 
has taken any drugs like cannabis, cocaine, 
amphetamines, opiates, benzodiazepines and 
barbiturates. 
Pregnancy test 
→ 
If your child is a girl who is able to have children, 
your daughter’s urine will be tested to see if she is 
pregnant, whether or not she is sexually active. 
ECG 
→ 
A test that is done by placing 12 sensors (like 
stickers) on your child’s skin for a short time to 
check how his/her heart is working.  
Chest X-Ray 
→ This is a photograph of your child’s lungs. 
TB and health 
questionnaire/s 
→ 
Your child will be asked to tell the study doctor 
about his/her TB symptoms and general health to 
check how he/she is feeling. 
Physical exam  
→ This is an assessment of your child’s body to 
check for signs of disease. 
Vital signs 
→ 
A measurement of your child’s blood pressure, 
heart rate, breathing, body temperature, height 
and weight. 
Pharmacokinetic (PK) test 
→ 
Blood will be taken at some visits to check what 
happens to the medicines once your child 
swallows them. Blood will be taken from your 
child by inserting a small needle into a vein in 
his/her arm. About 20 milliliters (4 teaspoons) of 
blood will be taken from your child for this test. 
Eye exam 
→ This is a check of your child’s vision by asking 
him/her to read the letters or symbols off a chart, 
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Parent or Legal Guardian Information and Informed Consent Form 
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PI Name:  XXX (Language) 
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Confidential | Page 9 of 28 
and to read numbers or symbols off cards with 
coloured patterns on them. There will also be an 
examination to look at the lens of your child’s 
eyes using a machine that shines a thin beam of 
light into the eye while the eye doctor looks into it 
with a type of magnifying glass.   
To test your child’s lens, the eye doctor will need 
to put a couple of drops of medicine in your 
child’s eyes that will enlarge his/her pupil for a 
short time. This allows the eye doctor to see easily 
into your child’s eyes. This is the same as what 
happens to your eyes in the dark. 
Study medicine check 
→ 
Your child will be asked how much study 
medicine he/she has taken or not taken, since 
the last time he/she was at the clinic. 
Hospital admission 
→ Your child may need to stay in the hospital if the 
study doctor considers it safer for him/her. 
Hospital check-out 
→ 
The study doctor will tell you when it is safe for 
your child to not be in hospital all the time. We 
will record when your child is discharged from the 
hospital.  
 
If your child is admitted to the hospital, but allowed to go home for the weekend, 
used/unused medicine should be returned when he/she returns to the hospital. 
 
After your child has stopped or completed the study medicines, the study doctor will 
decide if your child needs more TB treatment. If he/she does, the study doctor will 
give you a referral letter for your child to an MDR or XDR-TB unit or hospital. It is very 
important that your child goes to the hospital as soon as possible and continues anti-
TB treatment if the doctor recommends that. 
 
Treatment Extension 
 
If the study doctor decides that your child’s treatment should be extended, either 
due to treatment pause of all of your child’s study treatment, or if your child’s TB is 
not cured after 26 weeks of treatment, the following procedures will be performed 
at additional treatment visits.  
 
 
Optional Treatment Extension Visits 
Procedures 
 Every 3 weeks, for up to a total of 26 or 39 weeks of treatment 
Demography 
 
Medical and smoking history 
 
Eligibility assessment 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
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PI Name:  XXX (Language) 
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Sputum collection 
X 
Pregnancy Test 
 
CD4 Count 
X 
Blood tests 
X 
ECG 
 
Chest X-Ray 
 
TB Questionnaire/s 
 
Vital Signs 
X 
Physical Exam 
X 
Pharmacokinetic (PK) test  
 
Eye Exam 
X 
Nerve Exam 
X 
Study Medicine check 
X 
Other medicines 
X 
Adverse Events 
X 
 
Early Withdrawal 
 
If your child decides of his/her own free will, or your child’s study doctor decides 
he/she should stop treatment or withdraw from the study before he/she has finished 
the above visits, the procedures listed below may be performed at an Early 
Withdrawal Visit.  If your child received more than 15 doses of the study medication 
and has not had his/her 12 week follow-up visit when he/she is withdrawn from the 
study, we will request your child to come back for 1 more visit at the clinic so we can 
monitor his/her health, and your child will be contacted 2 more times for a visit that 
can take place at the clinic, your child’s home or on the phone with your child’s 
study doctor where the following procedures may be performed.   
 
 
Early Withdrawal During Treatment Period  
Procedures 
 
Early Withdrawal 
Visit During 
Treatment 
Follow-up  
Week 12 
Follow-up  
Week 26 
Follow-up 
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count 
X 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 11 of 28 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
If your child hasn’t had all of his/her follow-up visits when he/she is withdrawn from 
the study, we may request that your child come back for 1 more visit at the clinic so 
we can monitor his/her health as well.  
 
Early Withdrawal During Follow-up Period 
Procedures 
 
Early Withdrawal 
Visit During Follow-
up  
Follow-up  
Week 12 (If 
applicable) 
Follow-up  
Week 26 (if 
applicable) 
Follow-up  
Week 78 
Demography 
 
 
 
 
Medical and smoking history 
 
 
 
 
Eligibility assessment 
 
 
 
 
Sputum collection 
X 
 
 
 
Pregnancy Test 
X 
 
 
 
CD4 Count 
 
 
 
 
Blood tests 
X 
 
 
 
ECG 
X 
 
 
 
Chest X-Ray 
 
 
 
 
TB Questionnaire/s 
X 
 
 
 
Vital Signs 
X 
 
 
 
Physical Exam 
X 
 
 
 
Pharmacokinetic (PK) test  
X 
 
 
 
Eye Exam 
X 
X 
 
 
Nerve Exam 
X 
 
 
 
Study Medicine check 
X 
 
 
 
Other medicines 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
Survival/TB outcome 
 
 
X 
X 
 
If the study doctor feels it is necessary, you may be asked to come in for extra 
(unscheduled) visits that do not appear on the above charts. 
 
6. What can go wrong in the study? 
6 
 
There are some possible risks and inconveniences of being in the study. 
 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
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PI Name:  XXX (Language) 
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Tuberculosis is a serious disease that can be deadly; all combinations of medicines 
used together in treatment plans to treat tuberculosis have rarely been associated 
with serious side effects, including death.   
 
Your child should not drink alcohol while he/she is taking study 
medicine or other TB medicines as alcohol may damage his/her liver. 
You should tell the doctor if your child has heart problems, including a 
slow heart rate, or if your child has low thyroid hormone levels.  
Your child will have ECGs from time to time to monitor the electrical 
activity of his/her heart, including the QT interval. 
 
 
Details of the risks of taking the medicines in this study are noted below: 
 
Liver problems 
→ 
May be associated with symptoms such as 
nausea or vomiting, stomach pain, fever, 
weakness, itching, unusual tiredness, loss 
of appetite, light coloured bowel 
movements, dark coloured urine, 
yellowing of your skin or the white of your 
eyes.   
Liver problems may also be suggested by 
blood tests that show abnormalities in 
measures of your liver enzymes and other 
measures of how your liver is working. In 
rare cases liver problems may be serious 
and even lead to death. 
 
Pretomanid, 
Linezolid, 
Bedaquiline,  
Headache 
→ pain in any part of the head 
Pretomanid, 
Linezolid, 
Bedaquiline,  
Stomach 
problems 
→ 
Tenderness or pain of the stomach area  
Feeling like you want to throw up, or 
actually throwing up. Also not feeling 
hungry, having diarrhoea (loose bowel 
movements) or having an upset stomach. 
Linezolid, 
Pretomanid, 
Bedaquiline     
Dizziness 
→ 
A feeling of being ‘drunk’ or ‘light 
headed’, especially when you stand up or 
sit down quickly. 
 
Linezolid, 
Bedaquiline  
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
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PI Name:  XXX (Language) 
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The following are a list and description of side effects that are unique to each of the 
medicines: 
 
Pretomanid 
Besides the side effects mentioned above, the other side effects include: 
 
Reproductive 
organ 
changes  
 
→ 
Results from animal studies have shown that rats given 
pretomanid showed signs of damage to the male rats’ 
reproductive organs.  Recent studies in people have shown 
that there is no evidence that pretomanid damages the 
male reproductive organs. The potential for pretomanid to 
have an effect on the male reproductive organs will remain 
under evaluation. 
Cataracts 
(clouding of 
the lens in the 
eye) 
→ 
Other results from animal studies show that rats given 
Pretomanid developed cataracts at high doses over a 6-
month period of taking the medicine.  
It is not known if the effect found in rats indicates any risk for 
human beings. 
Fits 
(convulsions or 
seizures) 
→ 
were seen in some animal studies and in 1 patient treated 
with Pretomanid 
Skin problems 
→  
Inflamed areas on your skin, which may be red, itchy and/or 
painful. 
 
 
Linezolid 
Besides the side effects mentioned above, the other most common side effects seen 
in patients who took linezolid are: 
Changes in taste 
→ 
certain food or drinks may taste different to you 
Tongue 
discolouration 
→ 
the colour of your tongue changes 
Fungal infections 
→ 
when a fungus causes the infection 
Vaginal moniliasis → 
a fungal infection in the vagina 
Oral moniliasis 
→ 
a fungal infection in the mouth 
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Parent or Legal Guardian Information and Informed Consent Form 
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Fever 
→ 
When your body temperature goes higher than 38 °C or 
100.4 °F. 
Signs of nerve 
disturbances 
→ 
This is sometimes called ‘peripheral neuropathy’, which 
may be experienced as a painful burning, or stinging, 
tingling, sensation of pins and needles or numbness in your 
arms and legs. In some cases this can be permanent. 
 
Convulsions or 
seizures 
→ 
These are also commonly known as ‘fits’.   
A convulsion is when the body muscles contract and relax 
quickly and repeatedly / uncontrolled shaking of the 
body. 
A seizure is when there is a change in the normal electrical 
activity of the brain. 
 
 
 
Other side effects seen in patients who took linezolid include, but are not limited to: 
 
Myelo-
suppression 
→ 
a lack of certain cells in your blood that your body needs to 
function.  
can make you feel tired and make your body being unable 
to fight off other illnesses or heal an injury. This could also 
make you bleed or bruise easily. 
Lactic acidosis 
→ 
a build-up of waste products in your blood that can cause 
constant nausea and vomiting. 
Serotonin 
syndrome 
→ 
this rare but serious condition may occur when linezolid is 
given with certain types of medications that affect a 
chemical in the brain called serotonin. Some of these 
medications include antidepressants.  Be sure to tell your 
study doctor about all prescription and non-prescription 
medications you are taking. 
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It can cause many different symptoms, for example: 
confusion, restlessness, tremors, blushing, sweating and 
fever. 
Interactions with 
other medicines 
→ 
causing a rise in blood pressure 
Optic neuropathy 
→ 
A type of damage to the nerves in your eye that can lead 
to blindness if it is not treated.  This can be permanent. 
Low blood sugar 
→ 
This is often seen in patients with diabetes who have to take 
insulin or other medicines 
 
 
Bedaquiline 
From studies in 380 patients with TB who received Bedaquiline (312 of whom 
received Bedaquiline for as long as 6 months), we continued to see that Bedaquiline 
is generally safe and well tolerated.   Besides the side effects mentioned above, the 
other most common side effects seen in patients who took bedaquiline are: 
 
Serious side 
effects 
→ 
9 out of 79 patients (11%) taking bedaquiline with other 
TB medicines died, versus 2 out of 81 (3%) taking just the 
other TB medicines and no bedaquiline. 
It is not known why more patients in the bedaquiline 
group died. 
QTc interval 
increase 
→ 
An increase in the measure of the heart’s electrical 
activity. 
This was seen on the electrocardiogram in patients 
taking bedaquiline and in those taking other TB drugs. 
This may increase the risk that the heart does not beat 
in its normal, regular rhythm, which in rare cases cause 
death.  
However, no clinical side effects relating to heart 
rhythm problems were seen. 
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Effects on the 
pancreas 
 
Studies in mice and dogs showed that bedaquiline 
caused damage to the pancreas.  It is not known if the 
effect found in mice and dogs indicates any risk for 
humans. 
Joint pain 
→ 
One type of joint pain that may be caused or worsened 
by some medicines is called gout.  Gout is caused by too 
much of a normal chemical in your body called uric 
acid. Uric acid is a chemical that is created when the 
body breaks down substances called purines. 
Purines are found in some foods (like seafood) and drinks 
(like beer). 
Accumulation in 
the body 
→ 
Bedaquiline leaves your body slowly after the last tablet 
is taken.  It takes about a year for all the drug to be 
removed from your body. 
 
 
In addition to the listed side effects, the study doctor has information on side effects 
that may occur less often and the study doctor could discuss these with you and 
your child. 
 
Possible risks and side effects of procedures to be performed: 
 
• 
Drawing blood is normally done as part of normal medical care. There is a slight 
risk of discomfort. Drawing blood may rarely cause fainting, inflammation of the 
vein, pain, bruising or bleeding at the place on the skin where the needle goes 
in. There is also a slight risk of infection. Your child’s protection is that 
experienced staff will draw his/her blood under germ free conditions.  
• 
When an ECG is done, the sensors, or stickers, may cause slight discomfort 
when they are removed from your child’s skin. 
• 
An x-ray is a common test exposing a person to a small amount of radiation. 
The effect of radiation adds up over your lifetime, but small doses like the one 
used to take a picture of your child’s chest, is not likely to be a risk to your child’s 
health. 
• 
The eye tests are common. The drops put into your child’s eyes will cause his/her 
vision to be blurry and sensitive to light for a few hours after the examination, 
during which time your child should not drive (if applicable). In very rare cases 
they can cause increased pressure in the eye, with nausea and pain. If this 
happens, call the study doctor right away. 
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Parent or Legal Guardian Information and Informed Consent Form 
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Confidential | Page 17 of 28 
It is important that your child follows the study doctor’s and/or study nurses’ 
instructions precisely.  
 
You and/or your child must inform the study doctor immediately if: 
 
• 
your child takes any local or herbal remedies, prescribed or non-prescribed 
(over the counter) medicines, 
• 
your child’s medical condition changes, 
• 
your child has seen any other healthcare providers, 
• 
your child has any side effects,  
• 
your child has any complications*, or 
• 
your child has any injuries while taking the study medicine. 
 
The study doctor and/or nurse will ask your child at every visit about any other 
medicine he/she may have taken and how he/she is feeling.  
 
It is possible that your child’s condition will stay the same or get worse while he/she is 
in this study. However, the study doctor will watch your child closely and if he/she 
feels that participating in the study is not good for your child’s health, he/she will 
immediately take your child off the study. 
 
Using the study medicine may have risks that we do not know about yet. If we 
become aware of these, we will tell you and your child of any new important 
findings that may influence his/her willingness to stay in the study. 
 
7. Are there things that my child cannot do while he/she is in the study? 
7 
 
Your child cannot take part in this study if she is breastfeeding,              
pregnant or trying to get pregnant. 
 
This is because there may be risks to becoming pregnant and to an unborn child 
that we may not yet know of. If your daughter is participating in the study and can 
get pregnant, we will test her before she takes the study medicine and during the 
study to see if she is pregnant. 
 
Girl participants who CAN become pregnant: 
 
Your daughter must use 2 methods of birth control. Your daughter need to use birth 
control for as long as she is taking the study medicine and for up to 6 months after 
she has taken the last dose of study medicine. 
 
When taking the study medicine, birth control that are based on hormones only, 
such as the contraceptive pill or injection, may not work as well as usual. Because of 
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Parent or Legal Guardian Information and Informed Consent Form 
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PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 18 of 28 
this, either your daughter must be willing not to have sex, or she must use 2 methods 
of birth control, for example: 
 
a) Double (2 different types) barrier methods, which may include a male 
condom, diaphragm, cervical cap, or female condom; OR 
b) 1 barrier method described above used together with a hormone-based birth 
control (tablet or injection), or an intra-uterine device  
 
If your daughter becomes pregnant while she is participating in the study, it is very 
important for you and your daughter to tell the study doctor immediately.  If this 
happens, the study doctor will discuss with you and your daughter what to do.   
 
Since there might be unknown risks to an unborn child, we will ask your child to stop 
taking part in the study.  We may have questions about your daughter’s pregnancy 
and the baby and we may ask your daughter to visit the study doctor at certain 
times during and after your daughter’s pregnancy to check her health status and 
collect information on the outcome of her pregnancy.  
 
Boy participants’ female sex partner who CAN become pregnant:  
 
Your son and his female sex partner need to use at least 1 method of birth control for 
as long as he is taking the study medicine and for up to 12 weeks after he has taken 
the last dose of study medicine. Examples of methods of birth control are as follows: 
 
Double barrier (2 different types) method, which can include a male condom, 
diaphragm, cervical cap, or female condom; OR 
 
Hormone-based contraceptives, or an intra-uterine device for son’s your female 
partner. 
 
Talk to the study doctor if your child is unable to obtain birth control. The study 
doctor may be able to advise your child about the correct birth control.   
 
 
Girl participants, and boy participants’ female sex partner, who CANNOT become 
pregnant:  
 
Your child does do not need to use birth control if he/she is: 
 
a) Not an active heterosexual boy or girl participant, or he/she does not 
practice sex; OR 
b) A girl participant or boy participants’ female sex partner, and have had an 
operation to remove both ovaries, or both ovarian tubes have been tied or 
cut and or the uterus has been removed; OR 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 19 of 28 
c) A boy participant or girl participants’ male sex partner, who has had both 
testes tubes tied or cut, or have had both testes removed at least 3 months 
before the study. 
Foods and drinks that your child cannot eat or drink during the study 
• 
Your child should not eat or drink large amounts of foods or drinks that 
contain a lot of a protein called tyramine. Foods high in tyramine include 
those that may have had protein changes by aging, fermentation, pickling, 
or smoking to improve flavour. This include foods such as aged cheeses, 
fermented or air-dried meats (cold cuts and biltong), sauerkraut, soy sauce, 
tap beers and red wines. You and your child should talk to the study doctor if 
either of you have questions about how your child can avoid large amounts 
of tyramine.  
• 
Your child should not drink alcohol while he/she is taking study medicine as 
alcohol may damage his/her liver. 
 
Other medicines that your child cannot use 
• 
Your child cannot use certain medicines to treat depression while he/she is on 
the study medicine. There are other medicines that your child cannot use 
while he/she is on the study medicine because they may possibly cause 
abnormal heart rhythms, or because they may change the way your child’s 
body reacts to the study medicine after he/she takes them. The study doctor 
can tell you and your child which medicines these are.   
• 
If your child is HIV positive, certain HIV medicines should not be used. The 
study doctor can tell you and your child which HIV medicines can be used 
during this study.   
• 
You/your child should inform the study doctor if your child is taking any illegal 
drugs, because some illegal drugs can affect your child’s safety or your 
child’s ability to follow through with all the study procedures. 
 
8. How can the study help my child? 
8 
 
There is a chance that your child’s TB may get better because he/she is in this study, 
but we cannot guarantee this. If the study medicine does not work well, your child 
will not get any benefit from being in the study. However, the information that we 
get from the study can help in making future treatments for TB, and in the long run it 
will likely help other TB patients. 
 
The close medical attention your child will get by taking part in the study may help 
you and your child to learn useful information about his/her health status.  
 
9. What are my child’s other choices for treatment? 
9 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 20 of 28 
Your child does not have to take part in this study. If your child decides not to take 
part, he/she will not be disadvantaged and he/she will still receive care and 
treatment for his/her TB at <<TB clinic or specialized unit in a hospitalist location>> for 
at least <<add time period>>, per your country’s National TB Treatment Guidelines. 
 
 
If your child does not take part in the study, the doctor will make sure your child 
remain in or is sent to an MDR-TB unit or XDR-TB unit or hospital for treatment. 
 
10. What will happen if I my child is injured in the study? 
10 
 
<< For ABPI Countries:  
 
The sponsor has taken out insurance in case you get injured in this study.  
The sponsor will pay you for all reasonable medical expenses you may have 
because you are injured in this study, according to the guidelines of the Association 
of the British Pharmaceutical Industry (ABPI guidelines). These guidelines recommend 
that the sponsor of the study, without any legal commitment, should pay you, 
without you having to prove that it is at fault, for any injury resulting from giving the 
study medicine or other procedures carried out in accordance with the protocol for 
this study. Your study doctor has a copy of the ABPI guidelines if you would like to 
see them. 
The APBI guidelines do not require the sponsor to pay you if the injury: 
• 
resulted from a medicine or procedure that is not required by the study or if 
you did not stick to the rules of the study;   
• 
was not a serious injury that will last a long time and disable you. 
Because of the following reasons, you may be paid less or the sponsor may not have 
to pay you at all under the ABPI Guidelines: 
• 
how serious the disease is that is being treated, how likely you are to have 
adverse reactions and any warnings that were given to you; 
• 
the risks and benefits of normal or standard treatments compared to the risks 
and benefits that we know the study medicine have or think that it may have; 
• 
a wrongful act of someone outside the study, or if the study doctor does not 
properly deal with an adverse reaction; 
• 
if you have been negligent.  
Any payment that the sponsor makes to you because of the ABPI guidelines does 
not mean that the sponsor is legally responsible for your injury. You will not lose any of 
the legal rights you have if you are injured just because the sponsor has agreed to 
follow the ABPI guidelines. Please ask if you want more information on this.>> 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 21 of 28 
<<Country regulatory authorities that DO NOT require compliance to the ABPI clinical 
trial insurance guidelines,  
Text will be provided on an ‘as needed’ basis in consultation with TB Alliance 
Legal.>> 
11. What will happen to my child’s personal information? 
11 
 
All records with information that can identify your child will be kept confidential and, 
as far as the applicable laws and regulations allow, will not be made publicly 
available.   
 
The study doctor and research team will use personal information about your child 
to carry out this study. This may include your child’s name, address, medical history 
and information from your child’s study visits. However, this personal information will 
stay at the study site and will not be included in the study data that we will send to 
the sponsor or representatives of the sponsor. Your child will only be identified by a 
coded number in reports or publications that are produced from this study (study 
data). 
 
To confirm that the study data collected about your child is correct and related to 
him/her, selected people working for the sponsor, including auditors, as well as 
representatives of government regulatory authorities and ethics committees will 
have access to your child’s personal information at the study site. These persons 
know that they must keep your child’s information confidential. By signing this 
document, you are agreeing to let them have access to your child’s information. 
 
The sponsor may send your child’s coded study data that were collected from your 
child’s country to other countries. <<EU: “Your child’s data might be transferred to 
countries outside the EU”.>> However, they will obey all local and international laws 
and regulations on data privacy to protect your child’s personal and other 
information, even in countries where data privacy laws are less strict. 
 
The sponsor or representatives may use this study data for the following purposes: 
 
• 
To see if the study medicine works and is safe. 
• 
To compare the study medicine to other medicines. 
• 
For other activities related to the study medicine. 
 
You and your child have the right to ask the study doctor about the data we are 
collecting about your child. Your child can ask the study doctor to allow him/her to 
see your child’s personal information and your child can ask the study doctor to 
make any corrections, if needed. 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 22 of 28 
The results of the study will only be available once all participants have completed 
the study, the information has been collected and checked, and the results have 
been analysed (looked at and a decision made about them). If your child wants to 
know the results of the study, he/she may contact the study doctor and the study 
doctor will tell your child the results if they are ready. 
 
The results of this study will be made available to national and international 
medicine regulatory agencies to help them decide if the new treatments are 
helping to treat TB. In addition, the results may be published in international medical 
journals so that doctors and other health workers might learn from this work. Your 
child will not be named in any reports/publications. 
 
A description of this clinical study will be available on www.clinicaltrials.gov, as 
required by United States law << and other countries as required, e.g.  
www.sanctr.gov.za, as required by South African law>>. This <these>> website<
> 
will not show information that can identify your child. At most, the website<
> will 
include a summary of the results. You and your child can search this 
website<<these>> at any time. 
12. Will my child be paid to take part in this study? 
12 
 
Your child will not be paid to take part in this study. However, the sponsor will pay 
you/your child back for out-of-pocket expenses, such as for your child’s transport to 
and from the study site and other various costs that your child may have because of 
his/her study participation.   
 
You/your child will get, depending on the out-of-pocket expenses, an amount of - 
<<specify amount and frequency e.g. x per visit and add any pro-rata payments if 
applicable>>. If your child’s study-related costs are more than the specified amount 
and you have proof of such costs, please discuss it with the study doctor. 
 
13. Do I need to pay anything for my child to be in this study? 
13 
 
The sponsor will pay all costs related to the study, such as the study medicine, 
treatment, tests, examinations and procedures specified in the study plan. Not you, 
nor your and/or your child’s <<medical insurance / aid>>, healthcare provider will 
have to pay for these expenses. In other words, you will not have to pay for anything 
that is needed for your child’s participation in this study. 
 
Should your child need to visit any doctor, besides the study doctor, or if your child is 
hospitalised for any illness, including to treat his/her TB, then your child will need to 
visit the doctor or hospital as allowed by your/ your child’s healthcare provider <<or 
medical insurance / aid>>. These medical visits, that are not part of the clinical 
study, are not paid for by the study. 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 23 of 28 
14. Who is in charge of the study? 
14 
 
The study is sponsored by the Global Alliance for TB Drug Development (TB Alliance), 
a not-for-profit organisation based in New York in the United States.  
The TB Alliance will pay the study staff for doing this study. The study doctor will not 
benefit unduly if your child is included in the study. 
 
15. What happens if my child does not want to or cannot be in the study 
any more? 
15 
 
Your child’s participation in the study may be stopped for the following reasons: 
 
• 
Testing comes back that shows your child’s TB won’t respond to the study 
medicines 
• 
If your child does not follow the study doctor’s instructions. 
• 
If your child does not take the study medicine as prescribed. 
• 
Testing comes back that shows your child’s TB will respond to medicines that treat 
drug sensitive TB. 
• 
If the study doctor decides that it is in your child’s best interests (e.g. your child 
experiences certain adverse events* during the study). 
• 
If your child asks to stop (your child doesn’t have to explain why). 
• 
If the TB Alliance asks your child to stop. 
• 
If the TB Alliance stops the study or closes the study site. 
• 
If your child becomes pregnant (girls who can get pregnant). 
 
If your child decides to withdraw from the study, please tell us immediately. If your 
child withdraws from the study, it will not change his/her access to other medical 
care or the quality of the care.   
 
If your child leaves the study, the doctor would like to ask him/her some questions 
and check his/her health to make sure that your child is safe and any possible side 
effects from the study medicine are treated.  If your child’s study treatment is 
stopped, based on your/your child’s and your child’s study doctor’s choice, your 
child will be asked to continue to come to some of the study visits or be contacted 
in another way, unless your child decides to withdraw from the study completely. If 
your child’s treatment is stopped or he/she withdraws from the study completely, 
your study doctor/site staff may need to perform certain procedures previously 
mentioned in the “5. What will happen to my child in the study?” section.  
 
We may ask your child to come to the hospital/study site to complete these 
procedures. 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 24 of 28 
Once your child has left the study, the study doctor will give you a referral letter for 
your child to go to an MDR or XDR-TB unit or hospital for further treatment of his/her 
TB or to another physician for routine medical care if your TB infection is cured.  
 
16. Whom can I contact if something worries me or my child? 
16 
 
You can call the study doctor or another authorised person at the study 
site at any time of the day or night (24 hours) on Tel: <<add>> or 
<<add>>. 
 
  
For questions about your child’s rights as a participant in a study: 
 
If you or your child wants any information about your child’s rights as a study 
participant, or if you or your child has complaints about this study, you may contact 
the <<add name of Ethics Committee>>, which is an independent committee 
established to help protect the rights of research participants. Their contact details 
are as follows: 
 
<<Add name, address and contact telephone/fax numbers>> 
For complaints, if you or your child thinks that the study doctor or ethics committee 
did not help him/her: 
 
<<include per country as appropriate>> 
 
17. How do I agree for my child to be in this study? 
17 
 
If your child wants to take part in this study and you agree, please read the consent 
statement and sign on page <<XX>>. 
 
 
Personal doctor / specialist notification option: 
 
Please mark below, by writing your initials in the correct block, if you want us to tell 
your child’s personal doctor or his/her specialist that your child is taking part in this 
study: 
 
  YES, I want the study doctor to tell my child’s personal doctor / specialist that 
he/she is taking part in this study. 
  
NO, I do not want the study doctor to tell my child’s personal doctor / 
specialist that he/she is taking part in this study. 
  
My child does not have a personal doctor / specialist. 
104 of 124


Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 25 of 28 
 
 
 
 
Collection of Pre-screening Stored Sputum (or TB from your child’s sputum) Sample 
agreement: 
 
Please mark below, by writing your initials in the correct block, if you agree for your 
child’s stored sputum sample (taken before this visit/reading and signing this form) to 
be collected from the storing laboratory: 
 
 
YES, I agree if available, for my child’s stored sputum sample or TB from your 
child’s sputum to be collected from the laboratory and used for this study. 
 
NO, I do not want my child’s stored sputum sample or TB from your child’s 
sputum to be collected from the laboratory and used for this study. 
 
Parent or Legal Guardian Notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 26 of 28 
 
 
Glossary 
Technical term 
Explanation 
complications 
another disease or condition that makes your TB 
worse 
diaphragm 
a soft latex or silicone dome with a spring in the 
rim. The spring creates a seal against the wall of 
the vagina. 
adverse events 
unwanted events 
 
 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 27 of 28 
PARENT/LEGAL GUARDIAN INFORMED CONSENT FORM 
 
By signing below, I agree that: 
 
• 
I have read the information sheet and consent form for this study, or someone 
has read it to me, and I understand it. 
• 
I have had the chance to ask questions and I am happy with the answers. 
• 
I have had time to discuss the information with others and to decide if I want my 
child to take part. 
• 
I will get a signed and dated copy of this consent form on the day that I sign it. 
• 
I agree of my own free will to let my child take part in this study. I know my child 
has the right to stop taking part at any time, without giving any reason. If my 
child stops taking part, it will not change his/her medical care or legal rights. 
• 
Site staff, representatives from the sponsor, including auditors, regulatory 
authorities and ethics committees can have direct access to my child’s medical 
records. They will treat my child’s information as confidential. 
• 
If my child withdraws from the study, study data collected about him/her up to 
the point of his/her withdrawal can still be used to carry out this study.   
• 
Girls only: “if my child becomes pregnant while on the study, follow-up 
information on the outcome of my child’s pregnancy can be collected, if 
needed.” 
<<EU: “I consent to the processing/storing of my data and the transfer thereof to 
countries outside the EU.”>> 
 
 
 
Printed Name of Parent/Legal Guardian 
 
 
 
Signature/mark/thumb print of Parent/Legal 
Guardian 
 
Date 
 
 
( Parent or Legal Guardian/witness 
must write date) 
 
 
*Printed Name of Person Conducting Consent 
(If other than investigator/delegate) 
 
 
 
*Signature of Person Conducting Consent 
(If other than investigator/delegate) 
 
Date 
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Parent or Legal Guardian Information and Informed Consent Form 
Prot ocol Version and Dat e: V X  dd-mmm-yyyy                                M aster Parent IC Version 2.0 Date 13-Jun-2018 
Count ry/Site Version X Dat e dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by XXX EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 28 of 28 
 
 
(Person conducting consent must 
write date) 
 
I,   
(Insert name of investigator) 
hereby confirm that the above Parent or Legal Guardian has been fully informed about the 
nature, conduct and risks of the above study. 
 
 
 
Signature of Investigator 
 
Date 
 
 
(Inv estigator must write date) 
 
By signing below, I verify that the above Parent or Legal Guardian gave verbal 
informed consent. The Parent or Legal Guardian has been informed about the risks 
and the benefits of the study, understands such risks and benefits and is able to 
agree to participation, without coercion, undue influence or inappropriate 
incentives. 
 
 
 
*Printed Name of Witness 
 
 
 
*Signature of Witness 
 
Date 
 
 
(Witness must write date) 
* Where applicable 
 
108 of 124


Testing for HIV Paediatric Information and Informed Assent 
Prot ocol Version and Dat e: V X dd-mmm-yyyy                    M aster Paediatric HIV Assent Version 2.0 Date 13-Jun-2018 
Mast er Country/Site Version X dd-mm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 1 of 8 
 
PAEDIATRIC INFORMATION AND INFORMED ASSENT FORM  
TESTING FOR HIV  
 
Protocol Name/Number:  ZeNix/NC-007-(B-Pa-L) 
Protocol Title:  
 
 
A Phase 3 partially-blinded, randomised trial assessing the  
safety and efficacy of various doses and treatment durations of linezolid plus  
bedaquiline and pretomanid in participants with pulmonary infection of either  
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or  
non-responsive multi-drug resistant tuberculosis (MDR-TB). 
 
Participant Initials:  
 
 
Participant Number:________ 
 
 
 
Introduction  
 
This information sheet contains only information about testing for HIV in the study. 
Please read the main assent form that you have already signed for information 
about the main medical study. 
 
Please read this information sheet before you agree to have the HIV test done as part 
of the main study. This document will answer the following questions: 
 
1. What is HIV? 
1 
 
2. Why are you testing me for HIV? 
2 
 
3. How will you do the HIV test? 
3 
 
4. What can go wrong with the HIV test? 
4 
 
5. How can the HIV test help me? 
5 
 
6. What happens if I get hurt during the HIV test? 
6 
 
7. Will you keep my HIV test private? 
7 
 
8. Will you pay me to do the HIV test? 
8 
 
9. Will I have to pay for the HIV test? 
9 
 
10. Whom can I contact if something worries me? 
10 
 
11. How do I agree to have the HIV test? 
11 
 
If you have any other questions that are not answered in this document, please ask 
someone from the study staff for more information. We explained some difficult 
medical terms in the Glossary on page <<XX>>. 
 
 
 
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Testing for HIV Paediatric Information and Informed Assent 
Prot ocol Version and Dat e: V X dd-mmm-yyyy                    M aster Paediatric HIV Assent Version 2.0 Date 13-Jun-2018 
Mast er Country/Site Version X dd-mm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 2 of 8 
 
It is very important that you understand this information sheet before you agree to 
have your HIV test done. We would like you to ask as many questions as you need. 
If there is anything that you do not understand, please discuss this with the study 
doctor, the study staff, your own doctor, or with your family. 
 
Participant Notes 
 
 
 
 
 
 
1. What is HIV? 
1 
 
The human immunodeficiency virus (HIV) is a virus that causes Acquired 
Immunodeficiency Syndrome (AIDS). This is a condition in humans where the system 
that protects the body against getting sick (the immune system), stops working. This 
means that other infections can get worse. Normally, the immune system will help 
the body to fight against these infections so that you don’t get sick. These infections 
can be life-threatening and are called opportunistic infections*.  
How is HIV spread? 
Infection with HIV happens when you come into contact with blood, semen or 
another similar fluid, vaginal fluid or breastmilk which have HIV in (from a person who 
has HIV). The 3 most common ways of getting HIV are: 
• 
having sex without a condom,  
• 
sharing needles, and  
• 
when a mother who has HIV gives birth, or if she breastfeeds her baby.  
How does HIV affect my body? 
HIV mainly infects cells in the immune system* that are called CD4 cells, and it 
causes the number of CD4 cells to drop. When the number of CD4 cells drop below 
a certain amount, your body can no longer fight infection, and opportunistic 
infections may increase.  
How is HIV treated? 
If people who have HIV do not get treatment, most of them will get AIDS and die. 
However, about 1 in 10 people stay healthy for many years, with no obvious 
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Testing for HIV Paediatric Information and Informed Assent 
Prot ocol Version and Dat e: V X dd-mmm-yyyy                    M aster Paediatric HIV Assent Version 2.0 Date 13-Jun-2018 
Mast er Country/Site Version X dd-mm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 3 of 8 
 
symptoms. People with HIV are treated with anti-retrovirals* (i.e. the medications 
used to fight the virus that causes HIV). Using anti-retroviral medicine can help 
people to live longer.  
 
2. Why are you testing me for HIV? 
2 
 
This study has nothing to with HIV/AIDS or its treatment. However, we need to test 
you for HIV as part of the study, because it may be unsafe for you to take part in the 
study if: 
• 
your CD4 count is lower than a certain number (<100 cells/µL) 
• 
you have had an existing TB and HIV diagnosis, you are taking HIV medicine and 
your viral load ("viral load" is a term that people living with HIV use to talk about 
how much of the virus is in their body) is higher than a certain number (>1000 
copies/mL) 
• 
you are diagnosed with tuberculosis and HIV and your study doctor recommends 
that the start of your HIV medicine should not be postponed until you have 
received at least 2 weeks of an anti-tuberculosis regimen and/or; 
• 
you are currently receiving HIV medicine which cannot safely be taken with the 
study medicine and your study doctor decides it is not best for you to change 
your HIV medicine. 
 
You can take part in the study if you meet the other requirements for the study and if 
you test positive for HIV, and 
• 
your CD4 count is equal to or more than a certain number (≥ 100 cells/µL) 
• 
if you have previously been diagnosed with TB and your viral load is <1000 
copies/mL 
• 
you have a new TB and HIV diagnosis  
• 
you are diagnosed with tuberculosis and HIV and your Study Doctor agrees that 
the start of your HIV medicine may be postponed until you have received at 
least 2 weeks of an anti-tuberculosis regimen 
• 
HIV medicine that you will take during the study is safe to be taken with the study 
medicine; 
OR if you are HIV negative.  
 
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Testing for HIV Paediatric Information and Informed Assent 
Prot ocol Version and Dat e: V X dd-mmm-yyyy                    M aster Paediatric HIV Assent Version 2.0 Date 13-Jun-2018 
Mast er Country/Site Version X dd-mm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 4 of 8 
 
3. How will you do the HIV test? 
3 
 
We will take an extra blood sample of 5 ml (about 1 teaspoon) in the main study. We 
will take this extra blood sample at the same time as the routine blood samples in 
the clinical part of the study. It will not be necessary to prick you with a needle 
again. 
 
4. What can go wrong with the HIV test? 
4 
 
The risk when we take a blood sample includes discomfort where we prick you with 
the needle. You may get a bruise, bleed, and very rarely, you could get an 
infection, or you may faint. 
 
The following unpleasant things may happen if you have an HIV test (especially if the 
result is that you are HIV positive): 
• 
Friends, family and other students may reject you and discriminate against 
you. 
• 
 You may have emotional problems, feel more stressed and feel uncertain 
about the future. 
 
5. How can the HIV test help me? 
5 
 
If you test negative, you may feel less worried after knowing your HIV status, and you 
could take steps to stop yourself from getting HIV. If you know you are HIV positive, it 
may reduce the stress that you get because of not knowing. You can treat your HIV 
early, and check your health, by eating well and healthily. You will also know if you 
can infect others, and what to do to stop this from happening.   
Women who are thinking about getting pregnant and their partners can get 
treatments that can help to prevent their baby from getting HIV. You can also plan 
how to care for your children in the future. 
 
6. What happens if I get hurt during the HIV test? 
6 
 
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Testing for HIV Paediatric Information and Informed Assent 
Prot ocol Version and Dat e: V X dd-mmm-yyyy                    M aster Paediatric HIV Assent Version 2.0 Date 13-Jun-2018 
Mast er Country/Site Version X dd-mm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 5 of 8 
 
The insurance that the TB Alliance has taken out as required by the laws and 
regulations of your country covers the extra blood samples. For more details, see the 
information sheet describing the main clinical study. 
 
7. Will you keep my HIV test private? 
7 
 
We will respect your confidentiality* and only the study doctor and the research 
team will know the results of the test. Some people working for TB Alliance, as well as 
representatives of government regulatory authorities and ethics committees will also 
be able to see the results. These persons know that they must keep your information 
private. You are giving permission for those people to see your medical records 
when you sign this document. 
 
8. Will you pay me to do the HIV test? 
8 
 
No, we will not pay you for giving the blood sample to do the HIV test.  
The TB Alliance or the study site will not be responsible for paying any costs for your 
HIV treatment if you test positive. We will send you to a specialist HIV clinic for further 
testing and advice. 
 
9. Will I have to pay for the HIV test? 
9 
 
No, the HIV test will not cost you anything, 
<<If applicable add “You will receive HIV counseling before and after HIV test. The 
TB Alliance will pay for the test and the counseling.” 
 
10. Who can I contact if something worries me? 
10 
 
You can call the study doctor or another authorised person at any time 
of the day or night (24 hours) on Tel: <<add>> or <<add>>. 
 
  
Please refer to the main informed consent form for more information on whom to 
contact if you have complaints about this study. 
 
11. How do I agree to have the HIV test? 
11 
113 of 124


Testing for HIV Paediatric Information and Informed Assent 
Prot ocol Version and Dat e: V X dd-mmm-yyyy                    M aster Paediatric HIV Assent Version 2.0 Date 13-Jun-2018 
Mast er Country/Site Version X dd-mm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 6 of 8 
 
 
If you want to agree to have the HIV test, please read the statement on the 
following page and sign the form. 
 
Participant Notes 
 
 
 
 
 
 
Glossary 
Technical term 
Explanation 
HIV 
Human immunodeficiency virus 
AIDS 
Acquired immune deficiency syndrome 
opportunistic infections 
an infection that occurs when the immune system 
is weak 
immune system 
the system in your body that fights infections 
pulmonary 
of the lungs 
confidentiality 
a set of rules to keep information private 
 
 
 
114 of 124


Testing for HIV Paediatric Information and Informed Assent 
Prot ocol Version and Dat e: V X dd-mmm-yyyy                    M aster Paediatric HIV Assent Version 2.0 Date 13-Jun-2018 
Mast er Country/Site Version X dd-mm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 7 of 8 
 
PAEDIATRIC INFORMED ASSENT FORM FOR HIV TESTING 
 
By signing below, I agree that: 
 
• 
I have read the information sheet and consent form for this HIV testing, or 
someone has read it to me, and I understand it. 
• 
I have had the chance to ask questions and I am happy with the answers. 
• 
I have had time to discuss the information with others and to decide if I want to 
do the test. 
• 
I will get a signed and dated copy of this consent form on the day that I sign it. 
• 
I voluntarily agree for HIV testing to be done. 
• 
Site staff, representatives from the sponsor, regulatory authorities and ethics 
committees can have direct access to my medical records. They will treat my 
information as confidential. 
• 
I hereby give up all rights to the test findings and I am not entitled to be paid 
anything because of the test findings. 
• 
<<EU: “I consent to the processing/storing of my data and the transfer thereof to 
countries outside the EU.”>> 
 
 
 
Printed Name of Participant  
 
 
 
Signature/mark/thumb print of Participant 
 
Date 
 
 
(Participant/witness must write 
date) 
 
 
*Printed Name of Person Conducting Consent 
(If other than investigator / delegate) 
 
 
 
*Signature of Person Conducting Consent 
(If other than investigator / delegate) 
 
Date 
 
 
(Person conducting consent must 
write date) 
 
I,   
(Insert name of investigator) 
hereby confirm that the above participant has been fully informed about the nature, 
conduct and risks of the HIV test. 
 
 
115 of 124


Testing for HIV Paediatric Information and Informed Assent 
Prot ocol Version and Dat e: V X dd-mmm-yyyy                    M aster Paediatric HIV Assent Version 2.0 Date 13-Jun-2018 
Mast er Country/Site Version X dd-mm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 8 of 8 
 
 
Signature of Investigator 
 
Date 
 
 
(Inv estigator must write date) 
 
By signing below, I verify that the above participant gave verbal informed consent. 
The Participant has been informed about the risks and the benefits of the HIV test, 
understands such risks and benefits and is able to agree to have the HIV test, without 
coercion, undue influence or inappropriate incentives. 
 
 
 
*Printed Name of Witness 
 
 
 
*Signature of Witness 
 
Date 
 
 
(Witness must write date) 
* Where applicable 
 
116 of 124


Testing for HIV Parent or Legal Guardian Information and Informed Consent Form 
 
Protocol Version and Date: V X dd-mmm-yyyy                Master Parent/Guardian HIV IC Version 2.0 Date 13-Jun-2018  
Mast er Country/Site Version X Dat e: dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 1 of 8 
 
PARENT OR LEGAL GUARDIAN INFORMATION AND INFORMED 
CONSENT FORM TESTING FOR HIV  
 
Protocol Name/Number:  ZeNix/NC-007-(B-Pa-L) 
Protocol Title:  
 
 
A Phase 3 partially-blinded, randomized trial assessing the  
safety and efficacy of various doses and treatment durations of linezolid plus  
bedaquiline and pretomanid in participants with pulmonary infection of either  
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or  
non-responsive multi-drug resistant tuberculosis (MDR-TB). 
 
Participant Initials:  
 
 
  Participant Number: 
 
 
 
 
Introduction  
 
This information sheet contains only information about testing your child for HIV in the 
study. Please read the main Parent or Legal Guardian consent form that you have 
already signed for information about the main clinical study. 
 
Please read this information sheet before you agree to have your child’s HIV test done 
as part of the main study. This document will answer the following questions: 
 
1. What is HIV? 
1 
 
2. Why are you testing my child for HIV? 
2 
 
3. How will you do the HIV test? 
3 
 
4. What can go wrong with the HIV test? 
4 
 
5. How can the HIV test help my child? 
5 
 
6. What happens if my child is injured during the HIV test? 
6 
 
7. Will you keep my child’s HIV test private? 
7 
 
8. Will you pay my child to do the HIV test? 
8 
 
9. Will I have to pay for my child’s HIV test? 
9 
 
10. Whom can we contact if something worries me or my child? 
10 
 
11. How do I agree for my child to have the HIV test? 
11 
 
If you have any other questions that are not answered in this document, please ask 
someone from the study staff for more information. We explained some difficult 
medical terms in the Glossary on page <<XX>>. 
 
 
117 of 124


Testing for HIV Parent or Legal Guardian Information and Informed Consent Form 
 
Protocol Version and Date: V X dd-mmm-yyyy                Master Parent/Guardian HIV IC Version 2.0 Date 13-Jun-2018  
Mast er Country/Site Version X Dat e: dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 2 of 8 
 
It is very important that you understand this information sheet before you agree for 
your child to have his/her HIV test done. We would like you to ask as many 
questions as you need. If there is anything that you do not understand, please 
discuss this with the study doctor, the study staff, your own doctor, or with your 
family. 
 
Parent or Legal Guardian Notes 
 
 
 
 
 
 
1. What is HIV? 
1 
 
The human immunodeficiency virus (HIV) is a virus that causes acquired 
immunodeficiency syndrome (AIDS).  This is a condition in humans where the system 
that protects the body against diseases (immune system), begins to fail.  This leads to 
other infections, which the body would normally be able to fight, being able to grow 
and thrive. These infections can be life-threatening and are known as opportunistic 
infections*.  
How is HIV spread? 
Infection with HIV occurs by the transfer of blood, semen or other similar fluid, 
vaginal fluid, or breastmilk in which HIV is present.  The three major ways of getting 
HIV are: 
• 
having sex without a condom,  
• 
sharing needles, and  
• 
a mother with HIV gives birth, or if she breastfeeds her baby.  
How does HIV affect my body? 
HIV mainly infects cells in the immune system*, called CD4 cells, and causes the 
number of CD4 cells to drop.  When the number of CD4 cells drop below a certain 
amount, the body can no longer fight infection, and opportunistic infections may 
increase.  
 
 
118 of 124


Testing for HIV Parent or Legal Guardian Information and Informed Consent Form 
 
Protocol Version and Date: V X dd-mmm-yyyy                Master Parent/Guardian HIV IC Version 2.0 Date 13-Jun-2018  
Mast er Country/Site Version X Dat e: dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 3 of 8 
 
How is HIV treated? 
If left untreated, most people who are HIV positive will get AIDS and die. However, 
about 1 in 10 people remain healthy for many years, with no obvious symptoms. 
People with HIV are treated with anti-retrovirals (i.e. the medications used to fight 
the HIV virus). Using anti-retroviral medicine may help people to live longer.  
 
2. Why are you testing my child for HIV? 
2 
 
This study has nothing to with HIV/AIDS or its treatment.  However, we need to test 
your child for HIV as part of the study, and it may be unsafe for your child to take 
part in the study if: 
• 
your child’s CD4 count is lower than a certain number (<100 cells/µL) 
• 
your child has an existing TB and HIV diagnosis, your child is taking HIV medicine 
and your child’s viral load ("viral load" is a term that people living with HIV use to 
talk about how much of the virus is in their body) is higher than a certain number 
(>1000 copies/mL) 
• 
your child diagnosed with tuberculosis and HIV and your child’s study doctor 
recommends that the start of his/her HIV medicine should not be postponed until 
your child has received at least 2 weeks of an anti-tuberculosis regimen and/or; 
• 
your child is currently receiving HIV medicine which cannot safely be taken with 
the study medicine and the study doctor decides it is not best for your child to 
change his/her HIV medicine. 
 
Your child can take part in the study if he/she meets the other criteria for the study 
and if your child tests positive for HIV, and 
• 
your child’s CD4 count is equal to or more than a certain number (≥ 100 cells/µL) 
• 
if your child had previously been diagnosed with TB and your child’s viral load is 
<1000 copies/mL 
• 
your child has a new TB and HIV diagnosis  
• 
your child is diagnosed with tuberculosis and HIV and your child’s Study Doctor 
agrees that the start of his/her HIV medicine may be postponed until he/she has 
received at least 2 weeks of an anti-tuberculosis regimen. HIV medicine that your 
child will take during the study is safe to be taken with the study medicine; 
OR if your child is HIV negative.  
119 of 124


Testing for HIV Parent or Legal Guardian Information and Informed Consent Form 
 
Protocol Version and Date: V X dd-mmm-yyyy                Master Parent/Guardian HIV IC Version 2.0 Date 13-Jun-2018  
Mast er Country/Site Version X Dat e: dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 4 of 8 
 
3. How will you do the HIV test? 
3 
 
We will take an extra blood sample of 5 ml (about 1 teaspoon) in the main study. This 
extra blood sample will be taken at the same time as the routine blood samples in 
the clinical part of the study. It will not be necessary to prick your child with a needle 
again. 
 
4. What can go wrong with the HIV test? 
4 
 
The risk when we take a blood sample includes discomfort where we prick your child 
with the needle or your child may have a bruise, bleed, and only rarely, get an 
infection, or faint. 
 
The following negative things may happen if your child has an HIV test (especially if 
the result is that he/she is HIV positive): 
 
• 
friends, family and colleagues may possibly reject your child and discriminate 
against him/her; 
• 
 your child may have emotional problems, feel more stressed and feel 
uncertain about the future. 
 
5. How can the HIV test help my child? 
5 
 
If your child tests negative, he/she may feel less worried after knowing their HIV 
status, and take steps to prevent him-/herself from getting HIV.   If your child knows 
he/she is HIV positive, it may reduce the stress that comes with the uncertainty of not 
knowing. Your child can take advantage of treating his/her HIV early, monitoring 
his/her health, eating well and healthily.  Your child will also know if he/she can 
infect others, and what to do to stop this from happening.   
 
Women and their partners thinking about getting pregnant can take advantage of 
treatments that can help prevent their baby from getting HIV. Your child can also 
possibly plan for future care of his/her children. 
 
120 of 124


Testing for HIV Parent or Legal Guardian Information and Informed Consent Form 
 
Protocol Version and Date: V X dd-mmm-yyyy                Master Parent/Guardian HIV IC Version 2.0 Date 13-Jun-2018  
Mast er Country/Site Version X Dat e: dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 5 of 8 
 
6. What happens if my child is injured during the HIV test? 
6 
 
The insurance that the TB Alliance has taken out as required by the laws and 
regulations of your country covers the extra blood samples. For more details, see the 
information sheet describing the main clinical study. 
 
7. Will you keep my child’s HIV test private? 
7 
 
We will respect your child’s confidentiality* and only the study doctor and research 
team will know the results of the test.  Selected people working for TB Alliance, as 
well as representatives of government regulatory authorities and ethics committees 
will also have access to the results. These persons know that they must keep your 
child’s information private.  You are giving permission for those people to see your 
child’s medical records when you sign this document. 
 
8. Will you pay my child to do the HIV test? 
8 
 
No, we will not pay your child for giving the blood sample to do the HIV test.  
The TB Alliance or the study site will not be responsible for paying any costs related to 
your HIV treatment if your child tests positive. We will refer your child to an HIV clinic 
for further testing and advice. 
 
9. Will I have to pay for my child’s HIV test? 
9 
 
No, the HIV test will not cost you anything, 
<<If applicable add “You will receive HIV counseling before and after HIV test. The 
TB Alliance will pay for the test and the counseling.” 
 
 
 
10. Whom can we contact if something worries me or my child? 
10 
 
You can call the study doctor or another authorised person at any time 
of the day or night (24 hours) on Tel: <<add>> or <<add>>. 
 
121 of 124


Testing for HIV Parent or Legal Guardian Information and Informed Consent Form 
 
Protocol Version and Date: V X dd-mmm-yyyy                Master Parent/Guardian HIV IC Version 2.0 Date 13-Jun-2018  
Mast er Country/Site Version X Dat e: dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 6 of 8 
 
  
Please refer to the main informed consent form for more information on whom to 
contact if you or your child have complaints about this study. 
 
11. How do I agree for my child to have the HIV test? 
11 
 
If you want to agree to do the HIV test, please read the statement on the following 
page and sign the form. 
 
Parent or Legal Guardian Notes 
 
 
 
 
 
 
Glossary 
Technical term 
Explanation 
HIV 
Human immunodeficiency virus 
AIDS 
Acquired immune deficiency syndrome 
opportunistic infections 
an infection that occurs when the immune system 
is weak 
immune system 
the system in your body that fights infections 
pulmonary 
of the lungs 
confidentiality 
a set of rules to keep information private 
 
 
 
122 of 124


Testing for HIV Parent or Legal Guardian Information and Informed Consent Form 
 
Protocol Version and Date: V X dd-mmm-yyyy                Master Parent/Guardian HIV IC Version 2.0 Date 13-Jun-2018  
Mast er Country/Site Version X Dat e: dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 7 of 8 
 
PARENT/LEGAL GUARDIAN INFORMED CONSENT FORM FOR HIV 
TESTING 
 
By signing below, I agree that: 
 
• 
I have read, or someone has read the information sheet and consent form for this 
HIV testing of my child to me, and I understand it. 
• 
I have had the chance to ask questions and I am happy with the answers. 
• 
I have had time to discuss the information with others and to decide if I want my 
child to do the test. 
• 
I will get a signed and dated copy of this consent form on the day that I sign it. 
• 
I voluntarily agree for HIV testing to be done on my child. 
• 
Site staff, representatives from the sponsor, regulatory authorities and ethics 
committees can have direct access to my child’s medical records. They will treat 
my child’s information as confidential. 
• 
I hereby give up all rights to the test findings and my child is not entitled to be paid 
anything because of the test findings. 
• 
<<EU: “I consent to the processing/storing of my child’s data and the transfer 
thereof to countries outside the EU.”>> 
 
 
 
Printed Name of Parent/Legal Guardian  
 
 
 
Signature/mark/thumb print of Parent/Legal 
Guardian 
 
Date 
 
 
(Parent or Legal Guardian/witness 
must write date) 
 
 
*Printed Name of Person Conducting Consent 
(If other than investigator /delegate) 
 
 
 
*Signature of Person Conducting Consent 
(If other than investigator /delegate) 
 
Date 
 
 
(Person conducting consent must 
write date) 
 
I,   
(Insert name of investigator) 
hereby confirm that the above Parent or Legal Guardian has been fully informed about the 
nature, conduct and risks of the above study. 
123 of 124


Testing for HIV Parent or Legal Guardian Information and Informed Consent Form 
 
Protocol Version and Date: V X dd-mmm-yyyy                Master Parent/Guardian HIV IC Version 2.0 Date 13-Jun-2018  
Mast er Country/Site Version X Dat e: dd-mmm-yyyy 
PI Name:  XXX (Language) 
Approved by xxx EC/IRB on dd-mmm-yyyy 
 
 
Confidential | Page 8 of 8 
 
 
 
Signature of Investigator 
 
Date 
 
 
(Inv estigator must write date) 
 
By signing below, I verify that the above Parent or Legal Guardian gave verbal 
informed consent. The Parent or Legal Guardian has been informed about the risks 
and the benefits of his/her child’s HIV test, understands such risks and benefits and is 
able to agree for his/her child to have the HIV test, without coercion, undue 
influence or inappropriate incentives. 
 
 
 
*Printed Name of Witness 
 
 
 
*Signature of Witness 
 
Date 
 
 
(Witness must write date) 
* Where applicable 
 
124 of 124

Prot_000.pdf: 
Global Alliance for TB Drug Development 
Clinical Trial Report 
NC-007-(B-Pa-L) 
ZeNix 
CONFIDENTIAL 
16.1 
Trial Information 
16.1.1 
Protocol and Protocol Amendments 
NC-007 Protocol, Version 1.0, 23FEB2017 
NC-007 Protocol Amendment, Version 1.0, RUS/BEL, 28FEB2017 
NC-007 Protocol Amendment, Version 1.0, RUS, 15NOV2017 
NC-007 Protocol, Version 2.0, 13JUN2018 
NC-007 Protocol Amendment Summary of Changes, 13JUN2018 
NC-007 Protocol Amendment, Version 2.0, RUS, 13JUN2018 
NC-007 Protocol Amendment, Version 1.0, MDA, 13JUN2018 
NC-007 Protocol Amendment, Version 2.0 Summary of Changes, 10MAR2020 
NC-007 Protocol, Version 3.0, 10MAR2020 
NC-007 Protocol Amendment, Version 2.0, MDA, 10MAR2020 
NC-007 Protocol Amendment, Version 3.0, RUS, 18MAR2020 
1 of 784


CONFIDENTIAL 
Protocol Number 
NC-007-(B-Pa-L) 
Title: 
A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid 
plus bedaquiline and pretomanid in participants with pulmonary 
infection of either extensively drug-resistant tuberculosis (XDR-
TB), pre-XDR-TB or treatment intolerant or non-responsive multi-
drug resistant tuberculosis (MDR-TB). 
Drug(s)/Combination(s): Bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Initial Protocol 
Version/Date:  
1.0/23 February, 2017 
Protocol Name: 
ZeNix 
0 
TB ALLIANCE 
GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT 
ZeNix 
2 of 784


TB ALLIANCE 
0 
GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT 
ZeNiK 
PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XOR-TB), pre-XOR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MOR-TB). 
Protocol Number: NC-007-(B-L-Pa) 
Protocol Date: 22FEB2017 
Protocol Name: ZeNix 
SPONSOR 
Date 
LEAD INVESTIGATOR 
Printed Name 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone 646-616-8671 
email: daniel.everitt@tballiance.org 
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and local 
regulations. 
Signa~ 
9.-0 I ] 
Date 
Uc/) L-eJ c:::::ct 
Printed Name 
CONFIDENTIAL 
Page 2 of 99 
3 of 784


CONFIDENTIAL 
Page 3 of 99 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-resistant 
tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug 
resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-L-Pa) 
Protocol Date: 22FEB2017 
Protocol Name: ZeNix 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
Signature 
Printed Name 
Date 
Q 
TB ALLIANCE 
GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT 
ZeNix 
4 of 784


Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version 23FEB2017 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 4 of 99 
1 
Synopsis ............................................................................................................................................ 10 
1.1 
Synopsis Summary .................................................................................................................. 10 
1.2 
Synopsis Flowchart .................................................................................................................. 15 
2 
Introduction and Rationale .............................................................................................................. 20 
2.1 
Trial Rationale ........................................................................................................................... 21 
2.1.1 
Trial Design Rationale ..................................................................................................... 21 
2.1.2 
Trial Drug Rationale ......................................................................................................... 21 
2.1.3 
Pretomanid ........................................................................................................................ 23 
2.1.4 
Linezolid ............................................................................................................................. 23 
2.2 
Agents to be Studied ............................................................................................................... 24 
2.2.1 
Bedaquiline ........................................................................................................................ 24 
2.2.2 
Pretomanid ........................................................................................................................ 27 
2.2.3 
Linezolid ............................................................................................................................. 33 
2.3 
Regimens to be Studied .......................................................................................................... 38 
2.3.1 
Non-Clinical Studies ......................................................................................................... 38 
2.3.2 
Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or Linezolid ... 39 
2.4 
Overall Benefit/Risk Assessment ........................................................................................... 43 
3 
Trial Objectives ................................................................................................................................. 44 
3.1 
Primary Objectives ................................................................................................................... 44 
4 
Trial Design ....................................................................................................................................... 44 
4.1 
Summary of Trial Design ......................................................................................................... 44 
4.2 
Treatment Plan: Schedule of Assessments ......................................................................... 44 
5 
Trial Population ................................................................................................................................. 45 
5.1 
Inclusion Criteria ....................................................................................................................... 46 
5.2 
Exclusion Criteria ..................................................................................................................... 47 
5.3 
Restrictions ................................................................................................................................ 50 
5.3.1 
Prior and Concomitant Medications and Other Treatments ...................................... 50 
5.3.2 
Recommendations for Concomitant use of Anti-Malarials ......................................... 51 
5.3.3 
Antiretroviral Therapy ...................................................................................................... 51 
5.3.4 
Other Restrictions ............................................................................................................. 52 
5.4 
Discontinuation from Treatment/Trial .................................................................................... 52 
5.5 
Participant Progress Definitions ............................................................................................. 53 
5.6 
Trial Stopping Rules ................................................................................................................. 54 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version 23FEB2017 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 5 of 99 
6 
Treatment .......................................................................................................................................... 54 
6.1 
IMP Administration ................................................................................................................... 54 
6.2 
Participant Compliance ........................................................................................................... 55 
6.3 
Treatment Modification(s) ....................................................................................................... 55 
6.4 
IMP Packaging and Labelling ................................................................................................. 56 
6.5 
Method of Treatment Assignment .......................................................................................... 57 
6.6 
Blinding and Procedures for Breaking the Blind .................................................................. 57 
6.7 
Handling, Storage and Accountability ................................................................................... 58 
7 
Trial Variables and Procedures ...................................................................................................... 58 
7.1 
Demographic and Background Variables and Procedures ................................................ 58 
7.2 
Efficacy Variables and Procedures........................................................................................ 59 
7.3 
Safety and Tolerability Assessments .................................................................................... 60 
7.4 
PK Variables and Procedures ................................................................................................ 61 
7.5 
Mycobacteriology Characterization Variable and Procedures .......................................... 61 
8 
Adverse Events ................................................................................................................................. 62 
8.1 
Definitions .................................................................................................................................. 62 
8.1.1 
Adverse Event (AE).......................................................................................................... 62 
8.1.2 
Serious Adverse Event (SAE) ........................................................................................ 62 
8.1.3 
Attribution/Causality ......................................................................................................... 63 
8.1.4 
Severity .............................................................................................................................. 64 
8.2 
Reporting ................................................................................................................................... 64 
8.2.1 
Follow up of Adverse Events .......................................................................................... 65 
8.2.2 
Clinical Laboratory Adverse Events .............................................................................. 65 
8.2.3 
Disease under Study........................................................................................................ 65 
8.2.4 
Overdose ........................................................................................................................... 66 
8.2.5 
Drug Interaction ................................................................................................................ 66 
8.2.6 
Pregnancy ......................................................................................................................... 66 
8.3 
Monitoring for Specific Toxicities ........................................................................................... 66 
8.3.1 
Neurological ...................................................................................................................... 67 
8.3.2 
ALT, AST and Alkaline Phosphatase elevations: ........................................................ 67 
8.3.3 
Lipase ................................................................................................................................. 67 
8.3.4 
Musculoskeletal System and Cardiac Muscle ............................................................. 67 
8.3.5 
Cardiac Rhythm Disturbances ........................................................................................ 67 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version 23FEB2017 
Protocol Name: ZeNix
CONFIDENTIAL 
Page 6 of 99 
8.3.6 
Myelosuppression ............................................................................................................ 68 
8.3.7 
Peripheral Neuropathy ..................................................................................................... 69 
8.3.8 
Optic Neuropathy.............................................................................................................. 69 
8.3.9 
Lactic Acidosis .................................................................................................................. 69 
8.4 
Safety Monitoring by Data Monitoring Committee............................................................... 69 
9 
Statistical Analysis ........................................................................................................................... 70 
9.1 
Analysis Population .................................................................................................................. 70 
9.2 
Sample Size .............................................................................................................................. 70 
9.3 
Interim Analyses ....................................................................................................................... 71 
9.4 
Primary and Secondary Endpoint Analysis .......................................................................... 71 
9.5 
Safety and Tolerability Analysis ............................................................................................. 71 
9.6 
Pharmacokinetics ..................................................................................................................... 72 
9.7 
Pharmacokinetics/Pharmacodynamics ................................................................................. 73 
10 Records Management ..................................................................................................................... 73 
10.1 
Data Collection ......................................................................................................................... 73 
10.2 
Source Documents ................................................................................................................... 73 
10.3 
File Management at the Trial Centre ..................................................................................... 73 
10.4 
Records Retention at the Trial Centre .................................................................................. 73 
11 Quality Control and Assurance ...................................................................................................... 74 
11.1 
Site Procedures ........................................................................................................................ 74 
11.2 
Monitoring .................................................................................................................................. 74 
11.3 
Protocol Deviations .................................................................................................................. 75 
11.4 
Auditing ...................................................................................................................................... 75 
12 Ethics and Regulatory ..................................................................................................................... 75 
12.1 
Basic Principles ........................................................................................................................ 75 
12.2 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review .............. 75 
12.3 
Regulatory Authorities ............................................................................................................. 76 
12.4 
Informed Consent ..................................................................................................................... 76 
12.5 
Confidentiality ........................................................................................................................... 76 
13 Publication Policy ............................................................................................................................. 77 
14 Protocol Amendment Policy............................................................................................................ 77 
15 Sponsor, Financial Aspects, Insurance and Indemnity .............................................................. 77 
16 References ........................................................................................................................................ 79 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version 23FEB2017 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 7 of 99 
Appendix 1: 
The IUATLD Scale ....................................................................................................... 82 
Appendix 2: 
Division of Microbiology and Infectious Disease (DMID) Toxicity Table .............. 83 
Appendix 3: 
 Cardiovascular Safety ................................................................................................ 91 
Appendix 4: 
 Karnofsky Performance Status Scale Definitions Rating (%) Criteria ................. 92 
Appendix 5: 
 EQ-5D-5L Questionnaire ............................................................................................ 93 
Appendix 6: 
 Brief Peripheral Neuropathy Screening ................................................................... 95 
Appendix 7: 
 Tuberculosis Symptoms Profile ................................................................................ 97 
Appendix 8: 
 Liver Toxicity Management ........................................................................................ 98 
 
TABLES 
Table 1: 
ADRs C208 Stage 1 and Stage 2 ...................................................................................... 26 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies............................................ 28 
Table 3: 
Murine Lung CFU counts during Treatment with Linezolid ............................................ 33 
Table 4: 
Murine Relapse Data ........................................................................................................... 39 
Table 5: 
Summary Statistics for EBACFU(0-14) .................................................................................... 40 
Table 6: 
NC-003 Efficacy Results: Daily BAlogCFU(0-14)................................................................... 41 
Table 7: 
NC-003 Safety Data ............................................................................................................. 41 
Table 8: 
Treatment Groups ................................................................................................................ 45 
Table 9: 
Investigational Medicinal Product Details ......................................................................... 55 
Table 10: Adverse Events Attribution/Causality Ratings .................................................................. 63 
Table 11: Definitions for Adverse Event Severity Gradings ............................................................. 64 
  
 
FIGURES 
Figure 1: Log10 CFU Counts in Lungs ...................................................................................28 
Figure 2: Mean log Colony Forming Unit Values over Time Study CL-010 .............................31 
Figure 3:  Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin CL-001 35 
Figure 4: Trial Schematic........................................................................................................45 
 
 
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Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
ABaCavir 
ADR 
Adverse Drug Reactions 
AE 
Adverse Event  
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
ALanine aminoTransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
ASpartate aminoTransferase 
AT 
AminoTransferase 
AUCτ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BMI 
Body Mass Index 
bpm 
beats per minute 
BPNS 
Brief Peripheral Neuropathy Scale 
C 
Clofazimine 
CFU 
Colony Forming Units 
CK(-MB) 
Creatine Kinase(-MB isoenzyme) 
C(max), (min) 
plasma Concentration (maximum), (minimum) 
CO2 
Carbon diOxide 
CPK 
Creatine PhosphoKinase 
CS 
Clinically Significant 
Ctrough 
plasma Concentrationtrough 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
DeoxyriboNucleic Acid 
DOH 
Department of Health 
DILI 
Drug Induced Liver Injury 
DSMC 
Data Safety Monitoring Committee 
DST 
Drug Sensitivity Testing 
E 
Ethambutol 
EBA 
Early Bacteriocidal Activity 
EC 
Ethics Committee 
ECG 
ElectroCardioGram 
EFV 
EFaVirenz 
(e)CRF
(electronic) Case Report Form 
FQ
FluoroQuinolone 
FTC
Emtricitabine 
GI
GastroIntestinal 
GCP
Good Clinical Practice 
GGT
Gamma-Glutamyl Transferase 
GMR
Geometric Mean Ratio 
H
Isoniazid 
hERG
Human Ether-à-go-go Related Gene 
HIV
Human Immunodeficiency Virus 
HRZE
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
ICF
Informed Consent Form 
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ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
kilogram 
L 
Linezolid 
LLN 
Lower Limit of Normal 
LPV 
LoPinaVir 
M 
Moxifloxacin 
MAO(I) 
MonoAmine Oxidase (Inhibitor) 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
mg/dl 
milligrams per decilitre 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent To Treat 
ms 
millisecond 
NCS 
Not Clinically Significant 
NEJM 
New England Journal of Medicine 
NVP 
NeViraPine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
PharmacoDynamic 
PP 
Per Protocol 
PK 
PharmacoKinetic 
PR 
PR interval 
QD 
Once Daily 
R 
Rifampicin 
S 
Streptomycin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIRE 
Streptomycin Isoniazid Rifampicin Ethambutol 
SOC 
System Organ Class 
TB 
Tuberculosis 
TBL 
serum Total BiLirubin 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
T>MIC
Time above minimum inhibitory concentration 
t.i.w.
three times a week 
(BA) TTP 
(Bacteriocidal Activity) Time To Positivity 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
XDR-TB 
eXtensively Drug Resistant Tuberculosis 
μg(/dl) 
micrograms (per deciliter) 
Z 
pyraZinamide 
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1 
Synopsis 
1.1 Synopsis Summary 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Number/Title: 
NC-007: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB) 
Treatment Indication: 
Pulmonary XDR-TB, pre-XDR-TB, and treatment intolerant or non-responsive 
MDR-TB 
Trial Objective: 
To evaluate the efficacy, safety and tolerability of various doses and durations 
of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in 
participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment 
intolerant or non-responsive MDR-TB. 
Trial Design: 
A phase 3, multi-center, partially-blinded, randomized clinical trial in four parallel 
treatment groups. Bedaquiline and pretomanid treatment will not be blinded. 
Linezolid treatment dose and duration will be double-blinded. 
Participants will have a screening period of up to 9 days and will be randomized 
to receive one of the 4 active treatment arms. Participants will be randomized 
to one of the four regimens in a 1:1:1:1 ratio, using an interactive web response 
system (IWRS) which will utilize a dynamic randomization system using 
minimization with a random element to allocate participants evenly across the 
arms by HIV status and type of TB.   
Each participant will receive 26 weeks of treatment.  If participant’s week 16 
sample remains culture positive, Investigator may consider extending current 
treatment to 39 weeks, in consultation with the Sponsor Medical Monitor 
Participants will be followed for 78 weeks after end of treatment. 
Patient Population: 
A total of up to 180 participants: 
120 (30 per treatment arm) XDR-TB participants, and up to 60 (15 per arm) 
pre-XDR or treatment intolerant/non-responsive MDR pulmonary tuberculosis 
Participants, male and female, aged 14 and over. Enrollment will stop when 
120 XDR-TB participants are randomized. Sponsor may consider replacement 
of late screen failure and un-assessable (as detailed in the statistical analysis 
plan) participants. 
Test product, Dose and 
Mode of Administration: 
The test product will be supplied as: 
•
bedaquiline 100 mg tablets
•
pretomanid 200 mg tablets
•
linezolid (scored) 600 mg tablets
•
placebo linezolid (scored) 600 mg tablets
•
linezolid half tablet (pre-cut) 300 mg
•
placebo linezolid half tablet (pre-cut) 300 mg
Linezolid treatment will be supplied as 2 rows of full tablets and one row of 
half-tablets to allow for all possible dosing options while maintaining the blind. 
Treatment will be administered orally, once daily, with a full glass of water and 
a meal in the following dosing schemes (treatment arms): 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Participants will receive the following: 
•
bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for
18 weeks plus;
•
pretomanid 200 mg once daily for 26 weeks plus;
•
Linezolid- participants will be randomly assigned to receive one of the
following four linezolid treatment doses and durations:
Linezolid 1200 mg daily for 26 weeks 
•
2 linezolid 600 mg active tablets once daily for 26 weeks
•
1 placebo linezolid 300 mg half tablet once daily for 26 weeks
Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9 
•
2 linezolid 600 mg active tablets once daily for 9 weeks
•
1 placebo linezolid 300 mg half tablet once daily for 9 weeks
Weeks 10-26 
•
2 placebo linezolid 600 mg tablets once daily for 17 weeks
•
1 placebo linezolid 300 mg half tablet once daily for 17 weeks
Linezolid 600 mg daily for 26 weeks 
•
1 linezolid 600 mg active tablet once daily for 26 weeks
•
1 placebo linezolid 600 mg tablet once daily for 26 weeks
•
1 placebo linezolid 300 mg half tablet once daily for 26 weeks
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
•
1 linezolid 600 mg active tablet once daily for 9 weeks
•
1 placebo linezolid 600 mg tablet for 9 weeks
•
1 placebo linezolid 300 mg half tablet once daily for 9 weeks
Weeks 10-26 
•
2 placebo linezolid 600 mg tablets once daily for 17 weeks
•
1 placebo linezolid 300 mg half tablet once daily for 17 weeks
Treatment Modifications: 
The above treatment schemes may require modification due to toxicities as 
noted below. All dose modifications should be discussed with the Sponsor 
Medical Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be informed 
within 24 hours of the change if not discussed prior to implementation 
In the event of linezolid specific toxicities, the following should be considered 
and implemented per guidance in the monitoring and safety for specific 
toxicities section of protocol.  Every effort should be made for participants to 
receive a total of 9 weeks of linezolid, even if pauses are required: 
•
Blinded one step reductions (maximum 3 steps) in the dose of linezolid
(1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or 300mg QD to
placebo) managed by the IWRS as per instructions in pharmacy manual
and/or IWRS user manual.
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
• 
Temporary pause of linezolid due to a linezolid-specific toxicity should be 
considered and implemented per guidance in the monitoring and safety 
for specific toxicities section of protocol. 
• 
Permanent discontinuation of linezolid. 
 
For participants experiencing suspected drug related toxicities due to other 
drugs in the regimen (B-Pa), the full regimen may be halted for up to 35 
consecutive days.  
Interruptions/pauses of all Investigational Medicinal Product (IMP) must not 
exceed 8 weeks (56 days) cumulatively.  
 
If participant’s week 16 sample remains culture positive, Investigator may 
consider option to extend current treatment to 39 weeks, in consultation with 
the Sponsor Medical Monitor. When treatment is extended due to a positive 
culture at week 16, interruptions/pauses of all IMP must not exceed 13 weeks 
(91 days) cumulatively. 
 
At no time should the participant be treated with a single agent. 
Criteria for Evaluation: 
Primary Endpoint: 
Incidence of bacteriologic failure or relapse or clinical failure through follow up until 26 weeks after the end of 
treatment. 
 
Abbreviated Definitions, full definitions will be described in the Statistical Analysis Plan (SAP): 
• 
Bacteriologic failure: During the treatment period, failure to attain or maintain culture conversion to 
negative. 
• 
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative 
status, with culture conversion to positive status with a strain of Mycobacterium tuberculosis (MTB) 
genetically identical to the infecting strain at baseline.  
• 
Clinical failure: A change from protocol-specified TB treatment to a new regimen before end of 
protocol specified treatment due to treatment failure, retreatment for TB during follow up, or TB-
related death. 
 
Note: 
• 
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days 
apart. 
• 
Participants who are documented at a visit as unable to produce sputum and who are clinically 
considered to be responding well to treatment will be considered to be culture negative at that visit. 
Further details of definitions to be provided in the SAP. 
 
Secondary Endpoints: 
• 
Incidence of bacteriologic failure or relapse or clinical failure through follow up until 78 weeks after 
the end of treatment. 
• 
Time to sputum culture conversion to negative status through the treatment period. 
• 
Proportion of participants with sputum culture conversion to negative status at weeks 4, 6, 8, 12, 16 
and end of treatment. 
• 
Change from baseline TB symptoms. 
• 
Change from baseline in Patient Reported Health Status. 
• 
Change from baseline weight. 
 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations of bedaquiline and its M2, pretomanid and linezolid from sparse sampling (see Table 
1.2) will be measured and used to update population PK models for bedaquiline and its M2 metabolite, 
pretomanid, and linezolid to further evaluate the effects of covariates on model parameters in this study 
population. PK data from the current trial may be combined with prior data (e.g., from the NiX-TB trial) to 
enhance this population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between drug 
exposure and efficacy and safety endpoints.   
Safety and Tolerability: 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
•
All-cause mortality.
•
Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by, drug relatedness
and seriousness, leading to early withdrawal from treatment, leading to pauses of linezolid, leading
to linezolid reductions and leading to death.
•
Quantitative and qualitative clinical laboratory result measurements, including observed and change
from baseline.
•
Quantitative and qualitative measurement of electrocardiogram (ECG) results read by a central
cardiology service, including observed and change from baseline.
•
Descriptive statistics of ophthalmology slit lamp examination data (age related eye disease study 2
[AREDS2]) lens opacity classification and grading). Categorical data for lens opacity will be
summarized in a frequency table for the right and left eye, respectively, including change from
baseline.
•
Changes in ophthalmic exam for visual acuity and color vision, including observed and change from
baseline.
•
Changes noted in peripheral neuropathy signs and symptoms, including observed and change from
baseline.
Mycobacteriology: 
Sputum samples will be obtained at all scheduled visits.  The following tests will be performed. 
•
Smear microscopy for acid-fast bacilli (AFB);
•
Liquid Culture (MGIT), followed by a speciation test to detect presence or absence of MTB and
obtain time to positivity (TTP);
•
GeneXpert, Hain Genotype MTBDRplus or an alternative molecular to confirm MTB and rifamycin
resistance.
•
Minimum Inhibitory concentration (MIC) of bedaquiline, pretomanid and linezolid;
•
Drug Susceptibility Testing (DST) in liquid culture for rifampicin, isoniazid, streptomycin, ethambutol,
pyrazinamide and second line TB drugs including fluoroquinolones and injectable;
•
Genotyping.
Details on the testing and the collection and timing of samples are in sections 1.2 and 7.2.
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Statistical Methods: 
A general description of the statistical methods planned for the primary efficacy outcome is outlined below. 
Specific details will be provided in the SAP. 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT).  We will 
evaluate the hypothesis, separately for each of the experimental B-Pa-L treatment arms, that the incidence 
of bacteriologic and clinical cure at 26 weeks after the end of therapy is greater than 50%.   
The incidence will be estimated from the binomial proportion for participants with success criteria based on 
the lower bound of the confidence interval for this proportion being greater than 50%. 
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as the target, 
because it is above the entire range of the historical control for cure of XDR-TB and because a cure rate of 
50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a shortened, simplified, all oral, 
inexpensive and safer regimen would clearly represent an important therapeutic advancement.  
The primary analysis population will include both XDR and non-XDR participants (up to 45 per arm).  A 
secondary analysis will be restricted to the XDR participants only (30 per arm).   A sample size of 30-45 per 
arm will provide more than 90% power to demonstrate that the lower bound of the 95% confidence interval 
of this estimate is greater than 50%, using a 2-sided 5% significance level. This assumes that the true cure 
rate is 80 percent.   
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 6 months) with the 
L1200 2 months and L600 26 weeks only being tested if L1200 26 weeks is a success.  Similarly, L600 9 
weeks will only be tested if L600 26 weeks is a success.  A Bonferroni adjustment will be made for 
comparing the L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025.  For these 
comparisons the lower bound of the 97.5% confidence interval will need to exceed 50% for success.   
Both a Modified Intent to Treat (mITT) and a Per Protocol (PP) analysis for each arm will be conducted.  No 
formal statistical pairwise comparisons between the arms will be performed.   
Trial Duration: 
~3.5 Years (An enrolment period of at least 18 months plus 9 days pre-treatment plus 6 month treatment 
period plus 18 months post treatment follow-up). 
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1.2 Synopsis Flowchart 
Period Screeninga 
Treatment 
 Visits every 3 
weeks   if 
extended due to 
IMP pause or 
culture (+) at 
week 16b 
   
End of OR Early 
Withdrawal from 
Treatmentc 
Post Treatment Follow-up 
Time of Visit 
Up to 9 days 
prior to 
Treatment 
Day 1 
Week  1 
Week  2 
Week 3 
Week  4 
Week 5 
Week  6 
Week 7  
Week  8 
Week 10 
Week 12 
Week 14 
Week  16 
Week 18 
Week 20 
Week 23 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks 
Visit Windowq 
N/A 
+/- 3 days 
+/- 5 days 
+/- 7 days 
Post last 
dose IMP 
+7 days 
+/-  14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Trtmnt/Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusiond 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Statuse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 Count and Viral Loadf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest X-Rayg  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Testh 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Patient Reported Health Status 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Slit Lamp Exami 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
X 
 
 
 
 
 
Ophthalmic Examj 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X X X X X X 
Single 12-LeadECGk 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X   
 
 
 
 
X 
 
 
 
 
 
 
 
 
Limited Physical Examl 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X X X X X X 
Full Physical Exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Laboratory Safety Tests 
(includes Full Blood Count)m 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Full Blood Count 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X X X X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X X X X 
Study Medication/Compliancen 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PK Samplingo 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Xo 
 
 
 
 
 
 
 
 
Early Morning & Spot Sputumr 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X X X X X X X X 
Peripheral Neuropathy 
Assessment 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X X 
 
X 
 
X 
Investigator Assessmentp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
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GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
a.
Screening: Screening assessments can occur on different days within nine days prior to Day
1 dosing. If a participant fails screening, a full re-screen may occur at a later date post
discussion with Medical Monitor.  All screening procedures must be repeated at re-screen
visit, with the exception of the slit lamp examination, which can be used from a previous
screening if within 8 weeks of anticipated randomization.
b.
Visit Schedule: If the duration of treatment is extended due to dose pauses (e.g., takes
participant 35 weeks to complete 26 weeks of treatment) or positive week 16 culture,
unscheduled visits should be added every 3 weeks (+/- 7 days).  End of treatment visit (final
treatment visit) should be done within 7 days AFTER the last dose of IMP.
1. If participant completes treatment at week 26, end of treatment visit should be done
within 7 days after last dose of week 26.
2. If participant completes 26 weeks of therapy at week 33 due to pauses, visits can be
done at weeks 26, 29 and 33 (3 weeks from week 29 plus 7-day window). The week
33 visit would be the end of treatment visit and should be completed within 7 days after
last dose.
3. If participant completes treatment at week 39 due to post treatment extension related
to positive culture at week 16, visits can be completed at weeks 26, 29, 32, 35 and 39
(3 weeks plus 7-day window), visit at week 39 would be the end of treatment visit.
4. Follow-up visits should be scheduled based on timing of end of treatment/early
withdrawal from treatment (e.g., 4-week follow-up to be scheduled 4 weeks after last
dose of IMP).
c.
Follow-up Visits Early Withdrawal Participants: Once a participant has been discontinued
from treatment, they will be required to attend an Early Withdrawal visit. If participant:
1. Received/took < 14 doses, no additional follow-up visits are required.
2. Received 15 or more doses, follow-up after end of treatment at week 12, week 26 (if
not already performed) and week 78 are required. The week 12 visit will only require
the ophthalmologic exams. The week 26 and 78 follow-up visits will be to collect
Serious Adverse Event (SAE) information (including verification of survival) and patient
reported TB outcome information only and may be telephonic, a home or a site visit.
This includes participants who are withdrawn from the trial due to meeting the
treatment failure endpoint. Participant may need to return for visits to collect sputum
samples to determine outcome status as per section “r”.
d.
Inclusion/Exclusion: to be confirmed at screening and prior to randomization.
e.
HIV testing: If HIV status is a confirmed known positive, repeated HIV test is not needed
provided documentation is available. If HIV status is unknown or suspected negative, HIV test
should be requested. If an ELISA and/or Western Blot based HIV test was performed within 1
month prior to screening, it should not be repeated as long as documentation of testing
method and negative results can be provided.
f.
CD4 count and viral load:  For all HIV-positive participants. Viral load and CD4 at screening,
CD4 only at end of treatment or early withdrawal.
g.
Chest X-Ray: A chest x-ray (digital image) within one month prior to screening, will be
obtained and read locally by Investigator or designee. Digital images will be provided to
Sponsor, this process will be described in a separate document, the Radiology Manual.
h.
Urine Pregnancy: Women of child-bearing potential only, whether they are sexually active or
not.
i.
Slit-Lamp Exam: Slit Lamp examination will be performed by an Ophthalmologist with
AREDS2 training:
1. For participants who receive < 14 doses of IMP, exam at: Screening only.
2. For participants who receive 15 days to < 12 weeks of treatment, exams at: Screening
and the 12-week follow-up visit.
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3. Participants who complete > 12 weeks of treatment exams at: Screening, End of
Treatment or Early Withdrawal and the 12-week follow-up.
j.
Ophthalmic Exam: to include Ophthalmologic Medical history at Screening; All exams to
include Visual Acuity (distance testing) and Colour Vision assessment.   Can be done by any
trained study staff throughout study.  Screening exam must be done by Ophthalmologist in
addition to trained study staff that will perform exams throughout the study.
k.
Single 12-Lead ECG: To every extent possible, should be performed at approximately the
same time of day (+/- 1 hours) and in the same fed/fasted state throughout the trial (e.g. 4
hours after lunch). Central ECG analysis will be performed.
l.
Physical Exam:  Limited Physical exams should include weight and a gross neurological,
pulmonary, cardiovascular and abdominal exam.
m.
Safety Laboratory Assessments: The Safety Laboratory sampling methodology and
requirements will be described in a separate document, the Laboratory Manual, which will be
provided prior to the trial start. The following analyses will be performed:
1. Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count
with differential, platelet count).
2. Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin,
uric acid, total protein, alkaline phosphatase, aspartate aminotransferase (AST),
alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, calcium
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine
phosphokinase (CPK).
3. Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin,
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be
completed as follow up to abnormal urinalysis per discretion of Investigator.
4. Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates,
benzodiazepines, barbiturates, at Screening only. Investigator to utilize to determine
whether participant meets Exclusion criteria 2.  Positive results will not automatically
exclude participant from the trial.
n.
Study Medication/Compliance: Study medication administration will be supervised per local
site practice to assure compliance to regimen.
o.
PK Sampling:  Specific PK blood draws as follows:
1. Day 1; pre-dose (within 2 hours prior to dosing)
2. Week 2: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours
post-dose
3. Week 8: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours
post-dose
4. Week 12: pre-dose (within 2 hours prior to dosing)
5. Week 20 or at early withdrawal if prior to week 20: pre-dose (within 2 hours prior to
dosing) and 2–3 hours post-dose
When participant is discharged and seen as an outpatient, site should make every effort to 
collect 6-8 hour samples at weeks 8 and when operationally and logistically feasible. 
p.
Investigator Assessment: Principal Investigator to review participant status and assess
whether TB treatment at current visit is considered a “success” or “failure”.  If considered a
failure, should specify if based on bacteriology and/or clinical deterioration and/or radiological
deterioration. To be completed at 26 and 78 week post treatment follow-up visits and at any
time Investigator determines that participant fulfills criteria for outcome of treatment failure.
q.
Visit Windows: the windows noted on the flowchart for timing of visit also apply to timing
within a visit.  For example, procedures that are difficult to schedule such as ophthalmology
exams, should be scheduled within +/- 3 days of scheduled visit from Day 1 to Week 8 or +/-
14 days within scheduled visit at the week 12 post treatment follow-up visit.  Sites should
make every effort to ensure all other procedures should be done on the same day when
possible.
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r.
Sputum Sampling:
Visit 
Sample 
Tests 
EMS* 
Spot 
 AFB Smear 
microscopy 
MGIT culture, 
speciation 
Molecular 
testing 
MIC: 
B, Pa, L 
Liquid DST 
Genotyping 
Screening 
(Day -9 to -1) 
 
S 
S 
S 
Baseline (Day 1) 
or screen - wk4 if 
baseline negative or 
contaminated 
 
 
 S 
C 
C 
C 
All Visits Post 
Baseline 
 
 
S 
Positive for MTB 
at/after EoT 
 
S 
 S 
C 
C 
C 
C –   Central laboratory (specialized facility) 
S –   Study Laboratory (facility that receives samples directly from site) 
SPUTUM SAMPLES GENERAL: If EMS is not available, site should make every attempt to 
collect two spot samples at least 30 minutes apart.  
BASELINE: If available, site will request pre-screening culture that was used for the tests that 
qualified the participant for inclusion into the trial to be subcultured and shipped to the study lab 
from the applicable lab for relevant participants with no positive cultures from screening through 
week 4 (with consent). Samples should be stored according to the applicable lab procedures until 
shipment to the designated study lab. Included with each shipment will be a copy of the applicable 
lab reports and all participant identifying information redacted and a completed shipment inventory 
form with appropriate participant trial identifiers. Details on how samples will be packed and 
shipped will be provided in the lab manual. 
POSITIVE MTB AT/AFTER END OF TREATMENT: Only one isolate (preferably from EMS) 
should be shipped. Second isolate may be requested if first is contaminated.  
MOLECULAR TESTING: 
•
At Screening: GeneXpert, Hain MTBDRplus or equivalent to determine MTB complex and
R resistance.
•
Positive MTB at/after end of treatment: Hain MTBDRplus and HainMTBRsl
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including but not limited to FQ and 
injectables. 
STORAGE: MTB isolates from all positive cultures to be stored at the study laboratory until trial 
closure for the applicable study tests. The extracted MTB DNA from the applicable baseline and 
follow-up isolates will also be stored at the central lab for potential further work to validate new 
assay tools for 5 years after trial closure. 
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CENTRAL LAB: Results from testing at Central myco lab (MIC, DST and genotyping) will not 
routinely be provided to sites.  In the event of participant relapse/failure, Sponsor will provide 
available results to the site in order to inform appropriate participant treatment. 
UNSCHEDULED VISITS: If cultures of both spot sputum samples are contaminated at the 
following visits, or if necessary in order to help define a participant’s outcome status/assess 
culture status during follow-up, the participant should return for an unscheduled visit(s) to give 
additional samples or to document the participant is not able to produce sputum: 
•
End of treatment visit;
•
Week 26 post treatment follow-up visit;
•
Post treatment follow-up visits from week 8 through week 65 (in addition to week 26
follow-up);
•
End of Follow-up Period (week 78 post treatment completion visit);
•
Early Withdrawal (if applicable).
At the end of 26 weeks and 78 weeks post treatment completion, to define outcome status, need 
to confirm whether the participant has: 
•
At least two sequential negative sputum culture results; or
•
At least two sequential positive sputum culture results; or
•
Has been unable to produce sputum after documentation of at least two negative
sputum cultures with no intervening positive and are clinically asymptomatic.
If they do not fall into one of these categories, site should continue to collect sputum samples x 
2 (one Early Morning and one Spot at the research site or 2 spots samples at least 30 minutes 
apart, under the coaching and observation of the trial staff) at a minimum of 7 days or more apart 
until they fall into one of the above categories. 
If in any of the above scenarios the Investigator is unsure of the outcome, the Investigator must 
contact the Sponsor Medical Monitor to discuss and agree on how the patient is to be handled. 
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2 
Introduction and Rationale 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is now the world’s leading infectious 
disease killer and is responsible for more deaths than HIV.(43) It is the leading cause of death 
among HIV-infected individuals, and there is more TB in the world today than at any other time in 
history. As a result of poor treatment adherence, in addition to primary transmission, drug 
resistance is becoming more common and fears of an epidemic with strains of extensively drug-
resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs and regimens for TB 
are needed for the growing number of patients with XDR TB.  
Outcomes of treatment for XDR-TB using the best available treatments have traditionally been 
very poor.  The best treatment historically has been to use available second line drugs individually 
tailored based on drug susceptibility testing in an inpatient setting to assure adherence with 
treatment lasting from 24 months to much longer for patients without culture conversion.  The 
most detailed report using this approach with long term follow-up prior to the use of linezolid, 
bedaquiline or delamanid in regimens has come from South Africa, where the HIV co-infection 
rate among patients with XDR-TB ranges from 40 to 70%.  A cohort study of 107 patients with 
XDR-TB found cure or completion of therapy at 24 months to be 16%, with 46% having died.(28)  
In another report from South Africa of 114 patients with XDR-TB, 22% completed treatment 
successfully.(21)  The largest evaluation of treatment outcomes was noted in the WHO 2014 annual 
tuberculosis report of 1269 patients in 40 countries, where 22% of patients with XDR-TB 
completed treatment successfully and 35% died.(42) A meta-analysis of 397 patients with XDR-TB 
from 31 centers, with HIV coinfection <10%, reported 32% treatment success.(17)  Reports of the 
outcome of XDR-TB treatment from Peru (43 patients, 42% treatment success)(2) and Ukraine 
(114 patients, 22% treatment success)(11) have been similar.  Based on these reports, the success 
of traditionally available drug therapies for treating XDR-TB infection is substantially less than 
50% and in the most detailed and largest reports is less than 25%. 
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with XDR-TB might be improved when added to background regimens. Experience 
recently published from the C209 uncontrolled study of bedaquiline given on a background of 
multiple drugs notes that the subset of 38 patients with XDR-TB had rates of sputum culture 
conversion to negative of 62.2%.(29) However, in this study only one patient with XDR-TB was co-
infected with HIV. All participants were required to have Mycobacterium tuberculosis (MTB) 
isolates susceptible to at least 3 drugs at enrolment, and patients had a median of only 5.4 months 
of treatment-free follow-up. This study added bedaquiline for 6 months to a background regimen 
of many drugs given for 18 months or longer. 
While treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR-
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.(43)  This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% 
died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information.   
With such poor historical outcomes for patients with XDR-TB and with the complexity, expense 
and toxicity of treatments for all forms of drug resistant TB, novel drug combinations are 
desperately needed to improve treatment outcomes. Linezolid was identified in a small study as 
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a potentially efficacious drug in patients with XDR-TB when added to a failing regimen(9) and this 
drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of three drugs for which there is little, if any, pre-existing resistance 
among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]), there is the opportunity 
to evaluate a new regimen that may be administered orally once daily to treat patients with XDR-
TB. Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, it is 
hypothesized in the design of the ongoing Nix-TB clinical study that patients with pulmonary XDR-
TB may have relapse-free cure after as little as 6 months’ treatment with the B-Pa-L regimen. 
Therefore, since 2015, the TB Alliance has sponsored a study with a 6 month treatment duration 
with the B-Pa-L regimen in participants with XDR-TB or MDR TB not responsive to or intolerant 
to therapy (the Nix-TB study).(1) 
A key advantage of this regimen over standard of care for MDR-TB as well as XDR-TB is that this 
is an all-oral daily regimen for 6 months of treatment in comparison to standard regimens of 6-8 
drugs over 9-30 months of treatment that includes daily injections for a minimum of 6 months. 
The NC-007 trial takes this regimen into a randomized Phase 3 trial to optimize the dosing scheme 
for linezolid and the benefit relative to risk, and to expand the patient population to include 
individuals with pre-XDR TB. 
The information presented below first details the trial rationale, then key preclinical information 
and human efficacy and safety information for each of the drugs in the regimen and then presents 
preclinical and clinical data to support the combination of these drugs in a regimen to treat patients 
with XDR, pre-XDR and MDR treatment intolerant/failure-TB. 
2.1 Trial Rationale 
2.1.1 Trial Design Rationale 
This trial will provide a regimen containing 3 drugs against which there is no expected MTB 
resistance in the community for patients with limited treatment options while simultaneously 
gathering important efficacy and safety data on a regimen that could potentially treat all strains of 
MTB. Data from previous trials shows that the combination of B-Pa is well tolerated and has the 
potential to shorten treatment in patients who are susceptible to the drugs. The ongoing Nix-TB 
trial has shown that the B-Pa-L regimen has manageable toxicity and encouraging efficacy as an 
all oral 6 month regimen administered to patients with XDR-TB. This current trial will provide 
important information on the toxicity and efficacy of the regimen under alternate doses and 
durations of linezolid to optimize the dosing scheme for the best benefit to risk balance. 
2.1.2 Trial Drug Rationale 
2.1.2.1 Bedaquiline  
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this study bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 18 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 study that administered bedaquiline 200 mg daily over 8 weeks, and 
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by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
The NC-005 study allows the efficacy and safety to be compared for treatment arms that dosed 
bedaquiline at the currently registered dose and at 200 mg daily for the 8 weeks of the trial.  Briefly, 
Study NC-005 evaluated a regimen in patients with drug susceptible pulmonary TB given 
bedaquiline with pretomanid and pyrazinamide over an 8 week period.  One arm was to enroll 60 
patients who were to be given this regimen with bedaquiline dosed as approved for marketing 
(referred to as the B (loading dose/t.i.w.) PaZ arm), and another 60 patients were to be enrolled 
who would be given the regimen with bedaquiline dosed at 200 mg daily (referred to as the B 
(200mg) PaZ arm).  Another group of patients with DS TB were randomized to treatment with 
standard HRZE therapy.  Patients with MDR-TB were given the regimen with bedaquiline dosed 
at 200 mg daily in addition to moxifloxacin (referred to as the B (200 mg) MPaZ MDR-TB arm).  
The primary endpoint was The Bactericidal Activity (BATTP (0‐56)) as determined by the rate of 
change in time to sputum culture positivity (TTP) over 8 weeks of treatment in the Mycobacterial 
Growth Indicator Tube system, represented by the model‐fitted log (TTP) results as calculated by 
the regression of the observed log (TTP) results over time.  The assessments of safety and 
tolerability included the incidence of Treatment Emergent Adverse Events (TEAEs) presented by 
severity (DMID Grade), by drug relatedness and seriousness, and for those leading to early 
withdrawal and leading to death, by group.  In addition, quantitative and qualitative clinical 
laboratory result measurements were evaluated, including group summaries of observed values 
and changes from baseline.  Pharmacokinetics for all participants included pre-dose samples on 
9 days during and one day following dosing with the regimen.  Fifteen PK Sub‐study participants 
in each treatment arm had in addition intense PK sampling on Days 14 and 56. 
Efficacy of bedaquiline 200 mg daily dose vs the marketed dosing scheme over 8 weeks 
In the efficacy analysis of the NC-005 trial, based on liquid media collected from overnight sputum 
samples, the B(200 mg)MPaZ MDR-TB treatment group showed the highest bactericidal activity 
over the 8-week treatment period, followed by that of B(200 mg)PaZ, B(loading dose/t.i.w.)PaZ 
and then HRZE. It appears clear that the daily dosing regimen for bedaquiline provided at least 
as good a result in the primary efficacy analysis as the registered dosing scheme for bedaquiline.   
Safety of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
Adverse events, including serious adverse events and Grade III/IV adverse events were similar 
among groups.  In particular, the mean change from baseline in the corrected QTc intervals was 
numerically less in the participants given bedaquiline daily than in the participants given 
bedaquiline with the labelled dosing scheme.  Measures of potential hepatic toxicity, including 
participants with greater than 3 fold or 10 fold elevations in aminotransferase levels, were 
numerically greater in participants given the labelled dosing scheme than subjects given daily 
doses of bedaquiline.   
Pharmacokinetics of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
A population PK model published by McLeay in 2014 was used with PK data from Study NC-005 
to simulate the expected bedaquiline exposures when dosed at 200 mg daily followed by 100 mg 
daily for the remainder of the study in comparison to the labelled dosing scheme with bedaquiline 
administered for 6 months.(14)  The key findings from the simulations of the proposed dosing 
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scheme for NC-007 of bedaquiline administered 200 mg daily over 8 weeks followed by 100 mg 
daily for an additional 16 weeks are: 
• 
The exposures of the proposed dosing scheme (Cmax, mean or trough) are not expected to exceed 
the exposures associated with the labelled scheme on Day 14 at the end of the 400 mg daily 
dose.  With the labelled dosing scheme, the highest exposures are on Day 14 at the end of 
the 400 mg daily loading dose. 
• 
The average daily exposures with the proposed dosing scheme over 6 months are within (or 
not substantially different from) the range of exposures over 6 months of the labelled dosing 
scheme. 
• 
The cumulative exposure, in terms of AUC over time, is similar between the proposed dosing 
scheme and the labelled scheme 
2.1.3 Pretomanid 
Pretomanid has demonstrated good microbicidal activity at the 200mg daily dose as monotherapy 
in studies PA-824-CL-007 and PA-824-CL-010, in combination with either bedaquiline or 
pyrazinamide over 14 days in the early bacteriocidal activity (EBA) Study NC-001-(B-M-Pa-Z), in 
combination with either bedaquiline and/or pyrazinamide and/or clofazimine over 14 days in the 
EBA Study NC-003-(B-C-Pa-Z), and in combination with bedaquiline and linezolid over 6 months 
in the Nix-TB study.  In the EBA Study PA-824-CL-010 the 100mg dose demonstrated similar 
microbicidal activity to the 150 and the 200mg daily dose over 14 days. The Phase 2 trial NC-
002-(M-Pa-Z) evaluated this regimen at doses of pretomanid of both 100 mg and 200 mg relative 
to the HRZE control.   In this trial the efficacy results were similar between participants treated 
with 100 mg/day and 200 mg/day of pretomanid in the regimen, although for the primary endpoint, 
reduction in colony forming units of MTB from sputum, only the 200 mg/day dose group was 
statistically significantly better than the group randomized to standard HRZE therapy.  Safety was 
also similar between the groups, although the 200 mg/day group had more grade 2 adverse 
events than either the 100 mg/day group or the HRZE control group.  Because sterilizing relapse-
free cure of TB in patients with XDR-TB may ultimately require a regimen with higher drug 
exposures, the 200mg dose was chosen for evaluation in the Nix-TB study of the B-Pa-L regimen.  
The manageable toxicity of the regimen and very encouraging efficacy in the Nix-TB trial support 
taking the 200 mg dose of pretomanid forward in the NC-007 trial. 
2.1.4 Linezolid 
The standard dose of linezolid for a multitude of indications is 400mg or 600mg BID.  Doses of 
linezolid used to treat pulmonary TB in reported observational trials and case series range from 
300 mg to 1200 mg per day over periods of up to 20 months of treatment.  While the development 
of adverse events is generally higher with higher doses, the adverse events often ameliorate with 
a reduction of the dose or discontinuation of drug for several weeks and then reintroduction at a 
lower dose.  No controlled trials have clearly identified differences in anti-TB effect across a range 
of doses over long term treatment of TB. 
In this trial, each arm will vary the linezolid dosing to identify the optimal ratio of efficacy to adverse 
events as noted below. The 4 arms, to which participants will be randomly assigned in a blinded 
manner, are: 
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• 
Linezolid 1200 mg orally once daily for 26 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
• 
Linezolid 1200 mg orally once daily for the first 9 weeks, with the ability to interrupt or 
reduce the dose if needed based on toxicity.  
• 
Linezolid 600 mg orally once daily for 26 weeks, with the ability to interrupt or reduce the 
dose if needed based on toxicity. 
• 
Linezolid 600 mg orally once daily for the first 9 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
These dosing schemes for linezolid are chosen based on clinical experience in the Nix-TB trial, 
the company’s linezolid early bactericidal activity (EBA) study findings in the Lin CL-001 study, 
and preclinical data in the mouse model of infection. While the EBA study showed that a modestly 
greater bactericidal effect over 14 days at the highest 1200 mg daily dose (see further details 
below in Section 2.2.3), this dose appears to be associated in the Nix-TB trial and in published 
literature with a greater incidence of unwanted neuropathic and myelosuppressive effects than 
the 600 mg daily dose. While a full 6 months of linezolid therapy in the regimen may give greater 
culture conversion and avoid relapse, the mouse model found that linezolid dosing of only 1 or 2 
months, when B and Pa were given continuously for a total of 3 months, maximized relapse-free 
cure; in other words, similar to pyrazinamide in the present first line HRZE therapy, more than 2 
months of linezolid when combined with B and Pa does not increase relapse-free cure in the 
mouse model. Thus, the 4 treatment arms in this study will give randomized comparative 
information about the optimal duration and dose of linezolid in the regimen relative to efficacy and 
toxicity.  
The decision to give linezolid as a single daily dose is based on the results of the linezolid EBA 
study that showed over 14 days that similar bactericidal activity was noted whether the drug was 
given as a single daily dose or divided in to 2 doses. A single daily dose will ultimately enhance 
patient adherence and will reduce the total time the drug concentration is greater than the 
calculated concentration associated with mitochondrial toxicity (which we hypothesize to be the 
likely mechanism for the toxicities of peripheral neuropathy and myelosuppression). 
2.2 Agents to be Studied 
2.2.1 Bedaquiline 
Bedaquiline is being developed as part of combination therapies for pulmonary TB due to MDR-
TB and approved in 2012 in the USA under the provisions of accelerated approval regulations. 
Bedaquiline received conditional Marketing Authorization in the EU in 2014 and is approved in 
over 40 countries (EU countries counted individually). The approved indication may vary per 
country. Bedaquiline is marketed under the trade name SIRTUROTM.  Bedaquiline has a novel 
mechanism of action as it specifically inhibits mycobacterial ATP synthase, an enzyme that is 
essential for the generation of energy in MTB The inhibition of ATP synthase leads to bactericidal 
effects for both replicating and non-replicating tubercle bacilli. 
In the placebo-controlled Phase 2b study C208 conducted in newly-diagnosed patients with 
sputum smear-positive pulmonary MDR-TB (including pre-XDR-TB), the addition of bedaquiline 
to a preferred background regimen of MDR-TB treatment resulted in a decreased time to culture 
conversion and improved culture conversion rates compared to placebo. Median time to culture 
conversion according to the primary analysis method was 83 days for the bedaquiline group 
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compared to 125 days for the placebo group (p<0.0001; hazard ratio, 95% CI: 2.44 [1.57; 3.80]). 
The proportion of patients in the mITT population with sputum culture conversion after 24 weeks 
of treatment with bedaquiline or placebo in combination with background regimen (with patients 
who discontinued considered as non-responders), was 52/66 (78.8%) in the bedaquiline group 
and 38/66 (57.6%) in the placebo group. Durability of response seen in the bedaquiline treatment 
group was supported by the results at Week 120. The proportion of responders (with patients who 
discontinued considered as non-responders) at Week 120 was 41/66 (62.1%) in the bedaquiline 
group and 29/66 (43.9%) in the placebo group. 
In the Phase 2b, open-label study C209, conducted in 233 patients with sputum smear positive 
pulmonary MDR-TB, the median time to sputum culture conversion excluding patients with DS-TB 
and those that did not have a positive sputum culture at screening and/or baseline (mITT; 205 
patients), was 57 days. At Week 24, 163 of 205 (79.5%) patients responded to bedaquiline 
treatment as determined by sputum culture conversion rates. Conversion rates at Week 24 were 
highest (87.1%; 81/93) in patients with MDR-TB resistant to only RMP and INH, 77.3% (34/44) in 
pre-XDR-TB patients and lowest (54.1%; 20/37) in XDR-TB patients. 
The average terminal half-life of bedaquiline, is about 5.5 months. After reaching Cmax, however, 
there is initially a fairly rapid reduction in plasma bedaquiline concentrations over the dosing 
interval (with an estimated half-life of about 13 hours). Four weeks after ceasing bedaquiline 
intake, the mean bedaquiline concentrations were reduced by approximately 40% compared to 
the end of the bedaquiline treatment period in the C208 study. Administration of bedaquiline with 
food increased the relative bioavailability by about 2-fold compared to administration under fasted 
conditions. It is therefore recommended to take bedaquiline with food to enhance its oral 
bioavailability. 
CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline. Drug-
drug interaction (DDI) studies have showed reduced exposure to bedaquiline during combination 
with a strong or moderate inducer of CYP3A4 metabolism (i.e., rifampicin) and increased 
exposure during combination with a strong or moderate inhibitor of CYP3A4 metabolism (i.e., 
ketoconazole). Potential drug interactions with anti-retroviral drugs have been evaluated in three 
studies.  In an interaction study of single-dose bedaquiline and multiple-dose Lopinavir/ritonavir, 
exposure (AUC) to bedaquiline was increased by 22% (90% CI: 11-34). Co-administration of 
single-dose bedaquiline and multiple-dose nevaripine did not result in clinically relevant changes 
in the exposure to bedaquiline. Co-administration of a single dose of bedaquiline and multiple-
dose efavirenz (EFV) resulted in approximately a 20% decrease in the AUCinf of bedaquiline with 
no alteration in the Cmax.  Modeling based on the data from this DDI study predicts average steady-
state concentrations of bedaquiline and M2 to be reduced by 52% with chronic co-administration 
of bedaquiline and EFV.(5)  
Safety of Bedaquiline 
The Investigator’s Brochure for bedaquiline provides detailed safety information.5 
Data were used from 14 completed clinical studies to identify Adverse Drug Reactions (ADRs) 
according to the ICH guideline entitled, E6: Good Clinical Practice, Consolidated Guideline (ICH, 
1996): “…all noxious and unintended responses to a medicinal product related to any dose should 
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be considered adverse drug reactions. The phrase “responses to a medicinal product” means that 
a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out." 
The ADRs were identified from the pooled safety database of reported AEs in the Phase 2b clinical 
studies with bedaquiline, based upon a systematic well-documented approach and are presented 
for study C208 below in Table 1.  None of the ADRs reported in the controlled studies during the 
Investigational Treatment phase were considered serious. 
Table 1: 
ADRs C208 Stage 1 and Stage 2 
Adverse Drug Reactions (ADRs) in the Controlled Studies (C208 Stage 1 and Stage 2)  
During the Investigational Treatment Phase 
ADR (Grouped term), n (%) 
Frequency 
Any BDQ 
N=102 
Any Placebo 
N=105 
Nervous system disorders 
Headache 
Very Common 
24 (23.5) 
12 (11.4) 
Dizziness 
Very Common 
13 (12.7) 
12 (11.4) 
Cardiac disorders 
ECG QT prolonged 
Common 
3 (2.9) 
4 (3.8) 
Gastrointestinal disorders 
Nausea 
Very Common 
36 (35.3) 
27 (25.7) 
Vomiting 
Very Common 
21 (20.6) 
24 (22.9) 
Diarrhea 
Common 
6 (5.9) 
12 (11.4) 
Hepatobiliary disorders 
Transaminases increaseda 
Common 
7 (6.9) 
1 (1.0) 
Musculoskeletal and connective tissue disorders 
Arthralgia 
Very Common 
30 (29.4) 
21 (20.0) 
Myalgia 
Common 
6 (5.9) 
7 (6.7) 
 
a. 
Different AE preferred terms (i.e., transaminases increased, aspartate aminotransferase [AST] increased, 
alanine aminotransferase [ALT] increased, hepatic enzyme increased, and hepatic function abnormal) contribute 
to this ADR, while for the other ADRs the ADR is the preferred term. 
 
Of note, 13 deaths occurred in the C208 Stage 2 study: 10 subjects (12.7%) in the bedaquiline 
group and 3 subjects (3.7%) in the placebo group experienced an SAE leading to death. One 
death (alcohol poisoning) occurred during administration of bedaquiline. The median time to death 
for the remaining 9 subjects was 344 days after last intake of bedaquiline. One of the 10 deaths 
in the bedaquiline treatment group and 1 of the 3 deaths in the placebo group occurred after the 
Week 120 window. In the bedaquiline group, the most common cause of death as reported by the 
investigator was TB or TB-related illness (5 subjects). For all deaths due to TB, the subject’s last 
microbiological outcome was either failure to convert or relapse. The causes of death in the 
remaining bedaquiline subjects varied. The investigator considered all the SAEs leading to death 
not or doubtfully related to bedaquiline/placebo. The imbalance in deaths is unexplained. In 
addition, no discernible pattern between death and sputum culture conversion, relapse, sensitivity 
to other drugs used to treat TB, HIV status, or severity of disease was observed.  
During clinical studies with bedaquiline a prolongation of QTc interval on the ECG was observed.  
Consequently, bedaquiline treatment initiation is not recommended in patients with, personal or 
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family history of prolonged QT intervals, or additional risk factors for Torsades de Pointes. 
Detailed criteria are noted in Section 5.2, Exclusion Criteria. 
Increases in transaminases were seen in clinical studies during administration of bedaquiline in 
combination with a background regimen. Based on a review confirmed by an external 
hepatologist, it was concluded that bedaquiline has a signal for liver injury manifested by 
increases in AST and to a lesser extent ALT. Transaminase elevations are not unexpected given 
the number of other hepatotoxic drugs in the background regimens in clinical trials based on the 
publication by Keshavjee, which describes a 16.5% incidence of hepatotoxicity during MDR-TB 
treatment. (7) 
2.2.2 Pretomanid 
As detailed in the Investigator’s Brochure(6), pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti-
tuberculosis activity and a unique mechanism of action(35). Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB(10), and in vivo activity in a mouse model of tuberculosis(10, 
35).  
2.2.2.1 Pharmacology 
2.2.2.1.1 Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro studies demonstrated that pretomanid was active against actively growing 
drug-sensitive and drug-resistant MTB strains as well as against non-replicating MTB The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be similar to the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 
0.25 µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against 
drug-resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity. (6) 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO), (33) although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling studies also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.(12,13) 
2.2.2.1.2 Key Non-Clinical Studies of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse studies.(18,19,20,36,40) In a mouse model of established TB, 
the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 
22 days after inhalation infection with H37Rv MTB is shown in Figure 1. In this model, the 
minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the 
development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum 
bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony forming units 
(CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 
100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
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Figure 1: 
Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
2.2.2.2 Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology studies, 
in repeat-dose toxicity studies in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity studies, and in fertility and teratology studies in rats and rabbits.  
In the repeat-dose toxicity studies, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week study in rats, 50 mg/kg/day in a 13-week study in monkeys and 
<25 mg/kg/day (based on findings of thickening of the GI tract at all doses) in a 9-month study in 
monkeys. The major findings in safety and toxicity studies are listed below in Table 2 and are 
detailed in the Investigator’s Brochure.(6) 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development studies indicate no effects of PA-824 on fetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
8 
7 
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16, 
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5, 
.2 
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4 
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u 
81 
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l 
MIBD 
[:::---------------1-:::::} 
1 
O· 
Baseli n e 
0 
6. :25 
1:2 .5 
:25 
50 
100 
:200 
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toxicology studies and a Segment I fertility study. In this fertility study, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed study in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week study in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
study in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the electrocardiogram (ECG) as a prolonged QT interval corrected for heart 
rate (QTc). Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. 
Following a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation 
ranged from 21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-
administration of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog 
did not result in any greater effect on the QT interval than with either agent alone. After 
repeated daily doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
2.2.2.3 Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 studies with healthy adult 
male and female subjects, with 163 subjects receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 studies sponsored by the NIH included a Thorough QT study and a study 
of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the 
studies are in the Investigator’s Brochure. 
2.2.2.3.1 Pharmacokinetics 
Several Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200 mg dose that increases total 
exposure by 88%. Interaction studies with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Study CL-006 was an open-label, fixed-sequence drug-drug 
interaction study to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs metabolised 
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by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had 
minimal effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by 
measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax), area under the 
curve to the last available time point (AUC0-t), and area under the curve extrapolated to infinity 
(AUC0-inf). The Cmax and AUC values for midazolam after co-administration with pretomanid were 
approximately 85% of those observed after treatment with midazolam alone. Furthermore, 
midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and half-life (t1/2) 
values were not different in the presence or absence of pretomanid. Therefore, 14 days’ dosing 
with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH sponsored this 
drug interaction study with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy subjects. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for the maximum concentration (Cmax) was 0.71, the GMR for the 24-hour area 
under the time-concentration curve (AUC0-24h) was 0.65, and the GMR for the trough concentration 
(Cmin) was 0.54. Concentrations of EFV when given with pretomanid versus given alone were 
similar. Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg once daily for 
7 days, then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 days, then LPV/r 
+ pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + pretomanid, washout, then 
pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid alone from 16 PK-
evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and for Cmin was 0.78. 
In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg for 7 days, then 
pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin versus 
pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and Cmin were 
0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for maximum concentration (Cmax), area under the concentration-time curve (AUC0-
24h), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz; 13%, 17%, 
and 21% with LPV/r; and 53%, 66%, and 85% with rifampin, respectively. 
2.2.2.3.2 Pretomanid Clinical Efficacy 
The first two Phase 2 studies to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first study (CL-007) demonstrated 
good EBA, but all doses in this study (200 to 1200 mg/day) had the same activity. The second 
study (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA 
was seen at a dose of 100 mg/day over 14 days (4) (Figure 2). 
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Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010 
 
CFU = colony-forming unit; PA-824 = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Studies of Pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below in Section 2.3.2.  
2.2.2.3.3 Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure(6) provides detailed safety information. 
Across the 16 clinical studies with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy subjects across the 10 Phase 1 studies and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
studies.  Among the 289 healthy Subjects, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 1200 
mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical studies completed to date indicates pretomanid 
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
I : 
· 
I 
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is well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these studies, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical studies completed to date as likely caused by 
pretomanid is blood creatinine increased.  A study of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close surveillance 
and careful management of participants who have elevations in aminotransferases and/or 
bilirubin. Serious liver injury, including death in 3 participants taking a combination of 
pretomanid, pyrazinamide and moxifloxacin, has occurred during clinical studies and the risk 
of liver injury may be higher for participants taking a combination of PA-824 and pyrazinamide 
than it is for the standard HRZE treatment. Therefore, close monitoring of liver function is 
required for participants who are administered PA-824, especially when combined with 
pyrazinamide.  Administration of the regimen of PaMZ has been associated with death in 3 
participants associated with hepatic injury. Furthermore, the HRZE control regimen, and both 
pyrazinamide and moxifloxacin, has been associated with drug induced liver injury and in rare 
cases hepatic necrosis.  Consequently, hepatic safety will be under close surveillance in all 
clinical studies. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human studies that involve exposure to pretomanid longer than 
14 days.  These examinations will be conducted at baseline, near the end of the dosing period 
and 3 months after the end of study drug exposure.  These examinations are to follow up on 
the finding of cataracts in rats exposed to pretomanid in clinical studies. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple time 
points during the study.  Although the Thorough QT Study in healthy subjects found that 
pretomanid did not increase corrected QT intervals in a clinically meaningful way and did not 
add to the known effect of moxifloxacin, the ECGs will be carefully monitored during Phase 3.  
All ECGs will be interpreted and conduction intervals will be confirmed by a central cardiology 
service. 
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• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Study NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology studies have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 study for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology studies found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 studies have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 studies) or FSH values (3 studies) at baseline and after daily 
dosing of regimens containing pretomanid in various combinations with moxifloxacin, 
pyrazinamide and bedaquiline.  A review of data from the 3 studies by an independent 
reproductive endocrine expert concluded that, based on the hormone evaluations to date, there 
is no evidence that PA-824 is a testicular toxicant in men at the doses and exposure times 
evaluated. 
2.2.3 Linezolid 
Linezolid is a synthetic antibacterial agent of the oxazolidanone class approved in many countries 
around the world for drug-resistant, gram-positive bacterial infections, including gram positive 
organisms such as Staphylococcus aureus, coagulase negative Staphlococcus and Enterococcal 
infections.  The recommended dose for these infections is 600 mg twice daily for up to 28 days of 
therapy.(23,24,26) Antimicrobial effects likely come from inhibition of protein synthesis in the 
ribosomes of the infecting organism.(8)  Resistance of MTB to linezolid is rare, as this drug has 
not been widely used to treat tuberculosis.  In a recent study using linezolid to treat patients with 
XDR-TB in Korea, none of 41 patients had resistance to linezolid at baseline.(9) 
Preclinical in vitro data shows linezolid is active against MTB, including MDR strains with minimum 
inhibitory concentrations (MICs) that range from 0.125-1 μg/mL.(38)  Recent studies of the 
bactericidal and sterilizing activity of linezolid in a mouse model of MTB infection have 
demonstrated linezolid alone causes marked reductions in lung colony forming units (CFUs) from 
mice following 1-3 months of therapy.(36) (Table 3, below) 
Table 3: 
Murine Lung CFU counts during Treatment with Linezolid 
Monotherapy versus Standard Therapy 
 
Mean lung log10 CFU count (± S.D.) at: 
Regimen 
D0 
Month 1 
Month 2 
Month 3 
Untreated 
6.17 + 
0.27 
6.47 + 0.06 
 
 
2RHZ/4R
H 
 
3.47 + 0.37 
1.59 + 0.25 
0.50 + 0.51 
L 
 
4.97 + 0.26 
 
 
 
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In recent years linezolid has been used to treat patients with MDR(28) and XDR-TB, although there 
have been no fully controlled trials of linezolid in a regimen for this indication.  The World Health 
Organization management guidelines place linezolid in Group 5 (“Agents with unclear role in 
treatment of drug resistant-TB”) in their groups of drugs to treat MDR-TB.(41) Over the past 10 
years small retrospective observational studies have reported good results when linezolid has 
been added to failing regimens for patients with MDR-TB.(9, 27, 34) The most compelling recent 
evidence linezolid may be of benefit to patients with XDR-TB was reported by Lee and colleagues 
from a study in S. Korea.(9)  Forty-one patients who had sputum culture–positive XDR-TB and who 
had not had a response to any available chemotherapeutic option during the previous 6 months 
were randomized to start linezolid at 600 mg daily or to delay therapy with linezolid at 600 mg 
daily for 2 months without changing their failing background regimen.  After confirmed sputum-
smear conversion, or at 4 months, patients underwent a second randomization to continued 
linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 
months.  Thirty four of 39 (87%) of the patients had a negative sputum culture within 6 months 
after linezolid had been added to their drug regimen.  As of the cutoff date prior to publication, of 
the 38 patients who received linezolid, 17 were still receiving the treatment per protocol, and 13 
had completed treatment, including 6 with no relapse during the treatment period, 4 with no 
relapse at the 6-month follow-up, and 3 with no relapse at the 12-month follow-up (end of study).  
While the standard dose of linezolid for short term use for severe bacterial infections is 600 mg 
bid, some clinicians and clinical trials using linezolid as Group 5 therapy to treat TB use only 300 
mg or 600 mg daily due to concerns about toxicity developing when used over a period of months 
(see below for a review of linezolid toxicity). (9)  However, there are no data to indicate what dose 
of linezolid is required or optimal to effectively treat TB infection.  Consequently, TB Alliance has 
recently conducted and completed an Early Bactericidal Activity trial to evaluate the use of 
linezolid over 14 days in patients with newly diagnosed DS Pulmonary TB in dosing schedules 
including 300 mg daily, 300 mg bid, 600 mg daily, 600 mg bid, 1200 mg daily, and HRZE at 
standard doses daily.  Preliminary unpublished in-house results using Bayesian mixed effects 
modelling have noted that there is a bactericidal effect of linezolid over 14 days that is substantial, 
but less than for the full HRZE regimen.  There is little difference between daily or twice daily 
dosing of the same total daily dose of drug, and there is a dose-response relationship between 
total daily dose and daily reductions in either total CFU counts on solid culture or increases in 
Time to Positivity in liquid culture (a decreased load of MTB is associated with an increase in Time 
to Positivity).  Point estimates of the log of the daily increase in Time to Positivity over 14 days 
ranged from 2.278 for Linezolid 300 mg QD to 4.446 for linezolid 1200 mg QD, with the estimate 
of 6.860 for HRZE for reference. 
 
 
 
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Figure 3:  
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin 
CL-001 
Bayesian Nonlinear Mixed Effects Regression Model: Posterior Estimates and 95% 
Bayesian Confidence Intervals 
 
HRZE = isoniazid, rifampin, pyrazinamide, and ethambutol 
2.2.3.1 Linezolid Clinical Safety 
Linezolid is currently marketed globally for a variety of acute infectious diseases and has been 
studied for the treatment of XDR-TB in several recent trials.(3,9) The following list of known and 
potential risks is based on the warnings and precautions and adverse reactions sections of the 
current package label.(23,24,26)  Of note, the approved indication for linezolid is for administration 
up to 28 days. 
 Warnings and Precautions 
• 
Linezolid should not be used in patients taking any medicinal product which inhibits 
monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking 
any such product. 
• 
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) 
has been reported in patients receiving linezolid. In cases where the outcome is known, 
when linezolid was discontinued, the affected hematologic parameters have risen toward 
pretreatment levels. Complete blood counts should be monitored weekly in patients who 
receive linezolid, particularly in those who receive linezolid for longer than two weeks, 
those with pre-existing myelosuppression, those receiving concomitant drugs that produce 
bone marrow suppression or those with a chronic infection who have received previous or 
concomitant antibiotic therapy.  
• 
Lactic acidosis has been reported with the use of linezolid. In reported cases, patients 
experienced repeated episodes of nausea and vomiting. Patients who develop recurrent 
9 
8 
7 
6 
5 
4 
3 
2 
I 
I 
l l 
I 
I 
Treatment Group: 
• 
Linezolid 300 mg OD m 
Linezol d 300 mg BID IHl 
Linezolid 600 mg OD 
eet. 
Lirezolid 600 mg BID 
€e& Linezolid 1200 mg OD 
(:€0 
HRZE 
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nausea or vomiting, unexplained acidosis, or low bicarbonate level while receiving 
linezolid should receive immediate medical evaluation. 
• 
Spontaneous reports of serotonin syndrome associated with the co-administration of 
linezolid and serotonergic agents, including antidepressants such as selective serotonin 
reuptake inhibitors (SSRIs), have been reported.  Where administration of linezolid and 
concomitant serotonergic agents is clinically appropriate, patients should be closely 
observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, 
hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians 
should consider discontinuation of either one or both agents. If the concomitant 
serotonergic agent is withdrawn, discontinuation symptoms can be observed (see 
package insert of the specified agent(s) for a description of the associated discontinuation 
symptoms).  
• 
Peripheral and optic neuropathy has been reported in patients treated with linezolid, 
primarily those patients treated for longer than the maximum recommended duration of 28 
days. In cases of optic neuropathy that progressed to loss of vision, patients were treated 
for extended periods beyond the maximum recommended duration. Visual blurring has 
been reported in some patients treated with linezolid for less than 28 days. If patients 
experience symptoms of visual impairment, such as changes in visual acuity, changes in 
color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is 
recommended. Visual function should be monitored in all patients taking linezolid for 
extended periods and in all patients reporting new visual symptoms regardless of length 
of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of 
linezolid in these patients should be weighed against the potential risks.  Additional 
information on the neuropathies reported in recent studies of linezolid administered over 
prolonged periods to patients with TB infection is presented above in Section 2.2.3. 
• 
Convulsions have been reported in patients when treated with linezolid. In some of these 
cases, a history of seizures or risk factors for seizures was reported.  
• 
Postmarketing cases of symptomatic hypoglycemia have been reported in patients with 
diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, 
a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with 
hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. 
While a causal relationship between linezolid and hypoglycemia has not been established, 
diabetic patients should be cautioned of potential hypoglycemic reactions when treated 
with linezolid. 
In addition, the linezolid product label notes that there was an excess of abnormal liver function 
tests in comparator-controlled trials.  These abnormalities were noted in 0.4% of linezolid treated 
patients in trials of skin and skin structure infections vs in 0.2% of clarithromycin treated patients, 
and in 1.6% of patients treated with linezolid versus 0.8% of patients with other treatments in trials 
of all other infections. 
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Adverse events of linezolid long term therapy for Tuberculosis have been described in several 
literature reports. The most complete review is a meta-analysis by Cox which noted the proportion 
of adverse events necessitating treatment discontinuation was significantly different by dose: 
29.49% (95%CI 3.24–55.74) for ⩽600 mg daily vs. 60.75% (95%CI 42.69–78.81) for >600 mg 
daily (P = 0.05). (3) 
In a trial reported by Lee et al in S Korea(9), seven of 41 participants had myelosuppression, 
including anemia and neutropenia, primarily within the first 5 months, and only one participant 
withdrew due to anemia.  Six had clinically significant myelosuppression:  5 in 0-4 months and 1 
in 4-8 months, with 0 in 8-12 months. 
Peripheral and Optic Neuropathy:  
The linezolid product label notes these adverse events have been “ reported in patients, primarily 
those patients treated for longer than the maximum recommended duration of 28 days.  In cases 
of optic neuropathy that progressed to loss of vision, patients were treated for extended periods 
beyond the maximum recommended duration.  Visual function should be monitored in all patients 
taking ZVYOX for extended periods (>3 months) and in all patients reporting new visual 
symptoms, regardless of length of therapy.(26) 
In Lee, NEJM, 2012(9), the publication’s Supplemental Table 3 notes that 21 patients had clinically 
significant peripheral neuropathy spread over 12 months:  5 in months 0-4, 10 in months 4-8 and 
5 in months 8-12 (time of onset not noted for one).  Participants who developed any peripheral 
neuropathy had their dosing of linezolid interrupted, generally for several weeks, and then 
resumed at the lower dose of 300 mg/day (C. Barry, personal communication).  None of the 
participants withdrew from the study based on peripheral neuropathies.  At baseline, patients 
received visual acuity testing, contrast sensitivity and color vision tests. Seven cases were 
observed as having potential effects on vision; only two of 38 patients withdrew from study due to 
optic neuropathy.  For clinically significant optic neuropathy, one had this at 0-4 months, 2 at 4-8 
months and 3 at months 8-12.  Except for the 2 participants who withdrew from the study, the 
others resumed linezolid at the 300 mg dose after a hiatus of several weeks of treatment and 
completed the study with resolution of their visual acuity changes (C. Barry, personal 
communication). 
In the Schecter California Department of Health (DOH) review(32), peripheral neuropathy 
developed in 5 of 30 patients (no standardized monitoring), but only one withdrew from linezolid 
therapy.  One patient developed visual loss secondary to optic neuropathy after 10 months of 
linezolid therapy, but vision returned to normal 3-4 weeks after discontinuation. 
In Park, 2006(27), two patients of eight in the case series developed optic neuropathy after 8-9 
month and had linezolid discontinued; these patients also had peripheral neuropathy. After 
linezolid treatment was stopped, the optic neuropathy fully resolved after 2-3 months.  A total of 
4 patients developed peripheral neuropathy at 4, 5, 8, 11 months; in the patients with optic 
neuropathy who stopped treatment, the peripheral neuropathic symptoms continued or improved 
only marginally. 
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In Singla, 2012(34), two of 29 patients treated with linezolid, 600 mg daily over 12 months, stopped 
the drug because of peripheral neuritis (one patient) and optic neuritis (one patient).  The time 
course of these adverse events was not noted. 
2.3 Regimens to be Studied 
The regimen included in this study (B-Pa-L) has been selected based on the performance of the 
regimen in non-clinical pharmacology studies and on the combination of bedaquiline and 
pretomanid with other drugs in clinical studies NC-001 and NC-003.  In addition, improved 
treatment outcomes in XDR patients with the addition of linezolid to existing therapy provide 
support for combining linezolid with other drugs that have no pre-existing resistance.  Preliminary 
results from the ongoing Nix-TB clinical study demonstrate the encouraging potential of this 
regimen. 
This regimen has the potential to treat drug resistant strains of tuberculosis. This is an oral 
regimen, removing the need for injectables as part of drug resistant treatment, and is also 
projected to be markedly less expensive than current XDR-TB therapy. Treatment duration is 
anticipated to be shorter than current regimens for drug resistant TB, based on findings in mouse 
models of infection and the fact that all participants will be treated with three active drugs against 
TB for which there is no expected resistance.  
The key data supporting the use of the B-L-Pa regimen are described below. 
2.3.1 Non-Clinical Studies 
In the murine model of TB, addition of bedaquiline to HRZ results in accelerated clearance of MTB 
(5,36) when compared to HRZ alone. While the combination of bedaquiline and pretomanid in the 
murine model of TB in initial studies appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ(15) and in a subsequent study it was more 
active in the mouse model than HRZ.(16) Thus a novel regimen with bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance.   
Recent studies of the bactericidal and sterilising activity of linezolid in an animal model where 
mice were given high dose aerosol MTB infection have demonstrated that linezolid alone and in 
combination with bedaquiline and pretomanid causes marked reductions in lung CFUs from mice 
following 1 to 3 months of therapy (Table 4 below). Additionally, all mice treated daily with 
bedaquiline, pretomanid and linezolid (B-L-Pa) were cured of the infection after 3 months of 
therapy as evidenced by no MTB cultured from lungs when mice were sacrificed 3 months after 
the completion of therapy that lasted 3 months or more (Table 4, below). This is in contrast to the 
5-6 months required in previous studies to cure all mice when treated with the standard of care 
isoniazid, rifampicin and pyrazinamide (HRZ; note that typically ethambutol is not used in the 
mouse model of infection). Additional mouse studies were performed to determine whether 
shorter durations of linezolid, with continuation of the other drugs, would result in relapse-free 
cure in the mouse (Table 4 below). Treatment with linezolid for only the first 4 to 8 weeks of a 
3-month treatment also resulted in relapse-free cure when lungs from the mice were cultured 
3 months after the completion of therapy.(37) 
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Table 4: 
Murine Relapse Data 
Impact of Linezolid Treatment Duration on Lung Colony Forming Unit Counts 
Assessed during Treatment and Proportion of Mice Relapsing after Treatment 
Completion 
 
Proportion of mice relapsing after treatment for: 
Regimen 
2 months 
3 months 
2RHZ/RH* 
 
8/14 
(57%) 
BPa 
 
3/14 
(21%) 
3BPaL ** 
6/15 
(40%) 
0/15#† 
(0%) 
2BPaL/1BPa*** 
 
0/15#† 
(0%) 
1BPaL/2BPa 
9/15 
(60%) 
0/15#† 
(0%) 
#p = 0.11 vs. BPa; †p≤ 0.001 vs. RHZ 
*2RHZ/RH means 2 months on the full regimen and a third month on only RH 
**3BPaL means 3 months on the full regimen 
***2BPaL/1BPa means 2 months on the full regimen and a third month on only BPa 
****1BPaL/2Bpa means 1 month on the full regimen and a third month on only BPa 
B – bedaquiline, H-isoniazid, L-linezolid, Pa-pretomanid, R-rifampicin, Z-pyrazinamide 
 
In conclusion, linezolid increases the sterilising activity of the bedaquiline-pretomanid 
combination; no MTB could be cultured from the lungs of mice 3 months after cessation of 3 
months of treatment with the combination, in contrast to MTB cultured from 13 of 15 mice treated 
with the standard 2RHZ/4RH regimen over 3 months. In addition, limiting the duration of linezolid 
to the first month of treatment does not affect linezolid’s contribution to the sterilising activity of 
the regimen in the preclinical mouse study.   
Prior to the use of pretomanid in combination with bedaquiline in clinical study NC-001, a 
preclinical cardiovascular safety pharmacology study was conducted in unrestrained beagle dogs 
with both drugs to explore the potential for additive effects on QT prolongation induced by the 
combination.  Results indicate that administration of 100 mg/kg bedaquiline daily for 7 days 
causes a small increase in QTc interval by Day 6 in some animals that is not influenced by the 
addition of 100 mg/kg pretomanid on Day 7. The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the subcutaneous route of administration and not 
related to the plasma exposure.   
2.3.2 Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or 
Linezolid 
2.3.2.1 Clinical Study NC-001 
Study NC-001 was a partially double-blind, randomized, parallel group study in adult male and 
female participants with newly diagnosed, uncomplicated, smear-positive, pulmonary TB. A total 
of 85 participants met study eligibility criteria and were randomly assigned to one of the six 
treatment groups. All study treatments were given once daily for 14 days. Substantial EBA activity 
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was demonstrated across participants in all arms of the study and the daily reductions in cultured 
colony counts per mL of sputum are presented in Table 5 below. 
Table 5: 
Summary Statistics for EBACFU(0-14) 
Derived Using Bi-Linear Regression, Study NC-001 
Treatment Group 
N 
Daily Mean (SD)  
EBACFU(0-14) 
Pretomanid + pyrazinamide + moxifloxacin 
13 
0.23 (0.128) 
Pretomanid + pyrazinamide 
14 
0.15 (0.040) 
Pretomanid + bedaquiline  
15a 
0.11 (0.050) 
Bedaquiline alone 
14 
0.07 (0.068) 
Bedaquiline + pyrazinamide 
15 
0.13 (0.102) 
Rifafour e-275 
10 
0.14 (0.094) 
 
There were no Serious Adverse Events from the study among participants treated with 
pretomanid and bedaquiline.  Three participants in a bedaquiline-containing treatment arm were 
withdrawn: one participant on the bedaquiline only arm for a Grade 3 ALT and Gamma-Glutamyl 
Transferase (GGT) elevation (although the elevation occurred prior to the first dose of study 
medication), one on a bedaquiline plus pyrazinamide (weight banded) arm for a Grade 3 ALT 
and AST elevation, and one on a pretomanid and bedaquiline arm for to a Grade 3 ALT 
elevation. 
2.3.2.2 Clinical Study NC-003  
Efficacy 
In the 14 day EBA study NC-003 two monotherapy and four different combinations of bedaquiline, 
pretomanid, pyrazinamide and clofazimine were evaluated in DS-TB participants. Fifteen 
participants were randomized into 7 treatment arms: C, Z, B-Pa-Z-C, B-Pa-Z, B-Pa-C, B-Z-C, and 
HRZE control. This study demonstrated no EBA for the clofazimine monotherapy arm and modest 
EBA for the pyrazinamide monotherapy arm. However, all of the experimental regimens 
demonstrated EBA. In general, adding clofazimine to the various agents resulted in either no 
increase in EBA, or a decrease when compared to a similar regimen that did not include 
clofazimine. In this study, the experimental regimen with the best EBA was B-Pa-Z which 
demonstrated a rate of decrease in both logCFU and logTTP that was at least as good as the HRZE 
control. The daily logCFU results are presented in Table 6. Similar results were found when TTP 
was used to calculate the bactericidal activity over 14 days (BA(0-14)). 
 
 
 
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Table 6: 
NC-003 Efficacy Results: Daily BAlogCFU(0-14) 
Arm 
logCFU 
BPaZC 
.124 
BPaZ 
.180 
BPaC 
.086 
BZC 
.098 
Z 
.036 
C 
-.025 
Rifafour 
.152 
Safety 
Generally, the regimens in this study were well tolerated. Table 7 provides a list of the overall 
safety findings. The only SAE experienced in the study was in a participant in the clofazimine 
monotherapy arm. Otherwise, the rates of treatment emergent AEs (TEAEs) were similar across 
the treatment arms. One participant in the B-Pa-Z arm was withdrawn from the study due an 
adverse event of increased liver function tests (alanine aminotransferase (ALT), AST and GGT).  
Table 7: 
NC-003 Safety Data 
 
BPaZ
C 
BPaZ 
BPa
C 
BZC 
Z 
C 
HRZ
E 
Total 
N 
15 
15 
15 
15 
15 
15 
15 
105 
Participants with: 
TEAEs 
11 
9 
8 
10 
10 
9 
8 
65 
TEAEs leading to death: 
Serious TEAEs 
 
 
 
 
 
1 
 
1 
TEAES leading to early withdrawal 
 
1 
 
 
 
 
 
1 
TEAEs leading to discontinuation 
of study drug 
 
1 
 
 
 
 
 
1 
Drug-related TEAES 
8 
5 
7 
3 
5 
6 
5 
39 
Serious, drug-related TEAEs 
 
 
 
 
 
 
 
 
Grade III AEs 
 
2 
1 
2 
 
1 
 
6 
Grade IV AEs 
 
1 
1 
 
 
 
 
2 
Grade II/IV AEs 
 
2 
1 
2 
 
1 
 
6 
 
QT Prolongation 
Because bedaquiline and clofazimine are both known to prolong the QT interval, intensive ECG 
monitoring was included in the study endpoints. The mean change from baseline in QTcB and 
QTcF tended to be larger at 5 hours than at 10 hours post-dose in the (B-Pa-Z-C) arm and in the 
(B-Pa-C) arm.  No QTcB or QTcF ≥500 ms were reported.  An increase from baseline to Visit 5 
and subsequent visits of ≥60 ms in QTcB was reported for 2 participants in the (B-Pa-C) arm and 
for 1 participant in the clofazimine alone arm.  An increase from baseline to Visit 5 and subsequent 
I 
I 
I 
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visits of ≥60 msec in QTcF was reported for 4 participants in the (B-Pa-C) arm and for 1 participant 
in the clofazimine alone arm.  For both QTcB and QTcF, the (B-Pa-Z-C) arm and the (B-Pa-C) 
arm showed the largest increase from baseline. Clofazimine will not be used in any treatment 
arms in the NC-007 study. 
2.3.2.3 The Nix-TB Study  
The NiX-TB Study is an ongoing open-label study assessing the safety and efficacy of bedaquiline 
plus linezolid plus pretomanid in participants with pulmonary infection of either XDR-TB or 
treatment intolerant/non-responsive MDR-TB. The study regimen includes: bedaquiline 400 mg 
once daily for 2 weeks then 200 mg 3 times per week plus pretomanid 200 mg once daily plus 
linezolid 600 mg twice daily amended (22 Jan 2016 protocol) to 1200 mg once daily. Treatment 
duration is 6 months, although if participants are still culture positive at month 4, there is the option 
to extend treatment to 9 months or withdraw. The primary endpoint is the incidence of 
bacteriologic failure or relapse or clinical failure through follow-up until 6 months after the end of 
treatment. Secondary Endpoints include: incidence of bacteriologic failure or relapse or clinical 
failure through follow-up until 24 months after the end of treatment as a confirmatory analysis, 
time to sputum culture conversion to negative status through the treatment period, and the 
proportion of participants with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 
end of treatment. In addition, linezolid dosing (actual) and efficacy will be explored and changes 
from baseline will be evaluated for TB symptoms, Patient Reported Health Status, body weight, 
and measures of safety. 
Efficacy Experience to Date:   
Sixty-nine participants have been enrolled as of February 1, 2017, at 2 sites in South Africa. Forty-
nine percent of the participants are HIV positive, 79% have XDR-TB and 21% have MDR 
intolerant or resistant to prior therapy.  Forty have completed the 6 months of therapy with the 
drug regimen and 31 have been followed to the primary endpoint at 6 months after treatment. All 
surviving patients were culture negative by 4 months, with 74% negative at 8 wks. As of February 
1, 2017, there has been 1 microbiological relapse during follow up after drug therapy and 1 
participant has had a new infection during follow-up with Drug Sensitive TB.  This study will 
continue to enrol participants until the NC-007 study is initiated. 
Safety of the B-Pa-L Regimen in the Nix-TB Study:  As of December 2016, four participants have 
died in the study. The causes of death have varied and include: 2 with multi-organ disseminated 
TB who died within the first 5 weeks of therapy, 1 who had a gastrointestinal bleed and 1 with 
multi-organ failure and disseminated TB on autopsy. No deaths or SAEs have been caused by 
hepatic injury. No participants have been withdrawn from the study except for the 4 who died.  
The expected linezolid toxicities of peripheral neuropathy and myelosuppression were common 
but manageable.  Seventy-one percent of participants had at least one linezolid dose pause (22% 
of all participants due to myelosuppression and 28% due to peripheral neuropathy), during the 6 
months of treatment. One had peak ALT and AST > 3 X ULN and total bili > 2X ULN, but these 
improved and treatment restarted without a recurrence.  There were 7 cases of grade 3 or 4 
transaminitis and all resolved and allowed the study regimen to be continued. There were no 
cases of optic neuritis. While participants have required close surveillance for signs and 
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symptoms of neuropathies and bone marrow suppression, these toxicities have been 
manageable.  
2.4 Overall Benefit/Risk Assessment 
The recent report of the long term outcome of patients with XDR-TB treated in S. Africa highlighted 
the very poor prognosis for patients with this disease.  After 60 months of follow up 73% of 107 
patients had died and only 11% had a favourable outcome(28).  These patients have infection with 
MTB resistant to many/most of the available drugs to treat tuberculosis.  Patients with XDR-TB 
have limited treatment options due to their resistance profile, and the drugs that are typically used 
in Standard of Care have many side effects, some are administered as injectables and have poor 
treatment outcomes in XDR-TB.  Similarly, patients with Pre-XDR-TB and patients with MDR-TB 
who are failing or are intolerant to treatment have traditionally poor outcomes and are a challenge 
to treat. While treatment success for MDR-TB is better than for XDR-TB, overall success in 
treating MDR-TB is still approximately 50% according to the World Health Organization 2015 
Global TB Report.(43) and it would be lower for patients failing or not able to take an optimal 
traditional regimen.  This trial provides an opportunity to treat these high-need patients with three 
active drugs, for which there is no or minimal pre-existing resistance, in a very closely controlled 
and monitored clinical trial setting with the opportunity to define the optimal dosing scheme for 
linezolid.  Participants will be monitored closely and regular reviews of safety and efficacy will be 
made by the Data Safety Monitoring Committee (DSMC).  Preliminary results of the ongoing Nix-
TB trial from patients with XDR-TB and who are failing or intolerant to treatment of MDR-TB 
demonstrate that this regimen has the potential to give relapse-free cure of XDR-TB with a simple 
regimen in a much shorter period of time than currently required by the available drugs used in 
the best standard of care.  Preclinical studies of this regimen in a murine model of infection 
demonstrated relapse free cure of MTB in half the time (3 vs 6 months) required by standard HRZ 
therapy.  Clinical studies of linezolid alone and pretomanid and bedaquiline alone and in 
combination have demonstrated activity against TB infection. 
These three drugs have not been used in combination in humans prior to the Nix-TB trial, and 
thus their combined toxicity profile is emerging.  The greatest risks of key concern for participants 
in this trial from linezolid are from the adverse events of myelosuppression and peripheral and 
optic neuropathy.  Participants will be closely monitored with full blood counts, vision 
examinations, and screening for peripheral neuropathy.  The investigator may interrupt dosing of 
either linezolid or linezolid with pretomanid and bedaquiline if adverse events of concern develop, 
and a resumption of the drugs, with linezolid at the same or at a lower dose, may be made 
cautiously.  Participants will be under close surveillance for hepatotoxicity, as that risk for 
pretomanid and bedaquiline is not yet well characterized.   
Overall the benefit-risk balance justifies evaluating the B-Pa-L regimen in this study, with the 
cautious surveillance in place, to treat patients with XDR-TB who have few options for a 
successful outcome. 
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3 
Trial Objectives  
3.1 Primary Objectives 
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus 
bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary 
XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
4 
Trial Design 
4.1 Summary of Trial Design 
This is a Phase 3, multi-center, partially-blinded, randomized clinical trial conducted in 4 treatment 
groups.  Participants, trial investigators and staff, including laboratory staff, will be blinded to dose 
and scheduled duration of linezolid.   Bedaquiline and pretomanid dosing will not be blinded. 
The trial will be performed at multiple centers located in South Africa, Eastern Europe and Russia.  
A total of 120 XDR-TB and up to 60 Pre-XDR/MDR intolerant or non-responsive participants who 
meet all of the inclusion criteria and none of the exclusion criteria, aged 14 and over, will be 
randomized to receive one of the 4 active treatment arms. Enrolment will stop when 120 XDR-TB 
participants are randomized. Participants will be randomized to one of the four regimens in a 
1:1:1:1 ratio, using an interactive web response system (IWRS) which will utilize a dynamic 
randomization system using minimization with a random element to allocate participants evenly 
across the arms by HIV status and type of TB after they have given written, informed consent and 
met all eligibility criteria.  
Each participant will receive 26 weeks of treatment.  If participant’s week 16 sample remains 
culture positive, Investigator may consider option to extend current treatment to 39 weeks, in 
consultation with the Sponsor Medical Monitor. Participants will be followed for 78 weeks after 
end of treatment. 
4.2 Treatment Plan: Schedule of Assessments 
• 
Screening Period (Screening Visit up to 9 days prior to Treatment) 
• 
Treatment Period (Day 1 to Week 26. Additional visits every 3 weeks until last dose when 
dosing extended due to pauses or positive culture at Week 16  
• 
Follow-up Period (4 Week post end of treatment follow-up Visit to 78 Week post end of 
treatment follow-up Visit) 
Refer to: 
• 
Trial Flow Chart (Section 1.2) for the timing of all procedures and laboratory 
samples to done at each visit.   
• 
Trial Procedures (Section 7) for details regarding specific procedures or 
laboratory tests. 
Participants will receive oral daily dosing. They will be randomized to one of the following arms: 
 
 
 
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Table 8: 
Treatment Groups 
 
Treatment Group 
No of Participants 
1 
Linezolid 1200 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
2 
Linezolid 1200 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
3 
Linezolid 600 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
4 
Linezolid 600 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
 
Figure 4: 
Trial Schematic 
 
26 Weeks of Treatment* 
 
Weeks 1-9 
Weeks 10-26 
1 
1200 mg Linezolid QD 
 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
Primary Endpoint 
follow-up for relapse-
free cure 26 weeks 
after end of treatment 
 
Full follow up 78 
weeks after end of 
treatment 
2 
1200 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100mg QD week 9 
Pretomanid 200 mg QD 
1200 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
3 
600 mg Linezolid QD 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
4 
600 mg Linezolid QD 
Bedaquiline 200 mg QDweeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
600 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
Participants will be randomized to 1 of the 4 groups listed above.  
N = 45 Participants per group for a total of 180. 30 XDR-TB participants per group    
* Treatment will be extended to 39 weeks for participants who have a positive culture at week 16  
 
5 
Trial Population 
Participant must meet all inclusion and no exclusion criteria within the screening period.  Re-
testing for laboratory or ECG parameters is allowed within the 9-day screening period. Sponsor 
may consider replacement of late screen failure and un-assessable (as detailed in the statistical 
analysis plan) participants. 
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5.1 Inclusion Criteria 
Participants are required to meet all of the following inclusion criteria during the screening period 
in order to be randomized. 
1. Provide written, informed consent prior to all trial-related procedures (including any 
additional consent required for participants considered as minors per applicable regulatory 
authority or ethics committee). 
2. Willingness and ability to attend scheduled follow-up visits and undergo study 
assessments 
3. HIV testing (if an HIV test was performed within 1 month prior to screening, it should not 
be repeated as long as documentation can be provided [ELISA and/or Western Blot].  If 
HIV status is a confirmed known positive, repeated HIV test is not needed provided 
documentation is available. 
4. Male or female, aged 14 years or older.  
 
Disease Characteristics: 
 
5. Participants with one of the following pulmonary TB conditions: 
a. 
 XDR-TB with  
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
historical documented resistance to isoniazid, rifamycins, a fluoroquinolone 
AND an injectable during the current TB diagnosis/disease course;  
b. 
Pre-XDR-TB with 
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based molecular test within 3 months prior to or at 
screening and; 
ii. 
historical documented resistance to isoniazid, rifamycins, and to a 
fluoroquinolone OR an injectable during the current TB diagnosis/disease 
course. 
c. 
MDR-TB with 
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected results within 3 months prior to screening or 
MTB confirmed in sputum based on molecular test within 3 months prior to 
or at screening and; 
ii. 
historical documented resistance to isoniazid and rifamycins during the 
current TB diagnosis/disease course; 
iii. 
with documented non-response to treatment with the best available regimen 
for 6 months or more prior to enrolment who in the opinion of the Investigator 
have been adherent to treatment and will be adherent to study regimen.   
d. 
MDR-TB with  
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
historical documented resistance to isoniazid and rifamycins during the 
current TB diagnosis/disease course and; 
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iii. 
who are unable to continue second line drug regimen due to a documented 
intolerance to: 
a. PAS, ethionamide, aminoglycosides or fluoroquinolones or ; 
b. Current treatment not listed above that renders participant eligible for 
the study in the Investigator’s opinion.  
6. Chest X-Ray within one month prior to screening, obtained and read locally by investigator 
or designee with results consistent with pulmonary TB in the opinion of the Investigator. 
 
Contraception: 
7. Be of non-childbearing potential or using effective methods of birth control, as defined 
below: 
 
Non-childbearing potential: 
a. Participant - not heterosexually active or practices sexual abstinence; or  
b. Female participant/sexual partner - bilateral oophorectomy, bilateral tubal ligation 
and/or hysterectomy or has been postmenopausal with a history of no menses for 
at least 12 consecutive months; or  
c. Male participant/sexual partner - vasectomised or has had a bilateral 
orchidectomy at least three months prior to Screening. 
 
Effective birth control methods:                                                        
A double contraceptive method should be used as follows: 
a. Double barrier method which can include any 2 of the following: a male condom, 
diaphragm, cervical cap, or female condom (male and female condoms should not 
be used together); or  
b. Barrier method (one of the above) combined with hormone-based contraceptives 
or an intra-uterine device for the female participant/partner; 
 
And are willing to continue practicing birth control methods throughout treatment and for 6 
months (both male and female participants) after the last dose of study medication. 
 
Note: Hormone based contraception alone may not be reliable when taking IMP; 
therefore, hormone based contraceptives alone cannot be used by female participants 
or female partners of male participants to prevent pregnancy. 
 
5.2 Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria during 
the screening period: 
 
Medical History and Concurrent Conditions 
1. Any condition in the Investigator’s opinion (i.e., an unstable disease such as 
uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended 
treatment, cancer that could affect survival through the protocol-specified follow up 
period), where participation in the trial would compromise the well-being of participant 
or prevent, limit or confound protocol specified assessments.  
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2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations.  
3. In the judgment of the Investigator, the patient is not expected to survive for more than 
6 months. 
4. Karnofsky score < 60 at screening. 
5. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal 
Products or related substances. 
6. Body mass index (BMI) < 17 kg/m2 
7. TB infection with known resistance to pretomanid, delamanid, linezolid or bedaquiline. 
8. Participants who, upon the evaluation of their pulmonary disease, are expected to 
require a surgical procedure. 
9. Having participated in other clinical studies with dosing of investigational agents within 
8 weeks prior to screening or currently enrolled in an investigational study that includes 
treatment with medicinal agents.  Participants who are participating in observational 
studies or who are in a follow up period of a trial that included drug therapy may be 
considered for inclusion. 
10. Participants with any of the following at Screening: 
• 
QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrolment. 
• 
Heart failure 
• 
A personal or family history of congenital QT prolongation 
• 
A history of or known, untreated, ongoing hypothyroidism 
• 
A history of or ongoing bradyarrhythmia 
• 
A history of Torsade de Pointe 
11. Females who have a positive pregnancy test at Screening or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the study or within 6 
months of cessation of treatment.  Males planning to conceive a child during the study 
or within 6 months of cessation of treatment. 
12. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, 
participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the 
course of the study, in the opinion of the Investigator. 
 
Previous and Concomitant Therapy 
13. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 
weeks of randomization.  
14. Concomitant use of serotonergic antidepressants or prior use within 3 days of 
randomization if Investigator foresees potential risks for serotonin syndrome when 
combined with linezolid.  
15. Concomitant use of any drug known to prolong QTc interval (including, but not 
limited to, amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, 
cyclobenzaprine, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, 
erythromycin, fluoroquinolones, halofantrine, haloperidol, ibutilide, levomethadyl, 
mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, 
sparfloxacin, thioridazine).  
16. Concomitant use of any drug known to induce myelosuppression.  
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17. Concomitant use of any drugs or substances known to be strong inhibitors or 
inducers of cytochrome P450 enzymes (including but not limited to efavirenz, 
quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine, gestodene, 
metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, 
erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may 
include use of lopinavir/ritonavir regimen as noted in section 5.3.3. 
18. Participants who have received more than 2 weeks of bedaquiline, linezolid or 
delamanid prior to first dose of IMP. 
19.  Participants with an existing TB diagnosis (a diagnosis made > 4 weeks prior to 
screening) and HIV co-infection, must have been on an ART for at least 4 weeks prior 
to screening.  
20. Participants with newly diagnosed tuberculosis and HIV may be enrolled provided that 
appropriate HIV therapy will not be initiated until participant has received at least 2 
weeks of study medication.  
21. HIV infected participants: the following antiretroviral therapies should not be used: 
zidovudine, stavudine, didanosine. The antiretroviral therapy (ART) booster cobicistat 
should not be used. Please reference restrictions Section 5.3.3 Antiretroviral Therapy, 
for guidance on ART treatment during the treatment period.  
 
Diagnostic and Laboratory Abnormalities 
 
22. Participants with any of the following toxicities at Screening (labs may be repeated 
during screening period) as defined by the enhanced Division of Microbiology and 
Infectious Disease (DMID) adult toxicity table (November 2007): 
 
a. Viral load >1000 IU/ml (Unless newly diagnosed HIV and not yet on ART who 
otherwise qualify for participation); 
b. CD4+ count < 100 cells/µL (HIV positive participants); 
c. Serum potassium less than the lower limit of normal for the laboratory; 
d. Hemoglobin < 9.0 g/dL; 
e. Platelets <100,000/mm3; 
f. Absolute neutrophil count (ANC) < 1500/ mm3; 
g. Aspartate aminotransferase (AST)  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor Medical Monitor 
h. Alanine aminotransferase  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor medical monitor; 
i. 
Total bilirubin 
• 
greater than 1.5 x ULN to be excluded; 
• 
1-1.5 x ULN must be discussed with and approved by the Sponsor Medical 
Monitor  
j. 
Direct bilirubin 
• 
Greater than ULN to be excluded 
k. Serum creatinine level greater than 1.5 times upper limit of normal 
l. 
Albumin <3.0 mg/dl 
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All inclusion and no exclusion criteria must be met.  If no single variable/value is outside of the 
ranges of acceptability, but when multiple values are close to the limits and/or whenever the 
Investigator has reason to suspect that there might be a health problem (other than TB), enrolment 
should only be considered after discussing the case with the sponsor medical monitor. 
5.3 Restrictions 
5.3.1 Prior and Concomitant Medications and Other Treatments 
Concomitant medications should be kept to a minimum during the treatment period of the trial.  
However, if concomitant medications are considered to be necessary for the participant’s welfare 
and are unlikely to interfere with the IMP, they may be given at the discretion of the investigator.  
For any concomitant medications given as a treatment for a new condition or a worsening of an 
existing condition occurring after signing of the informed consent form, the condition must be 
documented on the Adverse Event pages of the electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be consulted and reviewed 
carefully.  The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected in order to prevent any potentially serious and/or life-threatening drug 
interactions. 
The following concomitant medications are prohibited during the treatment period to avoid 
possible drug interactions with the IMP: 
• 
Medicinal products used to treat pulmonary TB:  including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and metronidazole. 
• 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). (e.g., phenelzine, 
isocarboxazid) 
• 
Concomitant use of any drug known to prolong QTc interval (including but not limited to 
amiodarone, 
bepridil, 
chloroquine, 
chlorpromazine, 
cisapride, 
cyclobenzaprine, 
clarithromycin, 
disopyramide 
dofetilide, 
domperidone, 
droperidol, 
erythromycin, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, 
pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).  
• 
Treatment with fluoroquinolones (as they are known prolong QTc), are strongly 
discouraged in the trial. They should only be used to treat intercurrent non-TB infections 
and if the benefit of treatment outweighs the risk of prolonged QTc.   
• 
Concomitant use of any drug known to induce myelosuppression.  
• 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: ketoconazole, 
voriconazole, itraconazole, fluconazole; ketolids such as telithromycin; and macrolide 
antibiotics other than azithromycin) for more than 3 consecutive days; 
• 
The systemic use of CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, 
St. John’s wort, rifamycins and systemic dexamethasone. 
Concomitant use of serotonergic antidepressants should be avoided if possible as participants on 
these agents and linezolid are at risk for serotonin syndrome.  
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Caution should be used in treating diabetic patients receiving insulin or oral hypoglycemic agents 
as cases have been reported of hypoglycemic reactions when patients on these agents have 
been treated with linezolid. 
Any drug known to be hepatotoxic should be avoided as much as possible during screening and 
throughout the treatment period (including but not limited to acetaminophen/paracetamol,  
acetazolamide, allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, 
augmentin/co-amoxiclav, azathioprine, baclofen, bumetanide, captopril, carbamazepine, 
celecoxib, chlorpromazine, chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-
trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, 
fosamprenavir, furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, 
ketoconazole, lisinopril, loperamide, losartan, methotrexate, metolazone, mirtazepine, 
nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory drugs, paroxetine, 
phenobarbital, phenothiazines, phenytoin, pravastatin, probenecid, prochlorperazine, 
risperidone, rosuvastatin, sertraline, simeprevir, simvastatin, sodium valproate, sotalol, 
sulfasalazine, sumatriptan, tamsulosin, terbinafine, tetracycline, theophyllin/uniphyllin, tipranavir, 
tolazamide, tolbutamide, topiramate, trazodone, tricyclic antidepressants, trimethoprim, 
verapamil). 
5.3.2 Recommendations for Concomitant use of Anti-Malarials 
The following treatments for malaria are recommended for concomitant use with the IMP, should 
it be necessary: 
• 
Proguanil/atovaquone or  
• 
Artesunate plus sulfadoxine-pyrimethamine  
 
These recommendations are based on the potential for QT prolongation by bedaquiline and many 
anti-malarials. Due to the extended half-life of bedaquiline commencing anti-malarial treatment 
containing drugs that could prolong the QT interval, shortly after discontinuing bedaquiline, is not 
recommended. 
5.3.3 Antiretroviral Therapy 
For HIV infected participants, to avoid potentiating known key toxicities of linezolid (neuropathy 
and myelosuppression), the following antiretroviral therapies should not be used during the 
treatment period: zidovudine, stavudine, didanosine. The ART booster cobicistat should not be 
used. 
Only the following types of antiretroviral therapy (ART) are permissible during administration of 
regimens: 
• 
Nevirapine based regimen consisting of NVP in combination with any two NRTIs TDF/ABC 
and FTC/3TC.  
• 
Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any 
two NRTIs TDF/ABC and FTC/3TC. 
• 
Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC. 
• 
In patients who have viral load suppressed on efavirenz at the time of screening, their 
ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. If possible, 
the same nucleoside backbone should be used. 
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The investigator must assess the risks and benefits of these antiretroviral regimens in the 
context of co-infection with TB acknowledging the following caveats: 
• 
Triple NRTI is generally not considered optimal chronic ART; 
• 
Nevirapine based regimens are associated with higher ART failure in participants having 
or known to have previously had a viral load more than or equal to 100,000/ mL. 
5.3.4 Other Restrictions 
Large quantities of foods or beverages with high tyramine content should be avoided while taking 
linezolid.  Quantities of tyramine consumed should be less than 100mg per meal. Foods high in 
tyramine content include those that may have undergone protein changes by aging, fermentation, 
pickling, or smoking to improve flavour, such as aged cheeses (0 to 15 mg tyramine per ounce); 
fermented or air-dried meats (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 
ounces); soy sauce (5mg tyramine per 1 teaspoon). The tyramine content of any protein-rich food 
may be increased if stored for long periods or improperly refrigerated. 
Alcohol should be avoided while on IMP, especially in patients with impaired hepatic function. 
5.4 Discontinuation from Treatment/Trial  
The following may result in the discontinuation of trial treatment;  
• 
Pregnancy; 
• 
Investigator considers it for safety reasons in the best interest of the participant that he/she 
be discontinued. This could include, but is not limited to: 
o Adverse event(s); 
o Myco testing results from baseline (Screening through Week 4) indicate sensitivity 
to isoniazid and/or rifamycins; 
o Myco testing results from baseline (Screening through Week 4) indicate resistance 
to bedaquiline, pretomanid or linezolid; 
o In the opinion of the investigator, fails to comply with the protocol, including non-
compliance to IMP. 
All participants who discontinue trial treatment (but have not withdrawn consent) and received at 
least one dose of IMP will be requested to return for an early withdrawal visit and applicable safety 
Follow Up visits, as per flow chart (Section 1.2). 
In the event of the following, participants will be and/or are considered discontinued from the trial 
and no additional follow-up visits are required: 
• 
Withdrawal of informed consent; 
• 
Lost to follow-up; 
• 
Termination of the trial by the sponsor. 
A participant may discontinue from the trial at any time at his/her request (withdrawal of consent). 
 
 
 
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Discontinuation from treatment due to TB 
Ultimately it is the investigator’s decision whether a participant should discontinue treatment due 
to a concern that the participant has symptomatic worsening TB and/or bacteriological 
failure/relapse.  
Discontinuation is usually not indicated by a single positive culture.  Should a participant have a 
single positive culture result after being negative, the investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether it 
is in the participant’s best interest that he/she be discontinued. Prior to discontinuation of a 
participant due to TB, the investigator must discuss the participant with the sponsor medical 
monitor, unless the investigator cannot contact the sponsor medical monitor and considers that 
discontinuation must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the investigator decides to discontinue trial treatment for a participant due to TB, additional 
sputum samples may need to be collected in order to ensure the participant’s outcome status may 
be determined, details noted in trial flowchart (Section 1.2). 
All Early Withdrawal participants who are confirmed sputum positive (at least two sequential 
sputum positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to specialists who treat XDR-TB, pre-XDR TB or MDR-TB as 
applicable.  
5.5 Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who is not randomized 
Completed 
Treatment / 
Completed FU* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued FU 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
FU** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* Note that this includes treatment failures who complete all applicable follow-up visits 
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** Early Withdrawal 
5.6 Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific Investigational Site at any time, although this should 
only occur after consultation between involved parties.  Should this occur, the local and central 
Ethics Committee/Institutional review Board (EC/IRB) and Regulatory Authorities will be informed.  
Should the Trial/Investigational Site be closed prematurely, all trial materials (except 
documentation that has to remain stored at the Investigational Site) will be returned to the Sponsor 
or vendor.   The Investigator will retain all other documents until notification given by the Sponsor 
for destruction.  Participants currently on treatment will receive an appropriate regimen and all 
participants will be referred to a unit specializing in the treatment of XDR-TB, Pre-XDR-TB or 
MDR-TB as applicable. 
6 
Treatment 
6.1 IMP Administration  
  
Treatment will be administered orally, once daily, with a full glass of water and a meal in the 
dosing schemes (treatment arms) outlined in Table 9. The study drug regimen should be 
initiated as specified below regardless of whether participant has received any of the allowed 
prior exposure of bedaquiline or linezolid (up to 14 days), including a loading dose of 
bedaquiline. The Pharmacy Manual should be referenced for further details. 
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Table 9: 
 Investigational Medicinal Product Details  
Treatment Group 
Active and Placebo 
Linezolid 1200 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 2 linezolid 600 mg active tablets once daily for 26 weeks 
• 1 placebo linezolid 600 mg tablet once daily for 26 weeks  
Linezolid 1200 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9  
• 2 linezolid 600 mg active tablets once daily for 9 weeks  
• 1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
Linezolid 600 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 1 linezolid 600 mg active tablet once daily for 26 weeks 
• 1 placebo linezolid 600 mg tablet once daily for 26 weeks  
• 1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
Linezolid 600 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9 
• 1 linezolid 600 mg active tablet once daily for 9 weeks 
• 1 placebo linezolid 600 mg tablet for 9 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
6.2 Participant Compliance 
During site clinic visits or hospitalization, the IMP will be administered by the 
Investigator/designated site personnel. During the study, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully trained on how IMP is to be taken. When 
possible, participants will be checked for IMP compliance by the Investigators or trial 
personnel/National TB Treatment Program personnel via the hand-and-mouth procedure (both 
the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP).  Additionally, participant cards will be checked for unused tablets in the 
blisters. 
6.3 Treatment Modification(s) 
All dose modifications should be discussed with the Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required urgently for a safety concern; the 
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Medical Monitor should be informed within 24 hours of the change if not discussed prior to 
implementation. 
In the event of linezolid specific toxicities, the following should be considered and implemented 
per guidance in the monitoring and safety for specific toxicities section of protocol: 
• 
Blinded one step reductions (maximum 3 steps) in the dose of linezolid (1200 mg QD to 
600 mg QD, 600 mg QD to 300 mg QD or 300mg QD to placebo) managed by the IWRS 
as per instructions in pharmacy manual and/or IWRS user manual.  
• 
Temporary pause of linezolid due to a linezolid-specific toxicity should be considered and 
implemented per guidance in the monitoring and safety for specific toxicities section of 
protocol. 
• 
Permanent discontinuation of linezolid. 
Participants experiencing suspected drug related toxicities due to other drugs in the regimen (B-
Pa), the full regimen may be halted for up to 35 consecutive days.  
Pauses of the full regimen must not exceed 8 weeks (56 days) cumulatively.   
If participant’s week 16 sample remains culture positive, Investigator may consider option to 
extend current treatment to 39 weeks, in consultation with the Sponsor Medical Monitor. When 
treatment extended due to a positive culture at week 16, pauses of the full regimen must not 
exceed 13 weeks (91 days) cumulatively. 
When total of missed dosing days and/or pauses is greater than 7 days, additional make-up doses 
should be dispensed/treatment extended. 
At no time should the participant be treated with a single agent. 
6.4 IMP Packaging and Labelling 
The complete formulations of the IMP bedaquiline and pretomanid are found in the respective 
Investigator Brochures(5,6). The complete formulations of linezolid are found in the Package 
Inserts(23,24,26).  
The IMP will be packaged as follows: 
• 
Bedaquiline: Bottles containing: 
o 200 mg QD dose- 28 tablets- bedaquiline 100 mg 
o 100mg QD dose- 14 tablets- bedaquiline 100 mg  
• 
Pretomanid: Blister card containing 14 tablets- pretomanid 200 mg  
• 
Linezolid: Blister Card containing 7 days of dosing as follows: 
o 1200 mg QD Dose  
 
2 blister strips of 7 tablets each (14 tablets) containing active linezolid 600 
mg   
 
1 blister strip of 7 half tablets containing placebo linezolid 300 mg  
o 600 mg QD Dose:  
 
1 blister strip of 7 tablets containing active linezolid 600 mg   
 
1 blister strip of 7 tablets containing placebo linezolid 600 mg 
 
1 blister strip of 7 half tablets containing placebo linezolid 300 mg  
o 300 mg Dose (for reductions): 1 row of 7 active 600 mg tablets for 7 days of dosing 
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 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid 
600 mg   
 
1 blister strip of 7 half tablets containing active linezolid 300 mg  
o Placebo Linezolid Dose: 2 rows of 7 placebo 600 mg tablets for 7 days of dosing 
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid 
600 mg   
 
1 blister strip of 7 half tablets containing placebo linezolid 300 mg  
 
The packaging of each bottle/blister card will be labelled with, at a minimum, the following 
information: 
• 
Name, address and telephone number of Sponsor. 
• 
Name of medication. 
• 
Dosage, quantity and method of administration for bedaquiline and 
pretomanid. 
• 
Potential dosage, quantity and method of administration for linezolid. 
• 
Reference/Lot Number. 
• 
The statement “For Clinical Trial Use Only”. 
• 
Space for completion of Name of Investigator and Site Number. 
• 
MedID: medication identification number  
• 
Storage conditions. 
• 
Period of Use. 
• 
The statement “Keep out of reach of children”. 
• 
Expiry Date. 
• 
Directions for use. 
Space for completion of participant number and visit/date dispensed. 
6.5 Method of Treatment Assignment 
Participants will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
web response system (IWRS) which will utilize a dynamic randomization system using 
minimization with a random element to allocate participants evenly across the arms by HIV status 
and type of TB.  Information & directions will be provided to each site via the IWRS user manual. 
6.6 Blinding and Procedures for Breaking the Blind 
The blind must not be broken except in the case of a medical emergency, where treatment of the 
participant is influenced by the knowledge of what dose and duration of linezolid the participant is 
receiving. It is requested that the Investigator make every effort to contact the Sponsors medical 
monitor (or designee) prior to breaking the blind. IWRS will be programmed with blind-breaking 
instructions, described in the user manual. The sponsor reserves the right to break the blind in 
order to fulfil any regulatory requirements regarding reporting of SAEs. 
In the absence of any medical emergencies requiring a blind break, the blind for all participants 
will be broken once all clinical data and outcome parameters have been captured, no more data 
queries are pending and the statistical analysis plan has been finalized. 
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6.7 Handling, Storage and Accountability  
The investigator or designee must confirm appropriate temperature conditions as per details on 
IMP labelling, have been maintained during transit for all trial treatment received and any 
discrepancies are reported and resolved before use of the trial treatment. 
Only participants enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Upon completion or termination of the trial, all unused 
and/or partially used IMPs must either be returned to Sponsor (or designated vendor) who will 
arrange for destruction or destroyed at site as agreed by sponsor after final accountability has 
been confirmed, 
The Investigator/designee will immediately inform the sponsor of any quality issues arising with 
respect to the trial medication. The sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
7 
Trial Variables and Procedures 
The trial flowchart in Section (1.2) should be referenced for timing and sequence of 
assessments. 
7.1 Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written Informed Consent. 
• 
Visit Dates 
• 
Participant Disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and Exclusion criteria 
• 
Clinically significant medical and treatment history (including past and current TB 
diagnosis and smoking) 
• 
Screening Coached Spot Sputum Sample: 
o Smear microscopy for acid-fast bacilli. 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB 
complex and rifamycin resistance. 
• 
Urine pregnancy test: women of child-bearing potential only, whether they are 
sexually active or not. 
• 
Serology: HIV and CD4 count.  
o If an HIV test was performed within 1 month prior to trial start, it should not be 
repeated as long as documentation of results can be provided (ELISA and/or 
Western Blot). 
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o Where required by regulatory authorities or ethics committees: 
 
Separate approval for this to be performed will be obtained from 
participants in the written informed consent process.  
o prior to HIV testing and on receipt of the results, participants will be 
counselled on HIV by trained counsellors if they have indicated as such on 
the HIV consent form. If requested by the participant, HIV counselling 
provided to the participant by the study site should be clearly documented in 
the participant’s medical records/source.  Participants have the right to 
decline to know or receive their HIV test results. This decision should be 
clearly documented in the participant’s medical records/source.   
• 
Karnofsky Score (Appendix 4). 
• 
Chest X-Ray: A Chest X-Ray digital image will be obtained and read locally by the 
Investigator or designee.  Digital images will be provided to the Sponsor; this process 
will be documented in the Radiology Manual.  The Investigator is responsible for 
review and analysis for participant inclusion. 
• 
Method of Birth Control: Male and Female participants and their partners. 
• 
IMP Details: Randomization 
• 
IMP Compliance/Actual Dosing 
7.2 Efficacy Variables and Procedures 
Two Spot Sputum Samples are collected, one Early Morning brought from home or collected in 
the hospital ward and one spot collected at the research site under the coaching and observation 
of the trial staff or, if no early morning sample was provided, 2 samples collected on site at least 
30 minutes apart. The Mycobacteriology sampling methodology and requirements will be 
described in a separate document, the Laboratory Manual, which will be provided prior to the trial 
start.  
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the time to 
positivity (TTP) followed by a speciation test when applicable, to confirm MTB. 
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse; 
• 
Time to Sputum Culture Conversion; 
• 
Number of participants with Sputum Culture Conversion. 
Every effort is to be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favorable) result.  A participant 
who never achieves culture negative status due to inability to produce sputum, but has completed 
26 week /78 week post treatment completion follow-up and is without clinical or biological 
evidence of relapse, will be considered to have a favorable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (Appendix 7) will record participants’ ratings of the severity of 
common TB symptoms.  
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Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the trial flow chart. Patient Reported Health Status will be collected using the EQ-5D-5L 
Health Questionnaire (Appendix 5). This descriptive system consists of five health-related 
quality of life dimensions, each of which will be recorded using five levels of severity. 
Methodology: The Patient Reported Health Status methodology and requirements will be 
described in a separate document/guideline which will be provided prior to the trial start. 
 
7.3 Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
trial flow chart and assessed for evaluation of the safety endpoints: 
• 
Laboratory parameters. The Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, which will be provided prior to 
the trial start. The following analyses will be performed: 
o Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential, platelet count),  
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, 
calcium (corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, 
creatine phosphokinase (CPK).                  
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per discretion of Investigator.  
• 
12-lead Electrocardiogram (ECG): 
o Investigator Assessment: Normal, Abnormal. 
o Central Cardiologist Assessment: Heart rate, PR interval, RR interval, QT, 
corrected QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all 
participants and will be described in a separate document which will be 
provided prior to the trial start; 
 
Participants should be lying down (recumbent) for at least 5 minutes prior 
to each 12-lead ECG evaluation; 
 
ECGs are to be recorded for 10 seconds; 
 
All ECGs are to be performed in single. 
 
ECGs should be done before any labs when both included in a visit) 
 
For each participant, the ECGs should, to every extent possible, be 
collected at approximately the same time of day (+/- 1 hours) and in the 
same fed/fast state throughout the trial (e.g. 4 hours after lunch). 
• 
Vital signs: 
o Vital Signs, including weight (should be done before any labs) 
o Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 minutes of 
rest) using an appropriately sized cuff, and using the same type of sphygmomanometer, 
if possible by the same observer, at each relevant visit. 
o Heart rate (bpm). 
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o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C). 
• 
Physical Examination:  
o Height is measured at screening only. 
o Full (complete) and Limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will be 
recorded.   
o Weight (kg) (in light clothing and with no shoes).  
o Using the observed variables weight and height, calculated body mass index (BMI) will be 
derived. 
• 
Ophthalmology Slit Lamp Examination. To be done by an Ophthalmologist trained on 
AREDS2 assessment. The ophthalmology slit lamp methodology and requirements will be 
described in a separate document, the Ophthalmology Guideline. The following analyses will 
be performed: AREDS2 opacity typing and grading. 
• 
Ophthalmic Examination. The ophthalmic examinations can be performed by any trained 
study staff. The screening exams must be done by the trained study staff AND an 
Ophthalmologist.  Methodology and requirements will be detailed in the Ophthalmology 
Guideline. 
• 
Ophthalmology History (Screening only); 
• 
Visual Acuity Test – Corrected. Distance Vision; 
• 
Color Vision Assessment. 
• 
Adverse Events. 
• 
Brief Peripheral Neuropathy Screen (Appendix 6) will record ratings. 
• 
Investigator Assessment:  
Principal Investigator to review participant status at specified visits in flow chart including any 
time Investigator determines that participant fulfills criteria for primary outcome of treatment 
failure. Investigator to assess whether TB treatment is considered a “success” or “failure”.  If 
considered a failure, should specify if based on bacteriology and/or clinical deterioration 
and/or radiological deterioration. 
7.4 PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Synopsis Flowchart 1.2) will be used to update 
population PK models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study population.  PK data from 
the current trial may be combined with prior data (e.g., from the NiX-TB trial) to enhance this 
population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between 
drug exposure and efficacy and safety endpoints.   
7.5 Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between screening through Week 4; 
• 
Pre-screening culture that was used for the tests that qualified the participant for inclusion 
into the trial to be subcultured and shipped to the central from the applicable lab for relevant 
participants/with no positive cultures from screening through week 4 and appropriate 
consent 
• 
When applicable, end of treatment or visits with positive cultures during post-treatment 
follow-up. 
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The MTB isolates will be processed at the central lab(s) for: 
• 
MIC against bedaquiline, pretomanid and linezolid;   
• 
Drug Susceptibility Testing in liquid culture for rifampicin, isoniazid, streptomycin, 
ethambutol, pyrazinamide and second line TB drugs including but not limited to 
fluoroquinolones, and injectables; 
• 
Genotyping. 
 
The MTB isolates will be processed at the central lab(s) for: Positive MTB at/after end of 
treatment: Hain MTBDRplus and HainMTBRsl 
 
8 
Adverse Events 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; In general, 
hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event. 
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Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalization, 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.   A “suspected 
transmission of infectious agent by a medicinal product” is also considered a serious adverse 
event under the SAE criterion “Other medically important condition”.   
8.1.3 Attribution/Causality 
• 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration will 
be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor/designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
Table 10: 
Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive.  The relationship in time is reasonable; 
therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event, which might be due to the use of the drug.  The 
relationship in time is suggestive, e.g., confirmed by dechallenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).   
 
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8.1.4 Severity 
Table 11: 
Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
GRADE 4 
Potentially Life-
Threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected from the signing of the ICF until the 78-week post treatment follow-up 
visit at the time points specified in the Flowchart (Section 1.2) and recorded in the case report 
from (CRF). The exception is early withdrawal participants who will only have SAEs collected from 
the time of their early withdrawal through the 78-week post treatment visit. 
Medical occurrences that begin after obtaining informed consent will be recorded as adverse 
events. If an adverse event started before signing of the informed consent, but is ongoing at trial 
start, it should be recorded as medical history.  If the pre-existing medical occurrence worsens 
during the study, and adverse event will be recorded. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of information 
becoming known to the investigator.  
The sponsor/investigator/designee will inform Regulatory Authorities and/or IEC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the IEC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in former trial participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the trial, and he/she considers the event to be reasonably related to 
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the trial treatment or trial participation, the investigator must promptly notify the sponsor, IEC/IRB 
and regulatory authorities on an expedited basis in accordance with local requirements and ICH 
guidelines for GCP. 
8.2.1 Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
Until the end of the follow-up period; and  
• 
Until all queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases follow-up will be the responsibility of the treating physician.  However, this will have 
to be agreed upon with the Sponsor Medical Monitor. 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  Investigator should contact sponsor/designee to discuss 
appropriate medical follow-up if consultation required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide sponsor/representative with a copy of any post-mortem findings including 
histopathology. 
New or updated information on an SAE will be recorded in the originally completed CRF and 
submitted to sponsor within 24 hours of the information becoming known per SAE reporting 
guidelines. 
8.2.2 Clinical Laboratory Adverse Events 
Changes in the results of the Clinical Laboratory assessment results which the Investigator feels 
are clinically significant will be reported as adverse events.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an adverse event. 
8.2.3 Disease under Study 
Symptoms of the disease under trial (Pulmonary Tuberculosis) experienced by the participant 
while on the trial will be assessed by the Investigator.  If the symptom has: 
• 
worsened while the participant is in the trial; and 
• 
the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event.  
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If there is: 
• 
no change; and  
 
• 
the Investigator assesses the symptom as due to the participant’s TB; and  
• 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation.  
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 Overdose 
Overdose of IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an Adverse Event, including if the taking of 
the suspect medicine led to suicidal intention and subsequent overdose of the suspect medicine, 
or other medication. In this case it will be recorded as an adverse event. If it does not lead to an 
Adverse Event, it will not be recorded as an AE and this will be noted in the participant’s source 
documentation. 
8.2.5 Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 Pregnancy 
The Investigator will immediately notify the sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
Investigator will report to the sponsor follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed for 6 months.   
All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following time-
periods: 
• 
During the trial 
• 
Within 6 months after last dose of IMP 
If pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow up will be performed 
unless contraindicated by the pregnancy. 
Pregnancy reporting will follow the same time lines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in preclinical toxicity 
studies Investigator’s Brochures(5,6) and Package Inserts.(23,24,25,26) 
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AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization or until the end of the follow-up period and until all queries on these AEs 
have been resolved.  Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours where possible. The recommendations for managing participants 
below assumes the laboratory abnormalities of concern have been confirmed. 
8.3.1 Neurological 
Participants with co-administration of a serotonergic agent, including anti-depressants, should be 
monitored closely for signs of serotonin syndrome.  The Investigator should determine whether 
the full regimen or the concomitant agent should be discontinued for those who experience signs 
or symptoms of serotonin syndrome such as cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
Linezolid and/or the full regimen should be paused for participants experiencing a seizure. The 
Sponsor Medical Monitor should be contacted to review details and discuss whether linezolid or 
full regimen should be resumed.  
8.3.2 ALT, AST and Alkaline Phosphatase elevations: 
The Investigator should refer to Appendix 8 – Liver Toxicity Management to appropriately manage 
the participant for clinically significant elevations of AST, ALT or Alkaline Phosphatase. 
8.3.3 Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
Contact Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 4 elevations 
of lipase, Investigator should consider pausing the full regimen, pending further evaluation. 
8.3.4 Musculoskeletal System and Cardiac Muscle 
Myalgia 
Grade 2 (muscle tenderness at site other than sites of injection and/or venipuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
Participants with Grade 2 signs and symptoms should be followed closely. Participants with Grade 
3 or 4 signs and symptoms should be discussed with the Sponsor Medical Monitor to consider 
pausing study medication, pending further evaluation. 
CPK 
For participants having elevations in CPK of potential clinical concern, the Investigator should 
check the CK-MB subunit, if high, consider pausing regimen and discuss with Sponsor Medical 
Monitor.  
8.3.5 Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
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Participants should be monitored closely.  The Investigator should discuss with the Sponsor 
Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artifacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen 
 
Monitoring Linezolid Toxicities  
The following are guidelines for decisions to pause, reduce and to resume linezolid in response 
to the onset and resolution of known linezolid-specific toxicities.  These are guidelines, and 
decisions must be made in the context of the entire clinical status of the participant.  While the 
investigator may need to urgently interrupt dosing for potentially life threatening symptoms or 
laboratory findings, the Medical Monitor should be contacted and informed of any changes in dose 
within 24 hours.  Questions should be raised to the Sponsor’s Medical Monitor if the decision is 
not clear. 
8.3.6 Myelosuppression 
The hematologic parameters of hemoglobin and counts of Neutrophils and platelets are variable 
from measurement to measurement.  While decreases in any of these may be caused by linezolid 
toxicity, decreases of concern should be evaluated in the context of the participant’s full clinical 
status and alternate explanations.  Guidelines below are for situations of concern when it is 
considered likely that linezolid has caused the decrease. 
Anemia 
• 
Consider pausing linezolid if hemoglobin falls below 8 gm/dL (Grade 3) and significantly 
below baseline, or if hemoglobin falls > 25% of baseline. If it is clear that the anemia was 
caused by linezolid, consider resuming linezolid at half the dose when hemoglobin 
improves and linezolid is resumed.  
Leukopenia 
• 
Consider pausing linezolid if the Absolute Neutrophil Count (ANC) falls below 750/mm3 
(Grade 3) and significantly below baseline.  Ideally confirm with a repeat test before 
making further decisions as ANCs can have diurnal and other variability. If it is clear that 
the leukopenia was caused by linezolid, consider resuming linezolid at half the dose when 
ANC improves and linezolid is resumed.  
Thrombocytopenia 
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• 
Consider pausing linezolid if platelets fall below 50,000/mm3 (Grade 3) and significantly 
below baseline. Ideally confirm with a repeat test before making further decisions.  If it is 
clear that the thrombocytopenia was caused by linezolid, consider resuming linezolid at 
half the dose when platelets improves and linezolid is resumed. 
8.3.7 Peripheral Neuropathy 
The decision to reduce the dose, or to pause linezolid until symptoms improve is a judgment 
based on changes in signs and symptoms identified by the investigator and informed by 
discussion with the trial participant.  As general guidance, consider pausing and/or reducing 
linezolid when the grade of a neuropathy sign or symptom increases by a grade to grade two or 
greater.  If it is clear that linezolid caused the neuropathy, consider resuming linezolid at half the 
dose, when the neuropathy improves. 
8.3.8 Optic Neuropathy 
A participant with visual symptoms of concern or change in visual acuity of 2 lines or more or 
change in color vision of more than one plate should be referred to the site ophthalmologist for 
evaluation with a retinal examination.  Any changes as assessed by the ophthalmologist that raise 
concern that an optic neuropathy may be developing should be discussed with the medical 
monitor and linezolid should be paused.  If a likely or definite optic neuropathy is confirmed, 
linezolid should be permanently discontinued. 
8.3.9 Lactic Acidosis 
Lactic acidosis as a toxicity of linezolid should be considered if participants have gastrointestinal 
symptoms that are not explained by other more common causes of their symptoms.  Such 
participants should have lactate measured and, as indicated, a full evaluation of pH and 
bicarbonate. Note that lactate should not be measured in participants who have no symptoms of 
concern, as elevated asymptomatic lactate may be common and it is difficult to interpret the 
clinical relevance of this. Also evaluate whether any concomitant medications, such as anti-
retroviral therapies, may be associated with lactic acidosis and consider pausing them until the 
acidosis resolves. Consider pausing linezolid if a patient has GI symptoms and acidosis likely to 
be secondary to linezolid toxicity that is not otherwise explained. 
8.4 Safety Monitoring by Data Monitoring Committee 
A DSMC will be appointed for the study. The primary responsibility of the DSMC will be to act in 
an advisory capacity to the Sponsor to safeguard the interests of trial participants by monitoring 
participant safety, assess participant risk versus benefit, and assess data quality and general 
evaluation of the trial progress. Its activities will be delineated in a DSMC charter that will define 
the membership, responsibilities and the scope and frequency of data reviews. The DSMC will 
operate on a conflict-free basis independently of the Sponsor and the study team. It will comprise 
at least 3 voting members that include at least 2 clinicians and one statistician.  The DSMC may 
have an organizational meeting prior to commencement of the trial. The DSMC will have meetings 
where it will review unblinded data during a closed session. These meetings will be planned at 
regular intervals. The Sponsor or the DSMC may convene ad hoc meetings based on rates of 
SAEs and/or to review results of the futility analysis or if safety concerns arise during the trial.  
After its assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
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9 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 Analysis Population 
The primary analysis population will include both XDR and non-XDR (pre-XDR and MDR 
intolerant and non-responsive TB) participants (up to 45 per arm).  A secondary analysis will be 
restricted to the XDR participants only (30 per arm).    
A modified intent-to-treat (mITT) and a per-protocol (PP) analysis for each arm and analysis 
population will be conducted.    The mITT will be considered the primary analysis and will include 
all those in the ITT analysis with additional specific exclusions detailed in the statistical analysis 
plan (SAP). 
Other analyses will be performed (for sensitivity) including a full intent-to-treat (ITT) analysis with 
no exclusions, and an analysis excluding only those who were later found to be ineligible at 
baseline (based on data collected prior to randomization).    
The Safety analysis population will include data from all randomized participants who received at 
least one dose of IMP.  
Full details of all the analysis populations will be defined in the SAP. 
9.2 Sample Size 
The objective of this trial is to evaluate the efficacy, safety and tolerability of various doses and 
durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants 
with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
In order to fulfil this objective, it is planned to randomize 30 XDR-TB participants per treatment 
group and up to 15 pre-XDR and/or MDR intolerant/non-responsive -TB participants per group. A 
sample size of 30-45 per arm will provide more than 90% power to demonstrate that the lower 
bound of the 95% confidence interval of this estimate is greater than 50%, using a 2-sided 5% 
significance level. This assumes that the true cure rate is 80 percent.   
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as 
the target, because it is above the entire range of the historical control for cure of XDR-TB and 
because a cure rate of 50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a 
shortened, simplified, all oral, inexpensive and safer regimen would clearly represent an important 
therapeutic advancement. A standard-of-care control group cannot reasonably be included in the 
trial for several reasons.  1) Given that the regimens being tested contain B and L, these drugs 
would need to be excluded from the control group.  However, they are beginning to be used 
increasingly in XDR-TB, despite lack of firm evidence, but with positive anecdotal reports.  Asking 
patients in the control group to avoid these medications could present an ethical issue.  2) The 
success rate of standard-of-care treatment for XDR-TB, particularly without B and L (see below), 
and the risk and difficulty of its administration contrast markedly with the early findings of B-L-Pa 
in the Nix-TB trial.  It is unlikely that patients would sign informed consent to receive standard-of-
care treatment if there is an alternative, but even if they do there remains an ethical issue of 
comparing such a disadvantaged treatment with such an advantaged treatment.  3) The scientific 
validity of comparing a 12-month endpoint (B-L-Pa) with a 30- or 36-month endpoint (standard of 
care) would represent a significant challenge.   
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9.3 Interim Analyses 
No formal interim analyses are planned.  Primary analysis will be performed on the 26 week 
follow-up data (after end of treatment when the last randomized participant has completed 26 
weeks of follow-up after end of treatment). 
There will be either two database locks, data analyses and trial reports generated for this trial:  
1. 
When all participants have completed 26 weeks of follow-up after end of treatment.  
2. 
When all participants have completed 78 weeks of follow-up from after end of treatment.  
9.4 Primary and Secondary Endpoint Analysis 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT). 
A secondary analysis will be restricted to the XDR participants only (30 per arm). We will 
evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that 
the incidence of bacteriologic failure or relapse or clinical failure (including mortality) at 6 months 
(26 weeks) after the end of therapy is less than 50%.   
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and 
safety and to control the overall type I error rate the following analysis strategy will be adopted 
for both the primary and secondary analysis populations: 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 
weeks) with the L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a 
success.  Similarly, L600 9 weeks will only be tested if L600 26 weeks is a success.   A 
Bonferroni adjustment will be made for comparing the L1200 9 weeks and L600 26 weeks arms 
simultaneously, using p<0.025.  For these comparisons the lower bound of the 97.5% 
confidence interval will need to exceed 50% for success.   
No formal statistical pairwise comparisons between the arms will be performed. 
9.5 Safety and Tolerability Analysis 
• 
The incidence of all-cause mortality will be summarized. 
• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake.  Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
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o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
• 
Cardiovascular Safety:  QT intervals will be adjusted using Fridericia’s correction and Bazett’s 
correction. QT/QTc values and changes from pre-dose (average of Screening and Day 1 
values) at each time point will be summarized using descriptive statistics by group and time 
of collection.  These will be presented as descriptive analyses, and no inferential tests will be 
carried out. 
o Post-baseline QT/QTc intervals will be classified into the following categories:   
 
QT/QTc < 450 msec 
 
450 msec < QT/QTc < 480 msec 
 
480 msec < QT/QTc < 500 msec 
 
QT/QTc > 500 msec   
o QTc changes from baseline will be classified into the following categories: 
 
increase < 30 msec,  
 
30 msec and < 60 msec, and  
 
increase > 60 msec.  
o Frequency counts will be used to summarize the number of participants at each 
time point according to the above categories. 
o ECG results will be classified as normal or abnormal (investigator assessment) 
and summarized using frequency counts by dose group and time of collection. 
• 
Ophthalmology: Descriptive statistics, including changes from baseline, will be summarized 
and listed by participant for ophthalmology slit lamp examination (age related eye disease 
study 2 [AREDS2] lens opacity classification and grading). Categorical data for lens opacity 
will be summarized in a frequency table for the right and left eye, respectively.  
• 
Visual acuity and color vision:   Descriptive statistics, including changes from baseline, will be 
summarized and listed by participant for both Visual Acuity and Color Assessments. 
Categorical data for changes in visual acuity and color vision from baseline will be summarized 
in a frequency table for the right and left eye, respectively.  
• 
Descriptive statistics of neuropathy data derived from Brief Peripheral Neuropathy Screen. 
Categorical data for observed signs and symptoms of neuropathy will be summarized in 
frequency tables, including changes in signs and symptoms from baseline.  
• 
Other safety variables: Laboratory Parameters, Physical Examination, Vital signs (see 
Appendix 3), Concomitant medication, ophthalmic examination and peripheral neuropathy.  
Descriptive summary statistics will be presented. The incidence of liver related laboratory 
abnormalities will be explored. 
9.6 Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
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In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update population pharmacokinetic 
(PopPK) models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study population, and to derive 
individual exposure metrics for use in exposure-response analyses. PK data from the current trial 
may be combined with prior data (e.g., from the NiX-TB trial) to enhance this population PK 
analysis. Detailed plans for the PopPK analysis will be outlined in a separate modeling plan, and 
results will be reported in separate modeling report. 
9.7 Pharmacokinetics/Pharmacodynamics 
For each analyte, the PopPK model will be used to derive individual exposure metrics such as 
steady-state Ctrough, Cmax, AUCτ, and time-above-minimum-inhibitory-concentration (T>MIC), 
or alternative individual summaries of these metrics over the treatment period to account for dose 
adjustments and interruptions as appropriate. Relationships between such exposure metrics and 
efficacy and safety endpoints will be explored graphically and by model-based analyses as 
appropriate. Planning details and results will be included in the separate modeling plan and report. 
10 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants specific eCRF pages will be 
completed as described in the eCRF Completion Guidelines.  For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-Patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator 
has 
to 
permit 
trial 
related 
monitoring, 
audits, 
Independent 
Ethics 
Committee/Institutional Review Board (IEC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-Patient records while participants is on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial center files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection subsequent to trial completion.  The essential documents should be retained for 
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not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify sponsor/designees 
prior to destroying any records pertaining to the trial. 
11 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the Declaration 
of Helsinki.  
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures will be adhered to for all clinical and bioanalytical activities 
relevant to the quality of the trial.  Participant compliance will be monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-investigators. Written 
IEC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for the purpose of monitoring various aspects of the trial, and to assure appropriate conduct of 
the trial in accordance with ICH GCP.  Visits will take place usually within a predetermined interval, 
but this may vary during the course of the trial.  The Investigator and site staff will allow the trial 
monitor and authorized representatives of the Sponsor to (1) inspect all CRFs, written informed 
consent documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs, training records, facilities and other trial related 
systems/processes, and (2) access clinical supplies, dispensing and storage areas.  The 
Investigator and site staff should also (1) agree to assist with monitoring activities if requested 
and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
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maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Monitoring Plan 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. 
11.4 Auditing 
For the purpose of compliance with International GCP and regulatory agency guidelines, it may 
be necessary for Sponsor-authorized Quality Assurance personnel and/or authorized personnel 
from an external regulatory agency to conduct an audit or inspection of the investigational site.  
The purpose of an audit is to assess the quality of data with regard to accuracy, adequacy and 
consistency, and to assure that studies are in accordance with the guidelines.  Having the highest 
quality data from studies is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by GCP to be maintained 
by each site; drug storage, dispensing and return; all trial-related supplies; and source documents 
against the CRFs to assure the adequacy and accuracy of the information which has been 
recorded, including the verification of any AEs which have occurred. The auditors or inspectors 
may also review site SOPs, training records, site facilities and other trial related 
systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
12 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles that 
have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review 
The protocol and required trial related documents will be reviewed by the sites respective 
IEC/IRB.  The trial will not start until the IEC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, plus 
any other trial related documents required for review.  The IEC/IRB shall be constituted and shall 
operate in accordance with International GCP, the ethical principles that have their origin in the 
Declaration of Helsinki. The Investigator will maintain an accurate and complete record of all 
submissions made to, and responses from the IRB/IEC.  The records should be filed in the 
Investigator’s Trial File, and copies will be sent to the Sponsor. 
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12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for the purpose of determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
considered to be part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary The investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same IEC/IRB responsible for approval of this protocol.  Each 
informed consent form shall include the elements required by the international GCP and must 
adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
ICF. 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the IEC/IRB approved written informed consent form 
will be signed and dated by both the participant and the person obtaining consent (Investigators 
or designees), and by any other parties required by the IEC/IRB. Ongoing participants must be 
re-consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative.  Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s 
medical record. 
The monitor will inspect the original completed consent form(s) for all participants 
12.5 Confidentiality  
All site staff, the Sponsor, and any sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations.  Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
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permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the sponsor or designees. 
13 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible IEC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors. (30)  
Because the Study is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Study must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Study must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
14 Protocol Amendment Policy 
Any change to the protocol will be effected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the IEC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, IEC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant Authorities 
and/or IEC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the IEC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
15 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial sponsor is the Global Alliance for TB Drug Development (TB Alliance).  The TB Alliance 
is a not for profit, product development partnership accelerating the discovery and development 
of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, 
be compatible with antiretroviral therapies for those HIV-TB participants currently on such 
therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
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The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The sponsor certifies that it has liability insurance coverage for itself and will provide an associated 
certificate upon request.  The insurance does not relieve the Investigators of the obligation to 
maintain their own liability insurance as required by applicable law. The sponsor does not assume 
any obligation for the medical treatment of other injuries and illnesses.
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16 References  
1. “A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis”. ClinicalTrials.gov, 25 
January 2017. https://www.clinicaltrials.gov/ct2/show/NCT02333799 
2. Bonilla CA, Crossa A, Jave HO, Mitnick CD, Jamanca RB, Herrera C, Ascencios L, 
Mendoza A, Bayona J, Zignol M and Jaramillo E (2008).  “Management of Extensively 
Drug-Resistant Tuberculosis in Peru: Cure Is Possible”. PLoS One 3(8): e2957. 
3. Cox H, Ford, N. “Linezolid for the treatment of complicated drug-resistant tuberculosis: a 
systematic review and meta-analysis” INT J TUBERC LUNG DIS 16(4):447–454, 2012.  
4. Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, van Niekerk C, 
Erondu N, Ginsberg AM, Becker P and Spigelman MK (2012). “Phase II Dose-Ranging 
Trial of the Early Bactericidal Activity of PA-824”. Antimicrobial Agents and Chemotherapy; 
56(6): 3027-3031.  
5. Bedaquiline (TMC207) Investigator’s Brochure, Janssen Research and Development, 
Edition 9, 09 October 2015.  
6. Investigator’s Brochure Pretomanid (PA-824), Global Alliance for TB Drug Development, 
Version 17, 22 December 2016.  
7. Keshavjee S, Gelmanova IY, Shin SS, Mishushtin SP, Andreev YG, Atwood S, Furin JJ 
and Miller A (2012). “Hepatotoxicity during treatment for multidrug-resistant tuberculosis: 
occurrence, management and outcome”. Int J Tuberc Lung Dis 16(5):596-603.   
8. Leach KL, Brickner SJ, Noe MC, Miller PF. "Linezolid, the first oxazolidinone antibacterial 
agent" Ann NY Acad Sci. 2011 Mar; 1222:49-54. 2011.  
9. Lee, et al. "Linezolid for treatment of chronic extensively drug-resistant tuberculosis" N 
Engl J Med. 2012 Oct 18; 367(16):1508-18. 
10. Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, 
Reynolds RC, and Orme IM. “Preclinical Testing of the Nitroimidazopyran PA-824 for 
Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models” 
Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301. 
11. Lytvynenko N, Cherenko S, Feschenko Y, Pogrebna M, Senko Y, Barbova A, Manzi M, 
Denisiuk O, Ramsay A and Zachariah R (2014). “Management of multi and extensively 
drug resistant tuberculosis in Ukraine: how well are we doing?” IUALTD Public Health 
Action 4(3): S67-S72. 
12. Manjunatha U, Boshoff HI, Berry CE. The mechanism of action of PA-824: novel insights 
from transcriptional profiling. Commun Integr Biol. 2009; 2(3):215-218. 
13. Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton, JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci USA. 2006; 103(2):431-436. 
14. McLeay SC, Vis P, van Heeswijk RPG and Green B (2014). “Population Pharmacokinetics 
of Bedaquiline (TMC207), a Novel Antituberculosis Drug”. Antimicrobial Agents and 
Chemotherapy 58(9): 5315-5324. 
15. Mdluli K, Nuermberger, E. “Pre-Clinical Drug Combination Studies to Identify Novel 
Regimens for TB”. In: Recent Advances in TB Drug Development symposium, 40th Union 
World Conference, International Union Against TB and Lung Disease, Cancun, Mexico, 
2009. 
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16. Mdluli K, Nuermberger E, Taylor K, Williams N, Koen A, Khisimuzi E, Rokeya T, Si-Yang 
L, Peloquin C, Dinesh C. “Sterilizing activity of novel TMC207- and PA-824-containing 
regimens in a murine model of tuberculosis” Antimicrobial Agents and Chemotherapy 
2011; 55: 5485-5492. 
17. Migliori GB, Sotgiu G, Gandhi NR, Falzon D, DeRiemer K, Centis R, Hollm-Delgado MG, 
Palmero D, Perez-Guzman C, Vargas MH, D’Ambrosio L, Spanevello A, Bauer M, Chan 
ED, Schaaf HS, Keshavjee S, Holtz TH, Menzies D and “The Collaborative Group for 
Meta-Analysis of Individual Patient Data in MDR-TB” (2013). “Drug resistance beyond 
XDR-TB: results from a large individual patient data meta-analysis”. Eur Respir J. 42(1): 
169-179.  
18. Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006; 50(8):2621-2625. 
19. Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal, I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 2008; 
52(4):1522-1524. 
20. Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005; 172(11):1452-1456. 
21. O’Donnell MR, Padayatchi N, Master I, Osburn G and Horsbaugh CR. “Improved Early 
Results for Patients with Extensively Drug Resistant Tuberculosis and HIV in South 
Africa”. Int J Tuberc Lung Dis. 13(7): 855-861. 
22. Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
23. Package Insert for South Africa, ZYVOXID® (linezolid), Pfizer Pharmaceuticals, May 
2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=1045. Date last accessed: 15 April 
15 2016.  
24. Package Insert, Lizomac™ 600 (linezolid), MacLeods Pharmaceutical, 2014. 
25. Package 
Insert, 
SIRTURO®, 
Janssen 
Therapeutics, 
December 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204384s006lbl.pdf. Date last 
accessed: 15 April 2016. 
26. Package 
Insert, 
ZYVOX®, 
Pfizer 
Pharmaceuticals, 
June 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021130s030,021131s029,02
1132s034lbl.pdf. Date last accessed: 15 April 2016.  
27. Park IN, et al. “Efficacy and tolerability of daily-half dose linezolid in patients with 
intractable multidrug-resistant tuberculosis.” B Antimicrobial Chemotherapy 2006; 58:701-
704. 
28. Pietersen E, et al. "Long-term outcomes of patients with extensively drug-resistant 
tuberculosis in South Africa: a cohort study" Lancet, 2014 Jan 16. pii: S0140-
6736(13)62675-6.  
29. Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, Vasilyeca I, 
Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, Van 
Baelen B, van Heeswijk RPG and Dannemann B (2016). “Bedaquiline safety data in a 
broad patient population treated for drug-resistant TB including XDR-TB (C209 study)”. 
Tuberculosis 47: 394-402.  
30. “Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in 
Medical Journals”, December 2016 update.  http://www.icmje.org/icmje-recommendations.pdf,  
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31. Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578.  
32. Schecter GF, et al.  “Linezolid Treatment for MDR-TB”. Clinical Infectious Diseases 2010; 
50:49-55. 
33. Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008; 
322(5906):1392-1395. 
34. Singla R. "Linezolid: an Effective, Safe and Cheap Drug for Patients Failing Multidrug-
resistant Tuberculosis Treatment in India" Eur Respir J. 2012 Apr; 39(4):956-62. doi: 
10.1183/09031936.00076811. Epub 2011 Sep 29. 
35. Stover, C. K., P. Warrener, D. R. VanDevanter, et al. 2000. “A small-molecule 
nitroimidazopyran drug candidate for the treatment of tuberculosis”. Nature 405:962–966. 
36. Tasneen R, Betoudji F, Tyagi S, et al.  Contributions of oxazolidinones to the efficacy of 
novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis.  
Antimicrob. Agents Chemother Posted Online 26 October 2015.  Dol:10.1128/AAC.01691-
15. 
37. Tasneen R, Tyagi S, Williams K, Grosset J, Nuermberger E. “Enhanced bactericidal 
activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of 
tuberculosis”. Antimicrob Agents Chemother. 2008; 52(10):3664-3668. 
38. Tato M, et al. "In vitro activity of linezolid against Mycobacterium tuberculosis complex, 
including multidrug-resistant Mycobacterium bovis isolates". Int. J. Antimicrob Agents 
2006 Jul; 28(1)75-8.  
39. Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”.  
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
40. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. Bactericidal 
activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2005; 49(6): 2289-2293. 
41. WHO Treatment of Tuberculosis Guidelines, 4th Edition. 2010.  
42. World Health Organization. Global Tuberculosis Report 2014, 19th ed. 2014. 
43. World Health Organization. Global Tuberculosis Report 2015, 20th ed. 2015. 
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Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
exact figure/100/scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at 
least 20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life-
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization 
or hospice care probable. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common Toxicity 
Criteria (CTC), and World Health Organization (WHO)) have been adapted for use by the 
Division of Microbiology and Infectious Diseases (DMID) and modified to better meet the 
needs of Patients in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life-
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
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Hypocalcemia 
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life-
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life-
threatening arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function are in the  
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase  
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
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Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, with or 
without clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment required 
acute treatment 
required; 
outpatienttreatm
ent or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock;   
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
50% - 70% (of peak 
flow) 
no normalization with 
bronchodilator;FEV1 
25% - 50% of peak 
flow; or  retractions 
present 
cyanosis: FEV1 < 
25% of peak flow 
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea with normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
 
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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3-
4 loose stools/day 
or mild diarrhea 
last < 1 week 
moderate or 
persistent; 5-7 loose 
stools/day or 
diarrhea lasting >1 
week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization   
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
 
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NEUROLOGICAL 
 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
weakness no 
objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function 
objective 
weakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment  required 
moderate 
discomfort; non-
narcotic analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment (mod 
decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod 
degree in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis;  or 
seizures 
 
 
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MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics and/or 
pain interfering with 
function but not with 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain with 
inflammation, 
erythema or joint 
swelling – interfering 
with function, but 
not with activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected Stevens-
Johnson or  
necrosis requiring 
surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection 
Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 
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SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial narcotic 
therapy 
intractable; requires 
repeated narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 50% 
> 48 hours 
normal activity 
decreased > 50% 
can’t work 
unable to care for 
self 
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Appendix 3:  Cardiovascular Safety 
 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 90 mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or 
Grade 4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
 
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Appendix 4:  Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms of 
disease.  
80 
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
Cares for self; unable to carry on normal activity or to 
do active work. 
70 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
60 
Requires considerable assistance and frequent medical 
care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109(22). 
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Appendix 5:  EQ-5D-5L Questionnaire 
 
 
 
Under each heading, please tick the ONE box that best describes your health TODAY 
MOBILITY 
I have no problems in walking about 
I have slight problems in walking about 
I have moderate problems in walking about 
I have severe problems in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities) 
I have no problems doing my usual activities 
I have slight problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe problems doing my usual activities 
I am unable to do my usual activities 
PAIN / DISCOMFORT 
I have no pain or discomfort 
I have slight pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
• • • • • 
• • • • • 
• • • • • 
• • • • • 
• • • • • 
UK (English) v.2 C 2009 EuroQol Group. EQ-50"' Is a trade marlc of the EuroQol Group 
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• 
We would like to know how good or bad your health is 
TODAY. 
• 
This scale is numbered from O to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TODAY. 
• 
Now, please write the number you marked on the scale in the 
box below. 
YOURHEALTHTODAY = D 
3 
UK (English) v. 2 C> 2009 EuroQol Group. EQ-5D.,. is a trade merlc of the EuroQol Group 
The best health 
you can imagine 
100 
The worst health 
you can imagine 
95 
90 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
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Appendix 6:  Brief Peripheral Neuropathy Screening 
 
During Treatment 
Screening 
Week 
4 
Week 
8 
1. Visit 
{Circle One) 
Post Treatment 
12 Week 
26 Weeks 
52 Weeks 
78 Weeks 
Unscheduled 
Other 
End of or Early W ithdrawal 
from Treatment 
For ne,w onset or worsening peripheral ~
lhy OR 
lreabnent e):lension (+ ci.lture or interru,p6ons) 
2. Date of Assessment 
.. 
3. In the last two weeks, have pain, aching or burning in your feet interfered with your 
walking or sleeping? (Check one) 
If YES, as/<. the patient to rate the level of interference (1 to 10/ to his wall<.ing or steeping caused by this pain, 
ache or burning (circle one). 
3a. 
Minimal 
Modest 
Severe 
01 
02 
03 
08 
09 
10 
Using the faces below, ask the patient to rate the severity of the symptoms for the questions 4, 5, 6 on a scale 
of 1 (mild/ to 10 (severe) for both feet. If the severity is different between the left and right foot, record the 
s-everity of the most affected foot. 
Enter a score for each symptom. 
If a symptom has been present in the past, but not since the last visit, enter '00 - CurrenYy Absent' 
If a symptom has never been present, enter '11 - AIIVays Been Normal' 
® ® 
00 
02 
04 
06 
08 
10 
Very Happy, 
No Symptoms 
Just a little brt 
A little more 
Even more 
A whole lot 
Worst 
During the last 14 days, have 
you experienced: 
4. Pain, aching or bunning in feet or legs? 
5. "Pins and needles• in feet or legs? 
6. Numbness (lack of feeling) in feet or legs? 
19-Jan.17 ve™on 
Severity 
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• 
Press the ends of a 128 Hz tuning fork together so the sic/es touch and let g:J. Place the vibrating tuning fork 
on the bony prominence on the patient's wrist to be sure that they can recognize the vibration or "buzzing" 
quality of the tuning fork. 
• 
Again, press the ends of the tuning fork /1ard enour;/1 so that the sides touch and let g:J. Immediately place the 
vibrating tuning fork gently but firmly on the top of the distal interphalangeal (DIP) joint of the g-eat toe and 
begn counting the seconds. Instruct the Subject to tell you when they stop feeling the vibration or "buzzing" 
• 
Repeat for the g-eat toe on the other foot 
Vibration Perception Grade Scale: 
0 - Vibration felt for > 10 seconds (normal) 
1 - Vibration felt for 6-10 seconds (mild loss) 
2 - Vibration felt for 5 seconds or less (moderate loss)* 
3 - No feeling of vibration (severe loss)• 
9 - Unable to evaluate or did not assess• 
7. Measured vibration grade of great toe DIP joint 
Right 
Left 
• 
T/Je examiner uses one hand to press upward on t/Je ball of t/Je foot, dorsiflexing t/Je Subject's ankle to 90 
deg-ees. Using the reflex hammer (preferably long /Jane/led), the examiner strikes the Ac/Ji/Jes tendon. 
• 
The tendon reflex is felt by the examiner's /Janel as plantar flex ion of the foot, appearing after a slight delay 
from the time the Achilles /enc/on was struck. 
• 
Repeat for ankle on other leg 
Ankle reflex grade scale: 
0 - Absent 
1 - Hypoactive 
2 - Normal deep tendon reflexes 
3 - hyperactive deep tendon reflexes (e.g. with prominent spread of toes) 
4 - clonus 
9 - unable to evaluate or did not assess 
Right 
8. l'vleasured ankle reflex grade 
Name of Person 
Name of Clinician 
Comoletino Form 
(if required) 
Signature of Person 
Signature of Clinician 
Completing Form 
(ifn!!quited) 
Date I 
I 
I 
I 
I 
I 
I 
I 
Date I 
I 
19-Jan-17 version 
Left 
I 
I 
I 
I 
I 
I 
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Appendix 7:  Tuberculosis Symptoms Profile 
 
 
TUBERCULOSIS SYMPTOM PROFILE {V3) 
This questionnaire asks about symptoms that patients with tuberculosis may or may not experience. 
Please read each symptom carefully and think about your experience during the past 7 days when you make your 
response. Then tick (611) one box for each symptom. 
If you did not experience the symptom during the past 7 days, please tick (0) HNone" for that symptom. 
If you did experience the symptom during the past 7 days, please tick (611) whether the intensity of the 
symptom you experienced was "Mild", "Moderate" or "Severe". 
TB Symptom 
Rate your experience of each symptom over the past 7 days. 
Feeling feverish 
• None 
• Mild 
D Moderate 
D Severe 
Feeling chills 
• None 
• Mild 
D Moderate 
D Severe 
Excessive sweating 
• None 
• Mild 
D Moderate 
D Severe 
Shortness of breath 
• None 
• Mild 
D Moderate 
D Severe 
Chest pain 
• None 
• Mild 
D Moderate 
D Severe 
Feeling unwell 
• None 
• Mild 
D Moderate 
D Severe 
Tiredness/weakness 
• None 
• Mild 
D Moderate 
D Severe 
Cough 
• None 
• Mild 
D Moderate 
D Severe 
Coughing up mucus 
• None 
• M,ld 
D Moderate 
D Severe 
Coughing up blood 
• None 
• Mild 
D Moderate 
D Severe 
During the past 7 days, how would you rate your appetite? 
• Good 
D Fair 
D Poor 
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Appendix 8:  Liver Toxicity Management 
Standard anti-TB chemotherapy is known to cause derangement of liver function tests in a 
substantial number of patients. In many cases this will be asymptomatic and self-limiting. In some 
cases, severe hepatitis and even fulminant liver failure and death can occur.  
In pre-marketing clinical trials of new drugs and regimens it is especially important to identify and 
carefully manage any trial participants who are at risk of progression to serious liver injury.  The 
observation of altered liver function to a degree that has a high risk of progressing to liver failure 
has been referred to informally as Hy’s Law;(31,39); this reflects that pure hepatocellular injury 
sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, Hy’s Law cases have the following three components:  
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo.  
2. Among trial participants showing such aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show elevation of serum total bilirubin (TBL) 
to >2x ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase 
(ALP)).  
3. No other reason can be found to explain the combination of increased AT and total bilirubin 
level (TBL), such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury.  
During the trial, liver function will be monitored regularly with clinical assessment and blood tests 
in study participants and this will assist in follow up laboratory measurements that can document 
either resolution of abnormalities or signal the potential for drug-induced liver injury (DILI).  In a 
clinical trial of new drugs and combinations it is especially important for investigators to follow 
closely any participants who have evidence of hepatic inflammation or potential toxicity. The 
following procedure describes the management of deranged liver function tests in study 
participants. 
Procedure 
Blood tests for liver function will be taken routinely at screening (Day -9 to -1) and at the specific 
time points designated in the protocol, and at Early Withdrawal.  If at any other visit the clinician 
suspects derangement of liver function, e.g. the participant describes nausea and vomiting, right 
upper abdominal pain or is jaundiced, blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of hepatitis or hepatic impairment and any 
potentially contributing causes.  
Suspected liver toxicity (or elevated liver enzymes detected in the absence of symptoms) must 
be taken seriously and detailed guidance will be provided in a separate document “NC-007 Study 
Management of Hepatotoxicity Guideline”. Investigators should refer to this document as a guide 
to management in cases of suspected or proven liver toxicity.  Importantly, the trial Medical 
Monitor is available to provide further assistance if there is any uncertainty or additional questions. 
The laboratory source (print-out of any results) should be stored alongside or transcribed into the 
clinical source document. Each abnormal value should be marked as clinically significant (CS) or 
non-clinically significant (NCS); the assessment of significance is at the discretion of the 
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investigator. All clinically significant abnormal results must be recorded as Adverse Events in the 
eCRF and graded clinically as per the DMID adult toxicity table grading, (Appendix 2).  
Assessments and decision making for elevations in aminotransferase values or bilirubin of various 
levels of concern are detailed below: 
Elevated liver enzymes considered of clinical significance, but not accompanied by other signs 
and symptoms, should be reported as an adverse event and should usually be recorded as 
elevated liver enzymes. If the term "hepatitis" is used, the Safety Data Manager will question the 
site for additional evidence to support the diagnosis, such as clinical signs and serological or 
biopsy data. While a liver biopsy is not required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for cases where there is supportive evidence 
beyond a liver enzyme abnormality. However, if the investigator will confirm the diagnosis of 
hepatitis just on the basis of clinical signs and laboratory values the diagnosis will be accepted. 
Should other symptoms or signs be present, these should also be recorded as adverse events. 
Restarting Medication 
Liver function tests that are improving should be repeated regularly, such as every 3 days for the 
first week then once a week until they return to near baseline values for the participant. Manage 
the participant symptomatically as required using medications that are not potentially hepatotoxic. 
Infection control issues must be carefully managed whilst TB medications are being withheld, 
especially if the participant is still culture positive for acid fast bacilli. 
If medication has been temporarily stopped, once the liver function values have decreased 
substantially a decision must be made about further TB management.  This will be dependent on 
the clinical context and a decision must be made in discussion with the sponsor medical monitor. 
Treatment can only be restarted if the trial Medical Monitor is in agreement with the plan. In all 
cases treatment should be recommenced under close supervision for any evidence of recurrent 
liver function abnormalities.  
If there is a further significant elevation of hepatic enzymes or bilirubin or symptoms of clinical 
concern after resumption of study medication, the study medication should be withdrawn 
permanently. Participants who permanently discontinue study medication should be managed as 
clinically indicated according to local National TB Programme guidelines. The sponsor medical 
monitor can be contacted for further advice when referring to the National Treatment Program. 
The trial Medical Monitor is available to assist the Investigators in both the management of liver 
toxicity and decisions regarding the holding or re-introduction of trial medication. Investigators 
must involve the Medical Monitor in any decisions regarding medication hold or re-start, and there 
should always be a low threshold for contacting the Medical Monitor in cases of elevated liver 
enzymes. 
-
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CONFIDENTIAL  
Protocol Number 
NC-007-(B-Pa-L)  
Title: 
A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid 
plus bedaquiline and pretomanid in participants with pulmonary 
infection of either extensively drug-resistant tuberculosis (XDR-
TB), pre-XDR-TB or treatment intolerant or non-responsive multi-
drug resistant tuberculosis (MDR-TB). 
Drug(s)/Combination(s): Bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Initial Protocol 
Version/Date:  
1.0 RUS/BEL 28 February, 2017 
Protocol Name: 
ZeNix 
 
 
0-
TB ALLIANCE 
GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT 
ZeNix 
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TB ALLIANCE 
Q 
GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT 
ZeNIK 
PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolld plus 
bedaquillne and pretomanld in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XOR-TB), pre-XOR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MOR-TB}. 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version and Date: 1.0 RUS/BEL 28 February, 2017 
Protocol Name: ZeNix 
SPONSOR 
Date 
LEAD INVESTIGATOR 
Printed Name 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone 646-616-8671 
email: daniel.everitt@tballiance.org 
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and local 
regulat~ 
t'ren.c.e,scc:c. Co/vY~ 
Signatur 
Printed Name 
Date 
CONFIDENTIAL 
Page 2 of99 
102 of 784


 
CONFIDENTIAL 
Page 3 of 99 
 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-resistant 
tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug 
resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version and Date: 1.0 RUS/BEL 28 February, 2017 
Protocol Name: ZeNix 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
Q 
TB ALLIANCE 
GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT 
ZeNix 
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Page 4 of 99 
1 
Synopsis ............................................................................................................................................ 10 
1.1 
Synopsis Summary .................................................................................................................. 10 
1.2 
Synopsis Flowchart .................................................................................................................. 15 
2 
Introduction and Rationale .............................................................................................................. 20 
2.1 
Trial Rationale ........................................................................................................................... 21 
2.1.1 
Trial Design Rationale ..................................................................................................... 21 
2.1.2 
Trial Drug Rationale ......................................................................................................... 21 
2.1.3 
Pretomanid ........................................................................................................................ 23 
2.1.4 
Linezolid ............................................................................................................................. 23 
2.2 
Agents to be Studied ............................................................................................................... 24 
2.2.1 
Bedaquiline ........................................................................................................................ 24 
2.2.2 
Pretomanid ........................................................................................................................ 27 
2.2.3 
Linezolid ............................................................................................................................. 33 
2.3 
Regimens to be Studied .......................................................................................................... 38 
2.3.1 
Non-Clinical Studies ......................................................................................................... 38 
2.3.2 
Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or Linezolid ... 39 
2.4 
Overall Benefit/Risk Assessment ........................................................................................... 43 
3 
Trial Objectives ................................................................................................................................. 44 
3.1 
Primary Objectives ................................................................................................................... 44 
4 
Trial Design ....................................................................................................................................... 44 
4.1 
Summary of Trial Design ......................................................................................................... 44 
4.2 
Treatment Plan: Schedule of Assessments ......................................................................... 44 
5 
Trial Population ................................................................................................................................. 45 
5.1 
Inclusion Criteria ....................................................................................................................... 46 
5.2 
Exclusion Criteria ..................................................................................................................... 47 
5.3 
Restrictions ................................................................................................................................ 50 
5.3.1 
Prior and Concomitant Medications and Other Treatments ...................................... 50 
5.3.2 
Recommendations for Concomitant use of Anti-Malarials ......................................... 51 
5.3.3 
Antiretroviral Therapy ...................................................................................................... 51 
5.3.4 
Other Restrictions ............................................................................................................. 52 
5.4 
Discontinuation from Treatment/Trial .................................................................................... 52 
5.5 
Participant Progress Definitions ............................................................................................. 53 
5.6 
Trial Stopping Rules ................................................................................................................. 54 
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6 
Treatment .......................................................................................................................................... 54 
6.1 
IMP Administration ................................................................................................................... 54 
6.2 
Participant Compliance ........................................................................................................... 55 
6.3 
Treatment Modification(s) ....................................................................................................... 55 
6.4 
IMP Packaging and Labelling ................................................................................................. 56 
6.5 
Method of Treatment Assignment .......................................................................................... 57 
6.6 
Blinding and Procedures for Breaking the Blind .................................................................. 57 
6.7 
Handling, Storage and Accountability ................................................................................... 58 
7 
Trial Variables and Procedures ...................................................................................................... 58 
7.1 
Demographic and Background Variables and Procedures ................................................ 58 
7.2 
Efficacy Variables and Procedures........................................................................................ 59 
7.3 
Safety and Tolerability Assessments .................................................................................... 60 
7.4 
PK Variables and Procedures ................................................................................................ 61 
7.5 
Mycobacteriology Characterization Variable and Procedures .......................................... 61 
8 
Adverse Events ................................................................................................................................. 62 
8.1 
Definitions .................................................................................................................................. 62 
8.1.1 
Adverse Event (AE).......................................................................................................... 62 
8.1.2 
Serious Adverse Event (SAE) ........................................................................................ 62 
8.1.3 
Attribution/Causality ......................................................................................................... 63 
8.1.4 
Severity .............................................................................................................................. 64 
8.2 
Reporting ................................................................................................................................... 64 
8.2.1 
Follow up of Adverse Events .......................................................................................... 65 
8.2.2 
Clinical Laboratory Adverse Events .............................................................................. 65 
8.2.3 
Disease under Study........................................................................................................ 65 
8.2.4 
Overdose ........................................................................................................................... 66 
8.2.5 
Drug Interaction ................................................................................................................ 66 
8.2.6 
Pregnancy ......................................................................................................................... 66 
8.3 
Monitoring for Specific Toxicities ........................................................................................... 66 
8.3.1 
Neurological ...................................................................................................................... 67 
8.3.2 
ALT, AST and Alkaline Phosphatase elevations: ........................................................ 67 
8.3.3 
Lipase ................................................................................................................................. 67 
8.3.4 
Musculoskeletal System and Cardiac Muscle ............................................................. 67 
8.3.5 
Cardiac Rhythm Disturbances ........................................................................................ 67 
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8.3.6 
Myelosuppression ............................................................................................................ 68 
8.3.7 
Peripheral Neuropathy ..................................................................................................... 69 
8.3.8 
Optic Neuropathy.............................................................................................................. 69 
8.3.9 
Lactic Acidosis .................................................................................................................. 69 
8.4 
Safety Monitoring by Data Monitoring Committee............................................................... 69 
9 
Statistical Analysis ........................................................................................................................... 70 
9.1 
Analysis Population .................................................................................................................. 70 
9.2 
Sample Size .............................................................................................................................. 70 
9.3 
Interim Analyses ....................................................................................................................... 71 
9.4 
Primary and Secondary Endpoint Analysis .......................................................................... 71 
9.5 
Safety and Tolerability Analysis ............................................................................................. 71 
9.6 
Pharmacokinetics ..................................................................................................................... 72 
9.7 
Pharmacokinetics/Pharmacodynamics ................................................................................. 73 
10 Records Management ..................................................................................................................... 73 
10.1 
Data Collection ......................................................................................................................... 73 
10.2 
Source Documents ................................................................................................................... 73 
10.3 
File Management at the Trial Centre ..................................................................................... 73 
10.4 
Records Retention at the Trial Centre .................................................................................. 73 
11 Quality Control and Assurance ...................................................................................................... 74 
11.1 
Site Procedures ........................................................................................................................ 74 
11.2 
Monitoring .................................................................................................................................. 74 
11.3 
Protocol Deviations .................................................................................................................. 75 
11.4 
Auditing ...................................................................................................................................... 75 
12 Ethics and Regulatory ..................................................................................................................... 75 
12.1 
Basic Principles ........................................................................................................................ 75 
12.2 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review .............. 75 
12.3 
Regulatory Authorities ............................................................................................................. 76 
12.4 
Informed Consent ..................................................................................................................... 76 
12.5 
Confidentiality ........................................................................................................................... 76 
13 Publication Policy ............................................................................................................................. 77 
14 Protocol Amendment Policy............................................................................................................ 77 
15 Sponsor, Financial Aspects, Insurance and Indemnity .............................................................. 77 
16 References ........................................................................................................................................ 79 
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Appendix 1: 
The IUATLD Scale ....................................................................................................... 82 
Appendix 2: 
Division of Microbiology and Infectious Disease (DMID) Toxicity Table .............. 83 
Appendix 3: 
 Cardiovascular Safety ................................................................................................ 91 
Appendix 4: 
 Karnofsky Performance Status Scale Definitions Rating (%) Criteria ................. 92 
Appendix 5: 
 EQ-5D-5L Questionnaire ............................................................................................ 93 
Appendix 6: 
 Brief Peripheral Neuropathy Screening ................................................................... 95 
Appendix 7: 
 Tuberculosis Symptoms Profile ................................................................................ 97 
Appendix 8: 
 Liver Toxicity Management ........................................................................................ 98 
 
TABLES 
Table 1: 
ADRs C208 Stage 1 and Stage 2 ...................................................................................... 26 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies............................................ 28 
Table 3: 
Murine Lung CFU counts during Treatment with Linezolid ............................................ 33 
Table 4: 
Murine Relapse Data ........................................................................................................... 39 
Table 5: 
Summary Statistics for EBACFU(0-14) ................................................................................... 40 
Table 6: 
NC-003 Efficacy Results: Daily BAlogCFU(0-14) .................................................................. 41 
Table 7: 
NC-003 Safety Data ............................................................................................................. 41 
Table 8: 
Treatment Groups ................................................................................................................ 45 
Table 9: 
Investigational Medicinal Product Details ......................................................................... 55 
Table 10: Adverse Events Attribution/Causality Ratings .................................................................. 63 
Table 11: Definitions for Adverse Event Severity Gradings ............................................................. 64 
  
 
FIGURES 
Figure 1: Log10 CFU Counts in Lungs ...................................................................................28 
Figure 2: Mean log Colony Forming Unit Values over Time Study CL-010 .............................31 
Figure 3:  Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin CL-001 35 
Figure 4: Trial Schematic........................................................................................................45 
 
 
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Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
ABaCavir 
ADR 
Adverse Drug Reactions 
AE  
Adverse Event  
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
ALanine aminoTransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
ASpartate aminoTransferase 
AT 
AminoTransferase 
AUCτ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BMI 
Body Mass Index 
bpm 
beats per minute 
BPNS 
Brief Peripheral Neuropathy Scale 
C 
Clofazimine 
CFU 
Colony Forming Units 
CK(-MB) 
Creatine Kinase(-MB isoenzyme) 
C(max), (min) 
plasma Concentration (maximum), (minimum) 
CO2 
Carbon diOxide 
CPK 
Creatine PhosphoKinase 
CS 
Clinically Significant 
Ctrough 
plasma Concentrationtrough 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
DeoxyriboNucleic Acid 
DOH 
Department of Health 
DILI 
Drug Induced Liver Injury 
DSMC 
Data Safety Monitoring Committee 
DST 
Drug Sensitivity Testing 
E 
Ethambutol 
EBA 
Early Bacteriocidal Activity 
EC 
Ethics Committee 
ECG 
ElectroCardioGram 
EFV 
EFaVirenz 
(e)CRF 
(electronic) Case Report Form 
FQ  
FluoroQuinolone 
FTC 
Emtricitabine 
GI 
GastroIntestinal 
GCP  
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GMR 
Geometric Mean Ratio 
H 
Isoniazid 
hERG 
Human Ether-à-go-go Related Gene 
HIV  
Human Immunodeficiency Virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
ICF 
Informed Consent Form 
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ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
kilogram 
L 
Linezolid 
LLN 
Lower Limit of Normal 
LPV 
LoPinaVir 
M 
Moxifloxacin 
MAO(I) 
MonoAmine Oxidase (Inhibitor) 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
mg/dl 
milligrams per decilitre 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent To Treat 
ms 
millisecond 
NCS 
Not Clinically Significant 
NEJM 
New England Journal of Medicine 
NVP 
NeViraPine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
PharmacoDynamic 
PP 
Per Protocol 
PK 
PharmacoKinetic 
PR 
PR interval 
QD 
Once Daily 
R 
Rifampicin 
S 
Streptomycin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIRE 
Streptomycin Isoniazid Rifampicin Ethambutol 
SOC 
System Organ Class 
TB 
Tuberculosis 
TBL 
serum Total BiLirubin 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
T>MIC 
Time above minimum inhibitory concentration 
t.i.w. 
three times a week 
(BA) TTP 
(Bacteriocidal Activity) Time To Positivity  
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
XDR-TB 
eXtensively Drug Resistant Tuberculosis 
μg(/dl) 
micrograms (per deciliter) 
Z 
pyraZinamide 
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1 
Synopsis 
1.1 Synopsis Summary 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Number/Title: 
NC-007: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB) 
Treatment Indication: 
Pulmonary XDR-TB, pre-XDR-TB, and treatment intolerant or non-responsive 
MDR-TB 
Trial Objective: 
To evaluate the efficacy, safety and tolerability of various doses and durations 
of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in 
participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment 
intolerant or non-responsive MDR-TB. 
Trial Design: 
A phase 3, multi-center, partially-blinded, randomized clinical trial in four parallel 
treatment groups. Bedaquiline and pretomanid treatment will not be blinded.  
Linezolid treatment dose and duration will be double-blinded. 
 
Participants will have a screening period of up to 9 days and will be randomized 
to receive one of the 4 active treatment arms. Participants will be randomized 
to one of the four regimens in a 1:1:1:1 ratio, using an interactive web response 
system (IWRS) which will utilize a dynamic randomization system using 
minimization with a random element to allocate participants evenly across the 
arms by HIV status and type of TB.   
 
Each participant will receive 26 weeks of treatment.  If participant’s week 16 
sample remains culture positive, Investigator may consider extending current 
treatment to 39 weeks, in consultation with the Sponsor Medical Monitor 
 
Participants will be followed for 78 weeks after end of treatment. 
Patient Population: 
A total of up to 180 participants: 
120 (30 per treatment arm) XDR-TB participants, and up to 60 (15 per arm) 
pre-XDR or treatment intolerant/non-responsive MDR pulmonary tuberculosis 
Participants, male and female, aged 18 and over. Enrollment will stop when 
120 XDR-TB participants are randomized. Sponsor may consider replacement 
of late screen failure and un-assessable (as detailed in the statistical analysis 
plan) participants. 
Test product, Dose and 
Mode of Administration: 
The test product will be supplied as: 
• 
bedaquiline 100 mg tablets 
• 
pretomanid 200 mg tablets 
• 
linezolid (scored) 600 mg tablets 
• 
placebo linezolid (scored) 600 mg tablets 
• 
linezolid half tablet (pre-cut) 300 mg  
• 
placebo linezolid half tablet (pre-cut) 300 mg 
 
Linezolid treatment will be supplied as 2 rows of full tablets and one row of 
half-tablets to allow for all possible dosing options while maintaining the blind.  
 
Treatment will be administered orally, once daily, with a full glass of water and 
a meal in the following dosing schemes (treatment arms): 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Participants will receive the following: 
• 
bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 
18 weeks plus;  
• 
pretomanid 200 mg once daily for 26 weeks plus; 
• 
Linezolid- participants will be randomly assigned to receive one of the 
following four linezolid treatment doses and durations:  
Linezolid 1200 mg daily for 26 weeks 
• 
2 linezolid 600 mg active tablets once daily for 26 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
• 
2 linezolid 600 mg active tablets once daily for 9 weeks  
• 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
Linezolid 600 mg daily for 26 weeks 
• 
1 linezolid 600 mg active tablet once daily for 26 weeks 
• 
1 placebo linezolid 600 mg tablet once daily for 26 weeks  
• 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid 600 mg tablet for 9 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
  
Treatment Modifications: 
 
The above treatment schemes may require modification due to toxicities as 
noted below. All dose modifications should be discussed with the Sponsor 
Medical Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be informed 
within 24 hours of the change if not discussed prior to implementation 
 
In the event of linezolid specific toxicities, the following should be considered 
and implemented per guidance in the monitoring and safety for specific 
toxicities section of protocol.  Every effort should be made for participants to 
receive a total of 9 weeks of linezolid, even if pauses are required: 
• 
Blinded one step reductions (maximum 3 steps) in the dose of linezolid 
(1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or 300mg QD to 
placebo) managed by the IWRS as per instructions in pharmacy manual 
and/or IWRS user manual.  
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
• 
Temporary pause of linezolid due to a linezolid-specific toxicity should be 
considered and implemented per guidance in the monitoring and safety 
for specific toxicities section of protocol. 
• 
Permanent discontinuation of linezolid. 
 
For participants experiencing suspected drug related toxicities due to other 
drugs in the regimen (B-Pa), the full regimen may be halted for up to 35 
consecutive days.  
Interruptions/pauses of all Investigational Medicinal Product (IMP) must not 
exceed 8 weeks (56 days) cumulatively.  
 
If participant’s week 16 sample remains culture positive, Investigator may 
consider option to extend current treatment to 39 weeks, in consultation with 
the Sponsor Medical Monitor. When treatment is extended due to a positive 
culture at week 16, interruptions/pauses of all IMP must not exceed 13 weeks 
(91 days) cumulatively. 
 
At no time should the participant be treated with a single agent. 
Criteria for Evaluation: 
Primary Endpoint: 
Incidence of bacteriologic failure or relapse or clinical failure through follow up until 26 weeks after the end of 
treatment. 
 
Abbreviated Definitions, full definitions will be described in the Statistical Analysis Plan (SAP): 
• 
Bacteriologic failure: During the treatment period, failure to attain or maintain culture conversion to 
negative. 
• 
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative 
status, with culture conversion to positive status with a strain of Mycobacterium tuberculosis (MTB) 
genetically identical to the infecting strain at baseline.  
• 
Clinical failure: A change from protocol-specified TB treatment to a new regimen before end of 
protocol specified treatment due to treatment failure, retreatment for TB during follow up, or TB-
related death. 
 
Note: 
• 
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days 
apart. 
• 
Participants who are documented at a visit as unable to produce sputum and who are clinically 
considered to be responding well to treatment will be considered to be culture negative at that visit. 
Further details of definitions to be provided in the SAP. 
 
Secondary Endpoints: 
• 
Incidence of bacteriologic failure or relapse or clinical failure through follow up until 78 weeks after 
the end of treatment. 
• 
Time to sputum culture conversion to negative status through the treatment period. 
• 
Proportion of participants with sputum culture conversion to negative status at weeks 4, 6, 8, 12, 16 
and end of treatment. 
• 
Change from baseline TB symptoms. 
• 
Change from baseline in Patient Reported Health Status. 
• 
Change from baseline weight. 
 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations of bedaquiline and its M2, pretomanid and linezolid from sparse sampling (see Table 
1.2) will be measured and used to update population PK models for bedaquiline and its M2 metabolite, 
pretomanid, and linezolid to further evaluate the effects of covariates on model parameters in this study 
population. PK data from the current trial may be combined with prior data (e.g., from the NiX-TB trial) to 
enhance this population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between drug 
exposure and efficacy and safety endpoints.   
Safety and Tolerability: 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
•
All-cause mortality.
•
Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by, drug relatedness
and seriousness, leading to early withdrawal from treatment, leading to pauses of linezolid, leading
to linezolid reductions and leading to death.
•
Quantitative and qualitative clinical laboratory result measurements, including observed and change
from baseline.
•
Quantitative and qualitative measurement of electrocardiogram (ECG) results read by a central
cardiology service, including observed and change from baseline.
•
Descriptive statistics of ophthalmology slit lamp examination data (age related eye disease study 2
[AREDS2]) lens opacity classification and grading). Categorical data for lens opacity will be
summarized in a frequency table for the right and left eye, respectively, including change from
baseline.
•
Changes in ophthalmic exam for visual acuity and color vision, including observed and change from
baseline.
•
Changes noted in peripheral neuropathy signs and symptoms, including observed and change from
baseline.
Mycobacteriology: 
Sputum samples will be obtained at all scheduled visits.  The following tests will be performed. 
•
Smear microscopy for acid-fast bacilli (AFB);
•
Liquid Culture (MGIT), followed by a speciation test to detect presence or absence of MTB and
obtain time to positivity (TTP);
•
GeneXpert, Hain Genotype MTBDRplus or an alternative molecular to confirm MTB and rifamycin
resistance.
•
Minimum Inhibitory concentration (MIC) of bedaquiline, pretomanid and linezolid;
•
Drug Susceptibility Testing (DST) in liquid culture for rifampicin, isoniazid, streptomycin, ethambutol,
pyrazinamide and second line TB drugs including fluoroquinolones and injectable;
•
Genotyping.
Details on the testing and the collection and timing of samples are in sections 1.2 and 7.2. 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Statistical Methods: 
A general description of the statistical methods planned for the primary efficacy outcome is outlined below. 
Specific details will be provided in the SAP. 
 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT).  We will 
evaluate the hypothesis, separately for each of the experimental B-Pa-L treatment arms, that the incidence 
of bacteriologic and clinical cure at 26 weeks after the end of therapy is greater than 50%.   
 
The incidence will be estimated from the binomial proportion for participants with success criteria based on 
the lower bound of the confidence interval for this proportion being greater than 50%. 
 
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as the target, 
because it is above the entire range of the historical control for cure of XDR-TB and because a cure rate of 
50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a shortened, simplified, all oral, 
inexpensive and safer regimen would clearly represent an important therapeutic advancement.  
 
The primary analysis population will include both XDR and non-XDR participants (up to 45 per arm).  A 
secondary analysis will be restricted to the XDR participants only (30 per arm).   A sample size of 30-45 per 
arm will provide more than 90% power to demonstrate that the lower bound of the 95% confidence interval 
of this estimate is greater than 50%, using a 2-sided 5% significance level. This assumes that the true cure 
rate is 80 percent.   
 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 6 months) with the 
L1200 2 months and L600 26 weeks only being tested if L1200 26 weeks is a success.  Similarly, L600 9 
weeks will only be tested if L600 26 weeks is a success.  A Bonferroni adjustment will be made for 
comparing the L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025.  For these 
comparisons the lower bound of the 97.5% confidence interval will need to exceed 50% for success.   
 
Both a Modified Intent to Treat (mITT) and a Per Protocol (PP) analysis for each arm will be conducted.  No 
formal statistical pairwise comparisons between the arms will be performed.   
Trial Duration: 
~3.5 Years (An enrolment period of at least 18 months plus 9 days pre-treatment plus 6 month treatment 
period plus 18 months post treatment follow-up). 
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1.2 Synopsis Flowchart 
Period Screeninga 
Treatment 
 Visits every 3 
weeks   if 
extended due to 
IMP pause or 
culture (+) at 
week 16b 
   
End of OR Early 
Withdrawal from 
Treatmentc 
Post Treatment Follow-up 
Time of Visit 
Up to 9 days 
prior to 
Treatment 
Day 1 
Week  1 
Week  2 
Week 3 
Week  4 
Week 5 
Week  6 
Week 7  
Week  8 
Week 10 
Week 12 
Week 14 
Week  16 
Week 18 
Week 20 
Week 23 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks 
Visit Windowq 
N/A 
+/- 3 days 
+/- 5 days 
+/- 7 days 
Post last 
dose IMP 
+7 days 
+/-  14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Trtmnt/Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusiond 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Statuse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 Count and Viral Loadf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest X-Rayg  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Testh 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Patient Reported Health Status 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Slit Lamp Exami 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
X 
 
 
 
 
 
Ophthalmic Examj 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X X X X X X 
Single 12-LeadECGk 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X   
 
 
 
 
X 
 
 
 
 
 
 
 
 
Limited Physical Examl 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X X X X X X 
Full Physical Exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Laboratory Safety Tests 
(includes Full Blood Count)m 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Full Blood Count 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X X X X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X X X X 
Study Medication/Compliancen 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PK Samplingo 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Xo 
 
 
 
 
 
 
 
 
Early Morning & Spot Sputumr 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X X X X X X X X 
Peripheral Neuropathy 
Assessment 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X X 
 
X 
 
X 
Investigator Assessmentp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
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GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
 
a. 
Screening: Screening assessments can occur on different days within nine days prior to Day 
1 dosing. If a participant fails screening, a full re-screen may occur at a later date post 
discussion with Medical Monitor.  All screening procedures must be repeated at re-screen 
visit, with the exception of the slit lamp examination, which can be used from a previous 
screening if within 8 weeks of anticipated randomization. 
b. 
Visit Schedule: If the duration of treatment is extended due to dose pauses (e.g., takes 
participant 35 weeks to complete 26 weeks of treatment) or positive week 16 culture, 
unscheduled visits should be added every 3 weeks (+/- 7 days).  End of treatment visit (final 
treatment visit) should be done within 7 days AFTER the last dose of IMP.  
1. If participant completes treatment at week 26, end of treatment visit should be done 
within 7 days after last dose of week 26. 
2. If participant completes 26 weeks of therapy at week 33 due to pauses, visits can be 
done at weeks 26, 29 and 33 (3 weeks from week 29 plus 7-day window). The week 
33 visit would be the end of treatment visit and should be completed within 7 days after 
last dose. 
3. If participant completes treatment at week 39 due to post treatment extension related 
to positive culture at week 16, visits can be completed at weeks 26, 29, 32, 35 and 39 
(3 weeks plus 7-day window), visit at week 39 would be the end of treatment visit. 
4. Follow-up visits should be scheduled based on timing of end of treatment/early 
withdrawal from treatment (e.g., 4-week follow-up to be scheduled 4 weeks after last 
dose of IMP). 
c. 
Follow-up Visits Early Withdrawal Participants: Once a participant has been discontinued 
from treatment, they will be required to attend an Early Withdrawal visit. If participant: 
1. Received/took < 14 doses, no additional follow-up visits are required.   
2. Received 15 or more doses, follow-up after end of treatment at week 12, week 26 (if 
not already performed) and week 78 are required. The week 12 visit will only require 
the ophthalmologic exams. The week 26 and 78 follow-up visits will be to collect 
Serious Adverse Event (SAE) information (including verification of survival) and patient 
reported TB outcome information only and may be telephonic, a home or a site visit. 
This includes participants who are withdrawn from the trial due to meeting the 
treatment failure endpoint. Participant may need to return for visits to collect sputum 
samples to determine outcome status as per section “r”. 
d. 
Inclusion/Exclusion: to be confirmed at screening and prior to randomization.  
e. 
HIV testing: If HIV status is a confirmed known positive, repeated HIV test is not needed 
provided documentation is available. If HIV status is unknown or suspected negative, HIV test 
should be requested. If an ELISA and/or Western Blot based HIV test was performed within 1 
month prior to screening, it should not be repeated as long as documentation of testing 
method and negative results can be provided.   
f. 
CD4 count and viral load:  For all HIV-positive participants. Viral load and CD4 at screening, 
CD4 only at end of treatment or early withdrawal. 
g. 
Chest X-Ray: A chest x-ray (digital image) within one month prior to screening, will be 
obtained and read locally by Investigator or designee. Digital images will be provided to 
Sponsor, this process will be described in a separate document, the Radiology Manual. 
h. 
Urine Pregnancy: Women of child-bearing potential only, whether they are sexually active or 
not.   
i. 
Slit-Lamp Exam: Slit Lamp examination will be performed by an Ophthalmologist with 
AREDS2 training: 
1. For participants who receive < 14 doses of IMP, exam at: Screening only. 
2. For participants who receive 15 days to < 12 weeks of treatment, exams at: Screening 
and the 12-week follow-up visit. 
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3. Participants who complete > 12 weeks of treatment exams at: Screening, End of 
Treatment or Early Withdrawal and the 12-week follow-up. 
j. 
Ophthalmic Exam: to include Ophthalmologic Medical history at Screening; All exams to 
include Visual Acuity (distance testing) and Colour Vision assessment.   Can be done by any 
trained study staff throughout study.  Screening exam must be done by Ophthalmologist in 
addition to trained study staff that will perform exams throughout the study. 
k. 
Single 12-Lead ECG: To every extent possible, should be performed at approximately the 
same time of day (+/- 1 hours) and in the same fed/fasted state throughout the trial (e.g. 4 
hours after lunch). Central ECG analysis will be performed. 
l. 
Physical Exam:  Limited Physical exams should include weight and a gross neurological, 
pulmonary, cardiovascular and abdominal exam. 
m. Safety Laboratory Assessments: The Safety Laboratory sampling methodology and 
requirements will be described in a separate document, the Laboratory Manual, which will be 
provided prior to the trial start. The following analyses will be performed: 
1. Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential, platelet count).  
2. Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK). 
3. Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per discretion of Investigator. 
4. Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates, 
benzodiazepines, barbiturates, at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 2.  Positive results will not automatically 
exclude participant from the trial. 
n. 
Study Medication/Compliance: Study medication administration will be supervised per local 
site practice to assure compliance to regimen. 
o. 
PK Sampling:  Specific PK blood draws as follows: 
1. Day 1; pre-dose (within 2 hours prior to dosing) 
2. Week 2: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
3. Week 8: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
4. Week 12: pre-dose (within 2 hours prior to dosing)  
5. Week 20 or at early withdrawal if prior to week 20: pre-dose (within 2 hours prior to 
dosing) and 2–3 hours post-dose 
When participant is discharged and seen as an outpatient, site should make every effort to 
collect 6-8 hour samples at weeks 8 and when operationally and logistically feasible. 
p. 
Investigator Assessment: Principal Investigator to review participant status and assess 
whether TB treatment at current visit is considered a “success” or “failure”.  If considered a 
failure, should specify if based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. To be completed at 26 and 78 week post treatment follow-up visits and at any 
time Investigator determines that participant fulfills criteria for outcome of treatment failure. 
q. 
Visit Windows: the windows noted on the flowchart for timing of visit also apply to timing 
within a visit.  For example, procedures that are difficult to schedule such as ophthalmology 
exams, should be scheduled within +/- 3 days of scheduled visit from Day 1 to Week 8 or +/- 
14 days within scheduled visit at the week 12 post treatment follow-up visit.  Sites should 
make every effort to ensure all other procedures should be done on the same day when 
possible. 
 
 
 
 
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r. 
Sputum Sampling: 
Visit 
Sample 
Tests 
EMS* 
Spot 
 AFB Smear  
microscopy  
MGIT culture, 
speciation 
Molecular 
testing 
MIC:  
B, Pa, L 
 
Liquid DST  
 
Genotyping 
Screening  
(Day -9 to -1) 
  
 
S 
S 
S 
  
  
  
Baseline (Day 1) 
or screen - wk4 if 
baseline negative or 
contaminated 
 
 
  
 S 
  
C 
C 
C 
All Visits Post 
Baseline 
 
 
  
S 
  
  
  
  
Positive for MTB 
at/after EoT 
 
  
S 
 S 
C 
C  
C 
C –   Central laboratory (specialized facility) 
S –   Study Laboratory (facility that receives samples directly from site) 
 
SPUTUM SAMPLES GENERAL: If EMS is not available, site should make every attempt to 
collect two spot samples at least 30 minutes apart.  
 
BASELINE: If available, site will request pre-screening culture that was used for the tests that 
qualified the participant for inclusion into the trial to be subcultured and shipped to the study lab 
from the applicable lab for relevant participants with no positive cultures from screening through 
week 4 (with consent). Samples should be stored according to the applicable lab procedures until 
shipment to the designated study lab. Included with each shipment will be a copy of the applicable 
lab reports and all participant identifying information redacted and a completed shipment inventory 
form with appropriate participant trial identifiers. Details on how samples will be packed and 
shipped will be provided in the lab manual. 
 
POSITIVE MTB AT/AFTER END OF TREATMENT: Only one isolate (preferably from EMS) 
should be shipped. Second isolate may be requested if first is contaminated.  
 
MOLECULAR TESTING:  
• 
At Screening: GeneXpert, Hain MTBDRplus or equivalent to determine MTB complex and 
R resistance. 
• 
Positive MTB at/after end of treatment: Hain MTBDRplus and HainMTBRsl 
 
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including but not limited to FQ and 
injectables. 
 
STORAGE: MTB isolates from all positive cultures to be stored at the study laboratory until trial 
closure for the applicable study tests. The extracted MTB DNA from the applicable baseline and 
follow-up isolates will also be stored at the central lab for potential further work to validate new 
assay tools for 5 years after trial closure. 
 
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CENTRAL LAB: Results from testing at Central myco lab (MIC, DST and genotyping) will not 
routinely be provided to sites.  In the event of participant relapse/failure, Sponsor will provide 
available results to the site in order to inform appropriate participant treatment. 
 
UNSCHEDULED VISITS: If cultures of both spot sputum samples are contaminated at the 
following visits, or if necessary in order to help define a participant’s outcome status/assess 
culture status during follow-up, the participant should return for an unscheduled visit(s) to give 
additional samples or to document the participant is not able to produce sputum: 
  
• 
End of treatment visit; 
• 
Week 26 post treatment follow-up visit; 
• 
Post treatment follow-up visits from week 8 through week 65 (in addition to week 26 
follow-up); 
• 
End of Follow-up Period (week 78 post treatment completion visit); 
• 
Early Withdrawal (if applicable). 
 
At the end of 26 weeks and 78 weeks post treatment completion, to define outcome status, need 
to confirm whether the participant has: 
• 
At least two sequential negative sputum culture results; or  
• 
At least two sequential positive sputum culture results; or  
• 
Has been unable to produce sputum after documentation of at least two negative 
sputum cultures with no intervening positive and are clinically asymptomatic. 
 
If they do not fall into one of these categories, site should continue to collect sputum samples x 
2 (one Early Morning and one Spot at the research site or 2 spots samples at least 30 minutes 
apart, under the coaching and observation of the trial staff) at a minimum of 7 days or more apart 
until they fall into one of the above categories. 
 
If in any of the above scenarios the Investigator is unsure of the outcome, the Investigator must 
contact the Sponsor Medical Monitor to discuss and agree on how the patient is to be handled. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2 
Introduction and Rationale 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is now the world’s leading infectious 
disease killer and is responsible for more deaths than HIV.(43) It is the leading cause of death 
among HIV-infected individuals, and there is more TB in the world today than at any other time in 
history. As a result of poor treatment adherence, in addition to primary transmission, drug 
resistance is becoming more common and fears of an epidemic with strains of extensively drug-
resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs and regimens for TB 
are needed for the growing number of patients with XDR TB.  
Outcomes of treatment for XDR-TB using the best available treatments have traditionally been 
very poor.  The best treatment historically has been to use available second line drugs individually 
tailored based on drug susceptibility testing in an inpatient setting to assure adherence with 
treatment lasting from 24 months to much longer for patients without culture conversion.  The 
most detailed report using this approach with long term follow-up prior to the use of linezolid, 
bedaquiline or delamanid in regimens has come from South Africa, where the HIV co-infection 
rate among patients with XDR-TB ranges from 40 to 70%.  A cohort study of 107 patients with 
XDR-TB found cure or completion of therapy at 24 months to be 16%, with 46% having died.(28)  
In another report from South Africa of 114 patients with XDR-TB, 22% completed treatment 
successfully.(21)  The largest evaluation of treatment outcomes was noted in the WHO 2014 annual 
tuberculosis report of 1269 patients in 40 countries, where 22% of patients with XDR-TB 
completed treatment successfully and 35% died.(42) A meta-analysis of 397 patients with XDR-TB 
from 31 centers, with HIV coinfection <10%, reported 32% treatment success.(17)  Reports of the 
outcome of XDR-TB treatment from Peru (43 patients, 42% treatment success)(2) and Ukraine 
(114 patients, 22% treatment success)(11) have been similar.  Based on these reports, the success 
of traditionally available drug therapies for treating XDR-TB infection is substantially less than 
50% and in the most detailed and largest reports is less than 25%. 
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with XDR-TB might be improved when added to background regimens. Experience 
recently published from the C209 uncontrolled study of bedaquiline given on a background of 
multiple drugs notes that the subset of 38 patients with XDR-TB had rates of sputum culture 
conversion to negative of 62.2%.(29) However, in this study only one patient with XDR-TB was co-
infected with HIV. All participants were required to have Mycobacterium tuberculosis (MTB) 
isolates susceptible to at least 3 drugs at enrolment, and patients had a median of only 5.4 months 
of treatment-free follow-up. This study added bedaquiline for 6 months to a background regimen 
of many drugs given for 18 months or longer. 
While treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR-
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.(43)  This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% 
died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information.   
With such poor historical outcomes for patients with XDR-TB and with the complexity, expense 
and toxicity of treatments for all forms of drug resistant TB, novel drug combinations are 
desperately needed to improve treatment outcomes. Linezolid was identified in a small study as 
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a potentially efficacious drug in patients with XDR-TB when added to a failing regimen(9) and this 
drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of three drugs for which there is little, if any, pre-existing resistance 
among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]), there is the opportunity 
to evaluate a new regimen that may be administered orally once daily to treat patients with XDR-
TB. Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, it is 
hypothesized in the design of the ongoing Nix-TB clinical study that patients with pulmonary XDR-
TB may have relapse-free cure after as little as 6 months’ treatment with the B-Pa-L regimen. 
Therefore, since 2015, the TB Alliance has sponsored a study with a 6 month treatment duration 
with the B-Pa-L regimen in participants with XDR-TB or MDR TB not responsive to or intolerant 
to therapy (the Nix-TB study).(1) 
A key advantage of this regimen over standard of care for MDR-TB as well as XDR-TB is that this 
is an all-oral daily regimen for 6 months of treatment in comparison to standard regimens of 6-8 
drugs over 9-30 months of treatment that includes daily injections for a minimum of 6 months. 
The NC-007 trial takes this regimen into a randomized Phase 3 trial to optimize the dosing scheme 
for linezolid and the benefit relative to risk, and to expand the patient population to include 
individuals with pre-XDR TB. 
The information presented below first details the trial rationale, then key preclinical information 
and human efficacy and safety information for each of the drugs in the regimen and then presents 
preclinical and clinical data to support the combination of these drugs in a regimen to treat patients 
with XDR, pre-XDR and MDR treatment intolerant/failure-TB. 
2.1 Trial Rationale 
2.1.1 Trial Design Rationale 
This trial will provide a regimen containing 3 drugs against which there is no expected MTB 
resistance in the community for patients with limited treatment options while simultaneously 
gathering important efficacy and safety data on a regimen that could potentially treat all strains of 
MTB. Data from previous trials shows that the combination of B-Pa is well tolerated and has the 
potential to shorten treatment in patients who are susceptible to the drugs. The ongoing Nix-TB 
trial has shown that the B-Pa-L regimen has manageable toxicity and encouraging efficacy as an 
all oral 6 month regimen administered to patients with XDR-TB. This current trial will provide 
important information on the toxicity and efficacy of the regimen under alternate doses and 
durations of linezolid to optimize the dosing scheme for the best benefit to risk balance. 
2.1.2 Trial Drug Rationale 
2.1.2.1 Bedaquiline  
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this study bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 18 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 study that administered bedaquiline 200 mg daily over 8 weeks, and 
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by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
The NC-005 study allows the efficacy and safety to be compared for treatment arms that dosed 
bedaquiline at the currently registered dose and at 200 mg daily for the 8 weeks of the trial.  Briefly, 
Study NC-005 evaluated a regimen in patients with drug susceptible pulmonary TB given 
bedaquiline with pretomanid and pyrazinamide over an 8 week period.  One arm was to enroll 60 
patients who were to be given this regimen with bedaquiline dosed as approved for marketing 
(referred to as the B (loading dose/t.i.w.) PaZ arm), and another 60 patients were to be enrolled 
who would be given the regimen with bedaquiline dosed at 200 mg daily (referred to as the B 
(200mg) PaZ arm).  Another group of patients with DS TB were randomized to treatment with 
standard HRZE therapy.  Patients with MDR-TB were given the regimen with bedaquiline dosed 
at 200 mg daily in addition to moxifloxacin (referred to as the B (200 mg) MPaZ MDR-TB arm).  
The primary endpoint was The Bactericidal Activity (BATTP (0‐56)) as determined by the rate of 
change in time to sputum culture positivity (TTP) over 8 weeks of treatment in the Mycobacterial 
Growth Indicator Tube system, represented by the model‐fitted log (TTP) results as calculated by 
the regression of the observed log (TTP) results over time.  The assessments of safety and 
tolerability included the incidence of Treatment Emergent Adverse Events (TEAEs) presented by 
severity (DMID Grade), by drug relatedness and seriousness, and for those leading to early 
withdrawal and leading to death, by group.  In addition, quantitative and qualitative clinical 
laboratory result measurements were evaluated, including group summaries of observed values 
and changes from baseline.  Pharmacokinetics for all participants included pre-dose samples on 
9 days during and one day following dosing with the regimen.  Fifteen PK Sub‐study participants 
in each treatment arm had in addition intense PK sampling on Days 14 and 56. 
Efficacy of bedaquiline 200 mg daily dose vs the marketed dosing scheme over 8 weeks 
In the efficacy analysis of the NC-005 trial, based on liquid media collected from overnight sputum 
samples, the B(200 mg)MPaZ MDR-TB treatment group showed the highest bactericidal activity 
over the 8-week treatment period, followed by that of B(200 mg)PaZ, B(loading dose/t.i.w.)PaZ 
and then HRZE. It appears clear that the daily dosing regimen for bedaquiline provided at least 
as good a result in the primary efficacy analysis as the registered dosing scheme for bedaquiline.   
Safety of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
Adverse events, including serious adverse events and Grade III/IV adverse events were similar 
among groups.  In particular, the mean change from baseline in the corrected QTc intervals was 
numerically less in the participants given bedaquiline daily than in the participants given 
bedaquiline with the labelled dosing scheme.  Measures of potential hepatic toxicity, including 
participants with greater than 3 fold or 10 fold elevations in aminotransferase levels, were 
numerically greater in participants given the labelled dosing scheme than subjects given daily 
doses of bedaquiline.   
Pharmacokinetics of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
A population PK model published by McLeay in 2014 was used with PK data from Study NC-005 
to simulate the expected bedaquiline exposures when dosed at 200 mg daily followed by 100 mg 
daily for the remainder of the study in comparison to the labelled dosing scheme with bedaquiline 
administered for 6 months.(14)  The key findings from the simulations of the proposed dosing 
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scheme for NC-007 of bedaquiline administered 200 mg daily over 8 weeks followed by 100 mg 
daily for an additional 16 weeks are: 
• 
The exposures of the proposed dosing scheme (Cmax, mean or trough) are not expected to exceed 
the exposures associated with the labelled scheme on Day 14 at the end of the 400 mg daily 
dose.  With the labelled dosing scheme, the highest exposures are on Day 14 at the end of 
the 400 mg daily loading dose. 
• 
The average daily exposures with the proposed dosing scheme over 6 months are within (or 
not substantially different from) the range of exposures over 6 months of the labelled dosing 
scheme. 
• 
The cumulative exposure, in terms of AUC over time, is similar between the proposed dosing 
scheme and the labelled scheme 
2.1.3 Pretomanid 
Pretomanid has demonstrated good microbicidal activity at the 200mg daily dose as monotherapy 
in studies PA-824-CL-007 and PA-824-CL-010, in combination with either bedaquiline or 
pyrazinamide over 14 days in the early bacteriocidal activity (EBA) Study NC-001-(B-M-Pa-Z), in 
combination with either bedaquiline and/or pyrazinamide and/or clofazimine over 14 days in the 
EBA Study NC-003-(B-C-Pa-Z), and in combination with bedaquiline and linezolid over 6 months 
in the Nix-TB study.  In the EBA Study PA-824-CL-010 the 100mg dose demonstrated similar 
microbicidal activity to the 150 and the 200mg daily dose over 14 days. The Phase 2 trial NC-
002-(M-Pa-Z) evaluated this regimen at doses of pretomanid of both 100 mg and 200 mg relative 
to the HRZE control.   In this trial the efficacy results were similar between participants treated 
with 100 mg/day and 200 mg/day of pretomanid in the regimen, although for the primary endpoint, 
reduction in colony forming units of MTB from sputum, only the 200 mg/day dose group was 
statistically significantly better than the group randomized to standard HRZE therapy.  Safety was 
also similar between the groups, although the 200 mg/day group had more grade 2 adverse 
events than either the 100 mg/day group or the HRZE control group.  Because sterilizing relapse-
free cure of TB in patients with XDR-TB may ultimately require a regimen with higher drug 
exposures, the 200mg dose was chosen for evaluation in the Nix-TB study of the B-Pa-L regimen.  
The manageable toxicity of the regimen and very encouraging efficacy in the Nix-TB trial support 
taking the 200 mg dose of pretomanid forward in the NC-007 trial. 
2.1.4 Linezolid 
The standard dose of linezolid for a multitude of indications is 400mg or 600mg BID.  Doses of 
linezolid used to treat pulmonary TB in reported observational trials and case series range from 
300 mg to 1200 mg per day over periods of up to 20 months of treatment.  While the development 
of adverse events is generally higher with higher doses, the adverse events often ameliorate with 
a reduction of the dose or discontinuation of drug for several weeks and then reintroduction at a 
lower dose.  No controlled trials have clearly identified differences in anti-TB effect across a range 
of doses over long term treatment of TB. 
In this trial, each arm will vary the linezolid dosing to identify the optimal ratio of efficacy to adverse 
events as noted below. The 4 arms, to which participants will be randomly assigned in a blinded 
manner, are: 
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• 
Linezolid 1200 mg orally once daily for 26 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
• 
Linezolid 1200 mg orally once daily for the first 9 weeks, with the ability to interrupt or 
reduce the dose if needed based on toxicity.  
• 
Linezolid 600 mg orally once daily for 26 weeks, with the ability to interrupt or reduce the 
dose if needed based on toxicity. 
• 
Linezolid 600 mg orally once daily for the first 9 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
These dosing schemes for linezolid are chosen based on clinical experience in the Nix-TB trial, 
the company’s linezolid early bactericidal activity (EBA) study findings in the Lin CL-001 study, 
and preclinical data in the mouse model of infection. While the EBA study showed that a modestly 
greater bactericidal effect over 14 days at the highest 1200 mg daily dose (see further details 
below in Section 2.2.3), this dose appears to be associated in the Nix-TB trial and in published 
literature with a greater incidence of unwanted neuropathic and myelosuppressive effects than 
the 600 mg daily dose. While a full 6 months of linezolid therapy in the regimen may give greater 
culture conversion and avoid relapse, the mouse model found that linezolid dosing of only 1 or 2 
months, when B and Pa were given continuously for a total of 3 months, maximized relapse-free 
cure; in other words, similar to pyrazinamide in the present first line HRZE therapy, more than 2 
months of linezolid when combined with B and Pa does not increase relapse-free cure in the 
mouse model. Thus, the 4 treatment arms in this study will give randomized comparative 
information about the optimal duration and dose of linezolid in the regimen relative to efficacy and 
toxicity.  
The decision to give linezolid as a single daily dose is based on the results of the linezolid EBA 
study that showed over 14 days that similar bactericidal activity was noted whether the drug was 
given as a single daily dose or divided in to 2 doses. A single daily dose will ultimately enhance 
patient adherence and will reduce the total time the drug concentration is greater than the 
calculated concentration associated with mitochondrial toxicity (which we hypothesize to be the 
likely mechanism for the toxicities of peripheral neuropathy and myelosuppression). 
2.2 Agents to be Studied 
2.2.1 Bedaquiline 
Bedaquiline is being developed as part of combination therapies for pulmonary TB due to MDR-
TB and approved in 2012 in the USA under the provisions of accelerated approval regulations. 
Bedaquiline received conditional Marketing Authorization in the EU in 2014 and is approved in 
over 40 countries (EU countries counted individually). The approved indication may vary per 
country. Bedaquiline is marketed under the trade name SIRTUROTM.  Bedaquiline has a novel 
mechanism of action as it specifically inhibits mycobacterial ATP synthase, an enzyme that is 
essential for the generation of energy in MTB The inhibition of ATP synthase leads to bactericidal 
effects for both replicating and non-replicating tubercle bacilli. 
In the placebo-controlled Phase 2b study C208 conducted in newly-diagnosed patients with 
sputum smear-positive pulmonary MDR-TB (including pre-XDR-TB), the addition of bedaquiline 
to a preferred background regimen of MDR-TB treatment resulted in a decreased time to culture 
conversion and improved culture conversion rates compared to placebo. Median time to culture 
conversion according to the primary analysis method was 83 days for the bedaquiline group 
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compared to 125 days for the placebo group (p<0.0001; hazard ratio, 95% CI: 2.44 [1.57; 3.80]). 
The proportion of patients in the mITT population with sputum culture conversion after 24 weeks 
of treatment with bedaquiline or placebo in combination with background regimen (with patients 
who discontinued considered as non-responders), was 52/66 (78.8%) in the bedaquiline group 
and 38/66 (57.6%) in the placebo group. Durability of response seen in the bedaquiline treatment 
group was supported by the results at Week 120. The proportion of responders (with patients who 
discontinued considered as non-responders) at Week 120 was 41/66 (62.1%) in the bedaquiline 
group and 29/66 (43.9%) in the placebo group. 
In the Phase 2b, open-label study C209, conducted in 233 patients with sputum smear positive 
pulmonary MDR-TB, the median time to sputum culture conversion excluding patients with DS-TB 
and those that did not have a positive sputum culture at screening and/or baseline (mITT; 205 
patients), was 57 days. At Week 24, 163 of 205 (79.5%) patients responded to bedaquiline 
treatment as determined by sputum culture conversion rates. Conversion rates at Week 24 were 
highest (87.1%; 81/93) in patients with MDR-TB resistant to only RMP and INH, 77.3% (34/44) in 
pre-XDR-TB patients and lowest (54.1%; 20/37) in XDR-TB patients. 
The average terminal half-life of bedaquiline, is about 5.5 months. After reaching Cmax, however, 
there is initially a fairly rapid reduction in plasma bedaquiline concentrations over the dosing 
interval (with an estimated half-life of about 13 hours). Four weeks after ceasing bedaquiline 
intake, the mean bedaquiline concentrations were reduced by approximately 40% compared to 
the end of the bedaquiline treatment period in the C208 study. Administration of bedaquiline with 
food increased the relative bioavailability by about 2-fold compared to administration under fasted 
conditions. It is therefore recommended to take bedaquiline with food to enhance its oral 
bioavailability. 
CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline. Drug-
drug interaction (DDI) studies have showed reduced exposure to bedaquiline during combination 
with a strong or moderate inducer of CYP3A4 metabolism (i.e., rifampicin) and increased 
exposure during combination with a strong or moderate inhibitor of CYP3A4 metabolism (i.e., 
ketoconazole). Potential drug interactions with anti-retroviral drugs have been evaluated in three 
studies.  In an interaction study of single-dose bedaquiline and multiple-dose Lopinavir/ritonavir, 
exposure (AUC) to bedaquiline was increased by 22% (90% CI: 11-34). Co-administration of 
single-dose bedaquiline and multiple-dose nevaripine did not result in clinically relevant changes 
in the exposure to bedaquiline. Co-administration of a single dose of bedaquiline and multiple-
dose efavirenz (EFV) resulted in approximately a 20% decrease in the AUCinf of bedaquiline with 
no alteration in the Cmax.  Modeling based on the data from this DDI study predicts average steady-
state concentrations of bedaquiline and M2 to be reduced by 52% with chronic co-administration 
of bedaquiline and EFV.(5)  
Safety of Bedaquiline 
The Investigator’s Brochure for bedaquiline provides detailed safety information.5 
Data were used from 14 completed clinical studies to identify Adverse Drug Reactions (ADRs) 
according to the ICH guideline entitled, E6: Good Clinical Practice, Consolidated Guideline (ICH, 
1996): “…all noxious and unintended responses to a medicinal product related to any dose should 
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be considered adverse drug reactions. The phrase “responses to a medicinal product” means that 
a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out." 
The ADRs were identified from the pooled safety database of reported AEs in the Phase 2b clinical 
studies with bedaquiline, based upon a systematic well-documented approach and are presented 
for study C208 below in Table 1.  None of the ADRs reported in the controlled studies during the 
Investigational Treatment phase were considered serious. 
Table 1: 
ADRs C208 Stage 1 and Stage 2 
Adverse Drug Reactions (ADRs) in the Controlled Studies (C208 Stage 1 and Stage 2)  
During the Investigational Treatment Phase 
ADR (Grouped term), n (%) 
Frequency 
Any BDQ 
N=102 
Any Placebo 
N=105 
Nervous system disorders 
Headache 
Very Common 
24 (23.5) 
12 (11.4) 
Dizziness 
Very Common 
13 (12.7) 
12 (11.4) 
Cardiac disorders 
ECG QT prolonged 
Common 
3 (2.9) 
4 (3.8) 
Gastrointestinal disorders 
Nausea 
Very Common 
36 (35.3) 
27 (25.7) 
Vomiting 
Very Common 
21 (20.6) 
24 (22.9) 
Diarrhea 
Common 
6 (5.9) 
12 (11.4) 
Hepatobiliary disorders 
Transaminases increaseda 
Common 
7 (6.9) 
1 (1.0) 
Musculoskeletal and connective tissue disorders 
Arthralgia 
Very Common 
30 (29.4) 
21 (20.0) 
Myalgia 
Common 
6 (5.9) 
7 (6.7) 
 
a. 
Different AE preferred terms (i.e., transaminases increased, aspartate aminotransferase [AST] increased, 
alanine aminotransferase [ALT] increased, hepatic enzyme increased, and hepatic function abnormal) contribute 
to this ADR, while for the other ADRs the ADR is the preferred term. 
 
Of note, 13 deaths occurred in the C208 Stage 2 study: 10 subjects (12.7%) in the bedaquiline 
group and 3 subjects (3.7%) in the placebo group experienced an SAE leading to death. One 
death (alcohol poisoning) occurred during administration of bedaquiline. The median time to death 
for the remaining 9 subjects was 344 days after last intake of bedaquiline. One of the 10 deaths 
in the bedaquiline treatment group and 1 of the 3 deaths in the placebo group occurred after the 
Week 120 window. In the bedaquiline group, the most common cause of death as reported by the 
investigator was TB or TB-related illness (5 subjects). For all deaths due to TB, the subject’s last 
microbiological outcome was either failure to convert or relapse. The causes of death in the 
remaining bedaquiline subjects varied. The investigator considered all the SAEs leading to death 
not or doubtfully related to bedaquiline/placebo. The imbalance in deaths is unexplained. In 
addition, no discernible pattern between death and sputum culture conversion, relapse, sensitivity 
to other drugs used to treat TB, HIV status, or severity of disease was observed.  
During clinical studies with bedaquiline a prolongation of QTc interval on the ECG was observed.  
Consequently, bedaquiline treatment initiation is not recommended in patients with, personal or 
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family history of prolonged QT intervals, or additional risk factors for Torsades de Pointes. 
Detailed criteria are noted in Section 5.2, Exclusion Criteria. 
Increases in transaminases were seen in clinical studies during administration of bedaquiline in 
combination with a background regimen. Based on a review confirmed by an external 
hepatologist, it was concluded that bedaquiline has a signal for liver injury manifested by 
increases in AST and to a lesser extent ALT. Transaminase elevations are not unexpected given 
the number of other hepatotoxic drugs in the background regimens in clinical trials based on the 
publication by Keshavjee, which describes a 16.5% incidence of hepatotoxicity during MDR-TB 
treatment. (7) 
2.2.2 Pretomanid 
As detailed in the Investigator’s Brochure(6), pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti-
tuberculosis activity and a unique mechanism of action(35). Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB(10), and in vivo activity in a mouse model of tuberculosis(10, 
35).  
2.2.2.1 Pharmacology 
2.2.2.1.1 Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro studies demonstrated that pretomanid was active against actively growing 
drug-sensitive and drug-resistant MTB strains as well as against non-replicating MTB The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be similar to the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 
0.25 µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against 
drug-resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity. (6) 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO), (33) although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling studies also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.(12,13) 
2.2.2.1.2 Key Non-Clinical Studies of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse studies.(18,19,20,36,40) In a mouse model of established TB, 
the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 
22 days after inhalation infection with H37Rv MTB is shown in Figure 1. In this model, the 
minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the 
development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum 
bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony forming units 
(CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 
100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
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Figure 1: 
Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
2.2.2.2 Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology studies, 
in repeat-dose toxicity studies in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity studies, and in fertility and teratology studies in rats and rabbits.  
In the repeat-dose toxicity studies, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week study in rats, 50 mg/kg/day in a 13-week study in monkeys and 
<25 mg/kg/day (based on findings of thickening of the GI tract at all doses) in a 9-month study in 
monkeys. The major findings in safety and toxicity studies are listed below in Table 2 and are 
detailed in the Investigator’s Brochure.(6) 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development studies indicate no effects of PA-824 on fetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
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toxicology studies and a Segment I fertility study. In this fertility study, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed study in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week study in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
study in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the electrocardiogram (ECG) as a prolonged QT interval corrected for heart 
rate (QTc). Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. 
Following a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation 
ranged from 21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-
administration of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog 
did not result in any greater effect on the QT interval than with either agent alone. After 
repeated daily doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
2.2.2.3 Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 studies with healthy adult 
male and female subjects, with 163 subjects receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 studies sponsored by the NIH included a Thorough QT study and a study 
of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the 
studies are in the Investigator’s Brochure. 
2.2.2.3.1 Pharmacokinetics 
Several Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200 mg dose that increases total 
exposure by 88%. Interaction studies with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Study CL-006 was an open-label, fixed-sequence drug-drug 
interaction study to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs metabolised 
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by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had 
minimal effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by 
measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax), area under the 
curve to the last available time point (AUC0-t), and area under the curve extrapolated to infinity 
(AUC0-inf). The Cmax and AUC values for midazolam after co-administration with pretomanid 
were approximately 85% of those observed after treatment with midazolam alone. Furthermore, 
midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and half-life (t1/2) 
values were not different in the presence or absence of pretomanid. Therefore, 14 days’ dosing 
with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH sponsored this 
drug interaction study with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy subjects. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for the maximum concentration (Cmax) was 0.71, the GMR for the 24-hour area 
under the time-concentration curve (AUC0-24h) was 0.65, and the GMR for the trough 
concentration (Cmin) was 0.54. Concentrations of EFV when given with pretomanid versus given 
alone were similar. Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg 
once daily for 7 days, then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 
days, then LPV/r + pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + 
pretomanid, washout, then pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid 
alone from 16 PK-evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and 
for Cmin was 0.78. In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg 
for 7 days, then pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin 
versus pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and 
Cmin were 0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for maximum concentration (Cmax), area under the concentration-time curve (AUC0-
24h), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz; 13%, 17%, 
and 21% with LPV/r; and 53%, 66%, and 85% with rifampin, respectively. 
2.2.2.3.2 Pretomanid Clinical Efficacy 
The first two Phase 2 studies to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first study (CL-007) demonstrated 
good EBA, but all doses in this study (200 to 1200 mg/day) had the same activity. The second 
study (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA 
was seen at a dose of 100 mg/day over 14 days (4) (Figure 2). 
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Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010 
 
CFU = colony-forming unit; PA-824 = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Studies of Pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below in Section 2.3.2.  
2.2.2.3.3 Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure(6) provides detailed safety information. 
Across the 16 clinical studies with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy subjects across the 10 Phase 1 studies and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
studies.  Among the 289 healthy Subjects, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 1200 
mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical studies completed to date indicates pretomanid 
4
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is well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these studies, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical studies completed to date as likely caused by 
pretomanid is blood creatinine increased.  A study of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close surveillance 
and careful management of participants who have elevations in aminotransferases and/or 
bilirubin. Serious liver injury, including death in 3 participants taking a combination of 
pretomanid, pyrazinamide and moxifloxacin, has occurred during clinical studies and the risk 
of liver injury may be higher for participants taking a combination of PA-824 and pyrazinamide 
than it is for the standard HRZE treatment. Therefore, close monitoring of liver function is 
required for participants who are administered PA-824, especially when combined with 
pyrazinamide.  Administration of the regimen of PaMZ has been associated with death in 3 
participants associated with hepatic injury. Furthermore, the HRZE control regimen, and both 
pyrazinamide and moxifloxacin, has been associated with drug induced liver injury and in rare 
cases hepatic necrosis.  Consequently, hepatic safety will be under close surveillance in all 
clinical studies. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human studies that involve exposure to pretomanid longer than 
14 days.  These examinations will be conducted at baseline, near the end of the dosing period 
and 3 months after the end of study drug exposure.  These examinations are to follow up on 
the finding of cataracts in rats exposed to pretomanid in clinical studies. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple time 
points during the study.  Although the Thorough QT Study in healthy subjects found that 
pretomanid did not increase corrected QT intervals in a clinically meaningful way and did not 
add to the known effect of moxifloxacin, the ECGs will be carefully monitored during Phase 3.  
All ECGs will be interpreted and conduction intervals will be confirmed by a central cardiology 
service. 
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• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Study NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology studies have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 study for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology studies found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 studies have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 studies) or FSH values (3 studies) at baseline and after daily 
dosing of regimens containing pretomanid in various combinations with moxifloxacin, 
pyrazinamide and bedaquiline.  A review of data from the 3 studies by an independent 
reproductive endocrine expert concluded that, based on the hormone evaluations to date, there 
is no evidence that PA-824 is a testicular toxicant in men at the doses and exposure times 
evaluated. 
2.2.3 Linezolid 
Linezolid is a synthetic antibacterial agent of the oxazolidanone class approved in many countries 
around the world for drug-resistant, gram-positive bacterial infections, including gram positive 
organisms such as Staphylococcus aureus, coagulase negative Staphlococcus and Enterococcal 
infections.  The recommended dose for these infections is 600 mg twice daily for up to 28 days of 
therapy.(23,24,26) Antimicrobial effects likely come from inhibition of protein synthesis in the 
ribosomes of the infecting organism.(8)  Resistance of MTB to linezolid is rare, as this drug has 
not been widely used to treat tuberculosis.  In a recent study using linezolid to treat patients with 
XDR-TB in Korea, none of 41 patients had resistance to linezolid at baseline.(9) 
Preclinical in vitro data shows linezolid is active against MTB, including MDR strains with minimum 
inhibitory concentrations (MICs) that range from 0.125-1 μg/mL.(38)  Recent studies of the 
bactericidal and sterilizing activity of linezolid in a mouse model of MTB infection have 
demonstrated linezolid alone causes marked reductions in lung colony forming units (CFUs) from 
mice following 1-3 months of therapy.(36) (Table 3, below) 
Table 3: 
Murine Lung CFU counts during Treatment with Linezolid 
Monotherapy versus Standard Therapy 
 
Mean lung log10 CFU count (± S.D.) at: 
Regimen 
D0 
Month 1 
Month 2 
Month 3 
Untreated 
6.17 + 
0.27 
6.47 + 0.06 
 
 
2RHZ/4R
H 
 
3.47 + 0.37 
1.59 + 0.25 
0.50 + 0.51 
L 
 
4.97 + 0.26 
 
 
 
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In recent years linezolid has been used to treat patients with MDR(28) and XDR-TB, although there 
have been no fully controlled trials of linezolid in a regimen for this indication.  The World Health 
Organization management guidelines place linezolid in Group 5 (“Agents with unclear role in 
treatment of drug resistant-TB”) in their groups of drugs to treat MDR-TB.(41) Over the past 10 
years small retrospective observational studies have reported good results when linezolid has 
been added to failing regimens for patients with MDR-TB.(9, 27, 34) The most compelling recent 
evidence linezolid may be of benefit to patients with XDR-TB was reported by Lee and colleagues 
from a study in S. Korea.(9)  Forty-one patients who had sputum culture–positive XDR-TB and who 
had not had a response to any available chemotherapeutic option during the previous 6 months 
were randomized to start linezolid at 600 mg daily or to delay therapy with linezolid at 600 mg 
daily for 2 months without changing their failing background regimen.  After confirmed sputum-
smear conversion, or at 4 months, patients underwent a second randomization to continued 
linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 
months.  Thirty four of 39 (87%) of the patients had a negative sputum culture within 6 months 
after linezolid had been added to their drug regimen.  As of the cutoff date prior to publication, of 
the 38 patients who received linezolid, 17 were still receiving the treatment per protocol, and 13 
had completed treatment, including 6 with no relapse during the treatment period, 4 with no 
relapse at the 6-month follow-up, and 3 with no relapse at the 12-month follow-up (end of study).  
While the standard dose of linezolid for short term use for severe bacterial infections is 600 mg 
bid, some clinicians and clinical trials using linezolid as Group 5 therapy to treat TB use only 300 
mg or 600 mg daily due to concerns about toxicity developing when used over a period of months 
(see below for a review of linezolid toxicity). (9)  However, there are no data to indicate what dose 
of linezolid is required or optimal to effectively treat TB infection.  Consequently, TB Alliance has 
recently conducted and completed an Early Bactericidal Activity trial to evaluate the use of 
linezolid over 14 days in patients with newly diagnosed DS Pulmonary TB in dosing schedules 
including 300 mg daily, 300 mg bid, 600 mg daily, 600 mg bid, 1200 mg daily, and HRZE at 
standard doses daily.  Preliminary unpublished in-house results using Bayesian mixed effects 
modelling have noted that there is a bactericidal effect of linezolid over 14 days that is substantial, 
but less than for the full HRZE regimen.  There is little difference between daily or twice daily 
dosing of the same total daily dose of drug, and there is a dose-response relationship between 
total daily dose and daily reductions in either total CFU counts on solid culture or increases in 
Time to Positivity in liquid culture (a decreased load of MTB is associated with an increase in Time 
to Positivity).  Point estimates of the log of the daily increase in Time to Positivity over 14 days 
ranged from 2.278 for Linezolid 300 mg QD to 4.446 for linezolid 1200 mg QD, with the estimate 
of 6.860 for HRZE for reference. 
 
 
 
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Figure 3:  
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin 
CL-001 
Bayesian Nonlinear Mixed Effects Regression Model: Posterior Estimates and 95% 
Bayesian Confidence Intervals 
 
HRZE = isoniazid, rifampin, pyrazinamide, and ethambutol 
2.2.3.1 Linezolid Clinical Safety 
Linezolid is currently marketed globally for a variety of acute infectious diseases and has been 
studied for the treatment of XDR-TB in several recent trials.(3,9) The following list of known and 
potential risks is based on the warnings and precautions and adverse reactions sections of the 
current package label.(23,24,26)  Of note, the approved indication for linezolid is for administration 
up to 28 days. 
 Warnings and Precautions 
• 
Linezolid should not be used in patients taking any medicinal product which inhibits 
monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking 
any such product. 
• 
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) 
has been reported in patients receiving linezolid. In cases where the outcome is known, 
when linezolid was discontinued, the affected hematologic parameters have risen toward 
pretreatment levels. Complete blood counts should be monitored weekly in patients who 
receive linezolid, particularly in those who receive linezolid for longer than two weeks, 
those with pre-existing myelosuppression, those receiving concomitant drugs that produce 
bone marrow suppression or those with a chronic infection who have received previous or 
concomitant antibiotic therapy.  
• 
Lactic acidosis has been reported with the use of linezolid. In reported cases, patients 
experienced repeated episodes of nausea and vomiting. Patients who develop recurrent 
9 
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6 
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Linezolid 300 mg OD m 
Linezol d 300 mg BID IHl 
Linezolid 600 mg OD 
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Lirezolid 600 mg BID 
€e& Linezolid 1200 mg OD 
(:€0 
HRZE 
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nausea or vomiting, unexplained acidosis, or low bicarbonate level while receiving 
linezolid should receive immediate medical evaluation. 
• 
Spontaneous reports of serotonin syndrome associated with the co-administration of 
linezolid and serotonergic agents, including antidepressants such as selective serotonin 
reuptake inhibitors (SSRIs), have been reported.  Where administration of linezolid and 
concomitant serotonergic agents is clinically appropriate, patients should be closely 
observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, 
hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians 
should consider discontinuation of either one or both agents. If the concomitant 
serotonergic agent is withdrawn, discontinuation symptoms can be observed (see 
package insert of the specified agent(s) for a description of the associated discontinuation 
symptoms).  
• 
Peripheral and optic neuropathy has been reported in patients treated with linezolid, 
primarily those patients treated for longer than the maximum recommended duration of 28 
days. In cases of optic neuropathy that progressed to loss of vision, patients were treated 
for extended periods beyond the maximum recommended duration. Visual blurring has 
been reported in some patients treated with linezolid for less than 28 days. If patients 
experience symptoms of visual impairment, such as changes in visual acuity, changes in 
color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is 
recommended. Visual function should be monitored in all patients taking linezolid for 
extended periods and in all patients reporting new visual symptoms regardless of length 
of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of 
linezolid in these patients should be weighed against the potential risks.  Additional 
information on the neuropathies reported in recent studies of linezolid administered over 
prolonged periods to patients with TB infection is presented above in Section 2.2.3. 
• 
Convulsions have been reported in patients when treated with linezolid. In some of these 
cases, a history of seizures or risk factors for seizures was reported.  
• 
Postmarketing cases of symptomatic hypoglycemia have been reported in patients with 
diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, 
a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with 
hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. 
While a causal relationship between linezolid and hypoglycemia has not been established, 
diabetic patients should be cautioned of potential hypoglycemic reactions when treated 
with linezolid. 
In addition, the linezolid product label notes that there was an excess of abnormal liver function 
tests in comparator-controlled trials.  These abnormalities were noted in 0.4% of linezolid treated 
patients in trials of skin and skin structure infections vs in 0.2% of clarithromycin treated patients, 
and in 1.6% of patients treated with linezolid versus 0.8% of patients with other treatments in trials 
of all other infections. 
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Adverse events of linezolid long term therapy for Tuberculosis have been described in several 
literature reports. The most complete review is a meta-analysis by Cox which noted the proportion 
of adverse events necessitating treatment discontinuation was significantly different by dose: 
29.49% (95%CI 3.24–55.74) for ⩽600 mg daily vs. 60.75% (95%CI 42.69–78.81) for >600 mg 
daily (P = 0.05). (3) 
In a trial reported by Lee et al in S Korea(9), seven of 41 participants had myelosuppression, 
including anemia and neutropenia, primarily within the first 5 months, and only one participant 
withdrew due to anemia.  Six had clinically significant myelosuppression:  5 in 0-4 months and 1 
in 4-8 months, with 0 in 8-12 months. 
Peripheral and Optic Neuropathy:  
The linezolid product label notes these adverse events have been “ reported in patients, primarily 
those patients treated for longer than the maximum recommended duration of 28 days.  In cases 
of optic neuropathy that progressed to loss of vision, patients were treated for extended periods 
beyond the maximum recommended duration.  Visual function should be monitored in all patients 
taking ZVYOX for extended periods (>3 months) and in all patients reporting new visual 
symptoms, regardless of length of therapy.(26) 
In Lee, NEJM, 2012(9), the publication’s Supplemental Table 3 notes that 21 patients had clinically 
significant peripheral neuropathy spread over 12 months:  5 in months 0-4, 10 in months 4-8 and 
5 in months 8-12 (time of onset not noted for one).  Participants who developed any peripheral 
neuropathy had their dosing of linezolid interrupted, generally for several weeks, and then 
resumed at the lower dose of 300 mg/day (C. Barry, personal communication).  None of the 
participants withdrew from the study based on peripheral neuropathies.  At baseline, patients 
received visual acuity testing, contrast sensitivity and color vision tests. Seven cases were 
observed as having potential effects on vision; only two of 38 patients withdrew from study due to 
optic neuropathy.  For clinically significant optic neuropathy, one had this at 0-4 months, 2 at 4-8 
months and 3 at months 8-12.  Except for the 2 participants who withdrew from the study, the 
others resumed linezolid at the 300 mg dose after a hiatus of several weeks of treatment and 
completed the study with resolution of their visual acuity changes (C. Barry, personal 
communication). 
In the Schecter California Department of Health (DOH) review(32), peripheral neuropathy 
developed in 5 of 30 patients (no standardized monitoring), but only one withdrew from linezolid 
therapy.  One patient developed visual loss secondary to optic neuropathy after 10 months of 
linezolid therapy, but vision returned to normal 3-4 weeks after discontinuation. 
In Park, 2006(27), two patients of eight in the case series developed optic neuropathy after 8-9 
month and had linezolid discontinued; these patients also had peripheral neuropathy. After 
linezolid treatment was stopped, the optic neuropathy fully resolved after 2-3 months.  A total of 
4 patients developed peripheral neuropathy at 4, 5, 8, 11 months; in the patients with optic 
neuropathy who stopped treatment, the peripheral neuropathic symptoms continued or improved 
only marginally. 
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In Singla, 2012(34), two of 29 patients treated with linezolid, 600 mg daily over 12 months, stopped 
the drug because of peripheral neuritis (one patient) and optic neuritis (one patient).  The time 
course of these adverse events was not noted. 
2.3 Regimens to be Studied 
The regimen included in this study (B-Pa-L) has been selected based on the performance of the 
regimen in non-clinical pharmacology studies and on the combination of bedaquiline and 
pretomanid with other drugs in clinical studies NC-001 and NC-003.  In addition, improved 
treatment outcomes in XDR patients with the addition of linezolid to existing therapy provide 
support for combining linezolid with other drugs that have no pre-existing resistance.  Preliminary 
results from the ongoing Nix-TB clinical study demonstrate the encouraging potential of this 
regimen. 
This regimen has the potential to treat drug resistant strains of tuberculosis. This is an oral 
regimen, removing the need for injectables as part of drug resistant treatment, and is also 
projected to be markedly less expensive than current XDR-TB therapy. Treatment duration is 
anticipated to be shorter than current regimens for drug resistant TB, based on findings in mouse 
models of infection and the fact that all participants will be treated with three active drugs against 
TB for which there is no expected resistance.  
The key data supporting the use of the B-L-Pa regimen are described below. 
2.3.1 Non-Clinical Studies 
In the murine model of TB, addition of bedaquiline to HRZ results in accelerated clearance of MTB 
(5,36) when compared to HRZ alone. While the combination of bedaquiline and pretomanid in the 
murine model of TB in initial studies appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ(15) and in a subsequent study it was more 
active in the mouse model than HRZ.(16) Thus a novel regimen with bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance.   
Recent studies of the bactericidal and sterilising activity of linezolid in an animal model where 
mice were given high dose aerosol MTB infection have demonstrated that linezolid alone and in 
combination with bedaquiline and pretomanid causes marked reductions in lung CFUs from mice 
following 1 to 3 months of therapy (Table 4 below). Additionally, all mice treated daily with 
bedaquiline, pretomanid and linezolid (B-L-Pa) were cured of the infection after 3 months of 
therapy as evidenced by no MTB cultured from lungs when mice were sacrificed 3 months after 
the completion of therapy that lasted 3 months or more (Table 4, below). This is in contrast to the 
5-6 months required in previous studies to cure all mice when treated with the standard of care 
isoniazid, rifampicin and pyrazinamide (HRZ; note that typically ethambutol is not used in the 
mouse model of infection). Additional mouse studies were performed to determine whether 
shorter durations of linezolid, with continuation of the other drugs, would result in relapse-free 
cure in the mouse (Table 4 below). Treatment with linezolid for only the first 4 to 8 weeks of a 
3-month treatment also resulted in relapse-free cure when lungs from the mice were cultured 
3 months after the completion of therapy.(37) 
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Table 4: 
Murine Relapse Data 
Impact of Linezolid Treatment Duration on Lung Colony Forming Unit Counts 
Assessed during Treatment and Proportion of Mice Relapsing after Treatment 
Completion 
Proportion of mice relapsing after treatment for: 
Regimen 
2 months 
3 months 
2RHZ/RH* 
8/14 
(57%) 
BPa 
3/14 
(21%) 
3BPaL ** 
6/15 
(40%) 
0/15#† 
(0%) 
2BPaL/1BPa*** 
0/15#† 
(0%) 
1BPaL/2BPa 
9/15 
(60%) 
0/15#† 
(0%) 
#p = 0.11 vs. BPa; †p≤ 0.001 vs. RHZ 
*2RHZ/RH means 2 months on the full regimen and a third month on only RH 
**3BPaL means 3 months on the full regimen 
***2BPaL/1BPa means 2 months on the full regimen and a third month on only BPa 
****1BPaL/2Bpa means 1 month on the full regimen and a third month on only BPa 
B – bedaquiline, H-isoniazid, L-linezolid, Pa-pretomanid, R-rifampicin, Z-pyrazinamide 
 
In conclusion, linezolid increases the sterilising activity of the bedaquiline-pretomanid 
combination; no MTB could be cultured from the lungs of mice 3 months after cessation of 3 
months of treatment with the combination, in contrast to MTB cultured from 13 of 15 mice treated 
with the standard 2RHZ/4RH regimen over 3 months. In addition, limiting the duration of linezolid 
to the first month of treatment does not affect linezolid’s contribution to the sterilising activity of 
the regimen in the preclinical mouse study.   
Prior to the use of pretomanid in combination with bedaquiline in clinical study NC-001, a 
preclinical cardiovascular safety pharmacology study was conducted in unrestrained beagle dogs 
with both drugs to explore the potential for additive effects on QT prolongation induced by the 
combination.  Results indicate that administration of 100 mg/kg bedaquiline daily for 7 days 
causes a small increase in QTc interval by Day 6 in some animals that is not influenced by the 
addition of 100 mg/kg pretomanid on Day 7. The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the subcutaneous route of administration and not 
related to the plasma exposure.   
2.3.2 Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or 
Linezolid 
2.3.2.1 Clinical Study NC-001 
Study NC-001 was a partially double-blind, randomized, parallel group study in adult male and 
female participants with newly diagnosed, uncomplicated, smear-positive, pulmonary TB. A total 
of 85 participants met study eligibility criteria and were randomly assigned to one of the six 
treatment groups. All study treatments were given once daily for 14 days. Substantial EBA activity 
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was demonstrated across participants in all arms of the study and the daily reductions in cultured 
colony counts per mL of sputum are presented in Table 5 below. 
Table 5: 
Summary Statistics for EBACFU(0-14) 
Derived Using Bi-Linear Regression, Study NC-001 
Treatment Group 
N 
Daily Mean (SD)  
EBACFU(0-14) 
Pretomanid + pyrazinamide + moxifloxacin 
13 
0.23 (0.128) 
Pretomanid + pyrazinamide 
14 
0.15 (0.040) 
Pretomanid + bedaquiline  
15a 
0.11 (0.050) 
Bedaquiline alone 
14 
0.07 (0.068) 
Bedaquiline + pyrazinamide 
15 
0.13 (0.102) 
Rifafour e-275 
10 
0.14 (0.094) 
 
There were no Serious Adverse Events from the study among participants treated with 
pretomanid and bedaquiline.  Three participants in a bedaquiline-containing treatment arm were 
withdrawn: one participant on the bedaquiline only arm for a Grade 3 ALT and Gamma-Glutamyl 
Transferase (GGT) elevation (although the elevation occurred prior to the first dose of study 
medication), one on a bedaquiline plus pyrazinamide (weight banded) arm for a Grade 3 ALT 
and AST elevation, and one on a pretomanid and bedaquiline arm for to a Grade 3 ALT 
elevation. 
2.3.2.2 Clinical Study NC-003  
Efficacy 
In the 14 day EBA study NC-003 two monotherapy and four different combinations of bedaquiline, 
pretomanid, pyrazinamide and clofazimine were evaluated in DS-TB participants. Fifteen 
participants were randomized into 7 treatment arms: C, Z, B-Pa-Z-C, B-Pa-Z, B-Pa-C, B-Z-C, and 
HRZE control. This study demonstrated no EBA for the clofazimine monotherapy arm and modest 
EBA for the pyrazinamide monotherapy arm. However, all of the experimental regimens 
demonstrated EBA. In general, adding clofazimine to the various agents resulted in either no 
increase in EBA, or a decrease when compared to a similar regimen that did not include 
clofazimine. In this study, the experimental regimen with the best EBA was B-Pa-Z which 
demonstrated a rate of decrease in both logCFU and logTTP that was at least as good as the HRZE 
control. The daily logCFU results are presented in Table 6. Similar results were found when TTP 
was used to calculate the bactericidal activity over 14 days (BA(0-14)). 
 
 
 
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Table 6: 
NC-003 Efficacy Results: Daily BAlogCFU(0-14) 
Arm 
logCFU 
BPaZC 
.124 
BPaZ 
.180 
BPaC 
.086 
BZC 
.098 
Z 
.036 
C 
-.025 
Rifafour 
.152 
Safety 
Generally, the regimens in this study were well tolerated. Table 7 provides a list of the overall 
safety findings. The only SAE experienced in the study was in a participant in the clofazimine 
monotherapy arm. Otherwise, the rates of treatment emergent AEs (TEAEs) were similar across 
the treatment arms. One participant in the B-Pa-Z arm was withdrawn from the study due an 
adverse event of increased liver function tests (alanine aminotransferase (ALT), AST and GGT).  
Table 7: 
NC-003 Safety Data 
 
BPaZ
C 
BPaZ 
BPa
C 
BZC 
Z 
C 
HRZ
E 
Total 
N 
15 
15 
15 
15 
15 
15 
15 
105 
Participants with: 
TEAEs 
11 
9 
8 
10 
10 
9 
8 
65 
TEAEs leading to death: 
Serious TEAEs 
 
 
 
 
 
1 
 
1 
TEAES leading to early withdrawal 
 
1 
 
 
 
 
 
1 
TEAEs leading to discontinuation 
of study drug 
 
1 
 
 
 
 
 
1 
Drug-related TEAES 
8 
5 
7 
3 
5 
6 
5 
39 
Serious, drug-related TEAEs 
 
 
 
 
 
 
 
 
Grade III AEs 
 
2 
1 
2 
 
1 
 
6 
Grade IV AEs 
 
1 
1 
 
 
 
 
2 
Grade II/IV AEs 
 
2 
1 
2 
 
1 
 
6 
 
QT Prolongation 
Because bedaquiline and clofazimine are both known to prolong the QT interval, intensive ECG 
monitoring was included in the study endpoints. The mean change from baseline in QTcB and 
QTcF tended to be larger at 5 hours than at 10 hours post-dose in the (B-Pa-Z-C) arm and in the 
(B-Pa-C) arm.  No QTcB or QTcF ≥500 ms were reported.  An increase from baseline to Visit 5 
and subsequent visits of ≥60 ms in QTcB was reported for 2 participants in the (B-Pa-C) arm and 
for 1 participant in the clofazimine alone arm.  An increase from baseline to Visit 5 and subsequent 
I 
I 
I 
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visits of ≥60 msec in QTcF was reported for 4 participants in the (B-Pa-C) arm and for 1 participant 
in the clofazimine alone arm.  For both QTcB and QTcF, the (B-Pa-Z-C) arm and the (B-Pa-C) 
arm showed the largest increase from baseline. Clofazimine will not be used in any treatment 
arms in the NC-007 study. 
2.3.2.3 The Nix-TB Study  
The NiX-TB Study is an ongoing open-label study assessing the safety and efficacy of bedaquiline 
plus linezolid plus pretomanid in participants with pulmonary infection of either XDR-TB or 
treatment intolerant/non-responsive MDR-TB. The study regimen includes: bedaquiline 400 mg 
once daily for 2 weeks then 200 mg 3 times per week plus pretomanid 200 mg once daily plus 
linezolid 600 mg twice daily amended (22 Jan 2016 protocol) to 1200 mg once daily. Treatment 
duration is 6 months, although if participants are still culture positive at month 4, there is the option 
to extend treatment to 9 months or withdraw. The primary endpoint is the incidence of 
bacteriologic failure or relapse or clinical failure through follow-up until 6 months after the end of 
treatment. Secondary Endpoints include: incidence of bacteriologic failure or relapse or clinical 
failure through follow-up until 24 months after the end of treatment as a confirmatory analysis, 
time to sputum culture conversion to negative status through the treatment period, and the 
proportion of participants with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 
end of treatment. In addition, linezolid dosing (actual) and efficacy will be explored and changes 
from baseline will be evaluated for TB symptoms, Patient Reported Health Status, body weight, 
and measures of safety. 
Efficacy Experience to Date:   
Sixty-nine participants have been enrolled as of February 1, 2017, at 2 sites in South Africa. Forty-
nine percent of the participants are HIV positive, 79% have XDR-TB and 21% have MDR 
intolerant or resistant to prior therapy.  Forty have completed the 6 months of therapy with the 
drug regimen and 31 have been followed to the primary endpoint at 6 months after treatment. All 
surviving patients were culture negative by 4 months, with 74% negative at 8 wks. As of February 
1, 2017, there has been 1 microbiological relapse during follow up after drug therapy and 1 
participant has had a new infection during follow-up with Drug Sensitive TB.  This study will 
continue to enrol participants until the NC-007 study is initiated. 
Safety of the B-Pa-L Regimen in the Nix-TB Study:  As of December 2016, four participants have 
died in the study. The causes of death have varied and include: 2 with multi-organ disseminated 
TB who died within the first 5 weeks of therapy, 1 who had a gastrointestinal bleed and 1 with 
multi-organ failure and disseminated TB on autopsy. No deaths or SAEs have been caused by 
hepatic injury. No participants have been withdrawn from the study except for the 4 who died.  
The expected linezolid toxicities of peripheral neuropathy and myelosuppression were common 
but manageable.  Seventy-one percent of participants had at least one linezolid dose pause (22% 
of all participants due to myelosuppression and 28% due to peripheral neuropathy), during the 6 
months of treatment. One had peak ALT and AST > 3 X ULN and total bili > 2X ULN, but these 
improved and treatment restarted without a recurrence.  There were 7 cases of grade 3 or 4 
transaminitis and all resolved and allowed the study regimen to be continued. There were no 
cases of optic neuritis. While participants have required close surveillance for signs and 
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symptoms of neuropathies and bone marrow suppression, these toxicities have been 
manageable.  
2.4 Overall Benefit/Risk Assessment 
The recent report of the long term outcome of patients with XDR-TB treated in S. Africa highlighted 
the very poor prognosis for patients with this disease.  After 60 months of follow up 73% of 107 
patients had died and only 11% had a favourable outcome(28).  These patients have infection with 
MTB resistant to many/most of the available drugs to treat tuberculosis.  Patients with XDR-TB 
have limited treatment options due to their resistance profile, and the drugs that are typically used 
in Standard of Care have many side effects, some are administered as injectables and have poor 
treatment outcomes in XDR-TB.  Similarly, patients with Pre-XDR-TB and patients with MDR-TB 
who are failing or are intolerant to treatment have traditionally poor outcomes and are a challenge 
to treat. While treatment success for MDR-TB is better than for XDR-TB, overall success in 
treating MDR-TB is still approximately 50% according to the World Health Organization 2015 
Global TB Report.(43) and it would be lower for patients failing or not able to take an optimal 
traditional regimen.  This trial provides an opportunity to treat these high-need patients with three 
active drugs, for which there is no or minimal pre-existing resistance, in a very closely controlled 
and monitored clinical trial setting with the opportunity to define the optimal dosing scheme for 
linezolid.  Participants will be monitored closely and regular reviews of safety and efficacy will be 
made by the Data Safety Monitoring Committee (DSMC).  Preliminary results of the ongoing Nix-
TB trial from patients with XDR-TB and who are failing or intolerant to treatment of MDR-TB 
demonstrate that this regimen has the potential to give relapse-free cure of XDR-TB with a simple 
regimen in a much shorter period of time than currently required by the available drugs used in 
the best standard of care.  Preclinical studies of this regimen in a murine model of infection 
demonstrated relapse free cure of MTB in half the time (3 vs 6 months) required by standard HRZ 
therapy.  Clinical studies of linezolid alone and pretomanid and bedaquiline alone and in 
combination have demonstrated activity against TB infection. 
These three drugs have not been used in combination in humans prior to the Nix-TB trial, and 
thus their combined toxicity profile is emerging.  The greatest risks of key concern for participants 
in this trial from linezolid are from the adverse events of myelosuppression and peripheral and 
optic neuropathy.  Participants will be closely monitored with full blood counts, vision 
examinations, and screening for peripheral neuropathy.  The investigator may interrupt dosing of 
either linezolid or linezolid with pretomanid and bedaquiline if adverse events of concern develop, 
and a resumption of the drugs, with linezolid at the same or at a lower dose, may be made 
cautiously.  Participants will be under close surveillance for hepatotoxicity, as that risk for 
pretomanid and bedaquiline is not yet well characterized.   
Overall the benefit-risk balance justifies evaluating the B-Pa-L regimen in this study, with the 
cautious surveillance in place, to treat patients with XDR-TB who have few options for a 
successful outcome. 
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3 
Trial Objectives  
3.1 Primary Objectives 
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus 
bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary 
XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
4 
Trial Design 
4.1 Summary of Trial Design 
This is a Phase 3, multi-center, partially-blinded, randomized clinical trial conducted in 4 treatment 
groups.  Participants, trial investigators and staff, including laboratory staff, will be blinded to dose 
and scheduled duration of linezolid.   Bedaquiline and pretomanid dosing will not be blinded. 
The trial will be performed at multiple centers located in South Africa, Eastern Europe and Russia.  
A total of 120 XDR-TB and up to 60 Pre-XDR/MDR intolerant or non-responsive participants who 
meet all of the inclusion criteria and none of the exclusion criteria, aged 14 and over (aged 18 and 
over in Russia and Belarus), will be randomized to receive one of the 4 active treatment arms. 
Enrolment will stop when 120 XDR-TB participants are randomized. Participants will be 
randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive web response 
system (IWRS) which will utilize a dynamic randomization system using minimization with a 
random element to allocate participants evenly across the arms by HIV status and type of TB after 
they have given written, informed consent and met all eligibility criteria.  
Each participant will receive 26 weeks of treatment.  If participant’s week 16 sample remains 
culture positive, Investigator may consider option to extend current treatment to 39 weeks, in 
consultation with the Sponsor Medical Monitor. Participants will be followed for 78 weeks after 
end of treatment. 
4.2 Treatment Plan: Schedule of Assessments 
• 
Screening Period (Screening Visit up to 9 days prior to Treatment) 
• 
Treatment Period (Day 1 to Week 26. Additional visits every 3 weeks until last dose when 
dosing extended due to pauses or positive culture at Week 16  
• 
Follow-up Period (4 Week post end of treatment follow-up Visit to 78 Week post end of 
treatment follow-up Visit) 
Refer to: 
• 
Trial Flow Chart (Section 1.2) for the timing of all procedures and laboratory 
samples to done at each visit.   
• 
Trial Procedures (Section 7) for details regarding specific procedures or 
laboratory tests. 
Participants will receive oral daily dosing. They will be randomized to one of the following arms: 
 
 
 
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Table 8: 
Treatment Groups 
 
Treatment Group 
No of Participants 
1 
Linezolid 1200 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
2 
Linezolid 1200 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
3 
Linezolid 600 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
4 
Linezolid 600 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
 
Figure 4: 
Trial Schematic 
 
26 Weeks of Treatment* 
 
Weeks 1-9 
Weeks 10-26 
1 
1200 mg Linezolid QD 
 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
Primary Endpoint 
follow-up for relapse-
free cure 26 weeks 
after end of treatment 
 
Full follow up 78 
weeks after end of 
treatment 
2 
1200 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100mg QD week 9 
Pretomanid 200 mg QD 
1200 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
3 
600 mg Linezolid QD 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
4 
600 mg Linezolid QD 
Bedaquiline 200 mg QDweeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
600 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
Participants will be randomized to 1 of the 4 groups listed above.  
N = 45 Participants per group for a total of 180. 30 XDR-TB participants per group    
* Treatment will be extended to 39 weeks for participants who have a positive culture at week 16  
 
5 
Trial Population 
Participant must meet all inclusion and no exclusion criteria within the screening period.  Re-
testing for laboratory or ECG parameters is allowed within the 9-day screening period. Sponsor 
may consider replacement of late screen failure and un-assessable (as detailed in the statistical 
analysis plan) participants. 
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5.1 Inclusion Criteria 
Participants are required to meet all of the following inclusion criteria during the screening period 
in order to be randomized. 
1. Provide written, informed consent prior to all trial-related procedures (including any 
additional consent required for participants considered as minors per applicable regulatory 
authority or ethics committee). 
2. Willingness and ability to attend scheduled follow-up visits and undergo study 
assessments 
3. HIV testing (if an HIV test was performed within 1 month prior to screening, it should not 
be repeated as long as documentation can be provided [ELISA and/or Western Blot].  If 
HIV status is a confirmed known positive, repeated HIV test is not needed provided 
documentation is available. 
4. Male or female, aged 18 years or older.  
 
Disease Characteristics: 
 
5. Participants with one of the following pulmonary TB conditions: 
a. 
 XDR-TB with  
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
historical documented resistance to isoniazid, rifamycins, a fluoroquinolone 
AND an injectable during the current TB diagnosis/disease course;  
b. 
Pre-XDR-TB with 
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based molecular test within 3 months prior to or at 
screening and; 
ii. 
historical documented resistance to isoniazid, rifamycins, and to a 
fluoroquinolone OR an injectable during the current TB diagnosis/disease 
course. 
c. 
MDR-TB with 
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected results within 3 months prior to screening or 
MTB confirmed in sputum based on molecular test within 3 months prior to 
or at screening and; 
ii. 
historical documented resistance to isoniazid and rifamycins during the 
current TB diagnosis/disease course; 
iii. 
with documented non-response to treatment with the best available regimen 
for 6 months or more prior to enrolment who in the opinion of the Investigator 
have been adherent to treatment and will be adherent to study regimen.   
d. 
MDR-TB with  
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
historical documented resistance to isoniazid and rifamycins during the 
current TB diagnosis/disease course and; 
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iii. 
who are unable to continue second line drug regimen due to a documented 
intolerance to: 
a. PAS, ethionamide, aminoglycosides or fluoroquinolones or ; 
b. Current treatment not listed above that renders participant eligible for 
the study in the Investigator’s opinion.  
6. Chest X-Ray within one month prior to screening, obtained and read locally by investigator 
or designee with results consistent with pulmonary TB in the opinion of the Investigator. 
 
Contraception: 
7. Be of non-childbearing potential or using effective methods of birth control, as defined 
below: 
 
Non-childbearing potential: 
a. Participant - not heterosexually active or practices sexual abstinence; or  
b. Female participant/sexual partner - bilateral oophorectomy, bilateral tubal ligation 
and/or hysterectomy or has been postmenopausal with a history of no menses for 
at least 12 consecutive months; or  
c. Male participant/sexual partner - vasectomised or has had a bilateral 
orchidectomy at least three months prior to Screening. 
 
Effective birth control methods:                                                        
A double contraceptive method should be used as follows: 
a. Double barrier method which can include any 2 of the following: a male condom, 
diaphragm, cervical cap, or female condom (male and female condoms should not 
be used together); or  
b. Barrier method (one of the above) combined with hormone-based contraceptives 
or an intra-uterine device for the female participant/partner; 
 
And are willing to continue practicing birth control methods throughout treatment and for 6 
months (both male and female participants) after the last dose of study medication. 
 
Note: Hormone based contraception alone may not be reliable when taking IMP; 
therefore, hormone based contraceptives alone cannot be used by female participants 
or female partners of male participants to prevent pregnancy. 
 
5.2 Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria during 
the screening period: 
 
Medical History and Concurrent Conditions 
1. Any condition in the Investigator’s opinion (i.e., an unstable disease such as 
uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended 
treatment, cancer that could affect survival through the protocol-specified follow up 
period), where participation in the trial would compromise the well-being of participant 
or prevent, limit or confound protocol specified assessments.  
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2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations.  
3. In the judgment of the Investigator, the patient is not expected to survive for more than 
6 months. 
4. Karnofsky score < 60 at screening. 
5. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal 
Products or related substances. 
6. Body mass index (BMI) < 17 kg/m2 
7. TB infection with known resistance to pretomanid, delamanid, linezolid or bedaquiline. 
8. Participants who, upon the evaluation of their pulmonary disease, are expected to 
require a surgical procedure. 
9. Having participated in other clinical studies with dosing of investigational agents within 
8 weeks prior to screening or currently enrolled in an investigational study that includes 
treatment with medicinal agents.  Participants who are participating in observational 
studies or who are in a follow up period of a trial that included drug therapy may be 
considered for inclusion. 
10. Participants with any of the following at Screening: 
• 
QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrolment. 
• 
Heart failure 
• 
A personal or family history of congenital QT prolongation 
• 
A history of or known, untreated, ongoing hypothyroidism 
• 
A history of or ongoing bradyarrhythmia 
• 
A history of Torsade de Pointe 
11. Females who have a positive pregnancy test at Screening or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the study or within 6 
months of cessation of treatment.  Males planning to conceive a child during the study 
or within 6 months of cessation of treatment. 
12. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, 
participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the 
course of the study, in the opinion of the Investigator. 
 
Previous and Concomitant Therapy 
13. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 
weeks of randomization.  
14. Concomitant use of serotonergic antidepressants or prior use within 3 days of 
randomization if Investigator foresees potential risks for serotonin syndrome when 
combined with linezolid.  
15. Concomitant use of any drug known to prolong QTc interval (including, but not 
limited to, amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, 
cyclobenzaprine, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, 
erythromycin, fluoroquinolones, halofantrine, haloperidol, ibutilide, levomethadyl, 
mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, 
sparfloxacin, thioridazine).  
16. Concomitant use of any drug known to induce myelosuppression.  
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17. Concomitant use of any drugs or substances known to be strong inhibitors or 
inducers of cytochrome P450 enzymes (including but not limited to efavirenz, 
quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine, gestodene, 
metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, 
erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may 
include use of lopinavir/ritonavir regimen as noted in section 5.3.3. 
18. Participants who have received more than 2 weeks of bedaquiline, linezolid or 
delamanid prior to first dose of IMP. 
19.  Participants with an existing TB diagnosis (a diagnosis made > 4 weeks prior to 
screening) and HIV co-infection, must have been on an ART for at least 4 weeks prior 
to screening.  
20. Participants with newly diagnosed tuberculosis and HIV may be enrolled provided that 
appropriate HIV therapy will not be initiated until participant has received at least 2 
weeks of study medication.  
21. HIV infected participants: the following antiretroviral therapies should not be used: 
zidovudine, stavudine, didanosine. The antiretroviral therapy (ART) booster cobicistat 
should not be used. Please reference restrictions Section 5.3.3 Antiretroviral Therapy, 
for guidance on ART treatment during the treatment period.  
 
Diagnostic and Laboratory Abnormalities 
 
22. Participants with any of the following toxicities at Screening (labs may be repeated 
during screening period) as defined by the enhanced Division of Microbiology and 
Infectious Disease (DMID) adult toxicity table (November 2007): 
 
a. Viral load >1000 IU/ml (Unless newly diagnosed HIV and not yet on ART who 
otherwise qualify for participation); 
b. CD4+ count < 100 cells/µL (HIV positive participants); 
c. Serum potassium less than the lower limit of normal for the laboratory; 
d. Hemoglobin < 9.0 g/dL; 
e. Platelets <100,000/mm3; 
f. Absolute neutrophil count (ANC) < 1500/ mm3; 
g. Aspartate aminotransferase (AST)  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor Medical Monitor 
h. Alanine aminotransferase  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor medical monitor; 
i. 
Total bilirubin 
• 
greater than 1.5 x ULN to be excluded; 
• 
1-1.5 x ULN must be discussed with and approved by the Sponsor Medical 
Monitor  
j. 
Direct bilirubin 
• 
Greater than ULN to be excluded 
k. Serum creatinine level greater than 1.5 times upper limit of normal 
l. 
Albumin <3.0 mg/dl 
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All inclusion and no exclusion criteria must be met.  If no single variable/value is outside of the 
ranges of acceptability, but when multiple values are close to the limits and/or whenever the 
Investigator has reason to suspect that there might be a health problem (other than TB), enrolment 
should only be considered after discussing the case with the sponsor medical monitor. 
5.3 Restrictions 
5.3.1 Prior and Concomitant Medications and Other Treatments 
Concomitant medications should be kept to a minimum during the treatment period of the trial.  
However, if concomitant medications are considered to be necessary for the participant’s welfare 
and are unlikely to interfere with the IMP, they may be given at the discretion of the investigator.  
For any concomitant medications given as a treatment for a new condition or a worsening of an 
existing condition occurring after signing of the informed consent form, the condition must be 
documented on the Adverse Event pages of the electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be consulted and reviewed 
carefully.  The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected in order to prevent any potentially serious and/or life-threatening drug 
interactions. 
The following concomitant medications are prohibited during the treatment period to avoid 
possible drug interactions with the IMP: 
• 
Medicinal products used to treat pulmonary TB:  including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and metronidazole. 
• 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). (e.g., phenelzine, 
isocarboxazid) 
• 
Concomitant use of any drug known to prolong QTc interval (including but not limited to 
amiodarone, 
bepridil, 
chloroquine, 
chlorpromazine, 
cisapride, 
cyclobenzaprine, 
clarithromycin, 
disopyramide 
dofetilide, 
domperidone, 
droperidol, 
erythromycin, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, 
pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).  
• 
Treatment with fluoroquinolones (as they are known prolong QTc), are strongly 
discouraged in the trial. They should only be used to treat intercurrent non-TB infections 
and if the benefit of treatment outweighs the risk of prolonged QTc.   
• 
Concomitant use of any drug known to induce myelosuppression.  
• 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: ketoconazole, 
voriconazole, itraconazole, fluconazole; ketolids such as telithromycin; and macrolide 
antibiotics other than azithromycin) for more than 3 consecutive days; 
• 
The systemic use of CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, 
St. John’s wort, rifamycins and systemic dexamethasone. 
Concomitant use of serotonergic antidepressants should be avoided if possible as participants on 
these agents and linezolid are at risk for serotonin syndrome.  
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Caution should be used in treating diabetic patients receiving insulin or oral hypoglycemic agents 
as cases have been reported of hypoglycemic reactions when patients on these agents have 
been treated with linezolid. 
Any drug known to be hepatotoxic should be avoided as much as possible during screening and 
throughout the treatment period (including but not limited to acetaminophen/paracetamol,  
acetazolamide, allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, 
augmentin/co-amoxiclav, azathioprine, baclofen, bumetanide, captopril, carbamazepine, 
celecoxib, chlorpromazine, chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-
trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, 
fosamprenavir, furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, 
ketoconazole, lisinopril, loperamide, losartan, methotrexate, metolazone, mirtazepine, 
nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory drugs, paroxetine, 
phenobarbital, phenothiazines, phenytoin, pravastatin, probenecid, prochlorperazine, 
risperidone, rosuvastatin, sertraline, simeprevir, simvastatin, sodium valproate, sotalol, 
sulfasalazine, sumatriptan, tamsulosin, terbinafine, tetracycline, theophyllin/uniphyllin, tipranavir, 
tolazamide, tolbutamide, topiramate, trazodone, tricyclic antidepressants, trimethoprim, 
verapamil). 
5.3.2 Recommendations for Concomitant use of Anti-Malarials 
The following treatments for malaria are recommended for concomitant use with the IMP, should 
it be necessary: 
• 
Proguanil/atovaquone or  
• 
Artesunate plus sulfadoxine-pyrimethamine  
 
These recommendations are based on the potential for QT prolongation by bedaquiline and many 
anti-malarials. Due to the extended half-life of bedaquiline commencing anti-malarial treatment 
containing drugs that could prolong the QT interval, shortly after discontinuing bedaquiline, is not 
recommended. 
5.3.3 Antiretroviral Therapy 
For HIV infected participants, to avoid potentiating known key toxicities of linezolid (neuropathy 
and myelosuppression), the following antiretroviral therapies should not be used during the 
treatment period: zidovudine, stavudine, didanosine. The ART booster cobicistat should not be 
used. 
Only the following types of antiretroviral therapy (ART) are permissible during administration of 
regimens: 
• 
Nevirapine based regimen consisting of NVP in combination with any two NRTIs TDF/ABC 
and FTC/3TC.  
• 
Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any 
two NRTIs TDF/ABC and FTC/3TC. 
• 
Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC. 
• 
In patients who have viral load suppressed on efavirenz at the time of screening, their 
ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. If possible, 
the same nucleoside backbone should be used. 
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The investigator must assess the risks and benefits of these antiretroviral regimens in the 
context of co-infection with TB acknowledging the following caveats: 
• 
Triple NRTI is generally not considered optimal chronic ART; 
• 
Nevirapine based regimens are associated with higher ART failure in participants having 
or known to have previously had a viral load more than or equal to 100,000/ mL. 
5.3.4 Other Restrictions 
Large quantities of foods or beverages with high tyramine content should be avoided while taking 
linezolid.  Quantities of tyramine consumed should be less than 100mg per meal. Foods high in 
tyramine content include those that may have undergone protein changes by aging, fermentation, 
pickling, or smoking to improve flavour, such as aged cheeses (0 to 15 mg tyramine per ounce); 
fermented or air-dried meats (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 
ounces); soy sauce (5mg tyramine per 1 teaspoon). The tyramine content of any protein-rich food 
may be increased if stored for long periods or improperly refrigerated. 
Alcohol should be avoided while on IMP, especially in patients with impaired hepatic function. 
5.4 Discontinuation from Treatment/Trial  
The following may result in the discontinuation of trial treatment;  
• 
Pregnancy; 
• 
Investigator considers it for safety reasons in the best interest of the participant that he/she 
be discontinued. This could include, but is not limited to: 
o Adverse event(s); 
o Myco testing results from baseline (Screening through Week 4) indicate sensitivity 
to isoniazid and/or rifamycins; 
o Myco testing results from baseline (Screening through Week 4) indicate resistance 
to bedaquiline, pretomanid or linezolid; 
o In the opinion of the investigator, fails to comply with the protocol, including non-
compliance to IMP. 
All participants who discontinue trial treatment (but have not withdrawn consent) and received at 
least one dose of IMP will be requested to return for an early withdrawal visit and applicable safety 
Follow Up visits, as per flow chart (Section 1.2). 
In the event of the following, participants will be and/or are considered discontinued from the trial 
and no additional follow-up visits are required: 
• 
Withdrawal of informed consent; 
• 
Lost to follow-up; 
• 
Termination of the trial by the sponsor. 
A participant may discontinue from the trial at any time at his/her request (withdrawal of consent). 
 
 
 
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Discontinuation from treatment due to TB 
Ultimately it is the investigator’s decision whether a participant should discontinue treatment due 
to a concern that the participant has symptomatic worsening TB and/or bacteriological 
failure/relapse.  
Discontinuation is usually not indicated by a single positive culture.  Should a participant have a 
single positive culture result after being negative, the investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether it 
is in the participant’s best interest that he/she be discontinued. Prior to discontinuation of a 
participant due to TB, the investigator must discuss the participant with the sponsor medical 
monitor, unless the investigator cannot contact the sponsor medical monitor and considers that 
discontinuation must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the investigator decides to discontinue trial treatment for a participant due to TB, additional 
sputum samples may need to be collected in order to ensure the participant’s outcome status may 
be determined, details noted in trial flowchart (Section 1.2). 
All Early Withdrawal participants who are confirmed sputum positive (at least two sequential 
sputum positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to specialists who treat XDR-TB, pre-XDR TB or MDR-TB as 
applicable.  
5.5 Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who is not randomized 
Completed 
Treatment / 
Completed FU* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued FU 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
FU** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* Note that this includes treatment failures who complete all applicable follow-up visits 
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** Early Withdrawal 
5.6 Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific Investigational Site at any time, although this should 
only occur after consultation between involved parties.  Should this occur, the local and central 
Ethics Committee/Institutional review Board (EC/IRB) and Regulatory Authorities will be informed.  
Should the Trial/Investigational Site be closed prematurely, all trial materials (except 
documentation that has to remain stored at the Investigational Site) will be returned to the Sponsor 
or vendor.   The Investigator will retain all other documents until notification given by the Sponsor 
for destruction.  Participants currently on treatment will receive an appropriate regimen and all 
participants will be referred to a unit specializing in the treatment of XDR-TB, Pre-XDR-TB or 
MDR-TB as applicable. 
6 
Treatment 
6.1 IMP Administration  
  
Treatment will be administered orally, once daily, with a full glass of water and a meal in the 
dosing schemes (treatment arms) outlined in Table 9. The study drug regimen should be 
initiated as specified below regardless of whether participant has received any of the allowed 
prior exposure of bedaquiline or linezolid (up to 14 days), including a loading dose of 
bedaquiline. The Pharmacy Manual should be referenced for further details. 
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Table 9: 
 Investigational Medicinal Product Details  
Treatment Group 
Active and Placebo 
Linezolid 1200 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 2 linezolid 600 mg active tablets once daily for 26 weeks 
• 1 placebo linezolid 600 mg tablet once daily for 26 weeks  
Linezolid 1200 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9  
• 2 linezolid 600 mg active tablets once daily for 9 weeks  
• 1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
Linezolid 600 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 1 linezolid 600 mg active tablet once daily for 26 weeks 
• 1 placebo linezolid 600 mg tablet once daily for 26 weeks  
• 1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
Linezolid 600 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9 
• 1 linezolid 600 mg active tablet once daily for 9 weeks 
• 1 placebo linezolid 600 mg tablet for 9 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
6.2 Participant Compliance 
During site clinic visits or hospitalization, the IMP will be administered by the 
Investigator/designated site personnel. During the study, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully trained on how IMP is to be taken. When 
possible, participants will be checked for IMP compliance by the Investigators or trial 
personnel/National TB Treatment Program personnel via the hand-and-mouth procedure (both 
the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP).  Additionally, participant cards will be checked for unused tablets in the 
blisters. 
6.3 Treatment Modification(s) 
All dose modifications should be discussed with the Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required urgently for a safety concern; the 
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Medical Monitor should be informed within 24 hours of the change if not discussed prior to 
implementation. 
In the event of linezolid specific toxicities, the following should be considered and implemented 
per guidance in the monitoring and safety for specific toxicities section of protocol: 
• 
Blinded one step reductions (maximum 3 steps) in the dose of linezolid (1200 mg QD to 
600 mg QD, 600 mg QD to 300 mg QD or 300mg QD to placebo) managed by the IWRS 
as per instructions in pharmacy manual and/or IWRS user manual.  
• 
Temporary pause of linezolid due to a linezolid-specific toxicity should be considered and 
implemented per guidance in the monitoring and safety for specific toxicities section of 
protocol. 
• 
Permanent discontinuation of linezolid. 
Participants experiencing suspected drug related toxicities due to other drugs in the regimen (B-
Pa), the full regimen may be halted for up to 35 consecutive days.  
Pauses of the full regimen must not exceed 8 weeks (56 days) cumulatively.   
If participant’s week 16 sample remains culture positive, Investigator may consider option to 
extend current treatment to 39 weeks, in consultation with the Sponsor Medical Monitor. When 
treatment extended due to a positive culture at week 16, pauses of the full regimen must not 
exceed 13 weeks (91 days) cumulatively. 
When total of missed dosing days and/or pauses is greater than 7 days, additional make-up doses 
should be dispensed/treatment extended. 
At no time should the participant be treated with a single agent. 
6.4 IMP Packaging and Labelling 
The complete formulations of the IMP bedaquiline and pretomanid are found in the respective 
Investigator Brochures(5,6). The complete formulations of linezolid are found in the Package 
Inserts(23,24,26).  
The IMP will be packaged as follows: 
• 
Bedaquiline: Bottles containing: 
o 200 mg QD dose- 28 tablets- bedaquiline 100 mg 
o 100mg QD dose- 14 tablets- bedaquiline 100 mg  
• 
Pretomanid: Blister card containing 14 tablets- pretomanid 200 mg  
• 
Linezolid: Blister Card containing 7 days of dosing as follows: 
o 1200 mg QD Dose  
 
2 blister strips of 7 tablets each (14 tablets) containing active linezolid 600 
mg   
 
1 blister strip of 7 half tablets containing placebo linezolid 300 mg  
o 600 mg QD Dose:  
 
1 blister strip of 7 tablets containing active linezolid 600 mg   
 
1 blister strip of 7 tablets containing placebo linezolid 600 mg 
 
1 blister strip of 7 half tablets containing placebo linezolid 300 mg  
o 300 mg Dose (for reductions): 1 row of 7 active 600 mg tablets for 7 days of dosing 
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 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid 
600 mg   
 
1 blister strip of 7 half tablets containing active linezolid 300 mg  
o Placebo Linezolid Dose: 2 rows of 7 placebo 600 mg tablets for 7 days of dosing 
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid 
600 mg   
 
1 blister strip of 7 half tablets containing placebo linezolid 300 mg  
 
The packaging of each bottle/blister card will be labelled with, at a minimum, the following 
information: 
• 
Name, address and telephone number of Sponsor. 
• 
Name of medication. 
• 
Dosage, quantity and method of administration for bedaquiline and 
pretomanid. 
• 
Potential dosage, quantity and method of administration for linezolid. 
• 
Reference/Lot Number. 
• 
The statement “For Clinical Trial Use Only”. 
• 
Space for completion of Name of Investigator and Site Number. 
• 
MedID: medication identification number  
• 
Storage conditions. 
• 
Period of Use. 
• 
The statement “Keep out of reach of children”. 
• 
Expiry Date. 
• 
Directions for use. 
Space for completion of participant number and visit/date dispensed. 
6.5 Method of Treatment Assignment 
Participants will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
web response system (IWRS) which will utilize a dynamic randomization system using 
minimization with a random element to allocate participants evenly across the arms by HIV status 
and type of TB.  Information & directions will be provided to each site via the IWRS user manual. 
6.6 Blinding and Procedures for Breaking the Blind 
The blind must not be broken except in the case of a medical emergency, where treatment of the 
participant is influenced by the knowledge of what dose and duration of linezolid the participant is 
receiving. It is requested that the Investigator make every effort to contact the Sponsors medical 
monitor (or designee) prior to breaking the blind. IWRS will be programmed with blind-breaking 
instructions, described in the user manual. The sponsor reserves the right to break the blind in 
order to fulfil any regulatory requirements regarding reporting of SAEs. 
In the absence of any medical emergencies requiring a blind break, the blind for all participants 
will be broken once all clinical data and outcome parameters have been captured, no more data 
queries are pending and the statistical analysis plan has been finalized. 
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6.7 Handling, Storage and Accountability  
The investigator or designee must confirm appropriate temperature conditions as per details on 
IMP labelling, have been maintained during transit for all trial treatment received and any 
discrepancies are reported and resolved before use of the trial treatment. 
Only participants enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Upon completion or termination of the trial, all unused 
and/or partially used IMPs must either be returned to Sponsor (or designated vendor) who will 
arrange for destruction or destroyed at site as agreed by sponsor after final accountability has 
been confirmed, 
The Investigator/designee will immediately inform the sponsor of any quality issues arising with 
respect to the trial medication. The sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
7 
Trial Variables and Procedures 
The trial flowchart in Section (1.2) should be referenced for timing and sequence of 
assessments. 
7.1 Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written Informed Consent. 
• 
Visit Dates 
• 
Participant Disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and Exclusion criteria 
• 
Clinically significant medical and treatment history (including past and current TB 
diagnosis and smoking) 
• 
Screening Coached Spot Sputum Sample: 
o Smear microscopy for acid-fast bacilli. 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB 
complex and rifamycin resistance. 
• 
Urine pregnancy test: women of child-bearing potential only, whether they are 
sexually active or not. 
• 
Serology: HIV and CD4 count.  
o If an HIV test was performed within 1 month prior to trial start, it should not be 
repeated as long as documentation of results can be provided (ELISA and/or 
Western Blot). 
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o Where required by regulatory authorities or ethics committees: 
 
Separate approval for this to be performed will be obtained from 
participants in the written informed consent process.  
o prior to HIV testing and on receipt of the results, participants will be 
counselled on HIV by trained counsellors if they have indicated as such on 
the HIV consent form. If requested by the participant, HIV counselling 
provided to the participant by the study site should be clearly documented in 
the participant’s medical records/source.  Participants have the right to 
decline to know or receive their HIV test results. This decision should be 
clearly documented in the participant’s medical records/source.   
• 
Karnofsky Score (Appendix 4). 
• 
Chest X-Ray: A Chest X-Ray digital image will be obtained and read locally by the 
Investigator or designee.  Digital images will be provided to the Sponsor; this process 
will be documented in the Radiology Manual.  The Investigator is responsible for 
review and analysis for participant inclusion. 
• 
Method of Birth Control: Male and Female participants and their partners. 
• 
IMP Details: Randomization 
• 
IMP Compliance/Actual Dosing 
7.2 Efficacy Variables and Procedures 
Two Spot Sputum Samples are collected, one Early Morning brought from home or collected in 
the hospital ward and one spot collected at the research site under the coaching and observation 
of the trial staff or, if no early morning sample was provided, 2 samples collected on site at least 
30 minutes apart. The Mycobacteriology sampling methodology and requirements will be 
described in a separate document, the Laboratory Manual, which will be provided prior to the trial 
start.  
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the time to 
positivity (TTP) followed by a speciation test when applicable, to confirm MTB. 
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse; 
• 
Time to Sputum Culture Conversion; 
• 
Number of participants with Sputum Culture Conversion. 
Every effort is to be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favorable) result.  A participant 
who never achieves culture negative status due to inability to produce sputum, but has completed 
26 week /78 week post treatment completion follow-up and is without clinical or biological 
evidence of relapse, will be considered to have a favorable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (Appendix 7) will record participants’ ratings of the severity of 
common TB symptoms.  
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Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the trial flow chart. Patient Reported Health Status will be collected using the EQ-5D-5L 
Health Questionnaire (Appendix 5). This descriptive system consists of five health-related 
quality of life dimensions, each of which will be recorded using five levels of severity. 
Methodology: The Patient Reported Health Status methodology and requirements will be 
described in a separate document/guideline which will be provided prior to the trial start. 
 
7.3 Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
trial flow chart and assessed for evaluation of the safety endpoints: 
• 
Laboratory parameters. The Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, which will be provided prior to 
the trial start. The following analyses will be performed: 
o Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential, platelet count),  
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, 
calcium (corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, 
creatine phosphokinase (CPK).                  
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per discretion of Investigator.  
• 
12-lead Electrocardiogram (ECG): 
o Investigator Assessment: Normal, Abnormal. 
o Central Cardiologist Assessment: Heart rate, PR interval, RR interval, QT, 
corrected QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all 
participants and will be described in a separate document which will be 
provided prior to the trial start; 
 
Participants should be lying down (recumbent) for at least 5 minutes prior 
to each 12-lead ECG evaluation; 
 
ECGs are to be recorded for 10 seconds; 
 
All ECGs are to be performed in single. 
 
ECGs should be done before any labs when both included in a visit) 
 
For each participant, the ECGs should, to every extent possible, be 
collected at approximately the same time of day (+/- 1 hours) and in the 
same fed/fast state throughout the trial (e.g. 4 hours after lunch). 
• 
Vital signs: 
o Vital Signs, including weight (should be done before any labs) 
o Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 minutes of 
rest) using an appropriately sized cuff, and using the same type of sphygmomanometer, 
if possible by the same observer, at each relevant visit. 
o Heart rate (bpm). 
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o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C). 
• 
Physical Examination:  
o Height is measured at screening only. 
o Full (complete) and Limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will be 
recorded.   
o Weight (kg) (in light clothing and with no shoes).  
o Using the observed variables weight and height, calculated body mass index (BMI) will be 
derived. 
• 
Ophthalmology Slit Lamp Examination. To be done by an Ophthalmologist trained on 
AREDS2 assessment. The ophthalmology slit lamp methodology and requirements will be 
described in a separate document, the Ophthalmology Guideline. The following analyses will 
be performed: AREDS2 opacity typing and grading. 
• 
Ophthalmic Examination. The ophthalmic examinations can be performed by any trained 
study staff. The screening exams must be done by the trained study staff AND an 
Ophthalmologist.  Methodology and requirements will be detailed in the Ophthalmology 
Guideline. 
• 
Ophthalmology History (Screening only); 
• 
Visual Acuity Test – Corrected. Distance Vision; 
• 
Color Vision Assessment. 
• 
Adverse Events. 
• 
Brief Peripheral Neuropathy Screen (Appendix 6) will record ratings. 
• 
Investigator Assessment:  
Principal Investigator to review participant status at specified visits in flow chart including any 
time Investigator determines that participant fulfills criteria for primary outcome of treatment 
failure. Investigator to assess whether TB treatment is considered a “success” or “failure”.  If 
considered a failure, should specify if based on bacteriology and/or clinical deterioration 
and/or radiological deterioration. 
7.4 PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Synopsis Flowchart 1.2) will be used to update 
population PK models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study population.  PK data from 
the current trial may be combined with prior data (e.g., from the NiX-TB trial) to enhance this 
population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between 
drug exposure and efficacy and safety endpoints.   
7.5 Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between screening through Week 4; 
• 
Pre-screening culture that was used for the tests that qualified the participant for inclusion 
into the trial to be subcultured and shipped to the central from the applicable lab for relevant 
participants/with no positive cultures from screening through week 4 and appropriate 
consent 
• 
When applicable, end of treatment or visits with positive cultures during post-treatment 
follow-up. 
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The MTB isolates will be processed at the central lab(s) for: 
• 
MIC against bedaquiline, pretomanid and linezolid;   
• 
Drug Susceptibility Testing in liquid culture for rifampicin, isoniazid, streptomycin, 
ethambutol, pyrazinamide and second line TB drugs including but not limited to 
fluoroquinolones, and injectables; 
• 
Genotyping. 
 
The MTB isolates will be processed at the central lab(s) for: Positive MTB at/after end of 
treatment: Hain MTBDRplus and HainMTBRsl 
 
8 
Adverse Events 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; In general, 
hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event. 
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Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalization, 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.   A “suspected 
transmission of infectious agent by a medicinal product” is also considered a serious adverse 
event under the SAE criterion “Other medically important condition”.   
8.1.3 Attribution/Causality 
• 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration will 
be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor/designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
Table 10: 
Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive.  The relationship in time is reasonable; 
therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event, which might be due to the use of the drug.  The 
relationship in time is suggestive, e.g., confirmed by dechallenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).   
 
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8.1.4 Severity 
Table 11: 
Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
GRADE 4 
Potentially Life-
Threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected from the signing of the ICF until the 78-week post treatment follow-up 
visit at the time points specified in the Flowchart (Section 1.2) and recorded in the case report 
from (CRF). The exception is early withdrawal participants who will only have SAEs collected from 
the time of their early withdrawal through the 78-week post treatment visit. 
Medical occurrences that begin after obtaining informed consent will be recorded as adverse 
events. If an adverse event started before signing of the informed consent, but is ongoing at trial 
start, it should be recorded as medical history.  If the pre-existing medical occurrence worsens 
during the study, and adverse event will be recorded. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of information 
becoming known to the investigator.  
The sponsor/investigator/designee will inform Regulatory Authorities and/or IEC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the IEC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in former trial participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the trial, and he/she considers the event to be reasonably related to 
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the trial treatment or trial participation, the investigator must promptly notify the sponsor, IEC/IRB 
and regulatory authorities on an expedited basis in accordance with local requirements and ICH 
guidelines for GCP. 
8.2.1 Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
Until the end of the follow-up period; and  
• 
Until all queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases follow-up will be the responsibility of the treating physician.  However, this will have 
to be agreed upon with the Sponsor Medical Monitor. 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  Investigator should contact sponsor/designee to discuss 
appropriate medical follow-up if consultation required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide sponsor/representative with a copy of any post-mortem findings including 
histopathology. 
New or updated information on an SAE will be recorded in the originally completed CRF and 
submitted to sponsor within 24 hours of the information becoming known per SAE reporting 
guidelines. 
8.2.2 Clinical Laboratory Adverse Events 
Changes in the results of the Clinical Laboratory assessment results which the Investigator feels 
are clinically significant will be reported as adverse events.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an adverse event. 
8.2.3 Disease under Study 
Symptoms of the disease under trial (Pulmonary Tuberculosis) experienced by the participant 
while on the trial will be assessed by the Investigator.  If the symptom has: 
• 
worsened while the participant is in the trial; and 
• 
the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event.  
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If there is: 
• 
no change; and  
 
• 
the Investigator assesses the symptom as due to the participant’s TB; and  
• 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation.  
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 Overdose 
Overdose of IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an Adverse Event, including if the taking of 
the suspect medicine led to suicidal intention and subsequent overdose of the suspect medicine, 
or other medication. In this case it will be recorded as an adverse event. If it does not lead to an 
Adverse Event, it will not be recorded as an AE and this will be noted in the participant’s source 
documentation. 
8.2.5 Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 Pregnancy 
The Investigator will immediately notify the sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
Investigator will report to the sponsor follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed for 6 months.   
All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following time-
periods: 
• 
During the trial 
• 
Within 6 months after last dose of IMP 
If pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow up will be performed 
unless contraindicated by the pregnancy. 
Pregnancy reporting will follow the same time lines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in preclinical toxicity 
studies Investigator’s Brochures(5,6) and Package Inserts.(23,24,25,26) 
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AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization or until the end of the follow-up period and until all queries on these AEs 
have been resolved.  Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours where possible. The recommendations for managing participants 
below assumes the laboratory abnormalities of concern have been confirmed. 
8.3.1 Neurological 
Participants with co-administration of a serotonergic agent, including anti-depressants, should be 
monitored closely for signs of serotonin syndrome.  The Investigator should determine whether 
the full regimen or the concomitant agent should be discontinued for those who experience signs 
or symptoms of serotonin syndrome such as cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
Linezolid and/or the full regimen should be paused for participants experiencing a seizure. The 
Sponsor Medical Monitor should be contacted to review details and discuss whether linezolid or 
full regimen should be resumed.  
8.3.2 ALT, AST and Alkaline Phosphatase elevations: 
The Investigator should refer to Appendix 8 – Liver Toxicity Management to appropriately manage 
the participant for clinically significant elevations of AST, ALT or Alkaline Phosphatase. 
8.3.3 Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
Contact Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 4 elevations 
of lipase, Investigator should consider pausing the full regimen, pending further evaluation. 
8.3.4 Musculoskeletal System and Cardiac Muscle 
Myalgia 
Grade 2 (muscle tenderness at site other than sites of injection and/or venipuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
Participants with Grade 2 signs and symptoms should be followed closely. Participants with Grade 
3 or 4 signs and symptoms should be discussed with the Sponsor Medical Monitor to consider 
pausing study medication, pending further evaluation. 
CPK 
For participants having elevations in CPK of potential clinical concern, the Investigator should 
check the CK-MB subunit, if high, consider pausing regimen and discuss with Sponsor Medical 
Monitor.  
8.3.5 Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
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Participants should be monitored closely.  The Investigator should discuss with the Sponsor 
Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artifacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen 
 
Monitoring Linezolid Toxicities  
The following are guidelines for decisions to pause, reduce and to resume linezolid in response 
to the onset and resolution of known linezolid-specific toxicities.  These are guidelines, and 
decisions must be made in the context of the entire clinical status of the participant.  While the 
investigator may need to urgently interrupt dosing for potentially life threatening symptoms or 
laboratory findings, the Medical Monitor should be contacted and informed of any changes in dose 
within 24 hours.  Questions should be raised to the Sponsor’s Medical Monitor if the decision is 
not clear. 
8.3.6 Myelosuppression 
The hematologic parameters of hemoglobin and counts of Neutrophils and platelets are variable 
from measurement to measurement.  While decreases in any of these may be caused by linezolid 
toxicity, decreases of concern should be evaluated in the context of the participant’s full clinical 
status and alternate explanations.  Guidelines below are for situations of concern when it is 
considered likely that linezolid has caused the decrease. 
Anemia 
• 
Consider pausing linezolid if hemoglobin falls below 8 gm/dL (Grade 3) and significantly 
below baseline, or if hemoglobin falls > 25% of baseline. If it is clear that the anemia was 
caused by linezolid, consider resuming linezolid at half the dose when hemoglobin 
improves and linezolid is resumed.  
Leukopenia 
• 
Consider pausing linezolid if the Absolute Neutrophil Count (ANC) falls below 750/mm3 
(Grade 3) and significantly below baseline.  Ideally confirm with a repeat test before 
making further decisions as ANCs can have diurnal and other variability. If it is clear that 
the leukopenia was caused by linezolid, consider resuming linezolid at half the dose when 
ANC improves and linezolid is resumed.  
Thrombocytopenia 
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• 
Consider pausing linezolid if platelets fall below 50,000/mm3 (Grade 3) and significantly 
below baseline. Ideally confirm with a repeat test before making further decisions.  If it is 
clear that the thrombocytopenia was caused by linezolid, consider resuming linezolid at 
half the dose when platelets improves and linezolid is resumed. 
8.3.7 Peripheral Neuropathy 
The decision to reduce the dose, or to pause linezolid until symptoms improve is a judgment 
based on changes in signs and symptoms identified by the investigator and informed by 
discussion with the trial participant.  As general guidance, consider pausing and/or reducing 
linezolid when the grade of a neuropathy sign or symptom increases by a grade to grade two or 
greater.  If it is clear that linezolid caused the neuropathy, consider resuming linezolid at half the 
dose, when the neuropathy improves. 
8.3.8 Optic Neuropathy 
A participant with visual symptoms of concern or change in visual acuity of 2 lines or more or 
change in color vision of more than one plate should be referred to the site ophthalmologist for 
evaluation with a retinal examination.  Any changes as assessed by the ophthalmologist that raise 
concern that an optic neuropathy may be developing should be discussed with the medical 
monitor and linezolid should be paused.  If a likely or definite optic neuropathy is confirmed, 
linezolid should be permanently discontinued. 
8.3.9 Lactic Acidosis 
Lactic acidosis as a toxicity of linezolid should be considered if participants have gastrointestinal 
symptoms that are not explained by other more common causes of their symptoms.  Such 
participants should have lactate measured and, as indicated, a full evaluation of pH and 
bicarbonate. Note that lactate should not be measured in participants who have no symptoms of 
concern, as elevated asymptomatic lactate may be common and it is difficult to interpret the 
clinical relevance of this. Also evaluate whether any concomitant medications, such as anti-
retroviral therapies, may be associated with lactic acidosis and consider pausing them until the 
acidosis resolves. Consider pausing linezolid if a patient has GI symptoms and acidosis likely to 
be secondary to linezolid toxicity that is not otherwise explained. 
8.4 Safety Monitoring by Data Monitoring Committee 
A DSMC will be appointed for the study. The primary responsibility of the DSMC will be to act in 
an advisory capacity to the Sponsor to safeguard the interests of trial participants by monitoring 
participant safety, assess participant risk versus benefit, and assess data quality and general 
evaluation of the trial progress. Its activities will be delineated in a DSMC charter that will define 
the membership, responsibilities and the scope and frequency of data reviews. The DSMC will 
operate on a conflict-free basis independently of the Sponsor and the study team. It will comprise 
at least 3 voting members that include at least 2 clinicians and one statistician.  The DSMC may 
have an organizational meeting prior to commencement of the trial. The DSMC will have meetings 
where it will review unblinded data during a closed session. These meetings will be planned at 
regular intervals. The Sponsor or the DSMC may convene ad hoc meetings based on rates of 
SAEs and/or to review results of the futility analysis or if safety concerns arise during the trial.  
After its assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
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9 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 Analysis Population 
The primary analysis population will include both XDR and non-XDR (pre-XDR and MDR 
intolerant and non-responsive TB) participants (up to 45 per arm).  A secondary analysis will be 
restricted to the XDR participants only (30 per arm).    
A modified intent-to-treat (mITT) and a per-protocol (PP) analysis for each arm and analysis 
population will be conducted.    The mITT will be considered the primary analysis and will include 
all those in the ITT analysis with additional specific exclusions detailed in the statistical analysis 
plan (SAP). 
Other analyses will be performed (for sensitivity) including a full intent-to-treat (ITT) analysis with 
no exclusions, and an analysis excluding only those who were later found to be ineligible at 
baseline (based on data collected prior to randomization).    
The Safety analysis population will include data from all randomized participants who received at 
least one dose of IMP.  
Full details of all the analysis populations will be defined in the SAP. 
9.2 Sample Size 
The objective of this trial is to evaluate the efficacy, safety and tolerability of various doses and 
durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants 
with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
In order to fulfil this objective, it is planned to randomize 30 XDR-TB participants per treatment 
group and up to 15 pre-XDR and/or MDR intolerant/non-responsive -TB participants per group. A 
sample size of 30-45 per arm will provide more than 90% power to demonstrate that the lower 
bound of the 95% confidence interval of this estimate is greater than 50%, using a 2-sided 5% 
significance level. This assumes that the true cure rate is 80 percent.   
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as 
the target, because it is above the entire range of the historical control for cure of XDR-TB and 
because a cure rate of 50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a 
shortened, simplified, all oral, inexpensive and safer regimen would clearly represent an important 
therapeutic advancement. A standard-of-care control group cannot reasonably be included in the 
trial for several reasons.  1) Given that the regimens being tested contain B and L, these drugs 
would need to be excluded from the control group.  However, they are beginning to be used 
increasingly in XDR-TB, despite lack of firm evidence, but with positive anecdotal reports.  Asking 
patients in the control group to avoid these medications could present an ethical issue.  2) The 
success rate of standard-of-care treatment for XDR-TB, particularly without B and L (see below), 
and the risk and difficulty of its administration contrast markedly with the early findings of B-L-Pa 
in the Nix-TB trial.  It is unlikely that patients would sign informed consent to receive standard-of-
care treatment if there is an alternative, but even if they do there remains an ethical issue of 
comparing such a disadvantaged treatment with such an advantaged treatment.  3) The scientific 
validity of comparing a 12-month endpoint (B-L-Pa) with a 30- or 36-month endpoint (standard of 
care) would represent a significant challenge.   
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9.3 Interim Analyses 
No formal interim analyses are planned.  Primary analysis will be performed on the 26 week 
follow-up data (after end of treatment when the last randomized participant has completed 26 
weeks of follow-up after end of treatment). 
There will be either two database locks, data analyses and trial reports generated for this trial:  
1. 
When all participants have completed 26 weeks of follow-up after end of treatment.  
2. 
When all participants have completed 78 weeks of follow-up from after end of treatment.  
9.4 Primary and Secondary Endpoint Analysis 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT). 
A secondary analysis will be restricted to the XDR participants only (30 per arm). We will 
evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that 
the incidence of bacteriologic failure or relapse or clinical failure (including mortality) at 6 months 
(26 weeks) after the end of therapy is less than 50%.   
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and 
safety and to control the overall type I error rate the following analysis strategy will be adopted 
for both the primary and secondary analysis populations: 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 
weeks) with the L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a 
success.  Similarly, L600 9 weeks will only be tested if L600 26 weeks is a success.   A 
Bonferroni adjustment will be made for comparing the L1200 9 weeks and L600 26 weeks arms 
simultaneously, using p<0.025.  For these comparisons the lower bound of the 97.5% 
confidence interval will need to exceed 50% for success.   
No formal statistical pairwise comparisons between the arms will be performed. 
9.5 Safety and Tolerability Analysis 
• 
The incidence of all-cause mortality will be summarized. 
• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake.  Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
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o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
• 
Cardiovascular Safety:  QT intervals will be adjusted using Fridericia’s correction and Bazett’s 
correction. QT/QTc values and changes from pre-dose (average of Screening and Day 1 
values) at each time point will be summarized using descriptive statistics by group and time 
of collection.  These will be presented as descriptive analyses, and no inferential tests will be 
carried out. 
o Post-baseline QT/QTc intervals will be classified into the following categories:   
 
QT/QTc < 450 msec 
 
450 msec < QT/QTc < 480 msec 
 
480 msec < QT/QTc < 500 msec 
 
QT/QTc > 500 msec   
o QTc changes from baseline will be classified into the following categories: 
 
increase < 30 msec,  
 
30 msec and < 60 msec, and  
 
increase > 60 msec.  
o Frequency counts will be used to summarize the number of participants at each 
time point according to the above categories. 
o ECG results will be classified as normal or abnormal (investigator assessment) 
and summarized using frequency counts by dose group and time of collection. 
• 
Ophthalmology: Descriptive statistics, including changes from baseline, will be summarized 
and listed by participant for ophthalmology slit lamp examination (age related eye disease 
study 2 [AREDS2] lens opacity classification and grading). Categorical data for lens opacity 
will be summarized in a frequency table for the right and left eye, respectively.  
• 
Visual acuity and color vision:   Descriptive statistics, including changes from baseline, will be 
summarized and listed by participant for both Visual Acuity and Color Assessments. 
Categorical data for changes in visual acuity and color vision from baseline will be summarized 
in a frequency table for the right and left eye, respectively.  
• 
Descriptive statistics of neuropathy data derived from Brief Peripheral Neuropathy Screen. 
Categorical data for observed signs and symptoms of neuropathy will be summarized in 
frequency tables, including changes in signs and symptoms from baseline.  
• 
Other safety variables: Laboratory Parameters, Physical Examination, Vital signs (see 
Appendix 3), Concomitant medication, ophthalmic examination and peripheral neuropathy.  
Descriptive summary statistics will be presented. The incidence of liver related laboratory 
abnormalities will be explored. 
9.6 Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
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In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update population pharmacokinetic 
(PopPK) models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study population, and to derive 
individual exposure metrics for use in exposure-response analyses. PK data from the current trial 
may be combined with prior data (e.g., from the NiX-TB trial) to enhance this population PK 
analysis. Detailed plans for the PopPK analysis will be outlined in a separate modeling plan, and 
results will be reported in separate modeling report. 
9.7 Pharmacokinetics/Pharmacodynamics 
For each analyte, the PopPK model will be used to derive individual exposure metrics such as 
steady-state Ctrough, Cmax, AUCτ, and time-above-minimum-inhibitory-concentration (T>MIC), 
or alternative individual summaries of these metrics over the treatment period to account for dose 
adjustments and interruptions as appropriate. Relationships between such exposure metrics and 
efficacy and safety endpoints will be explored graphically and by model-based analyses as 
appropriate. Planning details and results will be included in the separate modeling plan and report. 
10 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants specific eCRF pages will be 
completed as described in the eCRF Completion Guidelines.  For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-Patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator 
has 
to 
permit 
trial 
related 
monitoring, 
audits, 
Independent 
Ethics 
Committee/Institutional Review Board (IEC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-Patient records while participants is on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial center files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection subsequent to trial completion.  The essential documents should be retained for 
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not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify sponsor/designees 
prior to destroying any records pertaining to the trial. 
11 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the Declaration 
of Helsinki.  
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures will be adhered to for all clinical and bioanalytical activities 
relevant to the quality of the trial.  Participant compliance will be monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-investigators. Written 
IEC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for the purpose of monitoring various aspects of the trial, and to assure appropriate conduct of 
the trial in accordance with ICH GCP.  Visits will take place usually within a predetermined interval, 
but this may vary during the course of the trial.  The Investigator and site staff will allow the trial 
monitor and authorized representatives of the Sponsor to (1) inspect all CRFs, written informed 
consent documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs, training records, facilities and other trial related 
systems/processes, and (2) access clinical supplies, dispensing and storage areas.  The 
Investigator and site staff should also (1) agree to assist with monitoring activities if requested 
and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
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maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Monitoring Plan 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. 
11.4 Auditing 
For the purpose of compliance with International GCP and regulatory agency guidelines, it may 
be necessary for Sponsor-authorized Quality Assurance personnel and/or authorized personnel 
from an external regulatory agency to conduct an audit or inspection of the investigational site.  
The purpose of an audit is to assess the quality of data with regard to accuracy, adequacy and 
consistency, and to assure that studies are in accordance with the guidelines.  Having the highest 
quality data from studies is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by GCP to be maintained 
by each site; drug storage, dispensing and return; all trial-related supplies; and source documents 
against the CRFs to assure the adequacy and accuracy of the information which has been 
recorded, including the verification of any AEs which have occurred. The auditors or inspectors 
may also review site SOPs, training records, site facilities and other trial related 
systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
12 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles that 
have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review 
The protocol and required trial related documents will be reviewed by the sites respective 
IEC/IRB.  The trial will not start until the IEC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, plus 
any other trial related documents required for review.  The IEC/IRB shall be constituted and shall 
operate in accordance with International GCP, the ethical principles that have their origin in the 
Declaration of Helsinki. The Investigator will maintain an accurate and complete record of all 
submissions made to, and responses from the IRB/IEC.  The records should be filed in the 
Investigator’s Trial File, and copies will be sent to the Sponsor. 
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12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for the purpose of determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
considered to be part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary The investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same IEC/IRB responsible for approval of this protocol.  Each 
informed consent form shall include the elements required by the international GCP and must 
adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
ICF. 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the IEC/IRB approved written informed consent form 
will be signed and dated by both the participant and the person obtaining consent (Investigators 
or designees), and by any other parties required by the IEC/IRB. Ongoing participants must be 
re-consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative.  Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s 
medical record. 
The monitor will inspect the original completed consent form(s) for all participants 
12.5 Confidentiality  
All site staff, the Sponsor, and any sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations.  Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
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permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the sponsor or designees. 
13 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible IEC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors. (30)  
Because the Study is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Study must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Study must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
14 Protocol Amendment Policy 
Any change to the protocol will be effected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the IEC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, IEC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant Authorities 
and/or IEC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the IEC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
15 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial sponsor is the Global Alliance for TB Drug Development (TB Alliance).  The TB Alliance 
is a not for profit, product development partnership accelerating the discovery and development 
of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, 
be compatible with antiretroviral therapies for those HIV-TB participants currently on such 
therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
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The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The sponsor certifies that it has liability insurance coverage for itself and will provide an associated 
certificate upon request.  The insurance does not relieve the Investigators of the obligation to 
maintain their own liability insurance as required by applicable law. The sponsor does not assume 
any obligation for the medical treatment of other injuries and illnesses.
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Mendoza A, Bayona J, Zignol M and Jaramillo E (2008).  “Management of Extensively 
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Erondu N, Ginsberg AM, Becker P and Spigelman MK (2012). “Phase II Dose-Ranging 
Trial of the Early Bactericidal Activity of PA-824”. Antimicrobial Agents and Chemotherapy; 
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5. Bedaquiline (TMC207) Investigator’s Brochure, Janssen Research and Development, 
Edition 9, 09 October 2015.  
6. Investigator’s Brochure Pretomanid (PA-824), Global Alliance for TB Drug Development, 
Version 17, 22 December 2016.  
7. Keshavjee S, Gelmanova IY, Shin SS, Mishushtin SP, Andreev YG, Atwood S, Furin JJ 
and Miller A (2012). “Hepatotoxicity during treatment for multidrug-resistant tuberculosis: 
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8. Leach KL, Brickner SJ, Noe MC, Miller PF. "Linezolid, the first oxazolidinone antibacterial 
agent" Ann NY Acad Sci. 2011 Mar; 1222:49-54. 2011.  
9. Lee, et al. "Linezolid for treatment of chronic extensively drug-resistant tuberculosis" N 
Engl J Med. 2012 Oct 18; 367(16):1508-18. 
10. Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, 
Reynolds RC, and Orme IM. “Preclinical Testing of the Nitroimidazopyran PA-824 for 
Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models” 
Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301. 
11. Lytvynenko N, Cherenko S, Feschenko Y, Pogrebna M, Senko Y, Barbova A, Manzi M, 
Denisiuk O, Ramsay A and Zachariah R (2014). “Management of multi and extensively 
drug resistant tuberculosis in Ukraine: how well are we doing?” IUALTD Public Health 
Action 4(3): S67-S72. 
12. Manjunatha U, Boshoff HI, Berry CE. The mechanism of action of PA-824: novel insights 
from transcriptional profiling. Commun Integr Biol. 2009; 2(3):215-218. 
13. Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton, JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci USA. 2006; 103(2):431-436. 
14. McLeay SC, Vis P, van Heeswijk RPG and Green B (2014). “Population Pharmacokinetics 
of Bedaquiline (TMC207), a Novel Antituberculosis Drug”. Antimicrobial Agents and 
Chemotherapy 58(9): 5315-5324. 
15. Mdluli K, Nuermberger, E. “Pre-Clinical Drug Combination Studies to Identify Novel 
Regimens for TB”. In: Recent Advances in TB Drug Development symposium, 40th Union 
World Conference, International Union Against TB and Lung Disease, Cancun, Mexico, 
2009. 
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16. Mdluli K, Nuermberger E, Taylor K, Williams N, Koen A, Khisimuzi E, Rokeya T, Si-Yang 
L, Peloquin C, Dinesh C. “Sterilizing activity of novel TMC207- and PA-824-containing 
regimens in a murine model of tuberculosis” Antimicrobial Agents and Chemotherapy 
2011; 55: 5485-5492. 
17. Migliori GB, Sotgiu G, Gandhi NR, Falzon D, DeRiemer K, Centis R, Hollm-Delgado MG, 
Palmero D, Perez-Guzman C, Vargas MH, D’Ambrosio L, Spanevello A, Bauer M, Chan 
ED, Schaaf HS, Keshavjee S, Holtz TH, Menzies D and “The Collaborative Group for 
Meta-Analysis of Individual Patient Data in MDR-TB” (2013). “Drug resistance beyond 
XDR-TB: results from a large individual patient data meta-analysis”. Eur Respir J. 42(1): 
169-179.  
18. Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006; 50(8):2621-2625. 
19. Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal, I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 2008; 
52(4):1522-1524. 
20. Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005; 172(11):1452-1456. 
21. O’Donnell MR, Padayatchi N, Master I, Osburn G and Horsbaugh CR. “Improved Early 
Results for Patients with Extensively Drug Resistant Tuberculosis and HIV in South 
Africa”. Int J Tuberc Lung Dis. 13(7): 855-861. 
22. Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
23. Package Insert for South Africa, ZYVOXID® (linezolid), Pfizer Pharmaceuticals, May 
2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=1045. Date last accessed: 15 April 
15 2016.  
24. Package Insert, Lizomac™ 600 (linezolid), MacLeods Pharmaceutical, 2014. 
25. Package 
Insert, 
SIRTURO®, 
Janssen 
Therapeutics, 
December 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204384s006lbl.pdf. Date last 
accessed: 15 April 2016. 
26. Package 
Insert, 
ZYVOX®, 
Pfizer 
Pharmaceuticals, 
June 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021130s030,021131s029,02
1132s034lbl.pdf. Date last accessed: 15 April 2016.  
27. Park IN, et al. “Efficacy and tolerability of daily-half dose linezolid in patients with 
intractable multidrug-resistant tuberculosis.” B Antimicrobial Chemotherapy 2006; 58:701-
704. 
28. Pietersen E, et al. "Long-term outcomes of patients with extensively drug-resistant 
tuberculosis in South Africa: a cohort study" Lancet, 2014 Jan 16. pii: S0140-
6736(13)62675-6.  
29. Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, Vasilyeca I, 
Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, Van 
Baelen B, van Heeswijk RPG and Dannemann B (2016). “Bedaquiline safety data in a 
broad patient population treated for drug-resistant TB including XDR-TB (C209 study)”. 
Tuberculosis 47: 394-402.  
30. “Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in 
Medical Journals”, December 2016 update.  http://www.icmje.org/icmje-recommendations.pdf,  
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31. Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578.  
32. Schecter GF, et al.  “Linezolid Treatment for MDR-TB”. Clinical Infectious Diseases 2010; 
50:49-55. 
33. Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008; 
322(5906):1392-1395. 
34. Singla R. "Linezolid: an Effective, Safe and Cheap Drug for Patients Failing Multidrug-
resistant Tuberculosis Treatment in India" Eur Respir J. 2012 Apr; 39(4):956-62. doi: 
10.1183/09031936.00076811. Epub 2011 Sep 29. 
35. Stover, C. K., P. Warrener, D. R. VanDevanter, et al. 2000. “A small-molecule 
nitroimidazopyran drug candidate for the treatment of tuberculosis”. Nature 405:962–966. 
36. Tasneen R, Betoudji F, Tyagi S, et al.  Contributions of oxazolidinones to the efficacy of 
novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis.  
Antimicrob. Agents Chemother Posted Online 26 October 2015.  Dol:10.1128/AAC.01691-
15. 
37. Tasneen R, Tyagi S, Williams K, Grosset J, Nuermberger E. “Enhanced bactericidal 
activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of 
tuberculosis”. Antimicrob Agents Chemother. 2008; 52(10):3664-3668. 
38. Tato M, et al. "In vitro activity of linezolid against Mycobacterium tuberculosis complex, 
including multidrug-resistant Mycobacterium bovis isolates". Int. J. Antimicrob Agents 
2006 Jul; 28(1)75-8.  
39. Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”.  
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
40. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. Bactericidal 
activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2005; 49(6): 2289-2293. 
41. WHO Treatment of Tuberculosis Guidelines, 4th Edition. 2010.  
42. World Health Organization. Global Tuberculosis Report 2014, 19th ed. 2014. 
43. World Health Organization. Global Tuberculosis Report 2015, 20th ed. 2015. 
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Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
exact figure/100/scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at 
least 20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life-
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization 
or hospice care probable. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common Toxicity 
Criteria (CTC), and World Health Organization (WHO)) have been adapted for use by the 
Division of Microbiology and Infectious Diseases (DMID) and modified to better meet the 
needs of Patients in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life-
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
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Hypocalcemia 
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life-
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life-
threatening arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function are in the  
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase  
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
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Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, with or 
without clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment required 
acute treatment 
required; 
outpatienttreatm
ent or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock;   
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
50% - 70% (of peak 
flow) 
no normalization with 
bronchodilator;FEV1 
25% - 50% of peak 
flow; or  retractions 
present 
cyanosis: FEV1 < 
25% of peak flow 
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea with normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
 
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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3-
4 loose stools/day 
or mild diarrhea 
last < 1 week 
moderate or 
persistent; 5-7 loose 
stools/day or 
diarrhea lasting >1 
week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization   
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
 
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NEUROLOGICAL 
 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
weakness no 
objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function 
objective 
weakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment  required 
moderate 
discomfort; non-
narcotic analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment (mod 
decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod 
degree in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis;  or 
seizures 
 
 
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MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics and/or 
pain interfering with 
function but not with 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain with 
inflammation, 
erythema or joint 
swelling – interfering 
with function, but 
not with activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected Stevens-
Johnson or  
necrosis requiring 
surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection 
Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 
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SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial narcotic 
therapy 
intractable; requires 
repeated narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 50% 
> 48 hours 
normal activity 
decreased > 50% 
can’t work 
unable to care for 
self 
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Appendix 3:  Cardiovascular Safety 
 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 90 mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or 
Grade 4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
 
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Appendix 4:  Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Descrip
Able to carry on normal activity and to work; no special care needed. 
N
A
N
Unable to work; able to live at home and care for most personal needs; varying amount of assistance 
needed. 
C
R
R
Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing 
rapidly. 
D
S
V
M
D
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109(22). 
-
-
-
-
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Appendix 5:  EQ-5D-5L Questionnaire 
 
 
 
Under each heading, please tick the ONE box that best describes your health TODAY 
MOBILITY 
I have no problems in walking about 
I have slight problems in walking about 
I have moderate problems in walking about 
I have severe problems in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities) 
I have no problems doing my usual activities 
I have slight problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe problems doing my usual activities 
I am unable to do my usual activities 
PAIN / DISCOMFORT 
I have no pain or discomfort 
I have slight pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
• • • • • 
• • • • • 
• • • • • 
• • • • • 
• • • • • 
UK (English) v.2 C 2009 EuroQol Group. EQ-50"' Is a trade marlc of the EuroQol Group 
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• 
We would like to know how good or bad your health is 
TODAY. 
• 
This scale is numbered from O to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TODAY. 
• 
Now, please write the number you marked on the scale in the 
box below. 
YOURHEALTHTODAY = D 
3 
UK (English) v. 2 C> 2009 EuroQol Group. EQ-5D.,. is a trade merlc of the EuroQol Group 
The best health 
you can imagine 
100 
The worst health 
you can imagine 
95 
90 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
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Appendix 6:  Brief Peripheral Neuropathy Screening 
 
During Treatment 
Screening 
Week 
4 
Week 
8 
1. Visit 
{Circle-One) 
Post Treatment 
12 Week 
26 Weeks 
52 Weeks 
78 Weeks 
Other 
End of or Early W ithdrawal 
from Treatment 
Unscheduled 
For ne,w onset or worsening peripheral neuropalhy OR 
lreabnent e):lension (+ ci.lture or interrup6ons) 
2. Date of Assessment 
.. 
3. In the last two weeks, have pain, aching or burning in your feet interfered with your 
walking or sleeping? (Check one) 
If YES, ask the patient to rate the level of interference (1 to 10/ to his wa/King or steeping cause<t oy this pain, 
ache or burning (circle one). 
3a. 
Minimal 
Modest 
Severe 
01 
02 
03 
08 
09 
10 
Using the faces oe/ow, ask the patient to rate the severity of the symptoms for the questions 4, 5, 6 on a scale 
of 1 (mild/ to 10 (severe) for both feet. If the severity is different between the left and right foot, recorcJ the 
severity of the most affected foot. 
Enter a score for each symptom. 
If a symptom has been present in the past, but not since the last visit, enter '00- CurrenYy Absent' 
If a symptom has never been present, enter '11 - AIIVays Been Normal' 
® 
00 
02 
04 
06 
08 
10 
Very Happy, 
No Symptoms 
Just a little brt 
A little more 
Even more 
A whole lot 
Worst 
During the last 14 days, have 
you experienced: 
4. Pain, aching or bunning in feet or legs? 
5. "Pins and needles• in feet or legs? 
6. Numbness (lack of feeling) in feet or legs? 
19-Jan.17ve™on 
Severity 
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• 
Press the ends of a 128 Hz tuning fork together so the sic/es touch and let g:J. Place the vibrating tuning fork 
on the bony prominence on the patient's wrist to be sure that they can recognize the vibration or "buzzing" 
quality of the tuning fork. 
• 
Again, press the ends of the tuning fork /1ard enour;/1 so that the sides touch and let gJ. Immediately place the 
vibrating tuning fork gently but firmly on the top of the distal interphalangeal (DIP) joint of the g-eat toe and 
begn counting the seconds. Instruct the Subject to tell you when they stop feeling the vibration or "buzzing" 
• 
Repeat for the g-eat toe on the other foot 
Vibration Perception Grade Scale: 
0 - Vibration felt for > 10 seconds (normal) 
1 - Vibration felt for 6- 10 seconds (mild loss) 
2 - Vibration felt for 5 seconds or less (moderate loss)* 
3 - No feeling of vibration (severe loss)• 
9 - Unable to evaluate or did not assess• 
7. Measured vibration grade of great toe DIP joint 
Right 
Left 
• 
The examiner uses one hand to press upward on the ball of the foot, dorsiflexing the Subject's ankle to 90 
deg-ees. Using the reflex hammer (preferably long /Jane/led), the examiner strikes the Achilles tendon. 
• 
The tendon reflex is felt by the examiner's /Janel as plantar flex ion of the foot, appearing after a slight delay 
from the time the Achilles /enc/on was struck. 
• 
Repeat for ankle on other leg 
Ankle reflex grade scale: 
0 - Absent 
1 - Hypoactive 
2 - Normal deep tendon reflexes 
3 - hyperactive deep tendon reflexes (e.g. with prominent spread of toes) 
4 - clonus 
9 - unable to evaluate or did not assess 
Right 
8. l'vleasured ankle reflex grade 
Name of Person 
Name of Clinician 
Comoletino Form 
(if required) 
Signature of Person 
Signature of Clinician 
Completing Form 
(ifn!!quited) 
Date I 
I 
I 
I 
I 
I 
I 
I 
Date I 
I 
19-Jan-17 version 
Left 
I 
I 
I 
I 
I 
I 
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Appendix 7:  Tuberculosis Symptoms Profile 
 
 
TUBERCULOSIS SYMPTOM PROFILE {V3) 
This questionnaire asks about symptoms that patients with tuberculosis may or may not experience. 
Please read each symptom carefully and think about your experience during the past 7 days when you make your 
response. Then tick (611) one box for each symptom. 
If you did not experience the symptom during the past 7 days, please tick (0) HNone" for that symptom. 
If you did experience the symptom during the past 7 days, please tick (611) whether the intensity of the 
symptom you experienced was "Mild", "Moderate" or "Severe". 
TB Symptom 
Rate your experience of each symptom over the past 7 days. 
Feeling feverish 
• None 
• Mild 
D Moderate 
D Severe 
Feeling chills 
• None 
• Mild 
D Moderate 
D Severe 
Excessive sweating 
• None 
• Mild 
D Moderate 
D Severe 
Shortness of breath 
• None 
• Mild 
D Moderate 
D Severe 
Chest pain 
• None 
• Mild 
D Moderate 
D Severe 
Feeling unwell 
• None 
• Mild 
D Moderate 
D Severe 
Tiredness/weakness 
• None 
• Mild 
D Moderate 
D Severe 
Cough 
• None 
• Mild 
D Moderate 
D Severe 
Coughing up mucus 
• None 
• M,ld 
D Moderate 
D Severe 
Coughing up blood 
• None 
• Mild 
D Moderate 
D Severe 
During the past 7 days, how would you rate your appetite? 
• Good 
D Fair 
D Poor 
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Appendix 8:  Liver Toxicity Management 
Standard anti-TB chemotherapy is known to cause derangement of liver function tests in a 
substantial number of patients. In many cases this will be asymptomatic and self-limiting. In some 
cases, severe hepatitis and even fulminant liver failure and death can occur.  
In pre-marketing clinical trials of new drugs and regimens it is especially important to identify and 
carefully manage any trial participants who are at risk of progression to serious liver injury.  The 
observation of altered liver function to a degree that has a high risk of progressing to liver failure 
has been referred to informally as Hy’s Law;(31,39); this reflects that pure hepatocellular injury 
sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, Hy’s Law cases have the following three components:  
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo.  
2. Among trial participants showing such aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show elevation of serum total bilirubin (TBL) 
to >2x ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase 
(ALP)).  
3. No other reason can be found to explain the combination of increased AT and total bilirubin 
level (TBL), such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury.  
During the trial, liver function will be monitored regularly with clinical assessment and blood tests 
in study participants and this will assist in follow up laboratory measurements that can document 
either resolution of abnormalities or signal the potential for drug-induced liver injury (DILI).  In a 
clinical trial of new drugs and combinations it is especially important for investigators to follow 
closely any participants who have evidence of hepatic inflammation or potential toxicity. The 
following procedure describes the management of deranged liver function tests in study 
participants. 
Procedure 
Blood tests for liver function will be taken routinely at screening (Day -9 to -1) and at the specific 
time points designated in the protocol, and at Early Withdrawal.  If at any other visit the clinician 
suspects derangement of liver function, e.g. the participant describes nausea and vomiting, right 
upper abdominal pain or is jaundiced, blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of hepatitis or hepatic impairment and any 
potentially contributing causes.  
Suspected liver toxicity (or elevated liver enzymes detected in the absence of symptoms) must 
be taken seriously and detailed guidance will be provided in a separate document “NC-007 Study 
Management of Hepatotoxicity Guideline”. Investigators should refer to this document as a guide 
to management in cases of suspected or proven liver toxicity.  Importantly, the trial Medical 
Monitor is available to provide further assistance if there is any uncertainty or additional questions. 
The laboratory source (print-out of any results) should be stored alongside or transcribed into the 
clinical source document. Each abnormal value should be marked as clinically significant (CS) or 
non-clinically significant (NCS); the assessment of significance is at the discretion of the 
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investigator. All clinically significant abnormal results must be recorded as Adverse Events in the 
eCRF and graded clinically as per the DMID adult toxicity table grading, (Appendix 2).  
Assessments and decision making for elevations in aminotransferase values or bilirubin of various 
levels of concern are detailed below: 
Elevated liver enzymes considered of clinical significance, but not accompanied by other signs 
and symptoms, should be reported as an adverse event and should usually be recorded as 
elevated liver enzymes. If the term "hepatitis" is used, the Safety Data Manager will question the 
site for additional evidence to support the diagnosis, such as clinical signs and serological or 
biopsy data. While a liver biopsy is not required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for cases where there is supportive evidence 
beyond a liver enzyme abnormality. However, if the investigator will confirm the diagnosis of 
hepatitis just on the basis of clinical signs and laboratory values the diagnosis will be accepted. 
Should other symptoms or signs be present, these should also be recorded as adverse events. 
Restarting Medication 
Liver function tests that are improving should be repeated regularly, such as every 3 days for the 
first week then once a week until they return to near baseline values for the participant. Manage 
the participant symptomatically as required using medications that are not potentially hepatotoxic. 
Infection control issues must be carefully managed whilst TB medications are being withheld, 
especially if the participant is still culture positive for acid fast bacilli. 
If medication has been temporarily stopped, once the liver function values have decreased 
substantially a decision must be made about further TB management.  This will be dependent on 
the clinical context and a decision must be made in discussion with the sponsor medical monitor. 
Treatment can only be restarted if the trial Medical Monitor is in agreement with the plan. In all 
cases treatment should be recommenced under close supervision for any evidence of recurrent 
liver function abnormalities.  
If there is a further significant elevation of hepatic enzymes or bilirubin or symptoms of clinical 
concern after resumption of study medication, the study medication should be withdrawn 
permanently. Participants who permanently discontinue study medication should be managed as 
clinically indicated according to local National TB Programme guidelines. The sponsor medical 
monitor can be contacted for further advice when referring to the National Treatment Program. 
The trial Medical Monitor is available to assist the Investigators in both the management of liver 
toxicity and decisions regarding the holding or re-introduction of trial medication. Investigators 
must involve the Medical Monitor in any decisions regarding medication hold or re-start, and there 
should always be a low threshold for contacting the Medical Monitor in cases of elevated liver 
enzymes. 
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CONFIDENTIAL  
Protocol Number 
NC-007-(B-Pa-L)  
Title: 
A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid 
plus bedaquiline and pretomanid in participants with pulmonary 
infection of either extensively drug-resistant tuberculosis (XDR-
TB), pre-XDR-TB or treatment intolerant or non-responsive multi-
drug resistant tuberculosis (MDR-TB). 
Drug(s)/Combination(s):  Bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Version/Date:  
1.0 RUS/BEL 28 February, 2017 
Country Amendment for 
the Russian Federation 1.0 / 15 November, 2017 
Protocol Name: 
ZeNix 
 
 
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Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 2 of 103 
SPONSOR PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version/Date:  1.0 RUS/BEL 28 February, 2017 
Local Amendment for the Russian Federation: 
1.0 / 15 November, 2017 
Protocol Name: ZeNix 
 
SPONSOR  
I agree to the terms of this trial protocol. 
 
 
 
 
 
 
 
Signature of Senior Medical Officer 
 
Printed Name 
 
 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone 646-616-8671 
email: daniel.everitt@tballiance.org 
Date 
 
 
Dan Everitt
November 16, 2017 | 4:48 PM EST
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CONFIDENTIAL 
Page 3 of 103 
LEAD INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3  partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version/Date:  1.0 RUS/BEL 28 February, 2017 
Local Amendment for the Russian Federation: 
1.0 / 15 November, 2017 
Protocol Name: ZeNix 
 
LEAD INVESTIGATOR 
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and local 
regulations. 
 
 
 
 
 
Signature  
 
Printed Name 
 
 
 
Date 
 
 
 
November 20, 2017 | 9:48 AM EST
Dr. Francesca Conradie
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CONFIDENTIAL 
Page 4 of 103 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-resistant 
tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug 
resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version/Date:  1.0 RUS/BEL 28 February, 2017 
Local Amendment for the Russian Federation: 
1.0 / 15 November, 2017 
Protocol Name: ZeNix 
 
PRINCIPAL INVESTIGATOR 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
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Page 5 of 103 
1 
Synopsis .........................................................................................................................12 
1.1 
Synopsis Summary ...................................................................................................12 
1.2 
Synopsis Flowchart...................................................................................................17 
2 
Introduction and Rationale ...............................................................................................22 
2.1 
Trial Rationale ..........................................................................................................23 
2.1.1 
Trial Design Rationale........................................................................................23 
2.1.2 
Trial Drug Rationale ...........................................................................................23 
2.1.3 
Pretomanid ........................................................................................................25 
2.1.4 
Linezolid ............................................................................................................25 
2.2 
Agents to be Studied ................................................................................................26 
2.2.1 
Bedaquiline .......................................................................................................26 
2.2.2 
Pretomanid ........................................................................................................29 
2.2.3 
Linezolid ............................................................................................................35 
2.3 
Regimens to be Studied............................................................................................40 
2.3.1 
Non-Clinical Studies ..........................................................................................40 
2.3.2 
Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or Linezolid ...42 
2.4 
Overall Benefit/Risk Assessment...............................................................................45 
3 
Trial Objectives ...............................................................................................................46 
3.1 
Primary Objectives....................................................................................................46 
4 
Trial Design .....................................................................................................................46 
4.1 
Summary of Trial Design...........................................................................................46 
4.2 
Treatment Plan: Schedule of Assessments ...............................................................46 
5 
Trial Population ...............................................................................................................48 
5.1 
Inclusion Criteria .......................................................................................................49 
5.2 
Exclusion Criteria......................................................................................................50 
5.3 
Restrictions ..............................................................................................................53 
5.3.1 
Prior and Concomitant Medications and Other Treatments .................................53 
5.3.2 
Recommendations for Concomitant use of Anti-Malarials ...................................54 
5.3.3 
Antiretroviral Therapy.........................................................................................55 
5.3.4 
Other Restrictions ..............................................................................................55 
5.4 
Discontinuation from Treatment/Trial .........................................................................55 
5.5 
Participant Progress Definitions ................................................................................57 
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5.6 
Trial Stopping Rules .................................................................................................57 
6 
Treatment .......................................................................................................................58 
6.1 
IMP Administration....................................................................................................58 
6.2 
Participant Compliance .............................................................................................58 
6.3 
Treatment Modification(s) .........................................................................................59 
6.4 
IMP Packaging and Labelling ....................................................................................59 
6.5 
Method of Treatment Assignment..............................................................................60 
6.6 
Blinding and Procedures for Breaking the Blind .........................................................60 
6.7 
Handling, Storage and Accountability ........................................................................61 
7 
Trial Variables and Procedures ........................................................................................61 
7.1 
Demographic and Background Variables and Procedures .........................................61 
7.2 
Efficacy Variables and Procedures ............................................................................62 
7.3 
Safety and Tolerability Assessments .........................................................................63 
7.4 
PK Variables and Procedures ...................................................................................65 
7.5 
Mycobacteriology Characterization Variable and Procedures .....................................65 
8 
Adverse Events ...............................................................................................................65 
8.1 
Definitions ................................................................................................................65 
8.1.1 
Adverse Event (AE) ...........................................................................................65 
8.1.2 
Serious Adverse Event (SAE) ............................................................................65 
8.1.3 
Attribution/Causality ...........................................................................................66 
8.1.4 
Severity .............................................................................................................67 
8.2 
Reporting .................................................................................................................67 
8.2.1 
Follow up of Adverse Events ..............................................................................68 
8.2.2 
Clinical Laboratory Adverse Events ....................................................................69 
8.2.3 
Disease under Study .........................................................................................69 
8.2.4 
Overdose ..........................................................................................................69 
8.2.5 
Drug Interaction .................................................................................................69 
8.2.6 
Pregnancy .........................................................................................................69 
8.3 
Monitoring for Specific Toxicities ...............................................................................70 
8.3.1 
Neurological ......................................................................................................70 
8.3.2 
ALT, AST and Alkaline Phosphatase elevations: ................................................70 
8.3.3 
Lipase ...............................................................................................................71 
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8.3.4 
Musculoskeletal System and Cardiac Muscle .....................................................71 
8.3.5 
Cardiac Rhythm Disturbances............................................................................71 
8.3.6 
Myelosuppression..............................................................................................72 
8.3.7 
Peripheral Neuropathy .......................................................................................72 
8.3.8 
Optic Neuropathy...............................................................................................72 
8.3.9 
Lactic Acidosis...................................................................................................73 
8.4 
Safety Monitoring by Data Monitoring Committee ......................................................73 
9 
Statistical Analysis...........................................................................................................73 
9.1 
Analysis Population ..................................................................................................73 
9.2 
Sample Size .............................................................................................................74 
9.3 
Interim Analyses .......................................................................................................74 
9.4 
Primary and Secondary Endpoint Analysis ................................................................74 
9.5 
Safety and Tolerability Analysis.................................................................................75 
9.6 
Pharmacokinetics .....................................................................................................76 
9.7 
Pharmacokinetics/Pharmacodynamics ......................................................................76 
10 Records Management .....................................................................................................77 
10.1 Data Collection .........................................................................................................77 
10.2 Source Documents ...................................................................................................77 
10.3 File Management at the Trial Centre .........................................................................77 
10.4 Records Retention at the Trial Centre .......................................................................77 
11 Quality Control and Assurance.........................................................................................77 
11.1 Site Procedures ........................................................................................................77 
11.2 Monitoring ................................................................................................................78 
11.3 Protocol Deviations ...................................................................................................78 
11.4 Auditing ....................................................................................................................78 
12 Ethics and Regulatory .....................................................................................................79 
12.1 Basic Principles ........................................................................................................79 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review .............79 
12.3 Regulatory Authorities...............................................................................................79 
12.4 Informed Consent .....................................................................................................79 
12.5 Confidentiality ...........................................................................................................80 
13 Publication Policy ............................................................................................................80 
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14 Protocol Amendment Policy .............................................................................................81 
15 Sponsor, Financial Aspects, Insurance and Indemnity ......................................................81 
16 References......................................................................................................................82 
Appendix 1: 
The IUATLD Scale .........................................................................................85 
Appendix 2: 
Division of Microbiology and Infectious Disease (DMID) Toxicity Table ............86 
Appendix 3: 
 Cardiovascular Safety....................................................................................94 
Appendix 4: 
 Karnofsky Performance Status Scale Definitions Rating (%) Criteria ...............95 
Appendix 5: 
 EQ-5D-5L Questionnaire ...............................................................................96 
Appendix 6: 
 Brief Peripheral Neuropathy Screening ..........................................................98 
Appendix 7: 
 Tuberculosis Symptoms Profile .................................................................... 101 
Appendix 8: 
 Liver Toxicity Management .......................................................................... 102 
 
TABLES 
Table 1: 
ADRs C208 Stage 1 and Stage 2 ..........................................................................28 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies......................................30 
Table 3: 
Murine Lung CFU counts during Treatment with Linezolid ......................................36 
Table 4: 
Murine Relapse Data.............................................................................................41 
Table 5: 
Summary Statistics for EBACFU(0-14) ........................................................................42 
Table 6: 
NC-003 Efficacy Results: Daily BAlogCFU(0-14)..........................................................43 
Table 7: 
NC-003 Safety Data ..............................................................................................43 
Table 8: 
Treatment Groups .................................................................................................48 
Table 9: 
Investigational Medicinal Product Details ...............................................................58 
Table 10: Adverse Events Attribution/Causality Ratings .........................................................67 
Table 11: Definitions for Adverse Event Severity Gradings.....................................................67 
  
 
FIGURES 
Figure 1: Log10 CFU Counts in Lungs ................................................................................ 30 
Figure 2: Mean log Colony Forming Unit Values over Time Study CL-010 ............................ 33 
Figure 3:  Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin CL-001 37 
Figure 4: Trial Schematic .................................................................................................... 48 
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Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
ABaCavir 
ADR 
Adverse Drug Reactions 
AE  
Adverse Event  
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
ALanine aminoTransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
ASpartate aminoTransferase 
AT 
AminoTransferase 
AUCτ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BMI 
Body Mass Index 
bpm 
beats per minute 
BPNS 
Brief Peripheral Neuropathy Scale 
C 
Clofazimine 
CFU 
Colony Forming Units 
CK(-MB) 
Creatine Kinase(-MB isoenzyme) 
C(max), (min) plasma Concentration (maximum), (minimum) 
CO2 
Carbon diOxide 
CPK 
Creatine PhosphoKinase 
CS 
Clinically Significant 
Ctrough 
plasma Concentrationtrough 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
DeoxyriboNucleic Acid 
DOH 
Department of Health 
DILI 
Drug Induced Liver Injury 
DSMC 
Data Safety Monitoring Committee 
DST 
Drug Sensitivity Testing 
E 
Ethambutol 
EBA 
Early Bacteriocidal Activity 
EC 
Ethics Committee 
ECG 
ElectroCardioGram 
EFV 
EFaVirenz 
(e)CRF 
(electronic) Case Report Form 
FQ  
FluoroQuinolone 
FTC 
Emtricitabine 
GI 
GastroIntestinal 
GCP  
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GMR 
Geometric Mean Ratio 
H 
Isoniazid 
hERG 
Human Ether-à-go-go Related Gene 
HIV  
Human Immunodeficiency Virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
kilogram 
L 
Linezolid 
LLN 
Lower Limit of Normal 
LPV 
LoPinaVir 
M 
Moxifloxacin 
MAO(I) 
MonoAmine Oxidase (Inhibitor) 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
mg/dl 
milligrams per decilitre 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent To Treat 
ms 
millisecond 
NCS 
Not Clinically Significant 
NEJM 
New England Journal of Medicine 
NVP 
NeViraPine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
PharmacoDynamic 
PP 
Per Protocol 
PK 
PharmacoKinetic 
PR 
PR interval 
QD 
Once Daily 
R 
Rifampicin 
S 
Streptomycin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIRE 
Streptomycin Isoniazid Rifampicin Ethambutol 
SOC 
System Organ Class 
TB 
Tuberculosis 
TBL 
serum Total BiLirubin 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
T>MIC 
Time above minimum inhibitory concentration 
t.i.w. 
three times a week 
(BA) TTP (Bacteriocidal Activity) Time To Positivity  
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
XDR-TB 
eXtensively Drug Resistant Tuberculosis 
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μg(/dl) 
micrograms (per deciliter) 
Z 
pyraZinamide 
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1 
Synopsis 
1.1 Synopsis Summary 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Number/Title: 
NC-007: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB) 
Treatment Indication: 
Pulmonary XDR-TB, pre-XDR-TB, and treatment intolerant or non-responsive 
MDR-TB 
Trial Objective: 
To evaluate the efficacy, safety and tolerability of various doses and durations 
of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in 
participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment 
intolerant or non-responsive MDR-TB. 
Trial Design: 
A phase 3, multi-center, partially-blinded, randomized clinical trial in four parallel 
treatment groups. Bedaquiline and pretomanid treatment will not be blinded.  
Linezolid treatment dose and duration will be double-blinded. 
 
Participants will have a screening period of up to 9 days and will be randomized 
to receive one of the 4 active treatment arms. Participants will be randomized 
to one of the four regimens in a 1:1:1:1 ratio, using an interactive web response 
system (IWRS) which will utilize a dynamic randomization system using 
minimization with a random element to allocate participants evenly across the 
arms by HIV status and type of TB.   
 
Each participant will receive 26 weeks of treatment.  If participant’s week 16 
sample remains culture positive, Investigator may consider extending current 
treatment to 39 weeks, in consultation with the Sponsor Medical Monitor 
 
Participants will be followed for 78 weeks after end of treatment. 
Patient Population: 
A total of up to 180 participants: 
120 (30 per treatment arm) XDR-TB participants, and up to 60 (15 per arm) 
pre-XDR or treatment intolerant/non-responsive MDR pulmonary tuberculosis 
Participants, male and female, aged 18 and over. Enrollment will stop when 
120 XDR-TB participants are randomized. Sponsor may consider replacement 
of late screen failure and un-assessable (as detailed in the statistical analysis 
plan) participants. 
Test product, Dose and 
Mode of Administration: 
The test product will be supplied as: 
• 
bedaquiline 100 mg tablets 
• 
pretomanid 200 mg tablets 
• 
linezolid (scored) 600 mg tablets 
• 
placebo linezolid (scored) 600 mg tablets 
• 
linezolid half tablet (pre-cut) 300 mg  
• 
placebo linezolid half tablet (pre-cut) 300 mg 
 
Linezolid treatment will be supplied as 2 rows of full tablets and one row of 
half-tablets to allow for all possible dosing options while maintaining the blind.  
 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Treatment will be administered orally, once daily, with a full glass of water and 
a meal in the following dosing schemes (treatment arms): 
Participants will receive the following: 
• 
bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 
18 weeks plus;  
• 
pretomanid 200 mg once daily for 26 weeks plus; 
• 
Linezolid- participants will be randomly assigned to receive one of the 
following four linezolid treatment doses and durations:  
Linezolid 1200 mg daily for 26 weeks 
• 
2 linezolid 600 mg active tablets once daily for 26 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
• 
2 linezolid 600 mg active tablets once daily for 9 weeks  
• 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
Linezolid 600 mg daily for 26 weeks 
• 
1 linezolid 600 mg active tablet once daily for 26 weeks 
• 
1 placebo linezolid 600 mg tablet once daily for 26 weeks  
• 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid 600 mg tablet for 9 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
  
Treatment Modifications: 
 
The above treatment schemes may require modification due to toxicities as 
noted below. All dose modifications should be discussed with the Sponsor 
Medical Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be informed 
within 24 hours of the change if not discussed prior to implementation 
 
In the event of linezolid specific toxicities, the following should be considered 
and implemented per guidance in the monitoring and safety for specific 
toxicities section of protocol.  Every effort should be made for participants to 
receive a total of 9 weeks of linezolid, even if pauses are required: 
• 
Blinded one step reductions (maximum 3 steps) in the dose of linezolid 
(1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or 300mg QD to 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
placebo) managed by the IWRS as per instructions in pharmacy manual 
and/or IWRS user manual.  
• 
Temporary pause of linezolid due to a linezolid-specific toxicity should be 
considered and implemented per guidance in the monitoring and safety 
for specific toxicities section of protocol. 
• 
Permanent discontinuation of linezolid. 
 
For participants experiencing suspected drug related toxicities due to other 
drugs in the regimen (B-Pa), the full regimen may be halted for up to 35 
consecutive days.  
Interruptions/pauses of all Investigational Medicinal Product (IMP) must not 
exceed 8 weeks (56 days) cumulatively.  
 
If participant’s week 16 sample remains culture positive, Investigator may 
consider option to extend current treatment to 39 weeks, in consultation with 
the Sponsor Medical Monitor. When treatment is extended due to a positive 
culture at week 16, interruptions/pauses of all IMP must not exceed 13 weeks 
(91 days) cumulatively. 
 
At no time should the participant be treated with a single agent. 
Criteria for Evaluation: 
Primary Endpoint: 
Incidence of bacteriologic failure or relapse or clinical failure through follow up until 26 weeks after the end of 
treatment. 
 
Abbreviated Definitions, full definitions will be described in the Statistical Analysis Plan (SAP): 
• 
Bacteriologic failure: During the treatment period, failure to attain or maintain culture conversion to 
negative. 
• 
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative 
status, with culture conversion to positive status with a strain of Mycobacterium tuberculosis (MTB) 
genetically identical to the infecting strain at baseline.  
• 
Clinical failure: A change from protocol-specified TB treatment to a new regimen before end of 
protocol specified treatment due to treatment failure, retreatment for TB during follow up, or TB-
related death. 
 
Note: 
• 
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days 
apart. 
• 
Participants who are documented at a visit as unable to produce sputum and who are clinically 
considered to be responding well to treatment will be considered to be culture negative at that visit. 
Further details of definitions to be provided in the SAP. 
 
Secondary Endpoints: 
• 
Incidence of bacteriologic failure or relapse or clinical failure through follow up until 78 weeks after 
the end of treatment. 
• 
Time to sputum culture conversion to negative status through the treatment period. 
• 
Proportion of participants with sputum culture conversion to negative status at weeks 4, 6, 8, 12, 16 
and end of treatment. 
• 
Change from baseline TB symptoms. 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
• 
Change from baseline in Patient Reported Health Status. 
• 
Change from baseline weight. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations of bedaquiline and its M2, pretomanid and linezolid from sparse sampling (see Table 
1.2) will be measured and used to update population PK models for bedaquiline and its M2 metabolite, 
pretomanid, and linezolid to further evaluate the effects of covariates on model parameters in this study 
population. PK data from the current trial may be combined with prior data (e.g., from the NiX-TB trial) to 
enhance this population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between drug 
exposure and efficacy and safety endpoints.   
 
Safety and Tolerability: 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
• 
All-cause mortality. 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by, drug relatedness 
and seriousness, leading to early withdrawal from treatment, leading to pauses of linezolid, leading 
to linezolid reductions and leading to death.   
• 
Quantitative and qualitative clinical laboratory result measurements, including observed and change 
from baseline.  
• 
Quantitative and qualitative measurement of electrocardiogram (ECG) results read by a central 
cardiology service, including observed and change from baseline. 
• 
Descriptive statistics of ophthalmology slit lamp examination data (age related eye disease study 2 
[AREDS2]) lens opacity classification and grading). Categorical data for lens opacity will be 
summarized in a frequency table for the right and left eye, respectively, including change from 
baseline. 
• 
Changes in ophthalmic exam for visual acuity and color vision, including observed and change from 
baseline. 
• 
Changes noted in peripheral neuropathy signs and symptoms, including observed and change from 
baseline. 
 
Mycobacteriology: 
Sputum samples will be obtained at all scheduled visits.  The following tests will be performed.   
• 
Smear microscopy for acid-fast bacilli (AFB); 
• 
Liquid Culture (MGIT), followed by a speciation test to detect presence or absence of MTB and 
obtain time to positivity (TTP); 
• 
GeneXpert, Hain Genotype MTBDRplus or an alternative molecular to confirm MTB and rifamycin 
resistance. 
• 
Minimum Inhibitory concentration (MIC) of bedaquiline, pretomanid and linezolid; 
• 
Drug Susceptibility Testing (DST) in liquid culture for rifampicin, isoniazid, streptomycin, ethambutol, 
pyrazinamide and second line TB drugs including fluoroquinolones and injectable; 
• 
Genotyping. 
 
Details on the testing and the collection and timing of samples are in sections 1.2 and 7.1.2. 
 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Statistical Methods: 
A general description of the statistical methods planned for the primary efficacy outcome is outlined below. 
Specific details will be provided in the SAP. 
 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT).  We will 
evaluate the hypothesis, separately for each of the experimental B-Pa-L treatment arms, that the incidence 
of bacteriologic and clinical cure at 26 weeks after the end of therapy is greater than 50%.   
 
The incidence will be estimated from the binomial proportion for participants with success criteria based on 
the lower bound of the confidence interval for this proportion being greater than 50%. 
 
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as the target, 
because it is above the entire range of the historical control for cure of XDR-TB and because a cure rate of 
50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a shortened, simplified, all oral, 
inexpensive and safer regimen would clearly represent an important therapeutic advancement.  
 
The primary analysis population will include both XDR and non-XDR participants (up to 45 per arm).  A 
secondary analysis will be restricted to the XDR participants only (30 per arm).   A sample size of 30-45 per 
arm will provide more than 90% power to demonstrate that the lower bound of the 95% confidence interval 
of this estimate is greater than 50%, using a 2-sided 5% significance level. This assumes that the true cure 
rate is 80 percent.   
 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 6 months) with the 
L1200 2 months and L600 26 weeks only being tested if L1200 26 weeks is a success.  Similarly, L600 9 
weeks will only be tested if L600 26 weeks is a success.  A Bonferroni adjustment will be made for 
comparing the L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025.  For these 
comparisons the lower bound of the 97.5% confidence interval will need to exceed 50% for success.   
 
Both a Modified Intent to Treat (mITT) and a Per Protocol (PP) analysis for each arm will be conducted.  No 
formal statistical pairwise comparisons between the arms will be performed.   
Trial Duration: 
~3.5 Years (An enrolment period of at least 18 months plus 9 days pre-treatment plus 6 month treatment 
period plus 18 months post treatment follow-up). 
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1.2 Synopsis Flowchart 
Period Screeninga 
Treatment 
 Visits every 3 
weeks   if 
extended due to 
IMP pause or 
culture (+) at 
week 16b 
   
End of OR Early 
Withdrawal from 
Treatmentc 
Post Treatment Follow-up 
Time of Visit 
Up to 9 days 
prior to 
Treatment 
Day 1 
Week  1 
Week  2 
Week 3 
Week  4 
Week 5 
Week  6 
Week 7  
Week  8 
Week 10 
Week 12 
Week 14 
Week  16 
Week 18 
Week 20 
Week 23 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks 
Visit Window q 
N/A 
+/- 3 days 
+/- 5 days 
+/- 7 days 
Post last 
dose IMP 
+7 days 
+/-  14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Trtmnt/Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusiond 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Statuse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 Count and Viral Loadf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest X-Rayg  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Testh 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Patient Reported Health Status 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Slit Lamp Exam i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
X 
 
 
 
 
 
Ophthalmic Exam j 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X X X 
Single 12-LeadECGk 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X   
 
 
 
 
X 
 
 
 
 
 
 
 
 
Limited Physical Exam l 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X X 
X X 
Full Physical Exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Laboratory Safety Tests 
(includes Full Blood Count)m 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Full Blood Count 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Study Medication/Compliancen 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PK Samplingo 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Xo 
 
 
 
 
 
 
 
 
Early Morning & Spot Sputum r 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Peripheral Neuropathy 
Assessment 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
Investigator Assessmentp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
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GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
 
a. 
Screening: Screening assessments can occur on different days within nine days prior to Day 
1 dosing. If a participant fails screening, a full re-screen may occur at a later date post 
discussion with Medical Monitor.  All screening procedures must be repeated at re-screen 
visit, with the exception of the slit lamp examination, which can be used from a previous 
screening if within 8 weeks of anticipated randomization. 
b. 
Visit Schedule: If the duration of treatment is extended due to dose pauses (e.g., takes 
participant 35 weeks to complete 26 weeks of treatment) or positive week 16 culture, 
unscheduled visits should be added every 3 weeks (+/- 7 days).  End of treatment visit (final 
treatment visit) should be done within 7 days AFTER the last dose of IMP.  
1. If participant completes treatment at week 26, end of treatment visit should be done 
within 7 days after last dose of week 26. 
2. If participant completes 26 weeks of therapy at week 33 due to pauses, visits can be 
done at weeks 26, 29 and 33 (3 weeks from week 29 plus 7-day window). The week 
33 visit would be the end of treatment visit and should be completed within 7 days after 
last dose. 
3. If participant completes treatment at week 39 due to post treatment extension related 
to positive culture at week 16, visits can be completed at weeks 26, 29, 32, 35 and 39 
(3 weeks plus 7-day window), visit at week 39 would be the end of treatment visit. 
4. Follow-up visits should be scheduled based on timing of end of treatment/early 
withdrawal from treatment (e.g., 4-week follow-up to be scheduled 4 weeks after last 
dose of IMP). 
c. 
Follow-up Visits Early Withdrawal Participants: Once a participant has been discontinued 
from treatment, they will be required to attend an Early Withdrawal visit. If participant: 
1. Received/took < 14 doses, no additional follow-up visits are required.   
2. Received 15 or more doses, follow-up after end of treatment at week 12, week 26 (if 
not already performed) and week 78 are required. The week 12 visit will only require 
the ophthalmologic exams. The week 26 and 78 follow-up visits will be to collect 
Serious Adverse Event (SAE) information (including verification of survival) and patient 
reported TB outcome information only and may be telephonic, a home or a site visit. 
This includes participants who are withdrawn from the trial due to meeting the 
treatment failure endpoint. Participant may need to return for visits to collect sputum 
samples to determine outcome status as per section “r”. 
d. 
Inclusion/Exclusion: to be confirmed at screening and prior to randomization.  
e. 
HIV testing: If HIV status is a confirmed known positive, repeated HIV test is not needed 
provided documentation is available. If HIV status is unknown or suspected negative, HIV test 
should be requested. If an ELISA and/or Western Blot based HIV test was performed within 1 
month prior to screening, it should not be repeated as long as documentation of testing 
method and negative results can be provided.   
f. 
CD4 count and viral load:  For all HIV-positive participants. Viral load and CD4 at screening, 
CD4 only at end of treatment or early withdrawal. 
g. 
Chest X-Ray: A chest x-ray (digital image) within one month prior to screening, will be 
obtained and read locally by Investigator or designee. Digital images will be provided to 
Sponsor, this process will be described in a separate document, the Radiology Manual. 
h. 
Urine Pregnancy: Women of child-bearing potential only, whether they are sexually active or 
not.   
i. 
Slit-Lamp Exam: Slit Lamp examination will be performed by an Ophthalmologist with 
AREDS2 training: 
1. For participants who receive < 14 doses of IMP, exam at: Screening only. 
2. For participants who receive 15 days to < 12 weeks of treatment, exams at: Screening 
and the 12-week follow-up visit. 
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3. Participants who complete > 12 weeks of treatment exams at: Screening, End of 
Treatment or Early Withdrawal and the 12-week follow-up. 
j. 
Ophthalmic Exam: to include Ophthalmologic Medical history at Screening; All exams to 
include Visual Acuity (distance testing) and Colour Vision assessment.   Can be done by any 
trained study staff throughout study.  Screening exam must be done by Ophthalmologist in 
addition to trained study staff that will perform exams throughout the study. 
k. 
Single 12-Lead ECG: To every extent possible, should be performed at approximately the 
same time of day (+/- 1 hours) and in the same fed/fasted state throughout the trial (e.g. 4 
hours after lunch). Central ECG analysis will be performed. 
l. 
Physical Exam:  Limited Physical exams should include weight and a gross neurological, 
pulmonary, cardiovascular and abdominal exam. 
m. Safety Laboratory Assessments: The Safety Laboratory sampling methodology and 
requirements will be described in a separate document, the Laboratory Manual, which will be 
provided prior to the trial start. The following analyses will be performed: 
1. Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential, platelet count).  
2. Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK). 
3. Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per discretion of Investigator. 
4. Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates, 
benzodiazepines, barbiturates, at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 2.  Positive results will not automatically 
exclude participant from the trial. 
n. 
Study Medication/Compliance: Study medication administration will be supervised per local 
site practice to assure compliance to regimen. 
o. 
PK Sampling:  Specific PK blood draws as follows: 
1. Day 1; pre-dose (within 2 hours prior to dosing) 
2. Week 2: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
3. Week 8: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
4. Week 12: pre-dose (within 2 hours prior to dosing)  
5. Week 20 or at early withdrawal if prior to week 20: pre-dose (within 2 hours prior to 
dosing) and 2–3 hours post-dose 
When participant is discharged and seen as an outpatient, site should make every effort to 
collect 6-8 hour samples at weeks 8 and when operationally and logistically feasible. 
p. 
Investigator Assessment: Principal Investigator to review participant status and assess 
whether TB treatment at current visit is considered a “success” or “failure”.  If considered a 
failure, should specify if based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. To be completed at 26 and 78 week post treatment follow-up visits and at any 
time Investigator determines that participant fulfills criteria for outcome of treatment failure. 
q. 
Visit Windows: the windows noted on the flowchart for timing of visit also apply to timing 
within a visit.  For example, procedures that are difficult to schedule such as ophthalmology 
exams, should be scheduled within +/- 3 days of scheduled visit from Day 1 to Week 8 or +/- 
14 days within scheduled visit at the week 12 post treatment follow-up visit.  Sites should 
make every effort to ensure all other procedures should be done on the same day when 
possible. 
 
 
 
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r. 
Sputum Sampling: 
Visit 
Sample 
Tests 
EMS* 
Spot 
 AFB Smear  
microscopy  
MGIT culture, 
speciation 
Molecular 
testing 
MIC:  
B, Pa, L 
 
Liquid DST  
 
Genotyping 
Screening  
(Day -9 to -1) 
  
 
S 
S 
S 
  
  
  
Baseline (Day 1) 
or screen - wk4 if 
baseline negative or 
contaminated 
 
 
  
 S 
  
C 
C 
C 
All Visits Post 
Baseline 
 
 
  
S 
  
  
  
  
Positive for MTB 
at/after EoT 
 
  
S 
 S 
C 
C  
C 
C –   Central laboratory (specialized facility) 
S –   Study Laboratory (facility that receives samples directly from site) 
 
SPUTUM SAMPLES GENERAL: If EMS is not available, site should make every attempt to 
collect two spot samples at least 30 minutes apart.  
 
BASELINE: If available, site will request pre-screening culture that was used for the tests that 
qualified the participant for inclusion into the trial to be subcultured and shipped to the study lab 
from the applicable lab for relevant participants with no positive cultures from screening through 
week 4 (with consent). Samples should be stored according to the applicable lab procedures until 
shipment to the designated study lab. Included with each shipment will be a copy of the applicable 
lab reports and all participant identifying information redacted and a completed shipment inventory 
form with appropriate participant trial identifiers. Details on how samples will be packed and 
shipped will be provided in the lab manual. 
 
POSITIVE MTB AT/AFTER END OF TREATMENT: Only one isolate (preferably from EMS) 
should be shipped. Second isolate may be requested if first is contaminated.  
 
MOLECULAR TESTING:  
• 
At Screening: GeneXpert, Hain MTBDRplus or equivalent to determine MTB complex and 
R resistance. 
• 
Positive MTB at/after end of treatment: Hain MTBDRplus and HainMTBRsl 
 
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including but not limited to FQ and 
injectables. 
 
STORAGE: MTB isolates from all positive cultures to be stored at the study laboratory until trial 
closure for the applicable study tests. The extracted MTB DNA from the applicable baseline and 
follow-up isolates will also be stored at the central lab for potential further work to validate new 
assay tools for 5 years after trial closure. 
 
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CENTRAL LAB: Results from testing at Central myco lab (MIC, DST and genotyping) will not 
routinely be provided to sites.  In the event of participant relapse/failure, Sponsor will provide 
available results to the site in order to inform appropriate participant treatment. 
 
UNSCHEDULED VISITS: If cultures of both spot sputum samples are contaminated at the 
following visits, or if necessary in order to help define a participant’s outcome status/assess 
culture status during follow-up, the participant should return for an unscheduled visit(s) to give 
additional samples or to document the participant is not able to produce sputum: 
  
• 
End of treatment visit; 
• 
Week 26 post treatment follow-up visit; 
• 
Post treatment follow-up visits from week 8 through week 65 (in addition to week 26 
follow-up); 
• 
End of Follow-up Period (week 78 post treatment completion visit); 
• 
Early Withdrawal (if applicable). 
 
At the end of 26 weeks and 78 weeks post treatment completion, to define outcome status, need 
to confirm whether the participant has: 
• 
At least two sequential negative sputum culture results; or  
• 
At least two sequential positive sputum culture results; or  
• 
Has been unable to produce sputum after documentation of at least two negative 
sputum cultures with no intervening positive and are clinically asymptomatic. 
 
If they do not fall into one of these categories, site should continue to collect sputum samples x 
2 (one Early Morning and one Spot at the research site or 2 spots samples at least 30 minutes 
apart, under the coaching and observation of the trial staff) at a minimum of 7 days or more apart 
until they fall into one of the above categories. 
 
If in any of the above scenarios the Investigator is unsure of the outcome, the Investigator must 
contact the Sponsor Medical Monitor to discuss and agree on how the patient is to be handled. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2 
Introduction and Rationale 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is now the world’s leading infectious 
disease killer and is responsible for more deaths than HIV.(43) It is the leading cause of death 
among HIV-infected individuals, and there is more TB in the world today than at any other time in 
history. As a result of poor treatment adherence, in addition to primary transmission, drug 
resistance is becoming more common and fears of an epidemic with strains of extensively drug-
resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs and regimens for TB 
are needed for the growing number of patients with XDR TB.  
Outcomes of treatment for XDR-TB using the best available treatments have traditionally been 
very poor.  The best treatment historically has been to use available second line drugs individually 
tailored based on drug susceptibility testing in an inpatient setting to assure adherence with 
treatment lasting from 24 months to much longer for patients without culture conversion.  The 
most detailed report using this approach with long term follow-up prior to the use of linezolid, 
bedaquiline or delamanid in regimens has come from South Africa, where the HIV co-infection 
rate among patients with XDR-TB ranges from 40 to 70%.  A cohort study of 107 patients with 
XDR-TB found cure or completion of therapy at 24 months to be 16%, with 46% having died.(28)  
In another report from South Africa of 114 patients with XDR-TB, 22% completed treatment 
successfully.(21)  The largest evaluation of treatment outcomes was noted in the WHO 2014 annual 
tuberculosis report of 1269 patients in 40 countries, where 22% of patients with XDR-TB 
completed treatment successfully and 35% died.(42) A meta-analysis of 397 patients with XDR-TB 
from 31 centers, with HIV coinfection <10%, reported 32% treatment success.(17)  Reports of the 
outcome of XDR-TB treatment from Peru (43 patients, 42% treatment success)(2) and Ukraine 
(114 patients, 22% treatment success)(11) have been similar.  Based on these reports, the success 
of traditionally available drug therapies for treating XDR-TB infection is substantially less than 
50% and in the most detailed and largest reports is less than 25%. 
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with XDR-TB might be improved when added to background regimens. Experience 
recently published from the C209 uncontrolled study of bedaquiline given on a background of 
multiple drugs notes that the subset of 38 patients with XDR-TB had rates of sputum culture 
conversion to negative of 62.2%.(29) However, in this study only one patient with XDR-TB was co-
infected with HIV. All participants were required to have Mycobacterium tuberculosis (MTB) 
isolates susceptible to at least 3 drugs at enrolment, and patients had a median of only 5.4 months 
of treatment-free follow-up. This study added bedaquiline for 6 months to a background regimen 
of many drugs given for 18 months or longer. 
While treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR-
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.(43)  This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% 
died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information.   
With such poor historical outcomes for patients with XDR-TB and with the complexity, expense 
and toxicity of treatments for all forms of drug resistant TB, novel drug combinations are 
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desperately needed to improve treatment outcomes. Linezolid was identified in a small study as 
a potentially efficacious drug in patients with XDR-TB when added to a failing regimen(9) and this 
drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of three drugs for which there is little, if any, pre-existing resistance 
among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]), there is the opportunity 
to evaluate a new regimen that may be administered orally once daily to treat patients with XDR-
TB. Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, it is 
hypothesized in the design of the ongoing Nix-TB clinical study that patients with pulmonary XDR-
TB may have relapse-free cure after as little as 6 months’ treatment with the B-Pa-L regimen. 
Therefore, since 2015, the TB Alliance has sponsored a study with a 6 month treatment duration 
with the B-Pa-L regimen in participants with XDR-TB or MDR TB not responsive to or intolerant 
to therapy (the Nix-TB study).(1) 
A key advantage of this regimen over standard of care for MDR-TB as well as XDR-TB is that this 
is an all-oral daily regimen for 6 months of treatment in comparison to standard regimens of 6-8 
drugs over 9-30 months of treatment that includes daily injections for a minimum of 6 months. 
The NC-007 trial takes this regimen into a randomized Phase 3 trial to optimize the dosing scheme 
for linezolid and the benefit relative to risk, and to expand the patient population to include 
individuals with pre-XDR TB. 
The information presented below first details the trial rationale, then key preclinical information 
and human efficacy and safety information for each of the drugs in the regimen and then presents 
preclinical and clinical data to support the combination of these drugs in a regimen to treat patients 
with XDR, pre-XDR and MDR treatment intolerant/failure-TB. 
2.1 Trial Rationale 
2.1.1 Trial Design Rationale 
This trial will provide a regimen containing 3 drugs against which there is no expected MTB 
resistance in the community for patients with limited treatment options while simultaneously 
gathering important efficacy and safety data on a regimen that could potentially treat all strains of 
MTB. Data from previous trials shows that the combination of B-Pa is well tolerated and has the 
potential to shorten treatment in patients who are susceptible to the drugs. The ongoing Nix-TB 
trial has shown that the B-Pa-L regimen has manageable toxicity and encouraging efficacy as an 
all oral 6 month regimen administered to patients with XDR-TB. This current trial will provide 
important information on the toxicity and efficacy of the regimen under alternate doses and 
durations of linezolid to optimize the dosing scheme for the best benefit to risk balance. 
2.1.2 Trial Drug Rationale 
2.1.2.1 Bedaquiline  
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this study bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 18 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
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combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 study that administered bedaquiline 200 mg daily over 8 weeks, and 
by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
The NC-005 study allows the efficacy and safety to be compared for treatment arms that dosed 
bedaquiline at the currently registered dose and at 200 mg daily for the 8 weeks of the trial.  Briefly, 
Study NC-005 evaluated a regimen in patients with drug susceptible pulmonary TB given 
bedaquiline with pretomanid and pyrazinamide over an 8 week period.  One arm was to enroll 60 
patients who were to be given this regimen with bedaquiline dosed as approved for marketing 
(referred to as the B (loading dose/t.i.w.) PaZ arm), and another 60 patients were to be enrolled 
who would be given the regimen with bedaquiline dosed at 200 mg daily (referred to as the B 
(200mg) PaZ arm).  Another group of patients with DS TB were randomized to treatment with 
standard HRZE therapy.  Patients with MDR-TB were given the regimen with bedaquiline dosed 
at 200 mg daily in addition to moxifloxacin (referred to as the B (200 mg) MPaZ MDR-TB arm).  
The primary endpoint was The Bactericidal Activity (BATTP (0‐56)) as determined by the rate of 
change in time to sputum culture positivity (TTP) over 8 weeks of treatment in the Mycobacterial 
Growth Indicator Tube system, represented by the model‐fitted log (TTP) results as calculated by 
the regression of the observed log (TTP) results over time.  The assessments of safety and 
tolerability included the incidence of Treatment Emergent Adverse Events (TEAEs) presented by 
severity (DMID Grade), by drug relatedness and seriousness, and for those leading to early 
withdrawal and leading to death, by group.  In addition, quantitative and qualitative clinical 
laboratory result measurements were evaluated, including group summaries of observed values 
and changes from baseline.  Pharmacokinetics for all participants included pre-dose samples on 
9 days during and one day following dosing with the regimen.  Fifteen PK Sub‐study participants 
in each treatment arm had in addition intense PK sampling on Days 14 and 56. 
Efficacy of bedaquiline 200 mg daily dose vs the marketed dosing scheme over 8 weeks 
In the efficacy analysis of the NC-005 trial, based on liquid media collected from overnight sputum 
samples, the B(200 mg)MPaZ MDR-TB treatment group showed the highest bactericidal activity 
over the 8-week treatment period, followed by that of B(200 mg)PaZ, B(loading dose/t.i.w.)PaZ 
and then HRZE. It appears clear that the daily dosing regimen for bedaquiline provided at least 
as good a result in the primary efficacy analysis as the registered dosing scheme for bedaquiline.   
Safety of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
Adverse events, including serious adverse events and Grade III/IV adverse events were similar 
among groups.  In particular, the mean change from baseline in the corrected QTc intervals was 
numerically less in the participants given bedaquiline daily than in the participants given 
bedaquiline with the labelled dosing scheme.  Measures of potential hepatic toxicity, including 
participants with greater than 3 fold or 10 fold elevations in aminotransferase levels, were 
numerically greater in participants given the labelled dosing scheme than subjects given daily 
doses of bedaquiline.   
Pharmacokinetics of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
A population PK model published by McLeay in 2014 was used with PK data from Study NC-005 
to simulate the expected bedaquiline exposures when dosed at 200 mg daily followed by 100 mg 
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daily for the remainder of the study in comparison to the labelled dosing scheme with bedaquiline 
administered for 6 months.(14)  The key findings from the simulations of the proposed dosing 
scheme for NC-007 of bedaquiline administered 200 mg daily over 8 weeks followed by 100 mg 
daily for an additional 16 weeks are: 
• 
The exposures of the proposed dosing scheme (Cmax, mean or trough) are not expected to exceed 
the exposures associated with the labelled scheme on Day 14 at the end of the 400 mg daily 
dose.  With the labelled dosing scheme, the highest exposures are on Day 14 at the end of 
the 400 mg daily loading dose. 
• 
The average daily exposures with the proposed dosing scheme over 6 months are within (or 
not substantially different from) the range of exposures over 6 months of the labelled dosing 
scheme. 
• 
The cumulative exposure, in terms of AUC over time, is similar between the proposed dosing 
scheme and the labelled scheme 
2.1.3 Pretomanid 
Pretomanid has demonstrated good microbicidal activity at the 200mg daily dose as monotherapy 
in studies PA-824-CL-007 and PA-824-CL-010, in combination with either bedaquiline or 
pyrazinamide over 14 days in the early bacteriocidal activity (EBA) Study NC-001-(B-M-Pa-Z), in 
combination with either bedaquiline and/or pyrazinamide and/or clofazimine over 14 days in the 
EBA Study NC-003-(B-C-Pa-Z), and in combination with bedaquiline and linezolid over 6 months 
in the Nix-TB study.  In the EBA Study PA-824-CL-010 the 100mg dose demonstrated similar 
microbicidal activity to the 150 and the 200mg daily dose over 14 days. The Phase 2 trial NC-
002-(M-Pa-Z) evaluated this regimen at doses of pretomanid of both 100 mg and 200 mg relative 
to the HRZE control.   In this trial the efficacy results were similar between participants treated 
with 100 mg/day and 200 mg/day of pretomanid in the regimen, although for the primary endpoint, 
reduction in colony forming units of MTB from sputum, only the 200 mg/day dose group was 
statistically significantly better than the group randomized to standard HRZE therapy.  Safety was 
also similar between the groups, although the 200 mg/day group had more grade 2 adverse 
events than either the 100 mg/day group or the HRZE control group.  Because sterilizing relapse-
free cure of TB in patients with XDR-TB may ultimately require a regimen with higher drug 
exposures, the 200mg dose was chosen for evaluation in the Nix-TB study of the B-Pa-L regimen.  
The manageable toxicity of the regimen and very encouraging efficacy in the Nix-TB trial support 
taking the 200 mg dose of pretomanid forward in the NC-007 trial. 
2.1.4 Linezolid 
The standard dose of linezolid for a multitude of indications is 400mg or 600mg BID.  Doses of 
linezolid used to treat pulmonary TB in reported observational trials and case series range from 
300 mg to 1200 mg per day over periods of up to 20 months of treatment.  While the development 
of adverse events is generally higher with higher doses, the adverse events often ameliorate with 
a reduction of the dose or discontinuation of drug for several weeks and then reintroduction at a 
lower dose.  No controlled trials have clearly identified differences in anti-TB effect across a range 
of doses over long term treatment of TB. 
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In this trial, each arm will vary the linezolid dosing to identify the optimal ratio of efficacy to adverse 
events as noted below. The 4 arms, to which participants will be randomly assigned in a blinded 
manner, are: 
• 
Linezolid 1200 mg orally once daily for 26 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
• 
Linezolid 1200 mg orally once daily for the first 9 weeks, with the ability to interrupt or 
reduce the dose if needed based on toxicity.  
• 
Linezolid 600 mg orally once daily for 26 weeks, with the ability to interrupt or reduce the 
dose if needed based on toxicity. 
• 
Linezolid 600 mg orally once daily for the first 9 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
These dosing schemes for linezolid are chosen based on clinical experience in the Nix-TB trial, 
the company’s linezolid early bactericidal activity (EBA) study findings in the Lin CL-001 study, 
and preclinical data in the mouse model of infection. While the EBA study showed that a modestly 
greater bactericidal effect over 14 days at the highest 1200 mg daily dose (see further details 
below in Section 2.2.3), this dose appears to be associated in the Nix-TB trial and in published 
literature with a greater incidence of unwanted neuropathic and myelosuppressive effects than 
the 600 mg daily dose. While a full 6 months of linezolid therapy in the regimen may give greater 
culture conversion and avoid relapse, the mouse model found that linezolid dosing of only 1 or 2 
months, when B and Pa were given continuously for a total of 3 months, maximized relapse-free 
cure; in other words, similar to pyrazinamide in the present first line HRZE therapy, more than 2 
months of linezolid when combined with B and Pa does not increase relapse-free cure in the 
mouse model. Thus, the 4 treatment arms in this study will give randomized comparative 
information about the optimal duration and dose of linezolid in the regimen relative to efficacy and 
toxicity.  
The decision to give linezolid as a single daily dose is based on the results of the linezolid EBA 
study that showed over 14 days that similar bactericidal activity was noted whether the drug was 
given as a single daily dose or divided in to 2 doses. A single daily dose will ultimately enhance 
patient adherence and will reduce the total time the drug concentration is greater than the 
calculated concentration associated with mitochondrial toxicity (which we hypothesize to be the 
likely mechanism for the toxicities of peripheral neuropathy and myelosuppression). 
2.2 Agents to be Studied 
2.2.1 Bedaquiline 
Bedaquiline is being developed as part of combination therapies for pulmonary TB due to MDR-
TB and approved in 2012 in the USA under the provisions of accelerated approval regulations. 
Bedaquiline received conditional Marketing Authorization in the EU in 2014 and is approved in 
over 40 countries (EU countries counted individually). The approved indication may vary per 
country. Bedaquiline is marketed under the trade name SIRTUROTM.  Bedaquiline has a novel 
mechanism of action as it specifically inhibits mycobacterial ATP synthase, an enzyme that is 
essential for the generation of energy in MTB The inhibition of ATP synthase leads to bactericidal 
effects for both replicating and non-replicating tubercle bacilli. 
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In the placebo-controlled Phase 2b study C208 conducted in newly-diagnosed patients with 
sputum smear-positive pulmonary MDR-TB (including pre-XDR-TB), the addition of bedaquiline 
to a preferred background regimen of MDR-TB treatment resulted in a decreased time to culture 
conversion and improved culture conversion rates compared to placebo. Median time to culture 
conversion according to the primary analysis method was 83 days for the bedaquiline group 
compared to 125 days for the placebo group (p<0.0001; hazard ratio, 95% CI: 2.44 [1.57; 3.80]). 
The proportion of patients in the mITT population with sputum culture conversion after 24 weeks 
of treatment with bedaquiline or placebo in combination with background regimen (with patients 
who discontinued considered as non-responders), was 52/66 (78.8%) in the bedaquiline group 
and 38/66 (57.6%) in the placebo group. Durability of response seen in the bedaquiline treatment 
group was supported by the results at Week 120. The proportion of responders (with patients who 
discontinued considered as non-responders) at Week 120 was 41/66 (62.1%) in the bedaquiline 
group and 29/66 (43.9%) in the placebo group. 
In the Phase 2b, open-label study C209, conducted in 233 patients with sputum smear positive 
pulmonary MDR-TB, the median time to sputum culture conversion excluding patients with DS-TB 
and those that did not have a positive sputum culture at screening and/or baseline (mITT; 205 
patients), was 57 days. At Week 24, 163 of 205 (79.5%) patients responded to bedaquiline 
treatment as determined by sputum culture conversion rates. Conversion rates at Week 24 were 
highest (87.1%; 81/93) in patients with MDR-TB resistant to only RMP and INH, 77.3% (34/44) in 
pre-XDR-TB patients and lowest (54.1%; 20/37) in XDR-TB patients. 
The average terminal half-life of bedaquiline, is about 5.5 months. After reaching Cmax, however, 
there is initially a fairly rapid reduction in plasma bedaquiline concentrations over the dosing 
interval (with an estimated half-life of about 13 hours). Four weeks after ceasing bedaquiline 
intake, the mean bedaquiline concentrations were reduced by approximately 40% compared to 
the end of the bedaquiline treatment period in the C208 study. Administration of bedaquiline with 
food increased the relative bioavailability by about 2-fold compared to administration under fasted 
conditions. It is therefore recommended to take bedaquiline with food to enhance its oral 
bioavailability. 
CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline. Drug-
drug interaction (DDI) studies have showed reduced exposure to bedaquiline during combination 
with a strong or moderate inducer of CYP3A4 metabolism (i.e., rifampicin) and increased 
exposure during combination with a strong or moderate inhibitor of CYP3A4 metabolism (i.e., 
ketoconazole). Potential drug interactions with anti-retroviral drugs have been evaluated in three 
studies.  In an interaction study of single-dose bedaquiline and multiple-dose Lopinavir/ritonavir, 
exposure (AUC) to bedaquiline was increased by 22% (90% CI: 11-34). Co-administration of 
single-dose bedaquiline and multiple-dose nevaripine did not result in clinically relevant changes 
in the exposure to bedaquiline. Co-administration of a single dose of bedaquiline and multiple-
dose efavirenz (EFV) resulted in approximately a 20% decrease in the AUCinf of bedaquiline with 
no alteration in the Cmax.  Modeling based on the data from this DDI study predicts average steady-
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state concentrations of bedaquiline and M2 to be reduced by 52% with chronic co-administration 
of bedaquiline and EFV.(5)  
Safety of Bedaquiline 
The Investigator’s Brochure for bedaquiline provides detailed safety information.5 
Data were used from 14 completed clinical studies to identify Adverse Drug Reactions (ADRs) 
according to the ICH guideline entitled, E6: Good Clinical Practice, Consolidated Guideline (ICH, 
1996): “…all noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. The phrase “responses to a medicinal product” means that 
a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out." 
The ADRs were identified from the pooled safety database of reported AEs in the Phase 2b clinical 
studies with bedaquiline, based upon a systematic well-documented approach and are presented 
for study C208 below in Table 1.  None of the ADRs reported in the controlled studies during the 
Investigational Treatment phase were considered serious. 
Table 1: 
ADRs C208 Stage 1 and Stage 2 
Adverse Drug Reactions (ADRs) in the Controlled Studies (C208 Stage 1 and Stage 2)  
During the Investigational Treatment Phase 
ADR (Grouped term), n (%) 
Frequency 
Any BDQ 
N=102 
Any Placebo 
N=105 
Nervous system disorders 
Headache 
Very Common 
24 (23.5) 
12 (11.4) 
Dizziness 
Very Common 
13 (12.7) 
12 (11.4) 
Cardiac disorders 
ECG QT prolonged 
Common 
3 (2.9) 
4 (3.8) 
Gastrointestinal disorders 
Nausea 
Very Common 
36 (35.3) 
27 (25.7) 
Vomiting 
Very Common 
21 (20.6) 
24 (22.9) 
Diarrhea 
Common 
6 (5.9) 
12 (11.4) 
Hepatobiliary disorders 
Transaminases increaseda 
Common 
7 (6.9) 
1 (1.0) 
Musculoskeletal and connective tissue disorders 
Arthralgia 
Very Common 
30 (29.4) 
21 (20.0) 
Myalgia 
Common 
6 (5.9) 
7 (6.7) 
 
a. 
Different AE preferred terms (i.e., transaminases increased, aspartate aminotransferase [AST] increased, 
alanine aminotransferase [ALT] increased, hepatic enzyme increased, and hepatic function abnormal) contribute 
to this ADR, w hile for the other ADRs the ADR is the preferred term. 
 
Of note, 13 deaths occurred in the C208 Stage 2 study: 10 subjects (12.7%) in the bedaquiline 
group and 3 subjects (3.7%) in the placebo group experienced an SAE leading to death. One 
death (alcohol poisoning) occurred during administration of bedaquiline. The median time to death 
for the remaining 9 subjects was 344 days after last intake of bedaquiline. One of the 10 deaths 
in the bedaquiline treatment group and 1 of the 3 deaths in the placebo group occurred after the 
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Week 120 window. In the bedaquiline group, the most common cause of death as reported by the 
investigator was TB or TB-related illness (5 subjects). For all deaths due to TB, the subject’s last 
microbiological outcome was either failure to convert or relapse. The causes of death in the 
remaining bedaquiline subjects varied. The investigator considered all the SAEs leading to death 
not or doubtfully related to bedaquiline/placebo. The imbalance in deaths is unexplained. In 
addition, no discernible pattern between death and sputum culture conversion, relapse, sensitivity 
to other drugs used to treat TB, HIV status, or severity of disease was observed.  
During clinical studies with bedaquiline a prolongation of QTc interval on the ECG was observed.  
Consequently, bedaquiline treatment initiation is not recommended in patients with, personal or 
family history of prolonged QT intervals, or additional risk factors for Torsades de Pointes. 
Detailed criteria are noted in Section 5.2, Exclusion Criteria. 
Increases in transaminases were seen in clinical studies during administration of bedaquiline in 
combination with a background regimen. Based on a review confirmed by an external 
hepatologist, it was concluded that bedaquiline has a signal for liver injury manifested by 
increases in AST and to a lesser extent ALT. Transaminase elevations are not unexpected given 
the number of other hepatotoxic drugs in the background regimens in clinical trials based on the 
publication by Keshavjee, which describes a 16.5% incidence of hepatotoxicity during MDR-TB 
treatment. (7) 
2.2.2 Pretomanid 
As detailed in the Investigator’s Brochure(6), pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti-
tuberculosis activity and a unique mechanism of action(35). Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB(10), and in vivo activity in a mouse model of tuberculosis(10, 
35).  
2.2.2.1 Pharmacology 
2.2.2.1.1 Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro studies demonstrated that pretomanid was active against actively growing 
drug-sensitive and drug-resistant MTB strains as well as against non-replicating MTB The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be similar to the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 
0.25 µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against 
drug-resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity. (6) 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO), (33) although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling studies also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.(12,13) 
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2.2.2.1.2 Key Non-Clinical Studies of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse studies.(18,19,20,36,40) In a mouse model of established TB, 
the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 
22 days after inhalation infection with H37Rv MTB is shown in Figure 1. In this model, the 
minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the 
development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum 
bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony forming units 
(CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 
100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
Figure 1: 
Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
2.2.2.2 Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology studies, 
in repeat-dose toxicity studies in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity studies, and in fertility and teratology studies in rats and rabbits.  
In the repeat-dose toxicity studies, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week study in rats, 50 mg/kg/day in a 13-week study in monkeys and 
<25 mg/kg/day (based on findings of thickening of the GI tract at all doses) in a 9-month study in 
monkeys. The major findings in safety and toxicity studies are listed below in Table 2 and are 
detailed in the Investigator’s Brochure.(6) 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
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repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development studies indicate no effects of PA-824 on fetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology studies and a Segment I fertility study. In this fertility study, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed study in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week study in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
study in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the electrocardiogram (ECG) as a prolonged QT interval corrected for heart 
rate (QTc). Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. 
Following a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation 
ranged from 21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-
administration of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog 
did not result in any greater effect on the QT interval than with either agent alone. After 
repeated daily doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
2.2.2.3 Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 studies with healthy adult 
male and female subjects, with 163 subjects receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 studies sponsored by the NIH included a Thorough QT study and a study 
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of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the 
studies are in the Investigator’s Brochure. 
2.2.2.3.1 Pharmacokinetics 
Several Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200 mg dose that increases total 
exposure by 88%. Interaction studies with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Study CL-006 was an open-label, fixed-sequence drug-drug 
interaction study to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs metabolised 
by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had 
minimal effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by 
measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax), area under the 
curve to the last available time point (AUC0-t), and area under the curve extrapolated to infinity 
(AUC0-inf). The Cmax and AUC values for midazolam after co-administration with pretomanid were 
approximately 85% of those observed after treatment with midazolam alone. Furthermore, 
midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and half-life (t1/2) 
values were not different in the presence or absence of pretomanid. Therefore, 14 days’ dosing 
with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH sponsored this 
drug interaction study with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy subjects. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for the maximum concentration (Cmax) was 0.71, the GMR for the 24-hour area 
under the time-concentration curve (AUC0-24h) was 0.65, and the GMR for the trough concentration 
(Cmin) was 0.54. Concentrations of EFV when given with pretomanid versus given alone were 
similar. Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg once daily for 
7 days, then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 days, then LPV/r 
+ pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + pretomanid, washout, then 
pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid alone from 16 PK-
evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and for Cmin was 0.78. 
In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg for 7 days, then 
pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin versus 
pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and Cmin were 
0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for maximum concentration (Cmax), area under the concentration-time curve (AUC0-
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24h), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz; 13%, 17%, 
and 21% with LPV/r; and 53%, 66%, and 85% with rifampin, respectively. 
2.2.2.3.2 Pretomanid Clinical Efficacy 
The first two Phase 2 studies to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first study (CL-007) demonstrated 
good EBA, but all doses in this study (200 to 1200 mg/day) had the same activity. The second 
study (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA 
was seen at a dose of 100 mg/day over 14 days (4) (Figure 2). 
Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010 
 
CFU = colony-forming unit; PA-824 = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Studies of Pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below in Section 2.3.2.  
2.2.2.3.3 Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure(6) provides detailed safety information. 
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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Across the 16 clinical studies with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy subjects across the 10 Phase 1 studies and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
studies.  Among the 289 healthy Subjects, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 1200 
mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical studies completed to date indicates pretomanid 
is well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these studies, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical studies completed to date as likely caused by 
pretomanid is blood creatinine increased.  A study of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close surveillance 
and careful management of participants who have elevations in aminotransferases and/or 
bilirubin. Serious liver injury, including death in 3 participants taking a combination of 
pretomanid, pyrazinamide and moxifloxacin, has occurred during clinical studies and the risk 
of liver injury may be higher for participants taking a combination of PA-824 and pyrazinamide 
than it is for the standard HRZE treatment. Therefore, close monitoring of liver function is 
required for participants who are administered PA-824, especially when combined with 
pyrazinamide.  Administration of the regimen of PaMZ has been associated with death in 3 
participants associated with hepatic injury. Furthermore, the HRZE control regimen, and both 
pyrazinamide and moxifloxacin, has been associated with drug induced liver injury and in rare 
cases hepatic necrosis.  Consequently, hepatic safety will be under close surveillance in all 
clinical studies. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human studies that involve exposure to pretomanid longer than 
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14 days.  These examinations will be conducted at baseline, near the end of the dosing period 
and 3 months after the end of study drug exposure.  These examinations are to follow up on 
the finding of cataracts in rats exposed to pretomanid in clinical studies. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple time 
points during the study.  Although the Thorough QT Study in healthy subjects found that 
pretomanid did not increase corrected QT intervals in a clinically meaningful way and did not 
add to the known effect of moxifloxacin, the ECGs will be carefully monitored during Phase 3.  
All ECGs will be interpreted and conduction intervals will be confirmed by a central cardiology 
service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Study NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology studies have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 study for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology studies found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 studies have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 studies) or FSH values (3 studies) at baseline and after daily 
dosing of regimens containing pretomanid in various combinations with moxifloxacin, 
pyrazinamide and bedaquiline.  A review of data from the 3 studies by an independent 
reproductive endocrine expert concluded that, based on the hormone evaluations to date, there 
is no evidence that PA-824 is a testicular toxicant in men at the doses and exposure times 
evaluated. 
2.2.3 Linezolid 
Linezolid is a synthetic antibacterial agent of the oxazolidanone class approved in many countries 
around the world for drug-resistant, gram-positive bacterial infections, including gram positive 
organisms such as Staphylococcus aureus, coagulase negative Staphlococcus and Enterococcal 
infections.  The recommended dose for these infections is 600 mg twice daily for up to 28 days of 
therapy.(23,24,26) Antimicrobial effects likely come from inhibition of protein synthesis in the 
ribosomes of the infecting organism.(8)  Resistance of MTB to linezolid is rare, as this drug has 
not been widely used to treat tuberculosis.  In a recent study using linezolid to treat patients with 
XDR-TB in Korea, none of 41 patients had resistance to linezolid at baseline.(9) 
Preclinical in vitro data shows linezolid is active against MTB, including MDR strains with minimum 
inhibitory concentrations (MICs) that range from 0.125-1 μg/mL.(38)  Recent studies of the 
bactericidal and sterilizing activity of linezolid in a mouse model of MTB infection have 
demonstrated linezolid alone causes marked reductions in lung colony forming units (CFUs) from 
mice following 1-3 months of therapy.(36) (Table 3, below) 
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Table 3: 
Murine Lung CFU counts during Treatment with Linezolid 
Monotherapy versus Standard Therapy 
 
Mean lung log10 CFU count (± S.D.) at: 
Regimen 
D0 
Month 1 
Month 2 
Month 3 
Untreated 
6.17 + 
0.27 
6.47 + 0.06 
 
 
2RHZ/4R
H 
 
3.47 + 0.37 
1.59 + 0.25 
0.50 + 0.51 
L 
 
4.97 + 0.26 
 
 
 
In recent years linezolid has been used to treat patients with MDR(28) and XDR-TB, although there 
have been no fully controlled trials of linezolid in a regimen for this indication.  The World Health 
Organization management guidelines place linezolid in Group 5 (“Agents with unclear role in 
treatment of drug resistant-TB”) in their groups of drugs to treat MDR-TB.(41) Over the past 10 
years small retrospective observational studies have reported good results when linezolid has 
been added to failing regimens for patients with MDR-TB.(9, 27, 34) The most compelling recent 
evidence linezolid may be of benefit to patients with XDR-TB was reported by Lee and colleagues 
from a study in S. Korea.(9)  Forty-one patients who had sputum culture–positive XDR-TB and who 
had not had a response to any available chemotherapeutic option during the previous 6 months 
were randomized to start linezolid at 600 mg daily or to delay therapy with linezolid at 600 mg 
daily for 2 months without changing their failing background regimen.  After confirmed sputum-
smear conversion, or at 4 months, patients underwent a second randomization to continued 
linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 
months.  Thirty four of 39 (87%) of the patients had a negative sputum culture within 6 months 
after linezolid had been added to their drug regimen.  As of the cutoff date prior to publication, of 
the 38 patients who received linezolid, 17 were still receiving the treatment per protocol, and 13 
had completed treatment, including 6 with no relapse during the treatment period, 4 with no 
relapse at the 6-month follow-up, and 3 with no relapse at the 12-month follow-up (end of study).  
While the standard dose of linezolid for short term use for severe bacterial infections is 600 mg 
bid, some clinicians and clinical trials using linezolid as Group 5 therapy to treat TB use only 300 
mg or 600 mg daily due to concerns about toxicity developing when used over a period of months 
(see below for a review of linezolid toxicity). (9)  However, there are no data to indicate what dose 
of linezolid is required or optimal to effectively treat TB infection.  Consequently, TB Alliance has 
recently conducted and completed an Early Bactericidal Activity trial to evaluate the use of 
linezolid over 14 days in patients with newly diagnosed DS Pulmonary TB in dosing schedules 
including 300 mg daily, 300 mg bid, 600 mg daily, 600 mg bid, 1200 mg daily, and HRZE at 
standard doses daily.  Preliminary unpublished in-house results using Bayesian mixed effects 
modelling have noted that there is a bactericidal effect of linezolid over 14 days that is substantial, 
but less than for the full HRZE regimen.  There is little difference between daily or twice daily 
dosing of the same total daily dose of drug, and there is a dose-response relationship between 
total daily dose and daily reductions in either total CFU counts on solid culture or increases in 
Time to Positivity in liquid culture (a decreased load of MTB is associated with an increase in Time 
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to Positivity).  Point estimates of the log of the daily increase in Time to Positivity over 14 days 
ranged from 2.278 for Linezolid 300 mg QD to 4.446 for linezolid 1200 mg QD, with the estimate 
of 6.860 for HRZE for reference. 
 
 
 
Figure 3:  
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin 
CL-001 
Bayesian Nonlinear Mixed Effects Regression Model: Posterior Estimates and 95% 
Bayesian Confidence Intervals 
 
HRZE = isoniazid, rifampin, pyrazinamide, and ethambutol 
2.2.3.1 Linezolid Clinical Safety 
Linezolid is currently marketed globally for a variety of acute infectious diseases and has been 
studied for the treatment of XDR-TB in several recent trials.(3,9) The following list of known and 
potential risks is based on the warnings and precautions and adverse reactions sections of the 
current package label.(23,24,26)  Of note, the approved indication for linezolid is for administration 
up to 28 days. 
 Warnings and Precautions 
• 
Linezolid should not be used in patients taking any medicinal product which inhibits 
monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking 
any such product. 
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• 
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) 
has been reported in patients receiving linezolid. In cases where the outcome is known, 
when linezolid was discontinued, the affected hematologic parameters have risen toward 
pretreatment levels. Complete blood counts should be monitored weekly in patients who 
receive linezolid, particularly in those who receive linezolid for longer than two weeks, 
those with pre-existing myelosuppression, those receiving concomitant drugs that produce 
bone marrow suppression or those with a chronic infection who have received previous or 
concomitant antibiotic therapy.  
• 
Lactic acidosis has been reported with the use of linezolid. In reported cases, patients 
experienced repeated episodes of nausea and vomiting. Patients who develop recurrent 
nausea or vomiting, unexplained acidosis, or low bicarbonate level while receiving 
linezolid should receive immediate medical evaluation. 
• 
Spontaneous reports of serotonin syndrome associated with the co-administration of 
linezolid and serotonergic agents, including antidepressants such as selective serotonin 
reuptake inhibitors (SSRIs), have been reported.  Where administration of linezolid and 
concomitant serotonergic agents is clinically appropriate, patients should be closely 
observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, 
hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians 
should consider discontinuation of either one or both agents. If the concomitant 
serotonergic agent is withdrawn, discontinuation symptoms can be observed (see 
package insert of the specified agent(s) for a description of the associated discontinuation 
symptoms).  
• 
Peripheral and optic neuropathy has been reported in patients treated with linezolid, 
primarily those patients treated for longer than the maximum recommended duration of 28 
days. In cases of optic neuropathy that progressed to loss of vision, patients were treated 
for extended periods beyond the maximum recommended duration. Visual blurring has 
been reported in some patients treated with linezolid for less than 28 days. If patients 
experience symptoms of visual impairment, such as changes in visual acuity, changes in 
color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is 
recommended. Visual function should be monitored in all patients taking linezolid for 
extended periods and in all patients reporting new visual symptoms regardless of length 
of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of 
linezolid in these patients should be weighed against the potential risks.  Additional 
information on the neuropathies reported in recent studies of linezolid administered over 
prolonged periods to patients with TB infection is presented above in Section 2.2.3. 
• 
Convulsions have been reported in patients when treated with linezolid. In some of these 
cases, a history of seizures or risk factors for seizures was reported.  
• 
Postmarketing cases of symptomatic hypoglycemia have been reported in patients with 
diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, 
a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with 
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hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. 
While a causal relationship between linezolid and hypoglycemia has not been established, 
diabetic patients should be cautioned of potential hypoglycemic reactions when treated 
with linezolid. 
In addition, the linezolid product label notes that there was an excess of abnormal liver function 
tests in comparator-controlled trials.  These abnormalities were noted in 0.4% of linezolid treated 
patients in trials of skin and skin structure infections vs in 0.2% of clarithromycin treated patients, 
and in 1.6% of patients treated with linezolid versus 0.8% of patients with other treatments in trials 
of all other infections. 
Adverse events of linezolid long term therapy for Tuberculosis have been described in several 
literature reports. The most complete review is a meta-analysis by Cox which noted the proportion 
of adverse events necessitating treatment discontinuation was significantly different by dose: 
29.49% (95%CI 3.24–55.74) for ⩽600 mg daily vs. 60.75% (95%CI 42.69–78.81) for >600 mg 
daily (P = 0.05). (3) 
In a trial reported by Lee et al in S Korea(9), seven of 41 participants had myelosuppression, 
including anemia and neutropenia, primarily within the first 5 months, and only one participant 
withdrew due to anemia.  Six had clinically significant myelosuppression:  5 in 0-4 months and 1 
in 4-8 months, with 0 in 8-12 months. 
Peripheral and Optic Neuropathy:  
The linezolid product label notes these adverse events have been “ reported in patients, primarily 
those patients treated for longer than the maximum recommended duration of 28 days.  In cases 
of optic neuropathy that progressed to loss of vision, patients were treated for extended periods 
beyond the maximum recommended duration.  Visual function should be monitored in all patients 
taking ZVYOX for extended periods (>3 months) and in all patients reporting new visual 
symptoms, regardless of length of therapy.(26) 
In Lee, NEJM, 2012(9), the publication’s Supplemental Table 3 notes that 21 patients had clinically 
significant peripheral neuropathy spread over 12 months:  5 in months 0-4, 10 in months 4-8 and 
5 in months 8-12 (time of onset not noted for one).  Participants who developed any peripheral 
neuropathy had their dosing of linezolid interrupted, generally for several weeks, and then 
resumed at the lower dose of 300 mg/day (C. Barry, personal communication).  None of the 
participants withdrew from the study based on peripheral neuropathies.  At baseline, patients 
received visual acuity testing, contrast sensitivity and color vision tests. Seven cases were 
observed as having potential effects on vision; only two of 38 patients withdrew from study due to 
optic neuropathy.  For clinically significant optic neuropathy, one had this at 0-4 months, 2 at 4-8 
months and 3 at months 8-12.  Except for the 2 participants who withdrew from the study, the 
others resumed linezolid at the 300 mg dose after a hiatus of several weeks of treatment and 
completed the study with resolution of their visual acuity changes (C. Barry, personal 
communication). 
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In the Schecter California Department of Health (DOH) review(32), peripheral neuropathy 
developed in 5 of 30 patients (no standardized monitoring), but only one withdrew from linezolid 
therapy.  One patient developed visual loss secondary to optic neuropathy after 10 months of 
linezolid therapy, but vision returned to normal 3-4 weeks after discontinuation. 
In Park, 2006(27), two patients of eight in the case series developed optic neuropathy after 8-9 
month and had linezolid discontinued; these patients also had peripheral neuropathy. After 
linezolid treatment was stopped, the optic neuropathy fully resolved after 2-3 months.  A total of 
4 patients developed peripheral neuropathy at 4, 5, 8, 11 months; in the patients with optic 
neuropathy who stopped treatment, the peripheral neuropathic symptoms continued or improved 
only marginally. 
In Singla, 2012(34), two of 29 patients treated with linezolid, 600 mg daily over 12 months, stopped 
the drug because of peripheral neuritis (one patient) and optic neuritis (one patient).  The time 
course of these adverse events was not noted. 
2.3 Regimens to be Studied 
The regimen included in this study (B-Pa-L) has been selected based on the performance of the 
regimen in non-clinical pharmacology studies and on the combination of bedaquiline and 
pretomanid with other drugs in clinical studies NC-001 and NC-003.  In addition, improved 
treatment outcomes in XDR patients with the addition of linezolid to existing therapy provide 
support for combining linezolid with other drugs that have no pre-existing resistance.  Preliminary 
results from the ongoing Nix-TB clinical study demonstrate the encouraging potential of this 
regimen. 
This regimen has the potential to treat drug resistant strains of tuberculosis. This is an oral 
regimen, removing the need for injectables as part of drug resistant treatment, and is also 
projected to be markedly less expensive than current XDR-TB therapy. Treatment duration is 
anticipated to be shorter than current regimens for drug resistant TB, based on findings in mouse 
models of infection and the fact that all participants will be treated with three active drugs against 
TB for which there is no expected resistance.  
The key data supporting the use of the B-L-Pa regimen are described below. 
2.3.1 Non-Clinical Studies 
In the murine model of TB, addition of bedaquiline to HRZ results in accelerated clearance of MTB 
(5,36) when compared to HRZ alone. While the combination of bedaquiline and pretomanid in the 
murine model of TB in initial studies appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ(15) and in a subsequent study it was more 
active in the mouse model than HRZ.(16) Thus a novel regimen with bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance.   
Recent studies of the bactericidal and sterilising activity of linezolid in an animal model where 
mice were given high dose aerosol MTB infection have demonstrated that linezolid alone and in 
combination with bedaquiline and pretomanid causes marked reductions in lung CFUs from mice 
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following 1 to 3 months of therapy (Table 4 below). Additionally, all mice treated daily with 
bedaquiline, pretomanid and linezolid (B-L-Pa) were cured of the infection after 3 months of 
therapy as evidenced by no MTB cultured from lungs when mice were sacrificed 3 months after 
the completion of therapy that lasted 3 months or more (Table 4, below). This is in contrast to the 
5-6 months required in previous studies to cure all mice when treated with the standard of care 
isoniazid, rifampicin and pyrazinamide (HRZ; note that typically ethambutol is not used in the 
mouse model of infection). Additional mouse studies were performed to determine whether 
shorter durations of linezolid, with continuation of the other drugs, would result in relapse-free 
cure in the mouse (Table 4 below). Treatment with linezolid for only the first 4 to 8 weeks of a 
3-month treatment also resulted in relapse-free cure when lungs from the mice were cultured 
3 months after the completion of therapy.(37) 
Table 4: 
Murine Relapse Data 
Impact of Linezolid Treatment Duration on Lung Colony Forming Unit Counts 
Assessed during Treatment and Proportion of Mice Relapsing after Treatment 
Completion 
Proportion of mice relapsing after treatment for: 
Regimen 
2 months 
3 months 
2RHZ/RH* 
8/14 
(57%) 
BPa 
3/14 
(21%) 
3BPaL ** 
6/15 
(40%) 
0/15#† 
(0%) 
2BPaL/1BPa*** 
 
0/15#† 
(0%) 
1BPaL/2BPa 
9/15 
(60%) 
0/15#† 
(0%) 
#p = 0.11 vs. BPa; †p≤ 0.001 vs. RHZ 
*2RHZ/RH means 2 months on the full regimen and a third month on only RH 
**3BPaL means 3 months on the full regimen 
***2BPaL/1BPa means 2 months on the full regimen and a third month on only BPa 
****1BPaL/2Bpa means 1 month on the full regimen and a third month on only BPa 
B – bedaquiline, H-isoniazid, L-linezolid, Pa-pretomanid, R-rifampicin, Z-pyrazinamide 
 
In conclusion, linezolid increases the sterilising activity of the bedaquiline-pretomanid 
combination; no MTB could be cultured from the lungs of mice 3 months after cessation of 3 
months of treatment with the combination, in contrast to MTB cultured from 13 of 15 mice treated 
with the standard 2RHZ/4RH regimen over 3 months. In addition, limiting the duration of linezolid 
to the first month of treatment does not affect linezolid’s contribution to the sterilising activity of 
the regimen in the preclinical mouse study.   
Prior to the use of pretomanid in combination with bedaquiline in clinical study NC-001, a 
preclinical cardiovascular safety pharmacology study was conducted in unrestrained beagle dogs 
with both drugs to explore the potential for additive effects on QT prolongation induced by the 
combination.  Results indicate that administration of 100 mg/kg bedaquiline daily for 7 days 
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causes a small increase in QTc interval by Day 6 in some animals that is not influenced by the 
addition of 100 mg/kg pretomanid on Day 7. The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the subcutaneous route of administration and not 
related to the plasma exposure.   
2.3.2 Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or 
Linezolid 
2.3.2.1 Clinical Study NC-001 
Study NC-001 was a partially double-blind, randomized, parallel group study in adult male and 
female participants with newly diagnosed, uncomplicated, smear-positive, pulmonary TB. A total 
of 85 participants met study eligibility criteria and were randomly assigned to one of the six 
treatment groups. All study treatments were given once daily for 14 days. Substantial EBA activity 
was demonstrated across participants in all arms of the study and the daily reductions in cultured 
colony counts per mL of sputum are presented in Table 5 below. 
Table 5: 
Summary Statistics for EBACFU(0-14) 
Derived Using Bi-Linear Regression, Study NC-001 
Treatment Group 
N 
Daily Mean (SD)  
EBACFU(0-14) 
Pretomanid + pyrazinamide + moxifloxacin 
13 
0.23 (0.128) 
Pretomanid + pyrazinamide 
14 
0.15 (0.040) 
Pretomanid + bedaquiline  
15a 
0.11 (0.050) 
Bedaquiline alone 
14 
0.07 (0.068) 
Bedaquiline + pyrazinamide 
15 
0.13 (0.102) 
Rifafour e-275 
10 
0.14 (0.094) 
 
There were no Serious Adverse Events from the study among participants treated with 
pretomanid and bedaquiline.  Three participants in a bedaquiline-containing treatment arm were 
withdrawn: one participant on the bedaquiline only arm for a Grade 3 ALT and Gamma-Glutamyl 
Transferase (GGT) elevation (although the elevation occurred prior to the first dose of study 
medication), one on a bedaquiline plus pyrazinamide (weight banded) arm for a Grade 3 ALT 
and AST elevation, and one on a pretomanid and bedaquiline arm for to a Grade 3 ALT 
elevation. 
2.3.2.2 Clinical Study NC-003  
Efficacy 
In the 14 day EBA study NC-003 two monotherapy and four different combinations of bedaquiline, 
pretomanid, pyrazinamide and clofazimine were evaluated in DS-TB participants. Fifteen 
participants were randomized into 7 treatment arms: C, Z, B-Pa-Z-C, B-Pa-Z, B-Pa-C, B-Z-C, and 
HRZE control. This study demonstrated no EBA for the clofazimine monotherapy arm and modest 
EBA for the pyrazinamide monotherapy arm. However, all of the experimental regimens 
demonstrated EBA. In general, adding clofazimine to the various agents resulted in either no 
increase in EBA, or a decrease when compared to a similar regimen that did not include 
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clofazimine. In this study, the experimental regimen with the best EBA was B-Pa-Z which 
demonstrated a rate of decrease in both logCFU and logTTP that was at least as good as the HRZE 
control. The daily logCFU results are presented in Table 6. Similar results were found when TTP 
was used to calculate the bactericidal activity over 14 days (BA(0-14)). 
 
 
 
Table 6: 
NC-003 Efficacy Results: Daily BAlogCFU(0-14) 
Arm 
logCFU 
BPaZC 
.124 
BPaZ 
.180 
BPaC 
.086 
BZC 
.098 
Z 
.036 
C 
-.025 
Rifafour 
.152 
Safety 
Generally, the regimens in this study were well tolerated. Table 7 provides a list of the overall 
safety findings. The only SAE experienced in the study was in a participant in the clofazimine 
monotherapy arm. Otherwise, the rates of treatment emergent AEs (TEAEs) were similar across 
the treatment arms. One participant in the B-Pa-Z arm was withdrawn from the study due an 
adverse event of increased liver function tests (alanine aminotransferase (ALT), AST and GGT).  
Table 7: 
NC-003 Safety Data 
 
BPaZ
C 
BPaZ 
BPa
C 
BZC 
Z 
C 
HRZ
E 
Total 
N 
15 
15 
15 
15 
15 
15 
15 
105 
Participants with: 
TEAEs 
11 
9 
8 
10 
10 
9 
8 
65 
TEAEs leading to death: 
Serious TEAEs 
 
 
 
 
 
1 
 
1 
TEAES leading to early withdrawal 
 
1 
 
 
 
 
 
1 
TEAEs leading to discontinuation 
of study drug 
 
1 
 
 
 
 
 
1 
Drug-related TEAES 
8 
5 
7 
3 
5 
6 
5 
39 
Serious, drug-related TEAEs 
 
 
 
 
 
 
 
 
Grade III AEs 
 
2 
1 
2 
 
1 
 
6 
Grade IV AEs 
 
1 
1 
 
 
 
 
2 
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BPaZ
C 
BPaZ 
BPa
C 
BZC 
Z 
C 
HRZ
E 
Total 
Grade II/IV AEs 
 
2 
1 
2 
 
1 
 
6 
 
QT Prolongation 
Because bedaquiline and clofazimine are both known to prolong the QT interval, intensive ECG 
monitoring was included in the study endpoints. The mean change from baseline in QTcB and 
QTcF tended to be larger at 5 hours than at 10 hours post-dose in the (B-Pa-Z-C) arm and in the 
(B-Pa-C) arm.  No QTcB or QTcF ≥500 ms were reported.  An increase from baseline to Visit 5 
and subsequent visits of ≥60 ms in QTcB was reported for 2 participants in the (B-Pa-C) arm and 
for 1 participant in the clofazimine alone arm.  An increase from baseline to Visit 5 and subsequent 
visits of ≥60 msec in QTcF was reported for 4 participants in the (B-Pa-C) arm and for 1 participant 
in the clofazimine alone arm.  For both QTcB and QTcF, the (B-Pa-Z-C) arm and the (B-Pa-C) 
arm showed the largest increase from baseline. Clofazimine will not be used in any treatment 
arms in the NC-007 study. 
2.3.2.3 The Nix-TB Study  
The NiX-TB Study is an ongoing open-label study assessing the safety and efficacy of bedaquiline 
plus linezolid plus pretomanid in participants with pulmonary infection of either XDR-TB or 
treatment intolerant/non-responsive MDR-TB. The study regimen includes: bedaquiline 400 mg 
once daily for 2 weeks then 200 mg 3 times per week plus pretomanid 200 mg once daily plus 
linezolid 600 mg twice daily amended (22 Jan 2016 protocol) to 1200 mg once daily. Treatment 
duration is 6 months, although if participants are still culture positive at month 4, there is the option 
to extend treatment to 9 months or withdraw. The primary endpoint is the incidence of 
bacteriologic failure or relapse or clinical failure through follow-up until 6 months after the end of 
treatment. Secondary Endpoints include: incidence of bacteriologic failure or relapse or clinical 
failure through follow-up until 24 months after the end of treatment as a confirmatory analysis, 
time to sputum culture conversion to negative status through the treatment period, and the 
proportion of participants with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 
end of treatment. In addition, linezolid dosing (actual) and efficacy will be explored and changes 
from baseline will be evaluated for TB symptoms, Patient Reported Health Status, body weight, 
and measures of safety. 
Efficacy Experience to Date:   
Sixty-nine participants have been enrolled as of February 1, 2017, at 2 sites in South Africa. Forty-
nine percent of the participants are HIV positive, 79% have XDR-TB and 21% have MDR 
intolerant or resistant to prior therapy.  Forty have completed the 6 months of therapy with the 
drug regimen and 31 have been followed to the primary endpoint at 6 months after treatment. All 
surviving patients were culture negative by 4 months, with 74% negative at 8 wks. As of February 
1, 2017, there has been 1 microbiological relapse during follow up after drug therapy and 1 
participant has had a new infection during follow-up with Drug Sensitive TB.  This study will 
continue to enrol participants until the NC-007 study is initiated. 
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Safety of the B-Pa-L Regimen in the Nix-TB Study:  As of December 2016, four participants have 
died in the study. The causes of death have varied and include: 2 with multi-organ disseminated 
TB who died within the first 5 weeks of therapy, 1 who had a gastrointestinal bleed and 1 with 
multi-organ failure and disseminated TB on autopsy. No deaths or SAEs have been caused by 
hepatic injury. No participants have been withdrawn from the study except for the 4 who died.  
The expected linezolid toxicities of peripheral neuropathy and myelosuppression were common 
but manageable.  Seventy-one percent of participants had at least one linezolid dose pause (22% 
of all participants due to myelosuppression and 28% due to peripheral neuropathy), during the 6 
months of treatment. One had peak ALT and AST > 3 X ULN and total bili > 2X ULN, but these 
improved and treatment restarted without a recurrence.  There were 7 cases of grade 3 or 4 
transaminitis and all resolved and allowed the study regimen to be continued. There were no 
cases of optic neuritis. While participants have required close surveillance for signs and 
symptoms of neuropathies and bone marrow suppression, these toxicities have been 
manageable.  
2.4 Overall Benefit/Risk Assessment 
The recent report of the long term outcome of patients with XDR-TB treated in S. Africa highlighted 
the very poor prognosis for patients with this disease.  After 60 months of follow up 73% of 107 
patients had died and only 11% had a favourable outcome(28).  These patients have infection with 
MTB resistant to many/most of the available drugs to treat tuberculosis.  Patients with XDR-TB 
have limited treatment options due to their resistance profile, and the drugs that are typically used 
in Standard of Care have many side effects, some are administered as injectables and have poor 
treatment outcomes in XDR-TB.  Similarly, patients with Pre-XDR-TB and patients with MDR-TB 
who are failing or are intolerant to treatment have traditionally poor outcomes and are a challenge 
to treat. While treatment success for MDR-TB is better than for XDR-TB, overall success in 
treating MDR-TB is still approximately 50% according to the World Health Organization 2015 
Global TB Report.(43) and it would be lower for patients failing or not able to take an optimal 
traditional regimen.  This trial provides an opportunity to treat these high-need patients with three 
active drugs, for which there is no or minimal pre-existing resistance, in a very closely controlled 
and monitored clinical trial setting with the opportunity to define the optimal dosing scheme for 
linezolid.  Participants will be monitored closely and regular reviews of safety and efficacy will be 
made by the Data Safety Monitoring Committee (DSMC).  Preliminary results of the ongoing Nix-
TB trial from patients with XDR-TB and who are failing or intolerant to treatment of MDR-TB 
demonstrate that this regimen has the potential to give relapse-free cure of XDR-TB with a simple 
regimen in a much shorter period of time than currently required by the available drugs used in 
the best standard of care.  Preclinical studies of this regimen in a murine model of infection 
demonstrated relapse free cure of MTB in half the time (3 vs 6 months) required by standard HRZ 
therapy.  Clinical studies of linezolid alone and pretomanid and bedaquiline alone and in 
combination have demonstrated activity against TB infection. 
These three drugs have not been used in combination in humans prior to the Nix-TB trial, and 
thus their combined toxicity profile is emerging.  The greatest risks of key concern for participants 
in this trial from linezolid are from the adverse events of myelosuppression and peripheral and 
optic neuropathy.  Participants will be closely monitored with full blood counts, vision 
examinations, and screening for peripheral neuropathy.  The investigator may interrupt dosing of 
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either linezolid or linezolid with pretomanid and bedaquiline if adverse events of concern develop, 
and a resumption of the drugs, with linezolid at the same or at a lower dose, may be made 
cautiously.  Participants will be under close surveillance for hepatotoxicity, as that risk for 
pretomanid and bedaquiline is not yet well characterized.   
Overall the benefit-risk balance justifies evaluating the B-Pa-L regimen in this study, with the 
cautious surveillance in place, to treat patients with XDR-TB who have few options for a 
successful outcome. 
3 
Trial Objectives  
3.1 Primary Objectives 
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus 
bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary 
XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
4 
Trial Design 
4.1 Summary of Trial Design 
This is a Phase 3, multi-center, partially-blinded, randomized clinical trial conducted in 4 treatment 
groups.  Participants, trial investigators and staff, including laboratory staff, will be blinded to dose 
and scheduled duration of linezolid.   Bedaquiline and pretomanid dosing will not be blinded. 
The trial will be performed at multiple centers located in South Africa, Eastern Europe and Russia.  
A total of 120 XDR-TB and up to 60 Pre-XDR/MDR intolerant or non-responsive participants who 
meet all of the inclusion criteria and none of the exclusion criteria, aged 14 and over (aged 18 and 
over in Russia and Belarus), will be randomized to receive one of the 4 active treatment arms. 
Enrolment will stop when 120 XDR-TB participants are randomized. Participants will be 
randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive web response 
system (IWRS) which will utilize a dynamic randomization system using minimization with a 
random element to allocate participants evenly across the arms by HIV status and type of TB after 
they have given written, informed consent and met all eligibility criteria.  
Each participant will receive 26 weeks of treatment.  If participant’s week 16 sample remains 
culture positive, Investigator may consider option to extend current treatment to 39 weeks, in 
consultation with the Sponsor Medical Monitor. Participants will be followed for 78 weeks after 
end of treatment. 
4.2 Treatment Plan: Schedule of Assessments 
• 
Screening Period (Screening Visit up to 9 days prior to Treatment) 
• 
Treatment Period (Day 1 to Week 26. Additional visits every 3 weeks until last dose when 
dosing extended due to pauses or positive culture at Week 16  
• 
Follow-up Period (4 Week post end of treatment follow-up Visit to 78 Week post end of 
treatment follow-up Visit) 
Refer to: 
• 
Trial Flow Chart (Section 1.2) for the timing of all procedures and laboratory 
samples to done at each visit.   
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• 
Trial Procedures (Section 7) for details regarding specific procedures or 
laboratory tests. 
Participants will receive oral daily dosing. They will be randomized to one of the following arms: 
 
 
 
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Table 8: 
Treatment Groups 
 
Treatment Group 
No of Participants 
1 
Linezolid 1200 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
2 
Linezolid 1200 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
3 
Linezolid 600 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
4 
Linezolid 600 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
 
Figure 4: 
Trial Schematic 
 
26 Weeks of Treatment* 
 
Weeks 1-9 
Weeks 10-26 
1 
1200 mg Linezolid QD 
 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
Primary Endpoint 
follow-up for relapse-
free cure 26 weeks 
after end of treatment 
 
Full follow up 78 
weeks after end of 
treatment 
2 
1200 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100mg QD week 9 
Pretomanid 200 mg QD 
1200 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
3 
600 mg Linezolid QD 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
4 
600 mg Linezolid QD 
Bedaquiline 200 mg QDweeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
600 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
Participants will be randomized to 1 of the 4 groups listed above.  
N = 45 Participants per group for a total of 180. 30 XDR-TB participants per group    
* Treatment will be extended to 39 weeks for participants who have a positive culture at week 16  
 
5 
Trial Population 
Participant must meet all inclusion and no exclusion criteria within the screening period.  Re-
testing for laboratory or ECG parameters is allowed within the 9-day screening period. Sponsor 
may consider replacement of late screen failure and un-assessable (as detailed in the statistical 
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analysis plan) participants. It is the intent of the protocol that the participants are hospitalized 
according to local practices and at the judgment of the treating physician. 
5.1 Inclusion Criteria 
Participants are required to meet all of the following inclusion criteria during the screening period 
in order to be randomized. 
1. Provide written, informed consent prior to all trial-related procedures (including any 
additional consent required for participants considered as minors per applicable regulatory 
authority or ethics committee). 
2. Willingness and ability to attend scheduled follow-up visits and undergo study 
assessments 
3. HIV testing (if an HIV test was performed within 1 month prior to screening, it should not 
be repeated as long as documentation can be provided [ELISA and/or Western Blot].  If 
HIV status is a confirmed known positive, repeated HIV test is not needed provided 
documentation is available. 
4. Male or female, aged 18 years or older.  
 
Disease Characteristics: 
 
5. Participants with one of the following pulmonary TB conditions: 
a. 
 XDR-TB with  
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
historical documented resistance to isoniazid, rifamycins, a fluoroquinolone 
AND an injectable during the current TB diagnosis/disease course;  
b. 
Pre-XDR-TB with 
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based molecular test within 3 months prior to or at 
screening and; 
ii. 
historical documented resistance to isoniazid, rifamycins, and to a 
fluoroquinolone OR an injectable during the current TB diagnosis/disease 
course. 
c. 
MDR-TB with 
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected results within 3 months prior to screening or 
MTB confirmed in sputum based on molecular test within 3 months prior to 
or at screening and; 
ii. 
historical documented resistance to isoniazid and rifamycins during the 
current TB diagnosis/disease course; 
iii. 
with documented non-response to treatment with the best available regimen 
for 6 months or more prior to enrolment who in the opinion of the Investigator 
have been adherent to treatment and will be adherent to study regimen.   
d. 
MDR-TB with  
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected within 3 months prior to screening or MTB 
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confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
historical documented resistance to isoniazid and rifamycins during the 
current TB diagnosis/disease course and; 
iii. 
who are unable to continue second line drug regimen due to a documented 
intolerance to: 
a. PAS, ethionamide, aminoglycosides or fluoroquinolones or ; 
b. Current treatment not listed above that renders participant eligible for 
the study in the Investigator’s opinion.  
6. Chest X-Ray within one month prior to screening, obtained and read locally by investigator 
or designee with results consistent with pulmonary TB in the opinion of the Investigator. 
 
Contraception: 
7. Be of non-childbearing potential or using effective methods of birth control, as defined 
below: 
 
Non-childbearing potential: 
a. Participant - not heterosexually active or practices sexual abstinence; or  
b. Female participant/sexual partner - bilateral oophorectomy, bilateral tubal ligation 
and/or hysterectomy or has been postmenopausal with a history of no menses for 
at least 12 consecutive months; or  
c. Male participant/sexual partner - vasectomised or has had a bilateral 
orchidectomy at least three months prior to Screening. 
 
Effective birth control methods:                                                        
A double contraceptive method should be used as follows: 
a. Double barrier method which can include any 2 of the following: a male condom, 
diaphragm, cervical cap, or female condom (male and female condoms should not 
be used together); or  
b. Barrier method (one of the above) combined with hormone-based contraceptives 
or an intra-uterine device for the female participant/partner; 
 
And are willing to continue practicing birth control methods throughout treatment and for 6 
months (both male and female participants) after the last dose of study medication. 
 
Note: Hormone based contraception alone may not be reliable when taking IMP; 
therefore, hormone based contraceptives alone cannot be used by female participants 
or female partners of male participants to prevent pregnancy. 
 
5.2 Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria during 
the screening period: 
 
Medical History and Concurrent Conditions 
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1. Any condition in the Investigator’s opinion (i.e., an unstable disease such as 
uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended 
treatment, cancer that could affect survival through the protocol-specified follow up 
period), where participation in the trial would compromise the well-being of participant 
or prevent, limit or confound protocol specified assessments.  
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations.  
3. In the judgment of the Investigator, the patient is not expected to survive for more than 
6 months. 
4. Karnofsky score < 60 at screening. 
5. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal 
Products or related substances. 
6. Body mass index (BMI) < 17 kg/m2 
7. TB infection with known resistance to pretomanid, delamanid, linezolid or bedaquiline. 
8. Participants who, upon the evaluation of their pulmonary disease, are expected to 
require a surgical procedure. 
9. Having participated in other clinical studies with dosing of investigational agents within 
8 weeks prior to screening or currently enrolled in an investigational study that includes 
treatment with medicinal agents.  Participants who are participating in observational 
studies or who are in a follow up period of a trial that included drug therapy may be 
considered for inclusion. 
10. Participants with any of the following at Screening: 
• 
QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrolment. 
• 
Heart failure 
• 
A personal or family history of congenital QT prolongation 
• 
A history of or known, untreated, ongoing hypothyroidism  
• 
A history of or ongoing bradyarrhythmia 
• 
A history of Torsade de Pointe 
11. Participants with any of the following conditions where the use of linezolid is 
contraindicated:  
• 
A history of thyrotoxicosis 
• 
A history of uncontrolled arterial hypertension 
• 
A history of pheochromocytoma 
• 
A history of carcinoid syndrome 
• 
A history of bipolar disorder 
• 
A history of schizoaffective disorder 
12. Females who have a positive pregnancy test at Screening or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the study or within 6 
months of cessation of treatment.  Males planning to conceive a child during the study 
or within 6 months of cessation of treatment. 
13. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, 
participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the 
course of the study, in the opinion of the Investigator.  
14. Participants with lactose intolerance, lactase deficiency and/or glucose-galactose 
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 malabsorption. 
 
 
Previous and Concomitant Therapy 
15. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 
weeks of randomization.  
16. Concomitant use of serotonergic antidepressants or prior use within 3 days of 
randomization if Investigator foresees potential risks for serotonin syndrome when 
combined with linezolid.  
17. Concomitant use of any drug known to prolong QTc interval (including, but not 
limited to, amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, 
cyclobenzaprine, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, 
erythromycin, fluoroquinolones, halofantrine, haloperidol, ibutilide, levomethadyl, 
mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, 
sparfloxacin, thioridazine).  
18. Concomitant use of any drug known to induce myelosuppression.  
19. Concomitant use of any drugs or substances known to be strong inhibitors or 
inducers of cytochrome P450 enzymes (including but not limited to efavirenz, 
quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine, gestodene, 
metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, 
erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may 
include use of lopinavir/ritonavir regimen as noted in section 5.3.3. 
20. Concomitant use of adrenomimetics (including, but not limited to 
pseudoephedrine, 
phenylpropanolamine, 
epinephrine, 
norepinephrine, 
dobutamine), dopaminomimetics (e.g. dopamine). 
21. Concomitant use of 5-HT1 agonists (triptans), meperidine or buspirone. 
22. Participants who have received more than 2 weeks of bedaquiline, linezolid or 
delamanid prior to first dose of IMP. 
23. Participants with an existing TB diagnosis (a diagnosis made > 4 weeks prior to 
screening) and HIV co-infection, must have been on an ART for at least 4 weeks prior 
to screening.  
24. Participants with newly diagnosed tuberculosis and HIV may be enrolled provided that 
appropriate HIV therapy will not be initiated until participant has received at least 2 
weeks of study medication.  
25. HIV infected participants: the following antiretroviral therapies should not be used: 
zidovudine, stavudine, didanosine. The antiretroviral therapy (ART) booster cobicistat 
should not be used. Please reference restrictions Section 5.3.3 Antiretroviral Therapy, 
for guidance on ART treatment during the treatment period.  
 
Diagnostic and Laboratory Abnormalities 
 
26. Participants with any of the following toxicities at Screening (labs may be repeated 
during screening period) as defined by the enhanced Division of Microbiology and 
Infectious Disease (DMID) adult toxicity table (November 2007): 
 
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a. Viral load >1000 IU/ml (Unless newly diagnosed HIV and not yet on ART who 
otherwise qualify for participation); 
b. CD4+ count < 100 cells/µL (HIV positive participants); 
c. Serum potassium less than the lower limit of normal for the laboratory; 
d. Hemoglobin < 9.0 g/dL; 
e. Platelets <100,000/mm3; 
f. Absolute neutrophil count (ANC) < 1500/ mm3; 
g. Aspartate aminotransferase (AST)  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor Medical Monitor 
h. Alanine aminotransferase  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor medical monitor; 
i. Total bilirubin 
• 
greater than 1.5 x ULN to be excluded; 
• 
1-1.5 x ULN must be discussed with and approved by the Sponsor Medical 
Monitor  
j. Direct bilirubin 
• 
Greater than ULN to be excluded 
k. Serum creatinine level greater than 1.5 times upper limit of normal 
l. Albumin <3.0 mg/dl 
 
All inclusion and no exclusion criteria must be met.  If no single variable/value is outside of the 
ranges of acceptability, but when multiple values are close to the limits and/or whenever the 
Investigator has reason to suspect that there might be a health problem (other than TB), enrolment 
should only be considered after discussing the case with the sponsor medical monitor. 
5.3 Restrictions 
5.3.1 Prior and Concomitant Medications and Other Treatments 
Concomitant medications should be kept to a minimum during the treatment period of the trial.  
However, if concomitant medications are considered to be necessary for the participant’s welfare 
and are unlikely to interfere with the IMP, they may be given at the discretion of the investigator.  
For any concomitant medications given as a treatment for a new condition or a worsening of an 
existing condition occurring after signing of the informed consent form, the condition must be 
documented on the Adverse Event pages of the electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be consulted and reviewed 
carefully.  The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected in order to prevent any potentially serious and/or life-threatening drug 
interactions. 
The following concomitant medications are prohibited during the treatment period to avoid 
possible drug interactions with the IMP: 
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• 
Medicinal products used to treat pulmonary TB:  including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and metronidazole. 
• 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). (e.g., phenelzine, 
isocarboxazid) 
• 
Concomitant use of any drug known to prolong QTc interval (including but not limited to 
amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, 
clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, 
pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).  
• 
Treatment with fluoroquinolones (as they are known prolong QTc), are strongly 
discouraged in the trial. They should only be used to treat intercurrent non-TB infections 
and if the benefit of treatment outweighs the risk of prolonged QTc.   
• 
Concomitant use of any drug known to induce myelosuppression.  
• 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: ketoconazole, 
voriconazole, itraconazole, fluconazole; ketolids such as telithromycin; and macrolide 
antibiotics other than azithromycin) for more than 3 consecutive days; 
• 
The systemic use of CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, 
St. John’s wort, rifamycins and systemic dexamethasone. 
Concomitant use of serotonergic antidepressants should be avoided if possible as participants on 
these agents and linezolid are at risk for serotonin syndrome.  
Caution should be used in treating diabetic patients receiving insulin or oral hypoglycemic agents 
as cases have been reported of hypoglycemic reactions when patients on these agents have 
been treated with linezolid. 
Any drug known to be hepatotoxic should be avoided as much as possible during screening and 
throughout the treatment period (including but not limited to acetaminophen/paracetamol,  
acetazolamide, allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, 
augmentin/co-amoxiclav, azathioprine, baclofen, bumetanide, captopril, carbamazepine, 
celecoxib, chlorpromazine, chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-
trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, 
fosamprenavir, furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, 
ketoconazole, lisinopril, loperamide, losartan, methotrexate, metolazone, mirtazepine, 
nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory drugs, paroxetine, 
phenobarbital, phenothiazines, phenytoin, pravastatin, probenecid, prochlorperazine, 
risperidone, rosuvastatin, sertraline, simeprevir, simvastatin, sodium valproate, sotalol, 
sulfasalazine, sumatriptan, tamsulosin, terbinafine, tetracycline, theophyllin/uniphyllin, tipranavir, 
tolazamide, tolbutamide, topiramate, trazodone, tricyclic antidepressants, trimethoprim, 
verapamil). 
5.3.2 Recommendations for Concomitant use of Anti-Malarials 
The following treatments for malaria are recommended for concomitant use with the IMP, should 
it be necessary: 
• 
Proguanil/atovaquone or  
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• 
Artesunate plus sulfadoxine-pyrimethamine  
 
These recommendations are based on the potential for QT prolongation by bedaquiline and many 
anti-malarials. Due to the extended half-life of bedaquiline commencing anti-malarial treatment 
containing drugs that could prolong the QT interval, shortly after discontinuing bedaquiline, is not 
recommended. 
5.3.3 Antiretroviral Therapy 
For HIV infected participants, to avoid potentiating known key toxicities of linezolid (neuropathy 
and myelosuppression), the following antiretroviral therapies should not be used during the 
treatment period: zidovudine, stavudine, didanosine. The ART booster cobicistat should not be 
used. 
Only the following types of antiretroviral therapy (ART) are permissible during administration of 
regimens: 
• 
Nevirapine based regimen consisting of NVP in combination with any two NRTIs TDF/ABC 
and FTC/3TC.  
• 
Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any 
two NRTIs TDF/ABC and FTC/3TC. 
• 
Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC. 
• 
In patients who have viral load suppressed on efavirenz at the time of screening, their 
ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. If possible, 
the same nucleoside backbone should be used. 
 
The investigator must assess the risks and benefits of these antiretroviral regimens in the 
context of co-infection with TB acknowledging the following caveats: 
• 
Triple NRTI is generally not considered optimal chronic ART; 
• 
Nevirapine based regimens are associated with higher ART failure in participants having 
or known to have previously had a viral load more than or equal to 100,000/ mL. 
5.3.4 Other Restrictions 
Large quantities of foods or beverages with high tyramine content should be avoided while taking 
linezolid.  Quantities of tyramine consumed should be less than 100mg per meal. Foods high in 
tyramine content include those that may have undergone protein changes by aging, fermentation, 
pickling, or smoking to improve flavour, such as aged cheeses (0 to 15 mg tyramine per ounce); 
fermented or air-dried meats (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 
ounces); soy sauce (5mg tyramine per 1 teaspoon). The tyramine content of any protein-rich food 
may be increased if stored for long periods or improperly refrigerated. 
Alcohol should be avoided while on IMP, especially in patients with impaired hepatic function. 
5.4 Discontinuation from Treatment/Trial  
The following may result in the discontinuation of trial treatment;  
• 
Pregnancy; 
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• 
Investigator considers it for safety reasons in the best interest of the participant that he/she 
be discontinued. This could include, but is not limited to: 
o Adverse event(s); 
o Myco testing results from baseline (Screening through Week 4) indicate sensitivity 
to isoniazid and/or rifamycins; 
o Myco testing results from baseline (Screening through Week 4) indicate resistance 
to bedaquiline, pretomanid or linezolid; 
o In the opinion of the investigator, fails to comply with the protocol, including non-
compliance to IMP. 
All participants who discontinue trial treatment (but have not withdrawn consent) and received at 
least one dose of IMP will be requested to return for an early withdrawal visit and applicable safety 
Follow Up visits, as per flow chart (Section 1.2). 
In the event of the following, participants will be and/or are considered discontinued from the trial 
and no additional follow-up visits are required: 
• 
Withdrawal of informed consent; 
• 
Lost to follow-up; 
• 
Termination of the trial by the sponsor. 
A participant may discontinue from the trial at any time at his/her request (withdrawal of consent). 
 
 
 
Discontinuation from treatment due to TB 
Ultimately it is the investigator’s decision whether a participant should discontinue treatment due 
to a concern that the participant has symptomatic worsening TB and/or bacteriological 
failure/relapse.  
Discontinuation is usually not indicated by a single positive culture.  Should a participant have a 
single positive culture result after being negative, the investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether it 
is in the participant’s best interest that he/she be discontinued. Prior to discontinuation of a 
participant due to TB, the investigator must discuss the participant with the sponsor medical 
monitor, unless the investigator cannot contact the sponsor medical monitor and considers that 
discontinuation must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the investigator decides to discontinue trial treatment for a participant due to TB, additional 
sputum samples may need to be collected in order to ensure the participant’s outcome status may 
be determined, details noted in trial flowchart (Section 1.2). 
All Early Withdrawal participants who are confirmed sputum positive (at least two sequential 
sputum positive cultures) and/or have symptomatic TB will require further TB treatment. These 
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participants will be referred to specialists who treat XDR-TB, pre-XDR TB or MDR-TB as 
applicable.  
5.5 Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who is not randomized 
Completed 
Treatment / 
Completed FU* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued FU 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
FU** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* Note that this includes treatment failures who complete all applicable follow-up visits 
** Early Withdrawal 
5.6 Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific Investigational Site at any time, although this should 
only occur after consultation between involved parties.  Should this occur, the local and central 
Ethics Committee/Institutional review Board (EC/IRB) and Regulatory Authorities will be informed.  
Should the Trial/Investigational Site be closed prematurely, all trial materials (except 
documentation that has to remain stored at the Investigational Site) will be returned to the Sponsor 
or vendor.   The Investigator will retain all other documents until notification given by the Sponsor 
for destruction.  Participants currently on treatment will receive an appropriate regimen and all 
participants will be referred to a unit specializing in the treatment of XDR-TB, Pre-XDR-TB or 
MDR-TB as applicable. 
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6 
Treatment 
6.1 IMP Administration  
  
Treatment will be administered orally, once daily, with a full glass of water and a meal in the 
dosing schemes (treatment arms) outlined in Table 9. The study drug regimen should be 
initiated as specified below regardless of whether participant has received any of the allowed 
prior exposure of bedaquiline or linezolid (up to 14 days), including a loading dose of 
bedaquiline. The Pharmacy Manual should be referenced for further details. 
Table 9: 
 Investigational Medicinal Product Details  
Treatment Group 
Active and Placebo 
Linezolid 1200 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 2 linezolid 600 mg active tablets once daily for 26 weeks 
• 1 placebo linezolid 600 mg tablet once daily for 26 weeks  
Linezolid 1200 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9  
• 2 linezolid 600 mg active tablets once daily for 9 weeks  
• 1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
Linezolid 600 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 1 linezolid 600 mg active tablet once daily for 26 weeks 
• 1 placebo linezolid 600 mg tablet once daily for 26 weeks  
• 1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
Linezolid 600 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9 
• 1 linezolid 600 mg active tablet once daily for 9 weeks 
• 1 placebo linezolid 600 mg tablet for 9 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
6.2 Participant Compliance 
During site clinic visits or hospitalization, the IMP will be administered by the 
Investigator/designated site personnel. During the study, sites will be responsible for ensuring 
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participants are taking IMP correctly and are fully trained on how IMP is to be taken. When 
possible, participants will be checked for IMP compliance by the Investigators or trial 
personnel/National TB Treatment Program personnel via the hand-and-mouth procedure (both 
the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP).  Additionally, participant cards will be checked for unused tablets in the 
blisters. 
6.3 Treatment Modification(s) 
All dose modifications should be discussed with the Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required urgently for a safety concern; the 
Medical Monitor should be informed within 24 hours of the change if not discussed prior to 
implementation. 
In the event of linezolid specific toxicities, the following should be considered and implemented 
per guidance in the monitoring and safety for specific toxicities section of protocol: 
• 
Blinded one step reductions (maximum 3 steps) in the dose of linezolid (1200 mg QD to 
600 mg QD, 600 mg QD to 300 mg QD or 300mg QD to placebo) managed by the IWRS 
as per instructions in pharmacy manual and/or IWRS user manual.  
• 
Temporary pause of linezolid due to a linezolid-specific toxicity should be considered and 
implemented per guidance in the monitoring and safety for specific toxicities section of 
protocol. 
• 
Permanent discontinuation of linezolid. 
Participants experiencing suspected drug related toxicities due to other drugs in the regimen (B-
Pa), the full regimen may be halted for up to 35 consecutive days.  
Pauses of the full regimen must not exceed 8 weeks (56 days) cumulatively.   
If participant’s week 16 sample remains culture positive, Investigator may consider option to 
extend current treatment to 39 weeks, in consultation with the Sponsor Medical Monitor. When 
treatment extended due to a positive culture at week 16, pauses of the full regimen must not 
exceed 13 weeks (91 days) cumulatively. 
When total of missed dosing days and/or pauses is greater than 7 days, additional make-up doses 
should be dispensed/treatment extended. 
At no time should the participant be treated with a single agent. 
6.4 IMP Packaging and Labelling 
The complete formulations of the IMP bedaquiline and pretomanid are found in the respective 
Investigator Brochures(5,6). The complete formulations of linezolid are found in the Package 
Inserts(23,24,26).  
The IMP will be packaged as follows: 
• 
Bedaquiline: Bottles containing: 
o 200 mg QD dose- 28 tablets- bedaquiline 100 mg 
o 100mg QD dose- 14 tablets- bedaquiline 100 mg  
• 
Pretomanid: Blister card containing 14 tablets- pretomanid 200 mg  
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• 
Linezolid: Blister Card containing 7 days of dosing as follows: 
o 1200 mg QD Dose  
 
2 blister strips of 7 tablets each (14 tablets) containing active linezolid 600 
mg   
 
1 blister strip of 7 half tablets containing placebo linezolid 300 mg  
o 600 mg QD Dose:  
 
1 blister strip of 7 tablets containing active linezolid 600 mg   
 
1 blister strip of 7 tablets containing placebo linezolid 600 mg 
 
1 blister strip of 7 half tablets containing placebo linezolid 300 mg  
o 300 mg Dose (for reductions): 1 row of 7 active 600 mg tablets for 7 days of dosing 
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid 
600 mg   
 
1 blister strip of 7 half tablets containing active linezolid 300 mg  
o Placebo Linezolid Dose: 2 rows of 7 placebo 600 mg tablets for 7 days of dosing 
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid 
600 mg   
 
1 blister strip of 7 half tablets containing placebo linezolid 300 mg  
 
The packaging of each bottle/blister card will be labelled with, at a minimum, the following 
information: 
• 
Name, address and telephone number of Sponsor. 
• 
Name of medication. 
• 
Dosage, quantity and method of administration for bedaquiline and 
pretomanid. 
• 
Potential dosage, quantity and method of administration for linezolid. 
• 
Reference/Lot Number. 
• 
The statement “For Clinical Trial Use Only”. 
• 
Space for completion of Name of Investigator and Site Number. 
• 
MedID: medication identification number  
• 
Storage conditions. 
• 
Period of Use. 
• 
The statement “Keep out of reach of children”. 
• 
Expiry Date. 
• 
Directions for use. 
Space for completion of participant number and visit/date dispensed. 
6.5 Method of Treatment Assignment 
Participants will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
web response system (IWRS) which will utilize a dynamic randomization system using 
minimization with a random element to allocate participants evenly across the arms by HIV status 
and type of TB.  Information & directions will be provided to each site via the IWRS user manual. 
6.6 Blinding and Procedures for Breaking the Blind 
Bedaquiline and pretomanid treatment will not be blinded.  Linezolid treatment dose and 
duration will be double-blinded. 
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The blind must not be broken except in the case of a medical emergency, where treatment of the 
participant is influenced by the knowledge of what dose and duration of linezolid the participant is 
receiving. It is requested that the Investigator make every effort to contact the Sponsors medical 
monitor (or designee) prior to breaking the blind. IWRS will be programmed with blind-breaking 
instructions, described in the user manual. The sponsor reserves the right to break the blind in 
order to fulfil any regulatory requirements regarding reporting of SAEs. 
Individuals who will have access to the linezolid randomization scheme will be restricted 
to the IWRS vendor and IMP supply administrator and the unblinded statisticians providing 
safety and efficacy outputs for the DSMC.  Individuals from pharmacovigilance and 
regulatory may be unblinded following controlled steps in order to fulfil any regulatory 
requirements regarding reporting of expedited reports. All other parties including the 
Sponsor, CRO, Vendors and site staff, will be blinded. 
In the absence of any medical emergencies requiring a blind break, the blind for all participants 
will be broken once all clinical data and outcome parameters have been captured, no more data 
queries are pending and the statistical analysis plan has been finalized. 
6.7 Handling, Storage and Accountability  
The investigator or designee must confirm appropriate temperature conditions as per details on 
IMP labelling, have been maintained during transit for all trial treatment received and any 
discrepancies are reported and resolved before use of the trial treatment. 
Only participants enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Upon completion or termination of the trial, all unused 
and/or partially used IMPs must either be returned to Sponsor (or designated vendor) who will 
arrange for destruction or destroyed at site as agreed by sponsor after final accountability has 
been confirmed, 
The Investigator/designee will immediately inform the sponsor of any quality issues arising with 
respect to the trial medication. The sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
7 
Trial Variables and Procedures 
The trial flowchart in Section (1.2) should be referenced for timing and sequence of 
assessments. 
7.1 Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
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• 
Written Informed Consent. 
• 
Visit Dates 
• 
Participant Disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and Exclusion criteria 
• 
Clinically significant medical and treatment history (including past and current TB 
diagnosis and smoking) 
• 
Screening Coached Spot Sputum Sample: 
o Smear microscopy for acid-fast bacilli. 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB 
complex and rifamycin resistance. 
• 
Urine pregnancy test: women of child-bearing potential only, whether they are 
sexually active or not. 
• 
Serology: HIV and CD4 count.  
o If an HIV test was performed within 1 month prior to trial start, it should not be 
repeated as long as documentation of results can be provided (ELISA and/or 
Western Blot). 
o Where required by regulatory authorities or ethics committees: 
 
Separate approval for this to be performed will be obtained from 
participants in the written informed consent process.  
o prior to HIV testing and on receipt of the results, participants will be 
counselled on HIV by trained counsellors if they have indicated as such on 
the HIV consent form. If requested by the participant, HIV counselling 
provided to the participant by the study site should be clearly documented in 
the participant’s medical records/source.  Participants have the right to 
decline to know or receive their HIV test results. This decision should be 
clearly documented in the participant’s medical records/source.   
• 
Karnofsky Score (Appendix 4). 
• 
Chest X-Ray: A Chest X-Ray digital image will be obtained and read locally by the 
Investigator or designee.  Digital images will be provided to the Sponsor; this process 
will be documented in the Radiology Manual.  The Investigator is responsible for 
review and analysis for participant inclusion. 
• 
Method of Birth Control: Male and Female participants and their partners. 
• 
IMP Details: Randomization 
• 
IMP Compliance/Actual Dosing 
7.2 Efficacy Variables and Procedures 
Two Spot Sputum Samples are collected, one Early Morning brought from home or collected in 
the hospital ward and one spot collected at the research site under the coaching and observation 
of the trial staff or, if no early morning sample was provided, 2 samples collected on site at least 
30 minutes apart. The Mycobacteriology sampling methodology and requirements will be 
described in a separate document, the Laboratory Manual, which will be provided prior to the trial 
start.  
The following analyses will be performed: 
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• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the time to 
positivity (TTP) followed by a speciation test when applicable, to confirm MTB. 
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse; 
• 
Time to Sputum Culture Conversion; 
• 
Number of participants with Sputum Culture Conversion. 
Every effort is to be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favorable) result.  A participant 
who never achieves culture negative status due to inability to produce sputum, but has completed 
26 week /78 week post treatment completion follow-up and is without clinical or biological 
evidence of relapse, will be considered to have a favorable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (Appendix 7) will record participants’ ratings of the severity of 
common TB symptoms.  
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the trial flow chart. Patient Reported Health Status will be collected using the EQ-5D-5L 
Health Questionnaire (Appendix 5). This descriptive system consists of five health-related 
quality of life dimensions, each of which will be recorded using five levels of severity. 
Methodology: The Patient Reported Health Status methodology and requirements will be 
described in a separate document/guideline which will be provided prior to the trial start. 
 
7.3 Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
trial flow chart and assessed for evaluation of the safety endpoints: 
• 
Laboratory parameters. The Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, which will be provided prior to 
the trial start. The following analyses will be performed: 
o Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential, platelet count),  
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, 
calcium (corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, 
creatine phosphokinase (CPK).                  
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per discretion of Investigator.  
• 
12-lead Electrocardiogram (ECG): 
o Investigator Assessment: Normal, Abnormal. 
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o Central Cardiologist Assessment: Heart rate, PR interval, RR interval, QT, 
corrected QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all 
participants and will be described in a separate document which will be 
provided prior to the trial start; 
 
Participants should be lying down (recumbent) for at least 5 minutes prior 
to each 12-lead ECG evaluation; 
 
ECGs are to be recorded for 10 seconds; 
 
All ECGs are to be performed in single. 
 
ECGs should be done before any labs when both included in a visit) 
 
For each participant, the ECGs should, to every extent possible, be 
collected at approximately the same time of day (+/- 1 hours) and in the 
same fed/fast state throughout the trial (e.g. 4 hours after lunch). 
• 
Vital signs: 
o Vital Signs, including weight (should be done before any labs) 
o Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 minutes of 
rest) using an appropriately sized cuff, and using the same type of sphygmomanometer, 
if possible by the same observer, at each relevant visit. 
o Heart rate (bpm). 
o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C). 
• 
Physical Examination:  
o Height is measured at screening only. 
o Full (complete) and Limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will be 
recorded.   
o Weight (kg) (in light clothing and with no shoes).  
o Using the observed variables weight and height, calculated body mass index (BMI) will be 
derived. 
• 
Ophthalmology Slit Lamp Examination. To be done by an Ophthalmologist trained on 
AREDS2 assessment. The ophthalmology slit lamp methodology and requirements will be 
described in a separate document, the Ophthalmology Guideline. The following analyses will 
be performed: AREDS2 opacity typing and grading. 
• 
Ophthalmic Examination. The ophthalmic examinations can be performed by any trained 
study staff. The screening exams must be done by the trained study staff AND an 
Ophthalmologist.  Methodology and requirements will be detailed in the Ophthalmology 
Guideline. 
• 
Ophthalmology History (Screening only); 
• 
Visual Acuity Test – Corrected. Distance Vision; 
• 
Color Vision Assessment. 
• 
Adverse Events. 
• 
Brief Peripheral Neuropathy Screen (Appendix 6) will record ratings. 
• 
Investigator Assessment:  
Principal Investigator to review participant status at specified visits in flow chart including any 
time Investigator determines that participant fulfills criteria for primary outcome of treatment 
failure. Investigator to assess whether TB treatment is considered a “success” or “failure”.  If 
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considered a failure, should specify if based on bacteriology and/or clinical deterioration 
and/or radiological deterioration. 
7.4 PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Synopsis Flowchart 1.2) will be used to update 
population PK models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study population.  PK data from 
the current trial may be combined with prior data (e.g., from the NiX-TB trial) to enhance this 
population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between 
drug exposure and efficacy and safety endpoints.   
7.5 Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between screening through Week 4; 
• 
Pre-screening culture that was used for the tests that qualified the participant for inclusion 
into the trial to be subcultured and shipped to the central from the applicable lab for relevant 
participants/with no positive cultures from screening through week 4 and appropriate 
consent 
• 
When applicable, end of treatment or visits with positive cultures during post-treatment 
follow-up. 
 
The MTB isolates will be processed at the central lab(s) for: 
• 
MIC against bedaquiline, pretomanid and linezolid;   
• 
Drug Susceptibility Testing in liquid culture for rifampicin, isoniazid, streptomycin, 
ethambutol, pyrazinamide and second line TB drugs including but not limited to 
fluoroquinolones, and injectables; 
• 
Genotyping. 
 
The MTB isolates will be processed at the central lab(s) for: Positive MTB at/after end of 
treatment: Hain MTBDRplus and HainMTBRsl 
 
8 
Adverse Events 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death. 
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• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; In general, 
hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event. 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalization, 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.   A “suspected 
transmission of infectious agent by a medicinal product” is also considered a serious adverse 
event under the SAE criterion “Other medically important condition”.   
8.1.3 Attribution/Causality 
• 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration will 
be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor/designee. 
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• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
Table 10: 
Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive.  The relationship in time is reasonable; 
therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event, which might be due to the use of the drug.  The 
relationship in time is suggestive, e.g., confirmed by dechallenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).   
 
8.1.4 Severity 
Table 11: 
Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
GRADE 4 
Potentially Life-
Threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
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All AEs will be collected from the signing of the ICF until the 78-week post treatment follow-up 
visit at the time points specified in the Flowchart (Section 1.2) and recorded in the case report 
from (CRF). The exception is early withdrawal participants who will only have SAEs collected from 
the time of their early withdrawal through the 78-week post treatment visit. 
Medical occurrences that begin after obtaining informed consent will be recorded as adverse 
events. If an adverse event started before signing of the informed consent, but is ongoing at trial 
start, it should be recorded as medical history.  If the pre-existing medical occurrence worsens 
during the study, and adverse event will be recorded. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of information 
becoming known to the investigator.  
The sponsor/investigator/designee will inform Regulatory Authorities and/or IEC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the IEC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in former trial participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the trial, and he/she considers the event to be reasonably related to 
the trial treatment or trial participation, the investigator must promptly notify the sponsor, IEC/IRB 
and regulatory authorities on an expedited basis in accordance with local requirements and ICH 
guidelines for GCP. 
8.2.1 Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
Until the end of the follow-up period; and  
• 
Until all queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases follow-up will be the responsibility of the treating physician.  However, this will have 
to be agreed upon with the Sponsor Medical Monitor. 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  Investigator should contact sponsor/designee to discuss 
appropriate medical follow-up if consultation required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide sponsor/representative with a copy of any post-mortem findings including 
histopathology. 
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New or updated information on an SAE will be recorded in the originally completed CRF and 
submitted to sponsor within 24 hours of the information becoming known per SAE reporting 
guidelines. 
8.2.2 Clinical Laboratory Adverse Events 
Changes in the results of the Clinical Laboratory assessment results which the Investigator feels 
are clinically significant will be reported as adverse events.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an adverse event. 
8.2.3 Disease under Study 
Symptoms of the disease under trial (Pulmonary Tuberculosis) experienced by the participant 
while on the trial will be assessed by the Investigator.  If the symptom has: 
• 
worsened while the participant is in the trial; and 
• 
the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event.  
If there is: 
• 
no change; and  
 
• 
the Investigator assesses the symptom as due to the participant’s TB; and  
• 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation.  
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 Overdose 
Overdose of IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an Adverse Event, including if the taking of 
the suspect medicine led to suicidal intention and subsequent overdose of the suspect medicine, 
or other medication. In this case it will be recorded as an adverse event. If it does not lead to an 
Adverse Event, it will not be recorded as an AE and this will be noted in the participant’s source 
documentation. 
8.2.5 Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 Pregnancy 
The Investigator will immediately notify the sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
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Investigator will report to the sponsor follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed for 6 months.   
All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following time-
periods: 
• 
During the trial 
• 
Within 6 months after last dose of IMP 
If pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow up will be performed 
unless contraindicated by the pregnancy. 
Pregnancy reporting will follow the same time lines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in preclinical toxicity 
studies Investigator’s Brochures(5,6) and Package Inserts.(23,24,25,26) 
AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization or until the end of the follow-up period and until all queries on these AEs 
have been resolved.  Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours where possible. The recommendations for managing participants 
below assumes the laboratory abnormalities of concern have been confirmed. 
8.3.1 Neurological 
Participants with co-administration of a serotonergic agent, including anti-depressants, should be 
monitored closely for signs of serotonin syndrome.  The Investigator should determine whether 
the full regimen or the concomitant agent should be discontinued for those who experience signs 
or symptoms of serotonin syndrome such as cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
Linezolid and/or the full regimen should be paused for participants experiencing a seizure. The 
Sponsor Medical Monitor should be contacted to review details and discuss whether linezolid or 
full regimen should be resumed.  
8.3.2 ALT, AST and Alkaline Phosphatase elevations: 
The Investigator should refer to Appendix 8 – Liver Toxicity Management to appropriately manage 
the participant for clinically significant elevations of AST, ALT or Alkaline Phosphatase. 
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8.3.3 Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
Contact Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 4 elevations 
of lipase, Investigator should consider pausing the full regimen, pending further evaluation. 
8.3.4 Musculoskeletal System and Cardiac Muscle 
Myalgia 
Grade 2 (muscle tenderness at site other than sites of injection and/or venipuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
Participants with Grade 2 signs and symptoms should be followed closely. Participants with Grade 
3 or 4 signs and symptoms should be discussed with the Sponsor Medical Monitor to consider 
pausing study medication, pending further evaluation. 
CPK 
For participants having elevations in CPK of potential clinical concern, the Investigator should 
check the CK-MB subunit, if high, consider pausing regimen and discuss with Sponsor Medical 
Monitor.  
8.3.5 Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
Participants should be monitored closely.  The Investigator should discuss with the Sponsor 
Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artifacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen 
 
Monitoring Linezolid Toxicities  
The following are guidelines for decisions to pause, reduce and to resume linezolid in response 
to the onset and resolution of known linezolid-specific toxicities.  These are guidelines, and 
decisions must be made in the context of the entire clinical status of the participant.  While the 
investigator may need to urgently interrupt dosing for potentially life threatening symptoms or 
laboratory findings, the Medical Monitor should be contacted and informed of any changes in dose 
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within 24 hours.  Questions should be raised to the Sponsor’s Medical Monitor if the decision is 
not clear. 
8.3.6 Myelosuppression 
The hematologic parameters of hemoglobin and counts of Neutrophils and platelets are variable 
from measurement to measurement.  While decreases in any of these may be caused by linezolid 
toxicity, decreases of concern should be evaluated in the context of the participant’s full clinical 
status and alternate explanations.  Guidelines below are for situations of concern when it is 
considered likely that linezolid has caused the decrease. 
Anemia 
• 
Consider pausing linezolid if hemoglobin falls below 8 gm/dL (Grade 3) and significantly 
below baseline, or if hemoglobin falls > 25% of baseline. If it is clear that the anemia was 
caused by linezolid, consider resuming linezolid at half the dose when hemoglobin 
improves and linezolid is resumed.  
Leukopenia 
• 
Consider pausing linezolid if the Absolute Neutrophil Count (ANC) falls below 750/mm3 
(Grade 3) and significantly below baseline.  Ideally confirm with a repeat test before 
making further decisions as ANCs can have diurnal and other variability. If it is clear that 
the leukopenia was caused by linezolid, consider resuming linezolid at half the dose when 
ANC improves and linezolid is resumed.  
Thrombocytopenia 
• 
Consider pausing linezolid if platelets fall below 50,000/mm3 (Grade 3) and significantly 
below baseline. Ideally confirm with a repeat test before making further decisions.  If it is 
clear that the thrombocytopenia was caused by linezolid, consider resuming linezolid at 
half the dose when platelets improves and linezolid is resumed. 
8.3.7 Peripheral Neuropathy 
The decision to reduce the dose, or to pause linezolid until symptoms improve is a judgment 
based on changes in signs and symptoms identified by the investigator and informed by 
discussion with the trial participant.  As general guidance, consider pausing and/or reducing 
linezolid when the grade of a neuropathy sign or symptom increases by a grade to grade two or 
greater.  If it is clear that linezolid caused the neuropathy, consider resuming linezolid at half the 
dose, when the neuropathy improves. 
8.3.8 Optic Neuropathy 
A participant with visual symptoms of concern or change in visual acuity of 2 lines or more or 
change in color vision of more than one plate should be referred to the site ophthalmologist for 
evaluation with a retinal examination.  Any changes as assessed by the ophthalmologist that raise 
concern that an optic neuropathy may be developing should be discussed with the medical 
monitor and linezolid should be paused.  If a likely or definite optic neuropathy is confirmed, 
linezolid should be permanently discontinued. 
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8.3.9 Lactic Acidosis 
Lactic acidosis as a toxicity of linezolid should be considered if participants have gastrointestinal 
symptoms that are not explained by other more common causes of their symptoms.  Such 
participants should have lactate measured and, as indicated, a full evaluation of pH and 
bicarbonate. Note that lactate should not be measured in participants who have no symptoms of 
concern, as elevated asymptomatic lactate may be common and it is difficult to interpret the 
clinical relevance of this. Also evaluate whether any concomitant medications, such as anti-
retroviral therapies, may be associated with lactic acidosis and consider pausing them until the 
acidosis resolves. Consider pausing linezolid if a patient has GI symptoms and acidosis likely to 
be secondary to linezolid toxicity that is not otherwise explained. 
8.4 Safety Monitoring by Data Monitoring Committee 
A DSMC will be appointed for the study. The primary responsibility of the DSMC will be to act in 
an advisory capacity to the Sponsor to safeguard the interests of trial participants by monitoring 
participant safety, assess participant risk versus benefit, and assess data quality and general 
evaluation of the trial progress. Its activities will be delineated in a DSMC charter that will define 
the membership, responsibilities and the scope and frequency of data reviews. The DSMC will 
operate on a conflict-free basis independently of the Sponsor and the study team. It will comprise 
at least 3 voting members that include at least 2 clinicians and one statistician.  The DSMC may 
have an organizational meeting prior to commencement of the trial. The DSMC will have meetings 
where it will review unblinded data during a closed session. These meetings will be planned at 
regular intervals. The Sponsor or the DSMC may convene ad hoc meetings based on rates of 
SAEs and/or to review results of the futility analysis or if safety concerns arise during the trial.  
After its assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
9 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 Analysis Population 
The primary analysis population will include both XDR and non-XDR (pre-XDR and MDR 
intolerant and non-responsive TB) participants (up to 45 per arm).  A secondary analysis will be 
restricted to the XDR participants only (30 per arm).    
A modified intent-to-treat (mITT) and a per-protocol (PP) analysis for each arm and analysis 
population will be conducted.    The mITT will be considered the primary analysis and will include 
all those in the ITT analysis with additional specific exclusions detailed in the statistical analysis 
plan (SAP). 
Other analyses will be performed (for sensitivity) including a full intent-to-treat (ITT) analysis with 
no exclusions, and an analysis excluding only those who were later found to be ineligible at 
baseline (based on data collected prior to randomization).    
The Safety analysis population will include data from all randomized participants who received at 
least one dose of IMP.  
Full details of all the analysis populations will be defined in the SAP. 
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9.2 Sample Size 
The objective of this trial is to evaluate the efficacy, safety and tolerability of various doses and 
durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants 
with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
In order to fulfil this objective, it is planned to randomize 30 XDR-TB participants per treatment 
group and up to 15 pre-XDR and/or MDR intolerant/non-responsive -TB participants per group. A 
sample size of 30-45 per arm will provide more than 90% power to demonstrate that the lower 
bound of the 95% confidence interval of this estimate is greater than 50%, using a 2-sided 5% 
significance level. This assumes that the true cure rate is 80 percent.   
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as 
the target, because it is above the entire range of the historical control for cure of XDR-TB and 
because a cure rate of 50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a 
shortened, simplified, all oral, inexpensive and safer regimen would clearly represent an important 
therapeutic advancement. A standard-of-care control group cannot reasonably be included in the 
trial for several reasons.  1) Given that the regimens being tested contain B and L, these drugs 
would need to be excluded from the control group.  However, they are beginning to be used 
increasingly in XDR-TB, despite lack of firm evidence, but with positive anecdotal reports.  Asking 
patients in the control group to avoid these medications could present an ethical issue.  2) The 
success rate of standard-of-care treatment for XDR-TB, particularly without B and L (see below), 
and the risk and difficulty of its administration contrast markedly with the early findings of B-L-Pa 
in the Nix-TB trial.  It is unlikely that patients would sign informed consent to receive standard-of-
care treatment if there is an alternative, but even if they do there remains an ethical issue of 
comparing such a disadvantaged treatment with such an advantaged treatment.  3) The scientific 
validity of comparing a 12-month endpoint (B-L-Pa) with a 30- or 36-month endpoint (standard of 
care) would represent a significant challenge.   
9.3 Interim Analyses 
No formal interim analyses are planned.  Primary analysis will be performed on the 26 week 
follow-up data (after end of treatment when the last randomized participant has completed 26 
weeks of follow-up after end of treatment). 
There will be either two database locks, data analyses and trial reports generated for this trial:  
1. 
When all participants have completed 26 weeks of follow-up after end of treatment.  
2. 
When all participants have completed 78 weeks of follow-up from after end of treatment.  
9.4 Primary and Secondary Endpoint Analysis 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT). 
A secondary analysis will be restricted to the XDR participants only (30 per arm). We will 
evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that 
the incidence of bacteriologic failure or relapse or clinical failure (including mortality) at 6 months 
(26 weeks) after the end of therapy is less than 50%.   
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and 
safety and to control the overall type I error rate the following analysis strategy will be adopted 
for both the primary and secondary analysis populations: 
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The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 
weeks) with the L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a 
success.  Similarly, L600 9 weeks will only be tested if L600 26 weeks is a success.   A 
Bonferroni adjustment will be made for comparing the L1200 9 weeks and L600 26 weeks arms 
simultaneously, using p<0.025.  For these comparisons the lower bound of the 97.5% 
confidence interval will need to exceed 50% for success.   
No formal statistical pairwise comparisons between the arms will be performed. 
9.5 Safety and Tolerability Analysis 
• 
The incidence of all-cause mortality will be summarized. 
• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake.  Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
• 
Cardiovascular Safety:  QT intervals will be adjusted using Fridericia’s correction and Bazett’s 
correction. QT/QTc values and changes from pre-dose (average of Screening and Day 1 
values) at each time point will be summarized using descriptive statistics by group and time 
of collection.  These will be presented as descriptive analyses, and no inferential tests will be 
carried out. 
o Post-baseline QT/QTc intervals will be classified into the following categories:   
 
QT/QTc < 450 msec 
 
450 msec < QT/QTc < 480 msec 
 
480 msec < QT/QTc < 500 msec 
 
QT/QTc > 500 msec   
o QTc changes from baseline will be classified into the following categories: 
 
increase < 30 msec,  
 
30 msec and < 60 msec, and  
 
increase > 60 msec.  
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o Frequency counts will be used to summarize the number of participants at each 
time point according to the above categories. 
o ECG results will be classified as normal or abnormal (investigator assessment) 
and summarized using frequency counts by dose group and time of collection. 
• 
Ophthalmology: Descriptive statistics, including changes from baseline, will be summarized 
and listed by participant for ophthalmology slit lamp examination (age related eye disease 
study 2 [AREDS2] lens opacity classification and grading). Categorical data for lens opacity 
will be summarized in a frequency table for the right and left eye, respectively.  
• 
Visual acuity and color vision:   Descriptive statistics, including changes from baseline, will be 
summarized and listed by participant for both Visual Acuity and Color Assessments. 
Categorical data for changes in visual acuity and color vision from baseline will be summarized 
in a frequency table for the right and left eye, respectively.  
• 
Descriptive statistics of neuropathy data derived from Brief Peripheral Neuropathy Screen. 
Categorical data for observed signs and symptoms of neuropathy will be summarized in 
frequency tables, including changes in signs and symptoms from baseline.  
• 
Other safety variables: Laboratory Parameters, Physical Examination, Vital signs (see 
Appendix 3), Concomitant medication, ophthalmic examination and peripheral neuropathy.  
Descriptive summary statistics will be presented. The incidence of liver related laboratory 
abnormalities will be explored. 
9.6 Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update population pharmacokinetic 
(PopPK) models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study population, and to derive 
individual exposure metrics for use in exposure-response analyses. PK data from the current trial 
may be combined with prior data (e.g., from the NiX-TB trial) to enhance this population PK 
analysis. Detailed plans for the PopPK analysis will be outlined in a separate modeling plan, and 
results will be reported in separate modeling report. 
9.7 Pharmacokinetics/Pharmacodynamics 
For each analyte, the PopPK model will be used to derive individual exposure metrics such as 
steady-state Ctrough, Cmax, AUCτ, and time-above-minimum-inhibitory-concentration (T>MIC), 
or alternative individual summaries of these metrics over the treatment period to account for dose 
adjustments and interruptions as appropriate. Relationships between such exposure metrics and 
efficacy and safety endpoints will be explored graphically and by model-based analyses as 
appropriate. Planning details and results will be included in the separate modeling plan and report. 
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10 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants specific eCRF pages will be 
completed as described in the eCRF Completion Guidelines.  For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-Patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator has 
to 
permit 
trial 
related 
monitoring, audits, 
Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-Patient records while participants is on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial center files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection subsequent to trial completion.  The essential documents should be retained for 
not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify sponsor/designees 
prior to destroying any records pertaining to the trial. 
11 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the Declaration 
of Helsinki.  
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures will be adhered to for all clinical and bioanalytical activities 
relevant to the quality of the trial.  Participant compliance will be monitored throughout the trial. 
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The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-investigators. Written 
IEC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for the purpose of monitoring various aspects of the trial, and to assure appropriate conduct of 
the trial in accordance with ICH GCP.  Visits will take place usually within a predetermined interval, 
but this may vary during the course of the trial.  The Investigator and site staff will allow the trial 
monitor and authorized representatives of the Sponsor to (1) inspect all CRFs, written informed 
consent documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs, training records, facilities and other trial related 
systems/processes, and (2) access clinical supplies, dispensing and storage areas.  The 
Investigator and site staff should also (1) agree to assist with monitoring activities if requested 
and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Monitoring Plan 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. 
11.4 Auditing 
For the purpose of compliance with International GCP and regulatory agency guidelines, it may 
be necessary for Sponsor-authorized Quality Assurance personnel and/or authorized personnel 
from an external regulatory agency to conduct an audit or inspection of the investigational site.  
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The purpose of an audit is to assess the quality of data with regard to accuracy, adequacy and 
consistency, and to assure that studies are in accordance with the guidelines.  Having the highest 
quality data from studies is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by GCP to be maintained 
by each site; drug storage, dispensing and return; all trial-related supplies; and source documents 
against the CRFs to assure the adequacy and accuracy of the information which has been 
recorded, including the verification of any AEs which have occurred. The auditors or inspectors 
may also review site SOPs, training records, site facilities and other trial related 
systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
12 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles that 
have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review 
The protocol and required trial related documents will be reviewed by the sites respective 
IEC/IRB.  The trial will not start until the IEC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, plus 
any other trial related documents required for review.  The IEC/IRB shall be constituted and shall 
operate in accordance with International GCP, the ethical principles that have their origin in the 
Declaration of Helsinki. The Investigator will maintain an accurate and complete record of all 
submissions made to, and responses from the IRB/IEC.  The records should be filed in the 
Investigator’s Trial File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for the purpose of determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
considered to be part of the research. 
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The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary The investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same IEC/IRB responsible for approval of this protocol.  Each 
informed consent form shall include the elements required by the international GCP and must 
adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
ICF. 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the IEC/IRB approved written informed consent form 
will be signed and dated by both the participant and the person obtaining consent (Investigators 
or designees), and by any other parties required by the IEC/IRB. Ongoing participants must be 
re-consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative.  Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s 
medical record. 
The monitor will inspect the original completed consent form(s) for all participants 
12.5 Confidentiality  
All site staff, the Sponsor, and any sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations.  Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the sponsor or designees. 
13 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible IEC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors. (30)  
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Because the Study is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Study must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Study must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
14 Protocol Amendment Policy 
Any change to the protocol will be effected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the IEC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, IEC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant Authorities 
and/or IEC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the IEC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
15 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial sponsor is the Global Alliance for TB Drug Development (TB Alliance).  The TB Alliance 
is a not for profit, product development partnership accelerating the discovery and development 
of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, 
be compatible with antiretroviral therapies for those HIV-TB participants currently on such 
therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The sponsor certifies that it has liability insurance coverage for itself and will provide an associated 
certificate upon request.  The insurance does not relieve the Investigators of the obligation to 
maintain their own liability insurance as required by applicable law. The sponsor does not assume 
any obligation for the medical treatment of other injuries and illnesses.
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16 References  
1. “A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis”. ClinicalTrials.gov, 25 
January 2017. https://www.clinicaltrials.gov/ct2/show/NCT02333799 
2. Bonilla CA, Crossa A, Jave HO, Mitnick CD, Jamanca RB, Herrera C, Ascencios L, 
Mendoza A, Bayona J, Zignol M and Jaramillo E (2008).  “Management of Extensively 
Drug-Resistant Tuberculosis in Peru: Cure Is Possible”. PLoS One 3(8): e2957. 
3. Cox H, Ford, N. “Linezolid for the treatment of complicated drug-resistant tuberculosis: a 
systematic review and meta-analysis” INT J TUBERC LUNG DIS 16(4):447–454, 2012.  
4. Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, van Niekerk C, 
Erondu N, Ginsberg AM, Becker P and Spigelman MK (2012). “Phase II Dose-Ranging 
Trial of the Early Bactericidal Activity of PA-824”. Antimicrobial Agents and Chemotherapy; 
56(6): 3027-3031.  
5. Bedaquiline (TMC207) Investigator’s Brochure, Janssen Research and Development, 
Edition 9, 09 October 2015.  
6. Investigator’s Brochure Pretomanid (PA-824), Global Alliance for TB Drug Development, 
Version 17, 22 December 2016.  
7. Keshavjee S, Gelmanova IY, Shin SS, Mishushtin SP, Andreev YG, Atwood S, Furin JJ 
and Miller A (2012). “Hepatotoxicity during treatment for multidrug-resistant tuberculosis: 
occurrence, management and outcome”. Int J Tuberc Lung Dis 16(5):596-603.   
8. Leach KL, Brickner SJ, Noe MC, Miller PF. "Linezolid, the first oxazolidinone antibacterial 
agent" Ann NY Acad Sci. 2011 Mar; 1222:49-54. 2011.  
9. Lee, et al. "Linezolid for treatment of chronic extensively drug-resistant tuberculosis" N 
Engl J Med. 2012 Oct 18; 367(16):1508-18. 
10. Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, 
Reynolds RC, and Orme IM. “Preclinical Testing of the Nitroimidazopyran PA-824 for 
Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models” 
Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301. 
11. Lytvynenko N, Cherenko S, Feschenko Y, Pogrebna M, Senko Y, Barbova A, Manzi M, 
Denisiuk O, Ramsay A and Zachariah R (2014). “Management of multi and extensively 
drug resistant tuberculosis in Ukraine: how well are we doing?” IUALTD Public Health 
Action 4(3): S67-S72. 
12. Manjunatha U, Boshoff HI, Berry CE. The mechanism of action of PA-824: novel insights 
from transcriptional profiling. Commun Integr Biol. 2009; 2(3):215-218. 
13. Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton, JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci USA. 2006; 103(2):431-436. 
14. McLeay SC, Vis P, van Heeswijk RPG and Green B (2014). “Population Pharmacokinetics 
of Bedaquiline (TMC207), a Novel Antituberculosis Drug”. Antimicrobial Agents and 
Chemotherapy 58(9): 5315-5324. 
15. Mdluli K, Nuermberger, E. “Pre-Clinical Drug Combination Studies to Identify Novel 
Regimens for TB”. In: Recent Advances in TB Drug Development symposium, 40th Union 
World Conference, International Union Against TB and Lung Disease, Cancun, Mexico, 
2009. 
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16. Mdluli K, Nuermberger E, Taylor K, Williams N, Koen A, Khisimuzi E, Rokeya T, Si-Yang 
L, Peloquin C, Dinesh C. “Sterilizing activity of novel TMC207- and PA-824-containing 
regimens in a murine model of tuberculosis” Antimicrobial Agents and Chemotherapy 
2011; 55: 5485-5492. 
17. Migliori GB, Sotgiu G, Gandhi NR, Falzon D, DeRiemer K, Centis R, Hollm-Delgado MG, 
Palmero D, Perez-Guzman C, Vargas MH, D’Ambrosio L, Spanevello A, Bauer M, Chan 
ED, Schaaf HS, Keshavjee S, Holtz TH, Menzies D and “The Collaborative Group for 
Meta-Analysis of Individual Patient Data in MDR-TB” (2013). “Drug resistance beyond 
XDR-TB: results from a large individual patient data meta-analysis”. Eur Respir J. 42(1): 
169-179.  
18. Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006; 50(8):2621-2625. 
19. Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal, I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 2008; 
52(4):1522-1524. 
20. Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005; 172(11):1452-1456. 
21. O’Donnell MR, Padayatchi N, Master I, Osburn G and Horsbaugh CR. “Improved Early 
Results for Patients with Extensively Drug Resistant Tuberculosis and HIV in South 
Africa”. Int J Tuberc Lung Dis. 13(7): 855-861. 
22. Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
23. Package Insert for South Africa, ZYVOXID® (linezolid), Pfizer Pharmaceuticals, May 
2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=1045. Date last accessed: 15 April 
15 2016.  
24. Package Insert, Lizomac™ 600 (linezolid), MacLeods Pharmaceutical, 2014. 
25. Package 
Insert, 
SIRTURO®, 
Janssen 
Therapeutics, 
December 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204384s006lbl.pdf. Date last 
accessed: 15 April 2016. 
26. Package 
Insert, 
ZYVOX®, 
Pfizer 
Pharmaceuticals, 
June 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021130s030,021131s029,02
1132s034lbl.pdf. Date last accessed: 15 April 2016.  
27. Park IN, et al. “Efficacy and tolerability of daily-half dose linezolid in patients with 
intractable multidrug-resistant tuberculosis.” B Antimicrobial Chemotherapy 2006; 58:701-
704. 
28. Pietersen E, et al. "Long-term outcomes of patients with extensively drug-resistant 
tuberculosis in South Africa: a cohort study" Lancet, 2014 Jan 16. pii: S0140-
6736(13)62675-6.  
29. Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, Vasilyeca I, 
Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, Van 
Baelen B, van Heeswijk RPG and Dannemann B (2016). “Bedaquiline safety data in a 
broad patient population treated for drug-resistant TB including XDR-TB (C209 study)”. 
Tuberculosis 47: 394-402.  
30. “Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in 
Medical Journals”, December 2016 update.  http://www.icmje.org/icmje-recommendations.pdf,  
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31. Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578.  
32. Schecter GF, et al.  “Linezolid Treatment for MDR-TB”. Clinical Infectious Diseases 2010; 
50:49-55. 
33. Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008; 
322(5906):1392-1395. 
34. Singla R. "Linezolid: an Effective, Safe and Cheap Drug for Patients Failing Multidrug-
resistant Tuberculosis Treatment in India" Eur Respir J. 2012 Apr; 39(4):956-62. doi: 
10.1183/09031936.00076811. Epub 2011 Sep 29. 
35. Stover, C. K., P. Warrener, D. R. VanDevanter, et al. 2000. “A small-molecule 
nitroimidazopyran drug candidate for the treatment of tuberculosis”. Nature 405:962–966. 
36. Tasneen R, Betoudji F, Tyagi S, et al.  Contributions of oxazolidinones to the efficacy of 
novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis.  
Antimicrob. Agents Chemother Posted Online 26 October 2015.  Dol:10.1128/AAC.01691-
15. 
37. Tasneen R, Tyagi S, Williams K, Grosset J, Nuermberger E. “Enhanced bactericidal 
activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of 
tuberculosis”. Antimicrob Agents Chemother. 2008; 52(10):3664-3668. 
38. Tato M, et al. "In vitro activity of linezolid against Mycobacterium tuberculosis complex, 
including multidrug-resistant Mycobacterium bovis isolates". Int. J. Antimicrob Agents 
2006 Jul; 28(1)75-8.  
39. Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”.  
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
40. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. Bactericidal 
activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2005; 49(6): 2289-2293. 
41. WHO Treatment of Tuberculosis Guidelines, 4th Edition. 2010.  
42. World Health Organization. Global Tuberculosis Report 2014, 19th ed. 2014. 
43. World Health Organization. Global Tuberculosis Report 2015, 20th ed. 2015. 
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Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
exact figure/100/scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at 
least 20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life-
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization 
or hospice care probable. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common Toxicity 
Criteria (CTC), and World Health Organization (WHO)) have been adapted for use by the 
Division of Microbiology and Infectious Diseases (DMID) and modified to better meet the 
needs of Patients in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low : 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low : 
<100 mg/dL 
High: 
>600 mg/dL 
Low : 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated w ith 
gross bleeding or 
w ith disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life-
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
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Hypocalcemia 
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life-
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life-
threatening arrhythmia 
Hyperbilirubinemia 
(w hen accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(w hen other liver 
function are in the  
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase  
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
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Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, w ith or 
w ithout clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment required 
acute treatment 
required; 
outpatienttreatm
ent or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension w ith 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable w ith oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock;   
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled w ith 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow  
requires treatment; 
normalizes w ith 
bronchodilator; FEV1 
50% - 70% (of peak 
flow ) 
no normalization w ith 
bronchodilator;FEV1 
25% - 50% of peak 
flow ; or  retractions 
present 
cyanosis: FEV1 < 
25% of peak flow  
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea w ith normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
 
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Protocol Version RUS/BEL V1.0 28FEB2017 Country Amendment for RUS v 1.0/15NOV2017 
Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 90 of 103 
GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3-
4 loose stools/day 
or mild diarrhea 
last < 1 w eek 
moderate or 
persistent; 5-7 loose 
stools/day or 
diarrhea lasting >1 
w eek 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization   
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
sw allow ing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
sw allow  solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version RUS/BEL V1.0 28FEB2017 Country Amendment for RUS v 1.0/15NOV2017 
Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 91 of 103 
NEUROLOGICAL 
 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
w eakness no 
objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function 
objective 
w eakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment  required 
moderate 
discomfort; non-
narcotic analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
w ith symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment (mod 
decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or w rists) or 
loss of sensation of 
at least mod 
degree in multiple 
different body 
areas (i.e., upper 
and low er 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis;  or 
seizures 
 
 
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Protocol Version RUS/BEL V1.0 28FEB2017 Country Amendment for RUS v 1.0/15NOV2017 
Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 92 of 103 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering w ith 
function 
moderate pain, 
analgesics and/or 
pain interfering w ith 
function but not w ith 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering w ith 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain w ith 
inflammation, 
erythema or joint 
sw elling – but not 
interfering w ith 
function 
moderate pain w ith 
inflammation, 
erythema or joint 
sw elling – interfering 
w ith function, but 
not w ith activities of 
daily living 
severe pain w ith 
inflammation, 
erythema or joint 
sw elling –and 
interfering w ith 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia w ith no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or w ith 
moderate 
impairment of 
activity 
severe muscle 
tenderness w ith 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected Stevens-
Johnson or  
necrosis requiring 
surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection 
Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version RUS/BEL V1.0 28FEB2017 Country Amendment for RUS v 1.0/15NOV2017 
Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 93 of 103 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus w ithout rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial narcotic 
therapy 
intractable; requires 
repeated narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 50% 
> 48 hours 
normal activity 
decreased > 50% 
can’t w ork 
unable to care for 
self 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version RUS/BEL V1.0 28FEB2017 Country Amendment for RUS v 1.0/15NOV2017 
Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 94 of 103 
Appendix 3:  Cardiovascular Safety 
 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 90 mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or 
Grade 4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
 
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Protocol Version RUS/BEL V1.0 28FEB2017 Country Amendment for RUS v 1.0/15NOV2017 
Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 95 of 103 
Appendix 4:  Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms of 
disease.  
80 
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
Cares for self; unable to carry on normal activity or to 
do active work. 
70 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
60 
Requires considerable assistance and frequent medical 
care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109(22). 
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Protocol Version RUS/BEL V1.0 28FEB2017 Country Amendment for RUS v 1.0/15NOV2017 
Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 96 of 103 
Appendix 5:  EQ-5D-5L Questionnaire 
 
 
 
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Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 97 of 103 
 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version RUS/BEL V1.0 28FEB2017 Country Amendment for RUS v 1.0/15NOV2017 
Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 98 of 103 
Appendix 6:  Brief Peripheral Neuropathy Screening 
 
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Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 99 of 103 
 
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Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 100 of 103 
 
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Protocol Version RUS/BEL V1.0 28FEB2017 Country Amendment for RUS v 1.0/15NOV2017 
Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 101 of 103 
Appendix 7:  Tuberculosis Symptoms Profile 
 
 
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CONFIDENTIAL 
Page 102 of 103 
Appendix 8:  Liver Toxicity Management 
Standard anti-TB chemotherapy is known to cause derangement of liver function tests in a 
substantial number of patients. In many cases this will be asymptomatic and self-limiting. In some 
cases, severe hepatitis and even fulminant liver failure and death can occur.  
In pre-marketing clinical trials of new drugs and regimens it is especially important to identify and 
carefully manage any trial participants who are at risk of progression to serious liver injury.  The 
observation of altered liver function to a degree that has a high risk of progressing to liver failure 
has been referred to informally as Hy’s Law;(31,39); this reflects that pure hepatocellular injury 
sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, Hy’s Law cases have the following three components:  
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo.  
2. Among trial participants showing such aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show elevation of serum total bilirubin (TBL) 
to >2x ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase 
(ALP)).  
3. No other reason can be found to explain the combination of increased AT and total bilirubin 
level (TBL), such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury.  
During the trial, liver function will be monitored regularly with clinical assessment and blood tests 
in study participants and this will assist in follow up laboratory measurements that can document 
either resolution of abnormalities or signal the potential for drug-induced liver injury (DILI).  In a 
clinical trial of new drugs and combinations it is especially important for investigators to follow 
closely any participants who have evidence of hepatic inflammation or potential toxicity. The 
following procedure describes the management of deranged liver function tests in study 
participants. 
Procedure 
Blood tests for liver function will be taken routinely at screening (Day -9 to -1) and at the specific 
time points designated in the protocol, and at Early Withdrawal.  If at any other visit the clinician 
suspects derangement of liver function, e.g. the participant describes nausea and vomiting, right 
upper abdominal pain or is jaundiced, blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of hepatitis or hepatic impairment and any 
potentially contributing causes.  
Suspected liver toxicity (or elevated liver enzymes detected in the absence of symptoms) must 
be taken seriously and detailed guidance will be provided in a separate document “NC-007 Study 
Management of Hepatotoxicity Guideline”. Investigators should refer to this document as a guide 
to management in cases of suspected or proven liver toxicity.  Importantly, the trial Medical 
Monitor is available to provide further assistance if there is any uncertainty or additional questions. 
The laboratory source (print-out of any results) should be stored alongside or transcribed into the 
clinical source document. Each abnormal value should be marked as clinically significant (CS) or 
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Protocol Name: ZeNix 
 
CONFIDENTIAL 
Page 103 of 103 
non-clinically significant (NCS); the assessment of significance is at the discretion of the 
investigator. All clinically significant abnormal results must be recorded as Adverse Events in the 
eCRF and graded clinically as per the DMID adult toxicity table grading, (Appendix 2).  
Assessments and decision making for elevations in aminotransferase values or bilirubin of various 
levels of concern are detailed below: 
Elevated liver enzymes considered of clinical significance, but not accompanied by other signs 
and symptoms, should be reported as an adverse event and should usually be recorded as 
elevated liver enzymes. If the term "hepatitis" is used, the Safety Data Manager will question the 
site for additional evidence to support the diagnosis, such as clinical signs and serological or 
biopsy data. While a liver biopsy is not required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for cases where there is supportive evidence 
beyond a liver enzyme abnormality. However, if the investigator will confirm the diagnosis of 
hepatitis just on the basis of clinical signs and laboratory values the diagnosis will be accepted. 
Should other symptoms or signs be present, these should also be recorded as adverse events. 
Restarting Medication 
Liver function tests that are improving should be repeated regularly, such as every 3 days for the 
first week then once a week until they return to near baseline values for the participant. Manage 
the participant symptomatically as required using medications that are not potentially hepatotoxic. 
Infection control issues must be carefully managed whilst TB medications are being withheld, 
especially if the participant is still culture positive for acid fast bacilli. 
If medication has been temporarily stopped, once the liver function values have decreased 
substantially a decision must be made about further TB management.  This will be dependent on 
the clinical context and a decision must be made in discussion with the sponsor medical monitor. 
Treatment can only be restarted if the trial Medical Monitor is in agreement with the plan. In all 
cases treatment should be recommenced under close supervision for any evidence of recurrent 
liver function abnormalities.  
If there is a further significant elevation of hepatic enzymes or bilirubin or symptoms of clinical 
concern after resumption of study medication, the study medication should be withdrawn 
permanently. Participants who permanently discontinue study medication should be managed as 
clinically indicated according to local National TB Programme guidelines. The sponsor medical 
monitor can be contacted for further advice when referring to the National Treatment Program. 
The trial Medical Monitor is available to assist the Investigators in both the management of liver 
toxicity and decisions regarding the holding or re-introduction of trial medication. Investigators 
must involve the Medical Monitor in any decisions regarding medication hold or re-start, and there 
should always be a low threshold for contacting the Medical Monitor in cases of elevated liver 
enzymes. 
 
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Certificate Of Completion
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Protocol Number 
NC-007-(B-Pa-L) 
A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid 
Title: 
plus bedaquiline and pretomanid in participants with pulmonary 
infection of either extensively drug-resistant tuberculosis (XDR- 
TB), pre-XDR-TB or treatment intolerant or non-responsive multi- 
drug resistant tuberculosis (MDR-TB). 
Drug(s)/Combination(s): Bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Amendment 
Version/Date: 
V 2.0/ 13 June 2018, Incorporating Amendment 1 
Protocol Name: 
ZeNix 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 97 
CONFIDENTIAL 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
CONFIDENTIAL 
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PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Date: V 2.0 13 JUNE 2018 
Protocol Name: ZeNix 
SPONSOR 
I agree to the terms of this trial protocol. 
                                Dan Everitt 
 
 
 
Signature of Senior Medical Officer 
Printed Name 
 
June 14, 2018 | 9:00 PM EDT 
Date 
 
LEAD INVESTIGATOR 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone 646-616-8671 
email: daniel.everitt@tballiance.org 
 
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and local 
regulations. 
 
 
 
 
 
Francesca Conradie 
 
 
Signature 
Printed Name 
 
 
June 20, 2018 | 11:12 AM EDT 
 
 
Date 
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Protocol Name: ZeNix 
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PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
 
 
 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-resistant 
tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug 
resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Date:  V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
 
 
 
 
 
 
 
 
 
Signature 
Printed Name 
 
 
 
 
 
Date 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
1 
Synopsis ...................................................................................................................11 
1.1 
Synopsis Summary................................................................................................... 11 
1.2 
Synopsis Flowchart................................................................................................... 16 
2 
Introduction and Rationale............................................................................................... 21 
2.1 
Trial Rationale .......................................................................................................... 22 
2.1.1 
Trial Design Rationale ........................................................................................ 22 
2.1.2 
Trial Drug Rationale ........................................................................................... 22 
2.1.3 
Pretomanid ........................................................................................................ 24 
2.1.4 
Linezolid ............................................................................................................ 24 
2.2 
Agents to be Studied................................................................................................. 25 
2.2.1 
Bedaquiline........................................................................................................ 25 
2.2.2 
Pretomanid ........................................................................................................ 28 
2.2.3 
Linezolid ............................................................................................................ 34 
2.3 
Regimens to be Studied ............................................................................................ 39 
2.3.1 
Non-Clinical Studies ........................................................................................... 39 
2.3.2 
Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or Linezolid ... 41 
2.4 
Overall Benefit/Risk Assessment............................................................................... 44 
3 
Trial Objectives............................................................................................................... 45 
3.1 
Primary Objectives.................................................................................................... 45 
4 
Trial Design .................................................................................................................... 45 
4.1 
Summary of Trial Design........................................................................................... 45 
4.2 
Treatment Plan: Schedule of Assessments ................................................................ 45 
5 
Trial Population .............................................................................................................. 46 
5.1 
Inclusion Criteria ....................................................................................................... 47 
5.2 
Exclusion Criteria ...................................................................................................... 48 
5.3 
Restrictions .............................................................................................................. 51 
5.3.1 
Prior and Concomitant Medications and Other Treatments .................................. 51 
5.3.2 
Recommendations for Concomitant use of Anti-Malarials .................................... 52 
5.3.3 
Antiretroviral Therapy ......................................................................................... 52 
5.3.4 
Other Restrictions .............................................................................................. 53 
5.4 
Trial Discontinuation and Visits.................................................................................. 53 
5.4.1 
Treatment Discontinuation and Early Withdrawal................................................. 53 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
5.4.2 
Early Withdrawal Follow-up ................................................................................ 54 
5.4.3 
Unscheduled Visits ............................................................................................ 54 
5.4.4 
Lost to Follow-up................................................................................................ 55 
5.4.5 
Early Withdrawal due to TB ................................................................................ 55 
5.5 
Participant Progress Definitions ................................................................................. 56 
5.6 
Trial Stopping Rules ................................................................................................. 56 
6 
      Treatment ............................................................................................................. 56 
6.1 
IMP Administration.................................................................................................... 56 
6.2 
Participant Compliance ............................................................................................. 57 
6.3 
Treatment Modification(s).......................................................................................... 58 
6.4 
IMP Packaging and Labelling .................................................................................... 58 
6.5 
Method of Treatment Assignment .............................................................................. 59 
6.6 
Blinding and Procedures for Breaking the Blind ......................................................... 60 
6.7 
Handling, Storage and Accountability ........................................................................ 60 
7 
Trial Variables and Procedures ....................................................................................... 60 
7.1 
Demographic and Background Variables and Procedures .......................................... 60 
7.2 
Efficacy Variables and Procedures ............................................................................ 61 
7.3 
Safety and Tolerability Assessments ......................................................................... 62 
7.4 
PK Variables and Procedures.................................................................................... 64 
7.5 
Mycobacteriology Characterization Variable and Procedures ..................................... 64 
8 
Adverse Events .............................................................................................................. 64 
8.1 
Definitions ................................................................................................................ 64 
8.1.1 
Adverse Event (AE) ........................................................................................... 64 
8.1.2 
Serious Adverse Event (SAE)............................................................................. 64 
8.1.3 
Attribution/Causality ........................................................................................... 65 
8.1.4 
Severity ............................................................................................................. 66 
8.2 
Reporting ................................................................................................................. 66 
8.2.1 
Follow up of Adverse Events .............................................................................. 67 
8.2.2 
Clinical Laboratory Adverse Events .................................................................... 68 
8.2.3 
Disease under Study .......................................................................................... 68 
8.2.4 
Overdose........................................................................................................... 68 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
 
 
8.2.5 
Drug Interaction ................................................................................................. 68 
8.2.6 
Pregnancy ......................................................................................................... 68 
8.3 
Monitoring for Specific Toxicities ............................................................................... 69 
8.3.1 
Neurological ...................................................................................................... 69 
8.3.2 
ALT, AST and Alkaline Phosphatase elevations .................................................. 70 
8.3.3 
Lipase ............................................................................................................... 70 
8.3.4 
Musculoskeletal System and Cardiac Muscle...................................................... 70 
8.3.5 
Cardiac Rhythm Disturbances ............................................................................ 70 
8.3.6 
Monitoring Linezolid Toxicities ............................................................................ 71 
8.4 
Safety Monitoring by Data Monitoring Committee....................................................... 72 
9 
Statistical Analysis .......................................................................................................... 72 
9.1 
Analysis Population .................................................................................................. 72 
9.2 
Sample Size ............................................................................................................. 73 
9.3 
Interim Analyses ....................................................................................................... 73 
9.4 
Primary and Secondary Endpoint Analysis................................................................. 73 
9.5 
Safety and Tolerability Analysis ................................................................................. 74 
9.6 
Pharmacokinetics ..................................................................................................... 75 
9.7 
Pharmacokinetics/Pharmacodynamics ...................................................................... 76 
10 Records Management..................................................................................................... 76 
10.1 Data Collection ......................................................................................................... 76 
10.2 Source Documents ................................................................................................... 76 
10.3 File Management at the Trial Centre.......................................................................... 76 
10.4 Records Retention at the Trial Centre........................................................................ 76 
11 Quality Control and Assurance ........................................................................................ 76 
11.1 Site Procedures ........................................................................................................ 76 
11.2 Monitoring ................................................................................................................ 77 
11.3 Protocol Deviations ................................................................................................... 77 
11.4 Auditing .................................................................................................................... 78 
12 Ethics and Regulatory ..................................................................................................... 78 
12.1 Basic Principles ........................................................................................................ 78 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review.............. 78 
12.3 Regulatory Authorities............................................................................................... 78 
12.4 Informed Consent ..................................................................................................... 79 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
12.5 Confidentiality ........................................................................................................... 79 
13 Publication Policy ........................................................................................................... 80 
14 Protocol Amendment Policy ............................................................................................ 80 
15 Sponsor, Financial Aspects, Insurance and Indemnity...................................................... 80 
16 References......................................................................................................................82 
Appendix 1: 
The IUATLD Scale......................................................................................... 85 
Appendix 2: 
Division of Microbiology and Infectious Disease (DMID) Toxicity Table ............ 86 
Appendix 3: 
Cardiovascular Safety................................................................................... 94 
Appendix 4: 
Karnofsky Performance Status Scale Definitions Rating (%) Criteria .............. 95 
Appendix 5: 
Liver Toxicity Management ............................................................................ 96 
TABLES 
Table 1: 
ADRs C208 Stage 1 and Stage 2 ........................................................................ 27 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies ....................................... 29 
Table 3: 
Murine Lung CFU counts during Treatment with Linezolid ....................................... 35 
Table 4: 
Murine Relapse Data......................................................................................... 40 
Table 5: 
Summary Statistics for EBA................................................................................ 41 
Table 6: 
NC-003 Efficacy Results: Daily BAlog .................................................................. 42 
Table 7: 
NC-003 Safety Data .......................................................................................... 42 
Table 8: 
Treatment Groups............................................................................................. 45 
Table 9: 
Follow-up Visits Required for Early Withdrawal Participants ..................................... 54 
Table 10: 
Investigational Medicinal Product Details .............................................................. 57 
Table 11: 
Adverse Events Attribution/Causality Ratings ........................................................ 66 
Table 12: 
Definitions for Adverse Event Severity Gradings .................................................... 66 
FIGURES 
Figure 1: 
Log10 CFU Counts in Lungs ..................................................................................... 29 
Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010 ...................................... 32 
Figure 3: 
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin CL-001............. 36 
Figure 4: 
Trial Schematic........................................................................................................ 46 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
Abacavir 
ADR 
Adverse drug reactions 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AREDS2 
Age related eye disease scale 2 
ART 
Anti-retroviral therapy 
AST 
Aspartate amino transferase 
AT 
Amino transferase 
AUCτ 
Area under curve over a dosing interval 
B 
Bedaquiline 
BMI 
Body mass index 
bpm 
Beats per minute 
BPNS 
Brief peripheral neuropathy scale 
C 
Clofazimine 
CFU 
Colony forming units 
CK(-MB) 
Creatine kinase (-MB isoenzyme) 
C(max), 
(min) 
Plasma concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine phosphokinase 
CS 
Clinically significant 
Ctrough 
Plasma concentration trough 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of microbiology and infection disease 
DNA 
Deoxyribonucleic acid 
DOH 
Department of health 
DILI 
Drug induced liver injury 
DSMC 
Data safety monitoring committee 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
 
 
DST 
Drug susceptibility testing 
E 
Ethambutol 
EBA 
Early bactericidal activity 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
Electronic case report form 
FQ 
Fluoroquinolone 
FTC 
Emtricitabine 
g/L 
Grams per liter 
GI 
Gastrointestinal 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMR 
Geometric mean ratio 
H 
Isoniazid 
hERG 
Human ether-à-go-go related gene 
HIV 
Human immunodeficiency virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IXRS 
Interactive Voice and Web Response System 
kg 
Kilogram 
/L 
Liter 
L 
Linezolid 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
M 
Moxifloxacin 
MAO(I) 
Monoamine oxidase (Inhibitor) 
MBD 
Minimum bactericidal dose 
MIC 
Minimum inhibitory concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi drug resistant tuberculosis 
MGIT 
Mycobacterial growth inhibiting tube 
mITT 
Modified intent to treat 
mL 
Milliliter 
ms 
Millisecond 
NCS 
Not clinically significant 
NEJM 
New England Journal of Medicine 
NVP 
Nevirapine 
NO 
Nitric oxide 
NOAEL 
No observed adverse effect level 
NRTI 
(Triple) nuleosidase reverse transcriptase inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
QD 
Once daily 
R 
Rifampicin 
S 
Streptomycin 
SAE 
Serious adverse event 
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SAP 
Statistical analysis plan 
SIRE 
Streptomycin isoniazid rifampicin ethambutol 
SOC 
System organ class 
TB 
Tuberculosis 
TBL 
Serum total bilirubin 
TDF 
Tenofovir 
TEAE 
Treatment emergent adverse events 
T>MIC 
Time above minimum inhibitory concentration 
t.i.w. 
Three times a week 
(BA) TTP 
(Bacteriocidal activity) time to positivity 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
XDR-TB 
Extensively drug resistant tuberculosis 
μg 
Microgram 
Z 
Pyrazinamide 
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1 
Synopsis 
1.1 Synopsis Summary 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Number/Title: 
NC-007: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB) 
Treatment Indication: 
Pulmonary XDR-TB, pre-XDR-TB, and treatment intolerant or non-responsive 
MDR-TB 
Trial Objective: 
To evaluate the efficacy, safety and tolerability of various doses and durations 
of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in 
participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment 
intolerant or non-responsive MDR-TB. 
Trial Design: 
A phase 3, multi-center, partially-blinded, randomized clinical trial in four parallel 
treatment groups. Bedaquiline and pretomanid treatment will not be blinded. 
Linezolid treatment dose and duration will be double-blinded. 
Participants will have a screening period of up to 14 days and will be 
randomized to receive one of the 4 active treatment arms. Participants will be 
randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
voice and web response system (IXRS) which will utilize a randomization 
system using stratification with a random element to allocate participants evenly 
across the arms by HIV status and type of TB. 
Each participant will receive 26 weeks of treatment. If participant’s sputum 
sample is culture positive between the week 16 and week 26 treatment visits 
and their clinical condition suggests they may have an ongoing TB infection, 
Investigator may consider extending current treatment to 39 weeks. If the 
culture results between week 16 and week 26 are contaminated, missing or 
considered an isolated positive without clinical significance, available culture 
results should be used to make this decision. All decisions regarding treatment 
extension should be discussed with and approved by the Sponsor Medical 
Monitor before implementation. 
Participants will be followed for 78 weeks after end of treatment. 
Patient Population: 
A total of up to 180 participants, male and female, aged 14 and over Sponsor 
may consider replacement of late screen failure and un-assessable (as 
detailed in the statistical analysis plan) participants. 
Test product, Dose and 
Mode of Administration: 
The regimen will be supplied as the following: 
Product 
Tablet Strength 
Abbreviation 
Bedaquiline 
100 mg 
(B) 
Pretomanid 
200 mg 
(Pa) 
Linezolid (scored) 
600 mg 
(L) 
Placebo Linezolid 
(scored) 
placebo 
(L) 
Linezolid 600 mg half 
tablet (pre-cut) 
300 mg 
(L) 
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Placebo linezolid half 
tablet (pre-cut) 
placebo 
(L) 
Linezolid treatment will be supplied as 2 rows of full tablets (active or 
placebo) and one row of half-tablets (active or placebo) to allow for all 
possible dosing options while maintaining the blind. 
Instructions for Dosing: 
Treatment will be administered orally, once daily, with a full glass of water and 
a meal in the following dosing schemes (treatment arms): 
Participants will receive the following: 
• 
Bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 
18 weeks plus; 
• 
Pretomanid 200 mg once daily for 26 weeks plus; 
• 
Linezolid- participants will be randomly assigned to receive one of the 
following four blinded linezolid treatment doses and durations: 
Linezolid 1200 mg daily for 26 weeks 
• 
2 linezolid 600 mg active tablets once daily for 26 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9 
• 
2 linezolid 600 mg active tablets once daily for 9 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
Linezolid 600 mg daily for 26 weeks 
• 
1 linezolid 600 mg active tablet once daily for 26 weeks 
• 
1 placebo linezolid tablet once daily for 26 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid tablet for 9 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
Treatment Modifications: 
The above treatment schemes may require modification due to toxicities as 
noted below. All dose modifications should be discussed with the Sponsor 
Medical Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be informed 
within 24 hours of the change if not discussed prior to implementation 
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In the event of linezolid specific toxicities, the following should be considered 
and implemented per guidance in the monitoring and safety for specific 
toxicities section (8.3) of protocol: 
• 
Blinded one step reductions (maximum 2 steps) in the dose of linezolid 
managed by the IXRS as per instructions in pharmacy manual and/or 
IXRS user manual. 
o 
1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or 
o 
600 mg QD to 300 mg QD, 300mg QD to placebo 
• 
Temporary pause of linezolid. 
• 
Permanent discontinuation of linezolid. 
• 
Participants who have a linezolid reduction can go back to a higher dose 
(1 step or 2 steps) post discussion with and approval by the Sponsor 
Medical Monitor. 
For participants experiencing suspected drug related toxicities due to other 
drugs in the regimen (B-Pa), the full regimen may be halted for up to 35 
consecutive days. 
Interruptions/pauses of all Investigational Medicinal Product (IMP) must not 
exceed 8 weeks (56 days) cumulatively. 
When treatment is extended to 39 weeks, interruptions/pauses of all IMP must 
not exceed 13 weeks (91 days) cumulatively. 
When the total of missed dosing days of the prescribed regimen and/or 
pauses is greater than 7 days, the same number of missed doses should be 
dispensed/treatment extended to make up for the total missed doses. 
At no time should the participant be treated with a single agent. 
Every effort should be made for participants to receive a total of 9 weeks of 
linezolid, even if pauses are required 
Criteria for Evaluation: 
Primary Endpoint: 
Incidence of bacteriologic failure or relapse, or clinical failure at 26 weeks after the end of treatment. 
Abbreviated Definitions, full definitions will be described in the Statistical Analysis Plan (SAP): 
• 
Bacteriologic failure: During the treatment period, failure to attain or maintain culture conversion to 
negative. 
• 
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative 
status, with culture conversion to positive status with a strain of Mycobacterium tuberculosis (MTB) 
genetically identical to the infecting strain at baseline. 
• 
Clinical failure: A change from protocol-specified TB treatment to a new regimen before end of 
protocol specified treatment due to treatment failure, retreatment for TB during follow up, or TB- 
related death. 
Note: 
• 
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days 
apart. 
• 
Participants who are documented at a visit as unable to produce sputum and who are clinically 
considered to be responding well to treatment will be considered to be culture negative at that visit. 
Further details of definitions to be provided in the SAP. 
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Secondary Endpoints: 
• 
Incidence of bacteriologic failure or relapse, or clinical failure through follow up until 78 weeks after 
the end of treatment. 
• 
Time to sputum culture conversion to negative status through the treatment period. 
• 
Proportion of participants with sputum culture conversion to negative status at weeks 4, 6, 8, 12, 16 
and end of treatment. 
• 
Change from baseline TB symptoms. 
• 
Change from baseline in Patient Reported Health Status. 
• 
Change from baseline weight. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations of bedaquiline and its M2, pretomanid and linezolid from sparse sampling (see Table 
1.2) will be measured and used to update population PK models for bedaquiline and its M2 metabolite, 
pretomanid, and linezolid to further evaluate the effects of covariates on model parameters in this study 
population. PK data from the current trial may be combined with prior data (e.g., from the NiX-TB trial) to 
enhance this population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax , AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between drug 
exposure and efficacy and safety endpoints. 
 
Safety and Tolerability: 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
• 
All-cause mortality. 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by, drug relatedness 
and seriousness, leading to early withdrawal from treatment, leading to pauses of linezolid, leading 
to linezolid reductions and leading to death. 
• 
Quantitative and qualitative clinical laboratory result measurements, including observed and change 
from baseline. 
• 
Quantitative and qualitative electrocardiogram (ECG) results read by a central cardiology service, 
including observed and change from baseline. 
• 
Descriptive statistics of ophthalmology slit lamp examination data (age related eye disease study 2 
[AREDS2]) lens opacity classification and grading). Categorical data for lens opacity will be 
summarized in a frequency table for the right and left eye, respectively, including observed and 
change from baseline. 
• 
Changes in ophthalmic exam for visual acuity and color vision, including observed and change from 
baseline. 
• 
Changes noted in peripheral neuropathy signs and symptoms, including observed and change from 
baseline. 
 
Mycobacteriology Assessments: 
Sputum samples will be obtained at all scheduled visits. The following tests will be performed. 
• 
Smear microscopy for acid-fast bacilli (AFB); 
• 
Liquid Culture (MGIT), followed by a speciation test to detect presence or absence of MTB and 
obtain time to positivity (TTP); 
• 
GeneXpert, Hain Genotype MTBDRplus or an alternative molecular to confirm MTB and rifamycin 
resistance. 
• 
Minimum Inhibitory concentration (MIC) of bedaquiline, pretomanid and linezolid; 
• 
Drug Susceptibility Testing (DST) in liquid culture for rifampicin, isoniazid, streptomycin, ethambutol, 
pyrazinamide and second line TB drugs including fluoroquinolones and injectable; 
• 
Genotyping. 
 
Details on the testing and the collection and timing of samples are in sections 1.2 and 7.2 
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Statistical Methods: 
A general description of the statistical methods planned for the primary efficacy outcome is outlined below. 
Specific details will be provided in the SAP. 
 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT). We will 
evaluate the hypothesis, separately for each of the experimental B-Pa-L treatment arms, that the incidence 
of bacteriologic and clinical cure at 26 weeks after the end of therapy is greater than 50%. 
 
The incidence will be estimated from the binomial proportion for participants with success criteria based on 
the lower bound of the confidence interval for this proportion being greater than 50%. 
 
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as the target, 
because it is above the entire range of the historical control for cure of XDR-TB and because a cure rate of 
50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a shortened, simplified, all oral, 
inexpensive and safer regimen would clearly represent an important therapeutic advancement. 
 
The primary analysis population will include both XDR and non-XDR participants (up to 45 per arm). A 
secondary analysis will be restricted to the XDR participants only (30 per arm).  A sample size of 30-45 per 
arm will provide more than 90% power to demonstrate that the lower bound of the 95% confidence interval 
of this estimate is greater than 50%, using a 2-sided 5% significance level. This assumes that the true cure 
rate is 80 percent. 
 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 6 months) with the 
L1200 2 months and L600 26 weeks only being tested if L1200 26 weeks is a success. Similarly, L600 9 
weeks will only be tested if L600 26 weeks is a success. A Bonferroni adjustment will be made for 
comparing the L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025. For these 
comparisons the lower bound of the 97.5% confidence interval will need to exceed 50% for success. 
 
Both a Modified Intent to Treat (mITT) and a Per Protocol (PP) analysis for each arm will be conducted. No 
formal statistical pairwise comparisons between the arms will be performed. 
Trial Duration: 
~3.5 Years (An enrolment period of at least 18 months plus 14 days pre-treatment plus 6 months treatment 
period plus 18 months post treatment follow-up). 
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1.2 Synopsis Flowchart 
Period Screeninga 
Treatment 
Visits every 3 
weeks if 
treatment 
extendedb 
End of OR Early 
Withdrawal from 
Treatmentc 
Post Treatment Follow-up 
Time of Visit 
Up to 14 days 
prior to first 
dose 
Day 1 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 20 
Week 23 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks/EWc 
Visit Window q 
N/A 
+/- 3 days 
+/- 5 days 
+/- 7 days 
Post last 
dose IMP 
+7 days 
+/-  14 days 
Informed Consent 
X 
Demography 
X 
Med/Trtmnt/Smoking History 
X 
Inclusion/Exclusiond 
X 
X 
Randomization 
X 
Karnofsky Assessment 
X 
HIV Statuse 
X 
CD4 Count and Viral Loadf 
X 
X 
Chest X-Rayg 
X 
X 
Urine Pregnancy Testh 
X 
X 
X 
X 
X 
TB Symptoms Profile 
X 
X 
X 
X 
X 
X 
X 
Patient Reported Health Status 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Exam i 
X 
Xi 
X 
Ophthalmic Exam j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
Single 12-LeadECGk 
X 
X 
X 
X 
X 
X 
X 
Limited Physical Exam l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
Full Physical Exam l 
X 
X 
X 
Laboratory Safety Tests 
(includes Full Blood Count)m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Blood Count 
X 
X 
X 
X 
X 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X X 
X 
X 
X 
Study Medication/Compliancen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Samplingo 
X 
X 
X 
X 
X 
Xo 
Early Morning & Spot Sputum r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X X 
X 
X 
X 
Peripheral Neuropathy 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessmentp 
X 
X 
 
 
CONFIDENTIAL 
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a. 
Screening: Screening assessments can occur on different days within 14 days prior to Day 
1 dosing (randomization). If a participant fails screening, a full re-screen may occur at a later 
date. All screening procedures must be repeated at re-screen visit, with the exception of the 
slit lamp examination, which can be used from a previous screening if within 8 weeks of 
anticipated randomization. 
b. 
Visit Schedule: If the duration of treatment is extended (see section 6.3, Treatment 
Modifications for details), unscheduled visits should be added every 3 weeks (+/- 7 days). 
1. End of treatment visit (final treatment visit) should be done within 7 days AFTER the 
last dose of IMP. 
2. If participant completes 26 weeks of therapy at week 33 due to full regimen pauses, 
an EXAMPLE of visit scheduling would be weeks 26, 29 and 33 (3 weeks from week 
29 plus 7-day window). In this scenario, the week 33 visit would be the end of treatment 
visit and should be completed within 7 days after last dose. 
3. If participant completes treatment at week 39 due to treatment extension, an example 
of visit scheduling would be visits at weeks 26, 29, 32, 35 and 39/End of treatment (3 
weeks plus 7-day window). 
4. Follow-up visits should be scheduled based on timing of last dose of IMP (e.g., 4-week 
follow-up to be scheduled 4 weeks after last dose of IMP). 
c. 
Follow-up Visits Early Withdrawal Participants: Once a participant has been discontinued, 
they will be required to attend an Early Withdrawal visit. If participant: 
1. Received/took < 14 doses, no additional follow-up visits are required. 
2. Received 15 or more doses and is withdrawn during treatment, follow-up after end of 
treatment/EW visit at week 12, week 26 (if not already performed) and week 78 are 
required. The week 12 visit will only require the ophthalmologic exams. The week 26 
and 78 follow-up visits will be to collect Serious Adverse Event (SAE) information 
(including verification of survival) and patient reported TB outcome information only 
and may be telephonic, a home or a site visit. This includes participants who are 
withdrawn from the trial due to meeting the treatment failure endpoint. Participant may 
need to return for visits to collect sputum samples to determine outcome status. 
3. For participants who are withdrawn during post treatment follow-up, site should 
perform study procedures required for week 78 post treatment follow-up visit. If 
participant will not return for visit, site should obtain information on SAE and patient 
reported TB outcome as noted above in no 2. 
d. 
Inclusion/Exclusion: to be confirmed at screening and prior to randomization. 
e. 
HIV testing: If HIV status is a confirmed known positive, repeated HIV test is not needed 
provided that a documented HIV test result (ELISA, Western Blot or Electro- 
Chemiluminescence) is available. If HIV status is unknown or suspected negative, HIV test 
will be requested. If an ELISA and/or Western Blot and/or Electro-Chemiluminescence based 
HIV test was performed within 4 weeks prior to screening, it should not be repeated if 
documentation of testing method and negative HIV results can be provided. Repeated HIV 
testing, during the Screening period is permitted for indeterminate HIV results. 
f. 
CD4 count and viral load: Required for all HIV-positive participants, viral load and CD4 
required at screening, CD4 will be tested at end of treatment or early withdrawal from 
treatment visit. 
g. 
Chest X-Ray: A chest x-ray (digital image) within 6 months prior to or at screening, will be 
obtained and read locally by Investigator or designee. Digital images will be provided to 
Sponsor, this process will be described in a separate document, the Radiology Manual. 
h. 
Urine Pregnancy: Women of child-bearing potential only, whether they are sexually active or 
not. 
GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
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i. 
Slit-Lamp Exam: Slit Lamp examination will be performed by an Ophthalmologist with 
AREDS2 training: 
1. For participants who receive < 14 doses of IMP, exam at: Screening only. 
2. For participants who receive 15 days to < 12 weeks of treatment, exams at: Screening 
and the 12-week post treatment follow-up visit. 
3. Participants who complete > 12 weeks of treatment exams at: Screening, End of 
Treatment or Early Withdrawal and the 12-week post treatment follow-up. 
j. 
Ophthalmic Exam: to include Ophthalmologic Medical history at Screening; All exams to 
include Visual Acuity (distance testing) and Colour Vision assessment. Can be done by any 
trained study staff throughout study. Screening exam must be done by Ophthalmologist in 
addition to trained study staff that will perform exams throughout the study. 
k. 
Single 12-Lead ECG: When possible, should be performed at approximately the same time 
of day (+/- 1 hours) and in the same fed/fasted state throughout the trial (e.g. 4 hours after 
lunch). Central ECG analysis will be performed. Central reading of screening results will be 
used to determine eligibility. 
l. 
Physical Exam: Limited Physical exams should include weight and a gross neurological, 
pulmonary, cardiovascular and abdominal exam. Height will only be collected as part of full 
exam at screening. 
m. Safety Laboratory Assessments/Urine Drug Screen: The Safety Laboratory sampling 
methodology and requirements will be described in a separate document, the Laboratory 
Manual, which will be provided prior to the trial start. The following analyses will be performed: 
• 
Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential, platelet count). 
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK). GGT will be done at screening. 
• 
When managing participants with elevated liver enzymes at an unscheduled visit, the 
Investigator can request additional tests, in addition to the repeated LFT [e.g. 
Gamma Glutamyl Transferase, screening for hepatitis A, B, C; to assist in ruling out 
other causes of abnormal liver test (e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection). 
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis. 
• 
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates, 
benzodiazepines, barbiturates, at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 2. Positive results will not automatically 
exclude participant from the trial. 
n. 
Study Medication/Compliance: Study medication administration will be supervised per local 
site practice to assure compliance to regimen. 
o. 
PK Sampling: The dates and times of the two doses of IMP taken prior to all pre-dose PK 
samples will be collected in the eCRF. 
Specific PK blood draws will be obtained as follows (pre-dose to be done after ECGs): 
1. Day 1; pre-dose (within 2 hours prior to dosing) 
2. Week 2: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
3. Week 8: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
4. Week 12: pre-dose (within 2 hours prior to dosing) 
5. Week 20 or at early withdrawal if prior to week 20: pre-dose (within 2 hours prior to 
dosing) and 2–3 hours post-dose 
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• When participant is discharged and seen as an outpatient, site should make every effort to 
collect 6-8 hour sample at week 8 when operationally and logistically feasible. 
• Hospitalization information (e.g. discharge date) will be collected in the eCRF. 
• If the full regimen or linezolid is paused, PK sampling should be delayed until full regimen 
or linezolid are resumed. 
• PK sampling should be completed even if the participant’s linezolid dose has been 
lowered or linezolid has been permanently discontinued. 
• Sites may bring participant back at a scheduled or unscheduled visit (can occur outside of 
visit windows) to collect PKs to ensure draw is done when IMP is administered. 
p. 
Investigator Assessment: Principal Investigator to review participant status and assess 
whether TB treatment at current visit is considered a “success” or “failure”. If considered a 
failure, should specify if based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. To be completed at 26 and 78 week post treatment follow-up visits and at any 
time Investigator determines that participant fulfills criteria for outcome of treatment failure. 
q. 
Visit Windows: the windows noted on the flowchart for timing of visit also apply to timing 
within a visit. For example, procedures that are difficult to schedule such as ophthalmology 
exams, should be scheduled within +/- 3 days of scheduled visit from Day 1 to Week 8 or +/- 
14 days within scheduled visit at the week 12 post treatment follow-up visit. Sites should 
make every effort to ensure all other procedures are done on the same day when possible. 
r. 
Sputum Sampling: 
 
Visit 
Sample 
Tests 
EMS 
SPOT 
ISOLATE* 
AFB Smear 
microscopy 
MGIT culture, 
speciation 
Molecular 
testing 
MIC: 
B, Pa, L 
MGIT DST 
Genotyping 
Extended 
DST (paired 
with baseline 
isolate) 
Screening 
(Day -14 to -1) 
 
 
S 
S 
S 
Baseline (Day 1) 
or 1st positive 
between screening 
and wk4 if Day 1 
negative or 
contaminated 
 
C 
 
C 
C 
 
L (when 
applicable, with 
isolate below) 
All Visits Post 
Screening 
  
S 
1st positive for MTB 
at/after week 16 for 
participant not 
responding to 
therapy and/or 1st 
positive during 
follow-up for 
potential new 
infection 
 
S 
C 
 
 
 
C 
C 
 
 
 
L 
C –   Central Mycobacteriology Laboratory (specialized facility) 
S –   Study Mycobacteriology Laboratory (facility that receives sputum samples directly from site) 
L –   Lab (as applicable per Country) that performs extended DST beyond panel at Central lab 
*Preferably from EMS Sample w hen available.  Alternate isolate can be requested if initial one is 
contaminated, or the test needs to be repeated. 
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SPUTUM SAMPLES GENERAL: If EMS (early morning sputum) is not available, site should 
make every attempt to collect two spot samples at least 30 minutes apart. 
 
PRE-SCREENING SAMPLES: If consent granted by participant, and when applicable, site can 
request pre-screening culture/isolate/DNA from current TB diagnosis/disease course to be sub- 
cultured and shipped and/or tested: 
• 
at the study lab if/when those samples could support inclusion in trial. 
• 
at the study/central lab for relevant participants with no baseline (no positive cultures from 
screening through week 4). 
 
MOLECULAR TESTING: 
• 
At Screening: GeneXpert, Hain MTBDRplus or equivalent to determine MTB complex and 
Rifampicin resistance. 
• 
Positive MTB at/after week 16: Hain MTBDRplus and HainMTBRsl 
 
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including but not limited to 
fluoroquinolones and injectables. 
 
STORAGE: MTB isolates from all positive cultures to be stored at the study laboratory until trial 
closure for the applicable study tests. The cultures as well as the extracted MTB DNA from the 
applicable baseline and follow-up isolates will also be stored at the central lab for potential further 
work to validate new assay tools for 5 years after trial closure. 
 
CENTRAL LAB: Results from testing at central lab (MIC, DST and genotyping) will not routinely 
be provided to sites. In the event that results are necessary to determine appropriate participant 
treatment, Sponsor will provide available drug susceptibility results to the site. Genotyping will be 
performed on paired DNA extracts to determine if the participant was a relapse or reinfection (See 
SAP for details). 
 
EXTENDED DST TESTING: Paired isolates from baseline and at/after week 16 should be 
shipped to a relevant lab (as applicable/available per Country) for DST extending beyond the 
panel of drugs tested at the central lab. Extended results will be provided to the site to inform 
appropriate participant treatment. 
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2 
Introduction and Rationale 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is now the world’s leading infectious 
disease killer and is responsible for more deaths than HIV.(43) It is the leading cause of death 
among HIV-infected individuals, and there is more TB in the world today than at any other time in 
history. As a result of poor treatment adherence, in addition to primary transmission, drug 
resistance is becoming more common and fears of an epidemic with strains of extensively drug- 
resistant TB (XDR-TB) that is very difficult to treat are growing. Novel drugs and regimens for TB 
are needed for the growing number of patients with XDR TB. 
Outcomes of treatment for XDR-TB using the best available treatments have traditionally been 
very poor. The best treatment historically has been to use available second line drugs individually 
tailored based on drug susceptibility testing in an inpatient setting to assure adherence with 
treatment lasting from 24 months to much longer for patients without culture conversion. The 
most detailed report using this approach with long term follow-up prior to the use of linezolid, 
bedaquiline or delamanid in regimens has come from South Africa, where the HIV co-infection 
rate among patients with XDR-TB ranges from 40 to 70%. A cohort study of 107 patients with 
XDR-TB found cure or completion of therapy at 24 months to be 16%, with 46% having died.(28) 
In another report from South Africa of 114 patients with XDR-TB, 22% completed treatment 
successfully.(21) The largest evaluation of treatment outcomes was noted in the WHO 2014 annual 
tuberculosis report of 1269 patients in 40 countries, where 22%  of patients  with XDR-TB 
completed treatment successfully and 35% died.(42) A meta-analysis of 397 patients with XDR-TB 
from 31 centers, with HIV coinfection <10%, reported 32% treatment success.(17) Reports of the 
outcome of XDR-TB treatment from Peru (43 patients, 42% treatment success)(2) and Ukraine 
(114 patients, 22% treatment success)(11) have been similar. Based on these reports, the success 
of traditionally available drug therapies for treating XDR-TB infection is substantially less than 
50% and in the most detailed and largest reports is less than 25%. 
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with XDR-TB might be improved when added to background regimens. Experience 
recently published from the C209 uncontrolled study of bedaquiline given on a background of 
multiple drugs notes that the subset of 38 patients with XDR-TB had rates of sputum culture 
conversion to negative of 62.2%.(29) However, in this study only one patient with XDR-TB was co- 
infected with HIV. All participants were required to have Mycobacterium tuberculosis (MTB) 
isolates susceptible to at least 3 drugs at enrolment, and patients had a median of only 5.4 months 
of treatment-free follow-up. This study added bedaquiline for 6 months to a background regimen 
of many drugs given for 18 months or longer. 
While treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR- 
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.(43) This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% 
died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information. 
With such poor historical outcomes for patients with XDR-TB and with the complexity, expense 
and toxicity of  treatments for all forms  of  drug resistant TB, novel drug combinations  are 
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desperately needed to improve treatment outcomes. Linezolid was identified in a small study as 
a potentially efficacious drug in patients with XDR-TB when added to a failing regimen(9) and this 
drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of three drugs for which there is little, if any, pre-existing resistance 
among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]), there is the opportunity 
to evaluate a new regimen that may be administered orally once daily to treat patients with XDR- 
TB. Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, it is 
hypothesized in the design of the ongoing Nix-TB clinical study that patients with pulmonary XDR- 
TB may have relapse-free cure after as little as 6 months’ treatment with the B-Pa-L regimen. 
Therefore, since 2015, the TB Alliance has sponsored a study with a 6 month treatment duration 
with the B-Pa-L regimen in participants with XDR-TB or MDR TB not responsive to or intolerant 
to therapy (the Nix-TB study).(1) 
A key advantage of this regimen over standard of care for MDR-TB as well as XDR-TB is that this 
is an all-oral daily regimen for 6 months of treatment in comparison to standard regimens of 6-8 
drugs over 9-30 months of treatment that includes daily injections for a minimum of 6 months. 
The NC-007 trial takes this regimen into a randomized Phase 3 trial to optimize the dosing scheme 
for linezolid and the benefit relative to risk, and to expand the patient population to include 
individuals with pre-XDR TB. 
The information presented below first details the trial rationale, then key preclinical information 
and human efficacy and safety information for each of the drugs in the regimen and then presents 
preclinical and clinical data to support the combination of these drugs in a regimen to treat patients 
with XDR, pre-XDR and MDR treatment intolerant/failure-TB. 
2.1 Trial Rationale 
2.1.1 Trial Design Rationale 
This trial will provide a regimen containing 3 drugs against which there is no expected MTB 
resistance in the community for patients with limited treatment options while simultaneously 
gathering important efficacy and safety data on a regimen that could potentially treat all strains of 
MTB. Data from previous trials shows that the combination of B-Pa is well tolerated and has the 
potential to shorten treatment in patients who are susceptible to the drugs. The ongoing Nix-TB 
trial has shown that the B-Pa-L regimen has manageable toxicity and encouraging efficacy as an 
all oral 6 month regimen administered to patients with XDR-TB. This current trial will provide 
important information on the toxicity and efficacy of the regimen under alternate doses and 
durations of linezolid to optimize the dosing scheme for the best benefit to risk balance. 
2.1.2 Trial Drug Rationale 
2.1.2.1   Bedaquiline 
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this study bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 18 weeks 
or 30 weeks if treatment is extended. This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
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combinations with other drugs. This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 study that administered bedaquiline 200 mg daily over 8 weeks, and 
by pharmacokinetic modelling and simulation of the daily dosing scheme. This supportive 
information is detailed below. 
The NC-005 study allows the efficacy and safety to be compared for treatment arms that dosed 
bedaquiline at the currently registered dose and at 200 mg daily for the 8 weeks of the trial. Briefly, 
Study NC-005 evaluated a regimen in patients  with drug susceptible pulmonary TB given 
bedaquiline with pretomanid and pyrazinamide over an 8 week period. One arm was to enroll 60 
patients who were to be given this regimen with bedaquiline dosed as approved for marketing 
(referred to as the B (loading dose/t.i.w.) PaZ arm), and another 60 patients were to be enrolled 
who would be given the regimen with bedaquiline dosed at 200 mg daily (referred to as the B 
(200mg) PaZ arm). Another group of patients with DS TB were randomized to treatment with 
standard HRZE therapy. Patients with MDR-TB were given the regimen with bedaquiline dosed 
at 200 mg daily in addition to moxifloxacin (referred to as the B (200 mg) MPaZ MDR-TB arm). 
The primary endpoint was The Bactericidal Activity (BATTP (0‐56)) as determined by the rate of 
change in time to sputum culture positivity (TTP) over 8 weeks of treatment in the Mycobacterial 
Growth Indicator Tube system, represented by the model‐fitted log (TTP) results as calculated by 
the regression of the observed log (TTP) results over time.   The assessments of safety and 
tolerability included the incidence of Treatment Emergent Adverse Events (TEAEs) presented by 
severity (DMID Grade), by drug relatedness and seriousness, and for those leading to early 
withdrawal and leading to death, by group.   In addition, quantitative and qualitative clinical 
laboratory result measurements were evaluated, including group summaries of observed values 
and changes from baseline.  Pharmacokinetics for all participants included pre-dose samples on 
9 days during and one day following dosing with the regimen.  Fifteen PK Sub‐study participants 
in each treatment arm had in addition intense PK sampling on Days 14 and 56. 
Efficacy of bedaquiline 200 mg daily dose vs the marketed dosing scheme over 8 weeks 
In the efficacy analysis of the NC-005 trial, based on liquid media collected from overnight sputum 
samples, the B(200 mg)MPaZ MDR-TB treatment group showed the highest bactericidal activity 
over the 8-week treatment period, followed by that of B(200 mg)PaZ, B(loading dose/t.i.w.)PaZ 
and then HRZE. It appears clear that the daily dosing regimen for bedaquiline provided at least 
as good a result in the primary efficacy analysis as the registered dosing scheme for bedaquiline. 
Safety of bedaquiline 200 mg daily dose vs the marketed dosing scheme 
Adverse events, including serious adverse events and Grade III/IV adverse events were similar 
among groups. In particular, the mean change from baseline in the corrected QTc intervals was 
numerically less in the participants given bedaquiline daily than in the participants given 
bedaquiline with the labelled dosing scheme. Measures of potential hepatic toxicity, including 
participants with greater than 3 fold or 10 fold elevations in aminotransferase levels, were 
numerically greater in participants given the labelled dosing scheme than subjects given daily 
doses of bedaquiline. 
Pharmacokinetics of bedaquiline 200 mg daily dose vs the marketed dosing scheme 
A population PK model published by McLeay in 2014 was used with PK data from Study NC-005 
to simulate the expected bedaquiline exposures when dosed at 200 mg daily followed by 100 mg 
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daily for the remainder of the study in comparison to the labelled dosing scheme with bedaquiline 
administered for 6 months.(14) The key findings from the simulations of the proposed dosing 
scheme for NC-007 of bedaquiline administered 200 mg daily over 8 weeks followed by 100 mg 
daily for an additional 16 weeks are: 
• 
The exposures of the proposed dosing scheme (Cmax, mean or trough) are not expected to exceed 
the exposures associated with the labelled scheme on Day 14 at the end of the 400 mg daily 
dose. With the labelled dosing scheme, the highest exposures are on Day 14 at the end of 
the 400 mg daily loading dose. 
• 
The average daily exposures with the proposed dosing scheme over 6 months are within (or 
not substantially different from) the range of exposures over 6 months of the labelled dosing 
scheme. 
• 
The cumulative exposure, in terms of AUC over time, is similar between the proposed dosing 
scheme and the labelled scheme 
2.1.3 Pretomanid 
Pretomanid has demonstrated good microbicidal activity at the 200mg daily dose as monotherapy 
in studies PA-824-CL-007 and PA-824-CL-010, in combination with either bedaquiline or 
pyrazinamide over 14 days in the early bacteriocidal activity (EBA) Study NC-001-(B-M-Pa-Z), in 
combination with either bedaquiline and/or pyrazinamide and/or clofazimine over 14 days in the 
EBA Study NC-003-(B-C-Pa-Z), and in combination with bedaquiline and linezolid over 6 months 
in the Nix-TB study. In the EBA Study PA-824-CL-010 the 100mg dose demonstrated similar 
microbicidal activity to the 150 and the 200mg daily dose over 14 days. The Phase 2 trial NC- 
002-(M-Pa-Z) evaluated this regimen at doses of pretomanid of both 100 mg and 200 mg relative 
to the HRZE control. In this trial the efficacy results were similar between participants treated 
with 100 mg/day and 200 mg/day of pretomanid in the regimen, although for the primary endpoint, 
reduction in colony forming units of MTB from sputum, only the 200 mg/day dose group was 
statistically significantly better than the group randomized to standard HRZE therapy. Safety was 
also similar between the groups, although the 200 mg/day group had more grade 2 adverse 
events than either the 100 mg/day group or the HRZE control group. Because sterilizing relapse- 
free cure of TB in patients with XDR-TB may ultimately require a regimen with higher drug 
exposures, the 200mg dose was chosen for evaluation in the Nix-TB study of the B-Pa-L regimen. 
The manageable toxicity of the regimen and very encouraging efficacy in the Nix-TB trial support 
taking the 200 mg dose of pretomanid forward in the NC-007 trial. 
2.1.4 Linezolid 
The standard dose of linezolid for a multitude of indications is 400mg or 600mg BID. Doses of 
linezolid used to treat pulmonary TB in reported observational trials and case series range from 
300 mg to 1200 mg per day over periods of up to 20 months of treatment. While the development 
of adverse events is generally higher with higher doses, the adverse events often ameliorate with 
a reduction of the dose or discontinuation of drug for several weeks and then reintroduction at a 
lower dose. No controlled trials have clearly identified differences in anti-TB effect across a range 
of doses over long term treatment of TB. 
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In this trial, each arm will vary the linezolid dosing to identify the optimal ratio of efficacy to adverse 
events as noted below. The 4 arms, to which participants will be randomly assigned in a blinded 
manner, are: 
• 
Linezolid 1200 mg orally once daily for 26 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity. 
• 
Linezolid 1200 mg orally once daily for the first 9 weeks, with the ability to interrupt or 
reduce the dose if needed based on toxicity. 
• 
Linezolid 600 mg orally once daily for 26 weeks, with the ability to interrupt or reduce the 
dose if needed based on toxicity. 
• 
Linezolid 600 mg orally once daily for the first 9 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity. 
These dosing schemes for linezolid are chosen based on clinical experience in the Nix-TB trial, 
the company’s linezolid early bactericidal activity (EBA) study findings in the Lin CL-001 study, 
and preclinical data in the mouse model of infection. While the EBA study showed that a modestly 
greater bactericidal effect over 14 days at the highest 1200 mg daily dose (see further details 
below in Section 2.2.3), this dose appears to be associated in the Nix-TB trial and in published 
literature with a greater incidence of unwanted neuropathic and myelosuppressive effects than 
the 600 mg daily dose. While a full 6 months of linezolid therapy in the regimen may give greater 
culture conversion and avoid relapse, the mouse model found that linezolid dosing of only 1 or 2 
months, when B and Pa were given continuously for a total of 3 months, maximized relapse-free 
cure; in other words, similar to pyrazinamide in the present first line HRZE therapy, more than 2 
months of linezolid when combined with B and Pa does not increase relapse-free cure in the 
mouse model. Thus, the 4 treatment arms in this study will give randomized comparative 
information about the optimal duration and dose of linezolid in the regimen relative to efficacy and 
toxicity. 
The decision to give linezolid as a single daily dose is based on the results of the linezolid EBA 
study that showed over 14 days that similar bactericidal activity was noted whether the drug was 
given as a single daily dose or divided in to 2 doses. A single daily dose will ultimately enhance 
patient adherence and will reduce the total time the drug concentration is greater than the 
calculated concentration associated with mitochondrial toxicity (which we hypothesize to be the 
likely mechanism for the toxicities of peripheral neuropathy and myelosuppression). 
2.2 Agents to be Studied 
2.2.1 Bedaquiline 
Bedaquiline is being developed as part of combination therapies for pulmonary TB due to MDR- 
TB and approved in 2012 in the USA under the provisions of accelerated approval regulations. 
Bedaquiline received conditional Marketing Authorization in the EU in 2014 and is approved in 
over 40 countries (EU countries counted individually). The approved indication may vary per 
country. Bedaquiline is marketed under the trade name SIRTUROTM. Bedaquiline has a novel 
mechanism of action as it specifically inhibits mycobacterial ATP synthase, an enzyme that is 
essential for the generation of energy in MTB The inhibition of ATP synthase leads to bactericidal 
effects for both replicating and non-replicating tubercle bacilli. 
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In the placebo-controlled Phase 2b study C208 conducted in newly-diagnosed patients with 
sputum smear-positive pulmonary MDR-TB (including pre-XDR-TB), the addition of bedaquiline 
to a preferred background regimen of MDR-TB treatment resulted in a decreased time to culture 
conversion and improved culture conversion rates compared to placebo. Median time to culture 
conversion according to the primary analysis method was 83 days for the bedaquiline group 
compared to 125 days for the placebo group (p<0.0001; hazard ratio, 95% CI: 2.44 [1.57; 3.80]). 
The proportion of patients in the mITT population with sputum culture conversion after 24 weeks 
of treatment with bedaquiline or placebo in combination with background regimen (with patients 
who discontinued considered as non-responders), was 52/66 (78.8%) in the bedaquiline group 
and 38/66 (57.6%) in the placebo group. Durability of response seen in the bedaquiline treatment 
group was supported by the results at Week 120. The proportion of responders (with patients who 
discontinued considered as non-responders) at Week 120 was 41/66 (62.1%) in the bedaquiline 
group and 29/66 (43.9%) in the placebo group. 
 
In the Phase 2b, open-label study C209, conducted in 233 patients with sputum smear positive 
pulmonary MDR-TB, the median time to sputum culture conversion excluding patients with DS-TB 
and those that did not have a positive sputum culture at screening and/or baseline (mITT; 205 
patients), was 57 days. At Week 24, 163 of 205 (79.5%) patients responded to bedaquiline 
treatment as determined by sputum culture conversion rates. Conversion rates at Week 24 were 
highest (87.1%; 81/93) in patients with MDR-TB resistant to only RMP and INH, 77.3% (34/44) in 
pre-XDR-TB patients and lowest (54.1%; 20/37) in XDR-TB patients. 
 
The average terminal half-life of bedaquiline, is about 5.5 months. After reaching Cmax, however, 
there is initially a fairly rapid reduction in plasma bedaquiline concentrations over the dosing 
interval (with an estimated half-life of about 13 hours). Four weeks after ceasing bedaquiline 
intake, the mean bedaquiline concentrations were reduced by approximately 40% compared to 
the end of the bedaquiline treatment period in the C208 study. Administration of bedaquiline with 
food increased the relative bioavailability by about 2-fold compared to administration under fasted 
conditions. It is therefore recommended to take  bedaquiline  with food to enhance its  oral 
bioavailability. 
 
CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline. Drug- 
drug interaction (DDI) studies have showed reduced exposure to bedaquiline during combination 
with a strong or moderate inducer  of CYP3A4 metabolism  (i.e., rifampicin) and increased 
exposure during combination with a strong or moderate inhibitor of CYP3A4 metabolism (i.e., 
ketoconazole). Potential drug interactions with anti-retroviral drugs have been evaluated in three 
studies. In an interaction study of single-dose bedaquiline and multiple-dose Lopinavir/ritonavir, 
exposure (AUC) to bedaquiline was increased by 22% (90% CI: 11-34). Co-administration of 
single-dose bedaquiline and multiple-dose nevaripine did not result in clinically relevant changes 
in the exposure to bedaquiline. Co-administration of a single dose of bedaquiline and multiple- 
dose efavirenz (EFV) resulted in approximately a 20% decrease in the AUCinf  of bedaquiline with 
no alteration in the Cmax. Modeling based on the data from this DDI study predicts average steady- 
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state concentrations of bedaquiline and M2 to be reduced by 52% with chronic co-administration 
of bedaquiline and EFV.(5) 
Safety of Bedaquiline 
The Investigator’s Brochure for bedaquiline provides detailed safety information.5 
 
Data were used from 14 completed clinical studies to identify Adverse Drug Reactions (ADRs) 
according to the ICH guideline entitled, E6: Good Clinical Practice, Consolidated Guideline (ICH, 
1996): “…all noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. The phrase “responses to a medicinal product” means that 
a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out." 
 
The ADRs were identified from the pooled safety database of reported AEs in the Phase 2b clinical 
studies with bedaquiline, based upon a systematic well-documented approach and are presented 
for study C208 below in Table 1. None of the ADRs reported in the controlled studies during the 
Investigational Treatment phase were considered serious. 
 
Table 1:         ADRs C208 Stage 1 and Stage 2 
 
Adverse Drug Reactions (ADRs) in the Controlled Studies (C208 Stage 1 and Stage 2) 
During the Investigational Treatment Phase 
ADR (Grouped term), n (%) 
Frequency 
Any BDQ 
N=102 
Any Placebo 
N=105 
Nervous system disorders 
Headache 
Very Common 
24 (23.5) 
12 (11.4) 
Dizziness 
Very Common 
13 (12.7) 
12 (11.4) 
Cardiac disorders 
ECG QT prolonged 
Common 
3 (2.9) 
4 (3.8) 
Gastrointestinal disorders 
Nausea 
Very Common 
36 (35.3) 
27 (25.7) 
Vomiting 
Very Common 
21 (20.6) 
24 (22.9) 
Diarrhea 
Common 
6 (5.9) 
12 (11.4) 
Hepatobiliary disorders 
Transaminases increaseda 
Common 
7 (6.9) 
1 (1.0) 
Musculoskeletal and connective tissue disorders 
Arthralgia 
Very Common 
30 (29.4) 
21 (20.0) 
Myalgia 
Common 
6 (5.9) 
7 (6.7) 
 
a. 
Different AE preferred terms (i.e., transaminases increased, aspartate aminotransferase [AST] increased, 
alanine aminotransferase [ALT] increased, hepatic enzyme increased, and hepatic function abnormal) contribute 
  
to this ADR, w hile for the other ADRs the ADR is the preferred term.  
 
 
Of note, 13 deaths occurred in the C208 Stage 2 study: 10 subjects (12.7%) in the bedaquiline 
group and 3 subjects (3.7%) in the placebo group experienced an SAE leading to death. One 
death (alcohol poisoning) occurred during administration of bedaquiline. The median time to death 
for the remaining 9 subjects was 344 days after last intake of bedaquiline. One of the 10 deaths 
in the bedaquiline treatment group and 1 of the 3 deaths in the placebo group occurred after the 
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Week 120 window. In the bedaquiline group, the most common cause of death as reported by the 
investigator was TB or TB-related illness (5 subjects). For all deaths due to TB, the subject’s last 
microbiological outcome was either failure to convert or relapse. The causes of death in the 
remaining bedaquiline subjects varied. The investigator considered all the SAEs leading to death 
not or doubtfully related to bedaquiline/placebo. The imbalance in deaths is unexplained. In 
addition, no discernible pattern between death and sputum culture conversion, relapse, sensitivity 
to other drugs used to treat TB, HIV status, or severity of disease was observed. 
 
During clinical studies with bedaquiline a prolongation of QTc interval on the ECG was observed. 
Consequently, bedaquiline treatment initiation is not recommended in patients with, personal or 
family history of prolonged QT intervals, or additional risk factors for Torsades de Pointes. 
Detailed criteria are noted in Section 5.2 Exclusion Criteria. 
 
Increases in transaminases were seen in clinical studies during administration of bedaquiline in 
combination with a background regimen. Based on a review confirmed by an external 
hepatologist, it was concluded that bedaquiline has a signal for liver  injury manifested by 
increases in AST and to a lesser extent ALT. Transaminase elevations are not unexpected given 
the number of other hepatotoxic drugs in the background regimens in clinical trials based on the 
publication by Keshavjee, which describes a 16.5% incidence of hepatotoxicity during MDR-TB 
treatment. (7) 
 
2.2.2 Pretomanid 
As detailed in the Investigator’s Brochure(6), pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti- 
tuberculosis activity and a unique mechanism of action(35). Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB(10), and in vivo activity in a mouse model of tuberculosis(10, 
35). 
 
2.2.2.1   Pharmacology 
2.2.2.1.1  Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro studies demonstrated that pretomanid was active against actively growing 
drug-sensitive and drug-resistant MTB strains as  well as  against non-replicating MTB The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be similar to the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 
0.25 µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against 
drug-resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity. (6) 
 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO), (33) although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling studies also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.(12,13) 
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2.2.2.1.2  Key Non-Clinical Studies of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse studies.(18,19,20,36,40) In a mouse model of established TB, 
the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 
22 days after inhalation infection with H37Rv MTB is shown in Figure 1. In this model, the 
minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the 
development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum 
bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony forming units 
(CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 
100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
 
Figure 1:        Log10 CFU Counts in Lungs 
 
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
 
2.2.2.2 Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology studies, 
in repeat-dose toxicity studies in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity studies, and in fertility and teratology studies in rats and rabbits. 
 
In the repeat-dose toxicity studies, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week study in rats, 50 mg/kg/day in a 13-week study in monkeys and 
<25 mg/kg/day (based on findings of thickening of the GI tract at all doses) in a 9-month study in 
monkeys. The major findings in safety and toxicity studies are listed below in Table 2 and are 
detailed in the Investigator’s Brochure .(6) 
 
Table 2:       Key findings of Pretomanid in Safety and Toxicity Studies 
 
 
Nervous system-related effects. 
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
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repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development studies indicate no effects of PA-824 on fetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology studies and a Segment I fertility study. In this fertility study, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed study in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing. 
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week study in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
study in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the electrocardiogram (ECG) as a prolonged QT interval corrected for heart 
rate (QTc). Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. 
Following a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation 
ranged from 21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co- 
administration of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog 
did not result in any greater effect on the QT interval than with either agent alone. After 
repeated daily doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
 
2.2.2.3 Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 studies with healthy adult 
male and female subjects, with 163 subjects receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 studies sponsored by the NIH included a Thorough QT study and a study 
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of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir. Further details of the 
studies are in the Investigator’s Brochure. 
 
2.2.2.3.1 Pharmacokinetics 
Several Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200 mg dose that increases total 
exposure by 88%. Interaction studies with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
 
Drug interaction with midazolam: Study CL-006 was an open-label, fixed-sequence drug-drug 
interaction study to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs metabolised 
by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had 
minimal effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by 
measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax), area under the 
curve to the last available time point (AUC0-t), and area under the curve extrapolated to infinity 
(AUC0-inf). The Cmax and AUC values for midazolam after co-administration with pretomanid 
were approximately 85% of those observed after treatment with midazolam alone. Furthermore, 
midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and half-life (t1/2) 
values were not different in the presence or absence of pretomanid. Therefore, 14 days’ dosing 
with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH sponsored this 
drug interaction study with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy subjects. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for the maximum concentration (Cmax) was 0.71, the GMR for the 24-hour area 
under the time-concentration curve (AUC0-24h) was 0.65, and the GMR for the trough 
concentration (Cmin) was 0.54. Concentrations of EFV when given with pretomanid versus given 
alone were similar. Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg 
once daily for 7 days, then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 
days, then LPV/r + pretomanid together for 7 days)  or Sequence 2 (LPV/r, then LPV/r + 
pretomanid, washout, then pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid 
alone from 16 PK-evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and 
for Cmin was 0.78. In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg 
for 7 days, then pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin 
versus pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and 
Cmin were 0.47, 0.34, and 0.15, respectively. 
 
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for maximum concentration (Cmax), area under the concentration-time curve (AUC0- 
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24h), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz; 13%, 17%, 
and 21% with LPV/r; and 53%, 66%, and 85% with rifampin, respectively. 
 
2.2.2.3.2 Pretomanid Clinical Efficacy 
The first two Phase 2 studies to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first study (CL-007) demonstrated 
good EBA, but all doses in this study (200 to 1200 mg/day) had the same activity. The second 
study (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA 
was seen at a dose of 100 mg/day over 14 days (4) (Figure 2). 
 
Figure 2:        Mean log Colony Forming Unit Values over Time Study CL-010 
 
 
 
 
CFU = colony-forming unit; PA-824 = pretomanid 
 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug. Studies of Pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below in Section 2.3.2. 
 
2.2.2.3.3 Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure(6) provides detailed safety information. 
6
Bi-linear regression of logCFU vs day over treatment 
0
2
4
6 
8 
10
12 
14 
Day
PA-824 50mg 
PA-824 150mg
Rifafour e275 
PA-824 100mg
PA-824 200mg
4
logCFU 
4.5 
5 
5.5
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Across the 16 clinical studies with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy subjects across the 10 Phase 1 studies and 
360 participants with newly diagnosed smear positive pulmonary TB across 5  Phase  2 
studies. Among the 289 healthy Subjects, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 1200 
mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks. The 
overall safety profile determined from the clinical studies completed to date indicates pretomanid 
is well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine. 
 
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and investigators should be vigilant to any adverse events noted in 
clinical trials. Across these studies, the most common side effects or AEs associated with 
pretomanid exposure include: 
 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea) 
• 
Skin and subcutaneous tissue disorders 
 
The only adverse drug reaction identified in clinical studies completed to date as likely caused by 
pretomanid is blood creatinine increased. A study of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse. 
 
The following parameters will be followed with particular care in the Phase 3 development 
program: 
 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close surveillance 
and careful management of participants who have elevations in aminotransferases and/or 
bilirubin. Serious liver injury, including death in 3 participants taking a combination of 
pretomanid, pyrazinamide and moxifloxacin, has occurred during clinical studies and the risk 
of liver injury may be higher for participants taking a combination of PA-824 and pyrazinamide 
than it is for the standard HRZE treatment. Therefore, close monitoring of liver function is 
required for participants who are administered PA-824, especially when combined with 
pyrazinamide. Administration of the regimen of PaMZ has been associated with death in 3 
participants associated with hepatic injury. Furthermore, the HRZE control regimen, and both 
pyrazinamide and moxifloxacin, has been associated with drug induced liver injury and in rare 
cases hepatic necrosis. Consequently, hepatic safety will be under close surveillance in all 
clinical studies. 
 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human studies that involve exposure to pretomanid longer than 
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14 days. These examinations will be conducted at baseline, near the end of the dosing period 
and 3 months after the end of study drug exposure. These examinations are to follow up on 
the finding of cataracts in rats exposed to pretomanid in clinical studies. 
 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple time 
points during the study. Although the Thorough QT Study in healthy subjects found that 
pretomanid did not increase corrected QT intervals in a clinically meaningful way and did not 
add to the known effect of moxifloxacin, the ECGs will be carefully monitored during Phase 3. 
All ECGs will be interpreted and conduction intervals will be confirmed by a central cardiology 
service. 
 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Study NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology studies have had 
seizures at high drug exposures. Consequently, close surveillance will be made of 
participants in the Phase 3 study for seizures or any central nervous system adverse events 
of potential concern. 
 
Of note, preclinical toxicology studies found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 studies have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 studies) or FSH values (3 studies) at baseline and after daily 
dosing of regimens containing pretomanid in various combinations with moxifloxacin, 
pyrazinamide and bedaquiline. A review of data from the 3 studies by an independent 
reproductive endocrine expert concluded that, based on the hormone evaluations to date, there 
is no evidence that PA-824 is a testicular toxicant in men at the doses and exposure times 
evaluated. 
 
2.2.3 Linezolid 
Linezolid is a synthetic antibacterial agent of the oxazolidanone class approved in many countries 
around the world for drug-resistant, gram-positive bacterial infections, including gram positive 
organisms such as Staphylococcus aureus, coagulase negative Staphlococcus and Enterococcal 
infections. The recommended dose for these infections is 600 mg twice daily for up to 28 days of 
therapy.(23,24,26) Antimicrobial effects likely come from inhibition of protein synthesis in the 
ribosomes of the infecting organism.(8) Resistance of MTB to linezolid is rare, as this drug has 
not been widely used to treat tuberculosis. In a recent study using linezolid to treat patients with 
XDR-TB in Korea, none of 41 patients had resistance to linezolid at baseline.(9) 
 
Preclinical in vitro data shows linezolid is active against MTB, including MDR strains with minimum 
inhibitory concentrations (MICs) that range from 0.125-1 μg/mL.(38) Recent studies of the 
bactericidal and sterilizing activity of linezolid in a mouse model of MTB infection have 
demonstrated linezolid alone causes marked reductions in lung colony forming units (CFUs) from 
mice following 1-3 months of therapy.(36) (Table 3, below) 
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Table 3: 
Murine Lung CFU counts during Treatment with Linezolid 
 
Monotherapy versus Standard Therapy 
 
Mean lung log10 CFU count (± S.D.) at: 
Regimen 
D0 
Month 1 
Month 2 
Month 3 
Untreated 
6.17 + 
0.27 
6.47 + 0.06 
2RHZ/4R 
H 
3.47 + 0.37 
1.59 + 0.25 
0.50 + 0.51 
L 
4.97 + 0.26 
 
 
In recent years linezolid has been used to treat patients with MDR(28) and XDR-TB, although there 
have been no fully controlled trials of linezolid in a regimen for this indication. The World Health 
Organization management guidelines place linezolid in Group 5 (“Agents with unclear role in 
treatment of drug resistant-TB”) in their groups of drugs to treat MDR-TB.(41) Over the past 10 
years small retrospective observational studies have reported good results when linezolid has 
been added to failing regimens for patients with MDR-TB.(9, 27, 34) The most compelling recent 
evidence linezolid may be of benefit to patients with XDR-TB was reported by Lee and colleagues 
from a study in S. Korea.(9) Forty-one patients who had sputum culture–positive XDR-TB and who 
had not had a response to any available chemotherapeutic option during the previous 6 months 
were randomized to start linezolid at 600 mg daily or to delay therapy with linezolid at 600 mg 
daily for 2 months without changing their failing background regimen. After confirmed sputum- 
smear conversion, or at 4 months, patients underwent a second randomization to continued 
linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 
months. Thirty four of 39 (87%) of the patients had a negative sputum culture within 6 months 
after linezolid had been added to their drug regimen. As of the cutoff date prior to publication, of 
the 38 patients who received linezolid, 17 were still receiving the treatment per protocol, and 13 
had completed treatment, including 6 with no relapse during the treatment period, 4 with no 
relapse at the 6-month follow-up, and 3 with no relapse at the 12-month follow-up (end of study). 
 
While the standard dose of linezolid for short term use for severe bacterial infections is 600 mg 
bid, some clinicians and clinical trials using linezolid as Group 5 therapy to treat TB use only 300 
mg or 600 mg daily due to concerns about toxicity developing when used over a period of months 
(see below for a review of linezolid toxicity). (9)  However, there are no data to indicate what dose 
of linezolid is required or optimal to effectively treat TB infection. Consequently, TB Alliance has 
recently conducted and completed an Early Bactericidal Activity trial to evaluate the use of 
linezolid over 14 days in patients with newly diagnosed DS Pulmonary TB in dosing schedules 
including 300 mg daily, 300 mg bid, 600 mg daily, 600 mg bid, 1200 mg daily, and HRZE at 
standard doses daily. Preliminary unpublished in-house results using Bayesian mixed effects 
modelling have noted that there is a bactericidal effect of linezolid over 14 days that is substantial, 
but less than for the full HRZE regimen. There is little difference between daily or twice daily 
dosing of the same total daily dose of drug, and there is a dose-response relationship between 
total daily dose and daily reductions in either total CFU counts on solid culture or increases in 
Time to Positivity in liquid culture (a decreased load of MTB is associated with an increase in Time 
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to Positivity). Point estimates of the log of the daily increase in Time to Positivity over 14 days 
ranged from 2.278 for Linezolid 300 mg QD to 4.446 for linezolid 1200 mg QD, with the estimate 
of 6.860 for HRZE for reference. 
 
Figure 3: 
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin 
CL-001 
 
Bayesian Nonlinear Mixed Effects Regression Model: Posterior Estimates and 95% 
Bayesian Confidence Intervals 
 
 
 
HRZE = isoniazid, rifampin, pyrazinamide, and ethambutol 
 
2.2.3.1 Linezolid Clinical Safety 
Linezolid is currently marketed globally for a variety of acute infectious diseases and has been 
studied for the treatment of XDR-TB in several recent trials.(3,9)  The following list of known and 
potential risks is based on the warnings and precautions and adverse reactions sections of the 
current package label.(23,24,26) Of note, the approved indication for linezolid is for administration 
up to 28 days. 
 
Warnings and Precautions 
 
• 
Linezolid should not be used in patients taking any medicinal product which inhibits 
monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking 
any such product. 
 
• 
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) 
has been reported in patients receiving linezolid. In cases where the outcome is known, 
when linezolid was discontinued, the affected hematologic parameters have risen toward 
pretreatment levels. Complete blood counts should be monitored weekly in patients who 
receive linezolid, particularly in those who receive linezolid for longer than two weeks, 
those with pre-existing myelosuppression, those receiving concomitant drugs that produce 
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bone marrow suppression or those with a chronic infection who have received previous or 
concomitant antibiotic therapy. 
•
Lactic acidosis has been reported with the use of linezolid. In reported cases, patients 
experienced repeated episodes of nausea and vomiting. Patients who develop recurrent 
nausea or vomiting, unexplained acidosis, or low bicarbonate level while receiving 
linezolid should receive immediate medical evaluation.
•
Spontaneous reports of serotonin syndrome associated with the co-administration of 
linezolid and serotonergic agents, including antidepressants such as selective serotonin 
reuptake inhibitors (SSRIs), have been reported. Where administration of linezolid and 
concomitant serotonergic agents is  clinically appropriate, patients  should be closely 
observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, 
hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians 
should consider discontinuation of either one or both agents. If the concomitant 
serotonergic agent is withdrawn, discontinuation symptoms can be observed (see 
package insert of the specified agent(s) for a description of the associated 
discontinuation symptoms).
•
Peripheral and optic neuropathy has been reported in patients treated with linezolid, 
primarily those patients treated for longer than the maximum recommended duration of 28 
days. In cases of optic neuropathy that progressed to loss of vision, patients were treated 
for extended periods beyond the maximum recommended duration. Visual blurring has 
been reported in some patients treated with linezolid for less than 28 days. If patients 
experience symptoms of visual impairment, such as changes in visual acuity, changes in 
color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is 
recommended. Visual function should be monitored in all patients taking linezolid for 
extended periods and in all patients reporting new visual symptoms regardless of length 
of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of 
linezolid in these patients should be weighed against the potential risks. Additional 
information on the neuropathies reported in recent studies of linezolid administered over 
prolonged periods to patients with TB infection is presented above in Section 2.2.3.
•
Convulsions have been reported in patients when treated with linezolid. In some of these 
cases, a history of seizures or risk factors for seizures was reported.
•
Postmarketing cases of symptomatic hypoglycemia have been reported in patients with 
diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, 
a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with 
hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. 
While a causal relationship between linezolid and hypoglycemia has not been established, 
diabetic patients should be cautioned of potential hypoglycemic reactions when treated 
with linezolid. 
In addition, the linezolid product label notes that there was an excess of abnormal liver function 
tests in comparator-controlled trials. These abnormalities were noted in 0.4% of linezolid treated 
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patients in trials of skin and skin structure infections vs in 0.2% of clarithromycin treated patients, 
and in 1.6% of patients treated with linezolid versus 0.8% of patients with other treatments in trials 
of all other infections. 
 
Adverse events of linezolid long term therapy for Tuberculosis have been described in several 
literature reports. The most complete review is a meta-analysis by Cox which noted the proportion 
of adverse events necessitating treatment discontinuation was significantly different by dose: 
29.49% (95%CI 3.24–55.74) for ⩽600 mg daily vs. 60.75% (95%CI 42.69–78.81) for >600 mg 
daily (P = 0.05). (3) 
 
In a trial reported by Lee et al in S Korea(9), seven of 41 participants had myelosuppression, 
including anemia and neutropenia, primarily within the first 5 months, and only one participant 
withdrew due to anemia. Six had clinically significant myelosuppression:  5 in 0-4 months and 1 
in 4-8 months, with 0 in 8-12 months. 
 
Peripheral and Optic Neuropathy: 
 
The linezolid product label notes these adverse events have been “ reported in patients, primarily 
those patients treated for longer than the maximum recommended duration of 28 days. In cases 
of optic neuropathy that progressed to loss of vision, patients were treated for extended periods 
beyond the maximum recommended duration. Visual function should be monitored in all patients 
taking ZVYOX for extended periods (>3 months) and in all patients reporting new visual 
symptoms, regardless of length of therapy.(26) 
 
In Lee, NEJM, 2012(9), the publication’s Supplemental Table 3 notes that 21 patients had clinically 
significant peripheral neuropathy spread over 12 months: 5 in months 0-4, 10 in months 4-8 and 
5 in months 8-12 (time of onset not noted for one). Participants who developed any peripheral 
neuropathy had their dosing of linezolid interrupted, generally for several weeks, and then 
resumed at the lower dose of 300 mg/day (C. Barry, personal communication). None of the 
participants withdrew from the study based on peripheral neuropathies. At baseline, patients 
received visual acuity testing, contrast sensitivity and color vision tests. Seven cases were 
observed as having potential effects on vision; only two of 38 patients withdrew from study due to 
optic neuropathy. For clinically significant optic neuropathy, one had this at 0-4 months, 2 at 4-8 
months and 3 at months 8-12. Except for the 2 participants who withdrew from the study, the 
others resumed linezolid at the 300 mg dose after a hiatus of several weeks of treatment and 
completed the study with resolution of their visual acuity changes (C. Barry, personal 
communication). 
 
In the Schecter California Department of Health (DOH) review(32), peripheral neuropathy 
developed in 5 of 30 patients (no standardized monitoring), but only one withdrew from linezolid 
therapy. One patient developed visual loss secondary to optic neuropathy after 10 months of 
linezolid therapy, but vision returned to normal 3-4 weeks after discontinuation. 
 
In Park, 2006(27), two patients of eight in the case series developed optic neuropathy after 8-9 
month and had linezolid discontinued; these patients also had peripheral neuropathy. After 
linezolid treatment was stopped, the optic neuropathy fully resolved after 2-3 months.  A total of 
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4 patients developed peripheral neuropathy at 4, 5, 8, 11 months; in the patients with optic 
neuropathy who stopped treatment, the peripheral neuropathic symptoms continued or improved 
only marginally. 
 
In Singla, 2012(34), two of 29 patients treated with linezolid, 600 mg daily over 12 months, stopped 
the drug because of peripheral neuritis (one patient) and optic neuritis (one patient). The time 
course of these adverse events was not noted. 
 
2.3 Regimens to be Studied 
The regimen included in this study (B-Pa-L) has been selected based on the performance of the 
regimen in non-clinical pharmacology studies and on the combination of bedaquiline and 
pretomanid with other drugs in clinical studies NC-001 and NC-003. In addition, improved 
treatment outcomes in XDR patients with the addition of linezolid to existing therapy provide 
support for combining linezolid with other drugs that have no pre-existing resistance. Preliminary 
results from the ongoing Nix-TB clinical study demonstrate the encouraging potential of this 
regimen. 
 
This regimen has the potential to treat drug resistant strains of tuberculosis. This is an oral 
regimen, removing the need for injectables as part of drug resistant treatment, and is also 
projected to be markedly less expensive than current XDR-TB therapy. Treatment duration is 
anticipated to be shorter than current regimens for drug resistant TB, based on findings in mouse 
models of infection and the fact that all participants will be treated with three active drugs against 
TB for which there is no expected resistance. 
 
The key data supporting the use of the B-L-Pa regimen are described below. 
 
2.3.1 Non-Clinical Studies 
In the murine model of TB, addition of bedaquiline to HRZ results in accelerated clearance of MTB 
(5,36) when compared to HRZ alone. While the combination of bedaquiline and pretomanid in the 
murine model of TB in initial studies appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ(15) and in a subsequent study it was more 
active in the mouse model than HRZ.(16) Thus a novel regimen with bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance. 
 
Recent studies of the bactericidal and sterilising activity of linezolid in an animal model where 
mice were given high dose aerosol MTB infection have demonstrated that linezolid alone and in 
combination with bedaquiline and pretomanid causes marked reductions in lung CFUs from mice 
following 1 to 3 months of therapy (Table 4 below). Additionally, all mice treated daily with 
bedaquiline, pretomanid and linezolid (B-L-Pa) were cured of the infection after 3 months of 
therapy as evidenced by no MTB cultured from lungs when mice were sacrificed 3 months after 
the completion of therapy that lasted 3 months or more (Table 4, below). This is in contrast to the 
5-6 months required in previous studies to cure all mice when treated with the standard of care 
isoniazid, rifampicin and pyrazinamide (HRZ; note that typically ethambutol is not used in the 
mouse model of infection). Additional mouse studies were performed to determine whether 
shorter durations of linezolid, with continuation of the other drugs, would result in relapse-free 
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cure in the mouse (Table 4 below). Treatment with linezolid for only the first 4 to 8 weeks of a 
3-month treatment also resulted in relapse-free cure when lungs from the mice were cultured 
3 months after the completion of therapy.(37) 
 
Table 4:         Murine Relapse Data 
 
Impact of Linezolid Treatment Duration on Lung Colony Forming Unit Counts 
Assessed during Treatment and Proportion of Mice Relapsing after Treatment 
Completion 
Proportion of mice relapsing after treatment for: 
Regimen 
2 months 
3 months 
2RHZ/RH* 
8/14 
(57%) 
BPa 
3/14 
(21%) 
3BPaL ** 
6/15 
(40%) 
0/15#† 
(0%) 
2BPaL/1BPa*** 
0/15#† 
(0%) 
1BPaL/2BPa 
9/15 
(60%) 
0/15#† 
(0%) 
#p = 0.11 vs. BPa; †p≤ 0.001 vs. RHZ 
*2RHZ/RH means 2 months on the full regimen and a third month on only RH 
**3BPaL means 3 months on the full regimen 
***2BPaL/1BPa means 2 months on the full regimen and a third month on only BPa 
****1BPaL/2Bpa means 1 month on the full regimen and a third month on only BPa 
B – bedaquiline, H-isoniazid, L-linezolid, Pa-pretomanid, R-rifampicin, Z-pyrazinamide 
 
In conclusion, linezolid increases the  sterilising activity of the  bedaquiline-pretomanid 
combination; no MTB could be cultured from the lungs of mice 3 months after cessation of 3 
months of treatment with the combination, in contrast to MTB cultured from 13 of 15 mice treated 
with the standard 2RHZ/4RH regimen over 3 months. In addition, limiting the duration of linezolid 
to the first month of treatment does not affect linezolid’s contribution to the sterilising activity of 
the regimen in the preclinical mouse study. 
 
Prior to the use of pretomanid in combination with bedaquiline in clinical study NC-001, a 
preclinical cardiovascular safety pharmacology study was conducted in unrestrained beagle dogs 
with both drugs to explore the potential for additive effects on QT prolongation induced by the 
combination. Results indicate that administration of 100 mg/kg bedaquiline daily for 7 days 
causes a small increase in QTc interval by Day 6 in some animals that is not influenced by the 
addition of 100 mg/kg pretomanid on Day 7. The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the subcutaneous route of administration and not 
related to the plasma exposure. 
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2.3.2 Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or 
Linezolid 
2.3.2.1 Clinical Study NC-001 
Study NC-001 was a partially double-blind, randomized, parallel group study in adult male and 
female participants with newly diagnosed, uncomplicated, smear-positive, pulmonary TB. A total 
of 85 participants met study eligibility criteria and were randomly assigned to one of the six 
treatment groups. All study treatments were given once daily for 14 days. Substantial EBA activity 
was demonstrated across participants in all arms of the study and the daily reductions in cultured 
colony counts per mL of sputum are presented in Table 5 below. 
 
Table 5:         Summary Statistics for EBACFU(0-14) 
Derived Using Bi-Linear Regression, Study NC-001 
 
Treatment Group 
N 
Daily Mean (SD) 
EBACFU(0-14) 
Pretomanid + pyrazinamide + moxifloxacin 
13 
0.23 (0.128) 
Pretomanid + pyrazinamide 
14 
0.15 (0.040) 
Pretomanid + bedaquiline 
15a 
0.11 (0.050) 
Bedaquiline alone 
14 
0.07 (0.068) 
Bedaquiline + pyrazinamide 
15 
0.13 (0.102) 
Rifafour e-275 
10 
0.14 (0.094) 
 
There were no Serious Adverse Events from the study among participants treated with 
pretomanid and bedaquiline.  Three participants in a bedaquiline-containing treatment arm were 
withdrawn: one participant on the bedaquiline only arm for a Grade 3 ALT and Gamma-Glutamyl 
Transferase (GGT) elevation (although the elevation occurred prior to the first dose of study 
medication), one on a bedaquiline plus pyrazinamide (weight banded) arm for a Grade 3 ALT 
and AST elevation, and one on a pretomanid and bedaquiline arm for to a Grade 3 ALT 
elevation. 
 
2.3.2.2 Clinical Study NC-003 
Efficacy 
 
In the 14 day EBA study NC-003 two monotherapy and four different combinations of bedaquiline, 
pretomanid, pyrazinamide and clofazimine were evaluated in DS-TB participants. Fifteen 
participants were randomized into 7 treatment arms: C, Z, B-Pa-Z-C, B-Pa-Z, B-Pa-C, B-Z-C, and 
HRZE control. This study demonstrated no EBA for the clofazimine monotherapy arm and modest 
EBA for the pyrazinamide monotherapy arm. However, all of the experimental regimens 
demonstrated EBA. In general, adding clofazimine to the various agents resulted in either no 
increase in EBA, or a decrease when compared to a similar regimen that did not include 
clofazimine. In this study, the experimental regimen with the best EBA was B-Pa-Z which 
demonstrated a rate of decrease in both logCFU and logTTP that was at least as good as the HRZE 
control. The daily logCFU results are presented in Table 6. Similar results were found when TTP 
was used to calculate the bactericidal activity over 14 days (BA(0-14)). 
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Table 6: 
NC-003 Efficacy Results: Daily BAlogCFU(0-14) 
 
Arm 
logCFU 
BPaZC 
.124 
BPaZ 
.180 
BPaC 
.086 
BZC 
.098 
Z 
.036 
C 
-.025 
Rifafour 
.152 
Safety 
 
Generally, the regimens in this study were well tolerated. Table 7 provides a list of the overall 
safety findings. The only SAE experienced in the study was in a participant in the clofazimine 
monotherapy arm. Otherwise, the rates of treatment emergent AEs (TEAEs) were similar across 
the treatment arms. One participant in the B-Pa-Z arm was withdrawn from the study due an 
adverse event of increased liver function tests (alanine aminotransferase (ALT), AST and GGT). 
 
Table 7:         NC-003 Safety Data 
 
BPaZ 
C 
BPaZ 
BPa 
C 
BZC 
Z 
C 
HRZ 
E 
Total 
N 
15 
15 
15 
15 
15 
15 
15 
105 
Participants with: 
TEAEs 
11 
9 
8 
10 
10 
9 
8 
65 
TEAEs leading to death: 
Serious TEAEs 
1 
1 
TEAES leading to early withdrawal 
1 
1 
TEAEs leading to discontinuation 
of study drug 
1 
1 
Drug-related TEAES 
8 
5 
7 
3 
5 
6 
5 
39 
Serious, drug-related TEAEs 
Grade III AEs 
2 
1 
2 
1 
6 
Grade IV AEs 
1 
1 
2 
Grade II/IV AEs 
2 
1 
2 
1 
6 
 
 
QT Prolongation 
 
Because bedaquiline and clofazimine are both known to prolong the QT interval, intensive ECG 
monitoring was included in the study endpoints. The mean change from baseline in QTcB and 
QTcF tended to be larger at 5 hours than at 10 hours post-dose in the (B-Pa-Z-C) arm and in the 
(B-Pa-C) arm. No QTcB or QTcF ≥500 ms were reported. An increase from baseline to Visit 5 
and subsequent visits of ≥60 ms in QTcB was reported for 2 participants in the (B-Pa-C) arm and 
for 1 participant in the clofazimine alone arm. An increase from baseline to Visit 5 and subsequent 
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visits of ≥60 msec in QTcF was reported for 4 participants in the (B-Pa-C) arm and for 1 participant 
in the clofazimine alone arm. For both QTcB and QTcF, the (B-Pa-Z-C) arm and the (B-Pa-C) 
arm showed the largest increase from baseline. Clofazimine will not be used in any treatment 
arms in the NC-007 study. 
 
2.3.2.3   The Nix-TB Study 
The NiX-TB Study is an ongoing open-label study assessing the safety and efficacy of bedaquiline 
plus linezolid plus pretomanid in participants with pulmonary infection of either XDR-TB or 
treatment intolerant/non-responsive MDR-TB. The study regimen includes: bedaquiline 400 mg 
once daily for 2 weeks then 200 mg 3 times per week plus pretomanid 200 mg once daily plus 
linezolid 600 mg twice daily amended (22 Jan 2016 protocol) to 1200 mg once daily. Treatment 
duration is 6 months, although if participants are still culture positive at month 4, there is the option 
to extend treatment to 9 months or withdraw. The primary endpoint is the incidence of 
bacteriologic failure or relapse or clinical failure through follow-up until 6 months after the end of 
treatment. Secondary Endpoints include: incidence of bacteriologic failure or relapse or clinical 
failure through follow-up until 24 months after the end of treatment as a confirmatory analysis, 
time to sputum culture conversion to negative status through the treatment period, and the 
proportion of participants with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 
end of treatment. In addition, linezolid dosing (actual) and efficacy will be explored and changes 
from baseline will be evaluated for TB symptoms, Patient Reported Health Status, body weight, 
and measures of safety. 
 
Efficacy Experience to Date: 
 
Sixty-nine participants have been enrolled as of February 1, 2017, at 2 sites in South Africa. Forty- 
nine percent of the participants are HIV positive, 79% have XDR-TB and 21% have MDR 
intolerant or resistant to prior therapy. Forty have completed the 6 months of therapy with the 
drug regimen and 31 have been followed to the primary endpoint at 6 months after treatment. All 
surviving patients were culture negative by 4 months, with 74% negative at 8 wks. As of February 
1, 2017, there has been 1 microbiological relapse during follow up after drug therapy and 1 
participant has had a new infection during follow-up with Drug Sensitive TB. This study will 
continue to enrol participants until the NC-007 study is initiated. 
 
Safety of the B-Pa-L Regimen in the Nix-TB Study: As of December 2016, four participants have 
died in the study. The causes of death have varied and include: 2 with multi-organ disseminated 
TB who died within the first 5 weeks of therapy, 1 who had a gastrointestinal bleed and 1 with 
multi-organ failure and disseminated TB on autopsy. No deaths or SAEs have been caused by 
hepatic injury. No participants have been withdrawn from the study except for the 4 who died. 
The expected linezolid toxicities of peripheral neuropathy and myelosuppression were common 
but manageable. Seventy-one percent of participants had at least one linezolid dose pause (22% 
of all participants due to myelosuppression and 28% due to peripheral neuropathy), during the 6 
months of treatment. One had peak ALT and AST > 3 X ULN and total bili > 2X ULN, but these 
improved and treatment restarted without a recurrence. There were 7 cases of grade 3 or 4 
transaminitis and all resolved and allowed the study regimen to be continued. There were no 
cases  of  optic  neuritis.  While  participants  have  required  close  surveillance  for  signs  and 
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symptoms of neuropathies and bone marrow suppression, these toxicities have been 
manageable. 
 
2.4 Overall Benefit/Risk Assessment 
The recent report of the long term outcome of patients with XDR-TB treated in S. Africa highlighted 
the very poor prognosis for patients with this disease. After 60 months of follow up 73% of 107 
patients had died and only 11% had a favourable outcome(28). These patients have infection with 
MTB resistant to many/most of the available drugs to treat tuberculosis. Patients with XDR-TB 
have limited treatment options due to their resistance profile, and the drugs that are typically used 
in Standard of Care have many side effects, some are administered as injectables and have poor 
treatment outcomes in XDR-TB. Similarly, patients with Pre-XDR-TB and patients with MDR-TB 
who are failing or are intolerant to treatment have traditionally poor outcomes and are a challenge 
to treat. While treatment success for MDR-TB is better than for XDR-TB, overall success in 
treating MDR-TB is still approximately 50% according to the World Health Organization 2015 
Global TB Report.(43) and it would be lower for patients failing or not able to take an optimal 
traditional regimen. This trial provides an opportunity to treat these high-need patients with three 
active drugs, for which there is no or minimal pre-existing resistance, in a very closely controlled 
and monitored clinical trial setting with the opportunity to define the optimal dosing scheme for 
linezolid. Participants will be monitored closely and regular reviews of safety and efficacy will be 
made by the Data Safety Monitoring Committee (DSMC). Preliminary results of the ongoing Nix- 
TB trial from patients with XDR-TB and who are failing or intolerant to treatment of MDR-TB 
demonstrate that this regimen has the potential to give relapse-free cure of XDR-TB with a simple 
regimen in a much shorter period of time than currently required by the available drugs used in 
the best standard of care. Preclinical studies of this regimen in a murine model of infection 
demonstrated relapse free cure of MTB in half the time (3 vs 6 months) required by standard HRZ 
therapy. Clinical studies of linezolid alone and pretomanid and bedaquiline alone and in 
combination have demonstrated activity against TB infection. 
 
These three drugs have not been used in combination in humans prior to the Nix-TB trial, and 
thus their combined toxicity profile is emerging. The greatest risks of key concern for participants 
in this trial from linezolid are from the adverse events of myelosuppression and peripheral and 
optic neuropathy. Participants will be closely monitored with full blood counts, vision 
examinations, and screening for peripheral neuropathy. The investigator may interrupt dosing of 
either linezolid or linezolid with pretomanid and bedaquiline if adverse events of concern develop, 
and a resumption of the drugs, with linezolid at the same or at a lower dose, may be made 
cautiously. Participants will be under close surveillance for hepatotoxicity, as that risk for 
pretomanid and bedaquiline is not yet well characterized. 
 
Overall the benefit-risk balance justifies evaluating the B-Pa-L regimen in this study, with the 
cautious surveillance in place, to treat patients  with XDR-TB who have few options for  a 
successful outcome. 
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3 
Trial Objectives 
3.1 Primary Objectives 
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus 
bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary 
XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
 
4 
Trial Design 
4.1 Summary of Trial Design 
This is a Phase 3, multi-center, partially-blinded, randomized clinical trial conducted in 4 treatment 
groups. Participants, trial investigators and staff, including laboratory staff, will be blinded to dose 
and scheduled duration of linezolid.   Bedaquiline and pretomanid dosing will not be blinded. 
The trial will be performed at multiple centers located in South Africa, Eastern Europe and Russia. 
A total of 180 XDR-TB and Pre-XDR/MDR intolerant or non-responsive participants who meet all 
of the inclusion criteria and none of the exclusion criteria, aged 14 and over, will be randomized 
to receive one of the 4 active treatment arms. Participants will be randomized to one of the four 
regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will 
utilize a randomization system using stratification with a random element to allocate participants 
evenly across the arms by HIV status and type of TB after they have given written, informed 
consent and met all eligibility criteria. 
Each participant will receive 26 weeks of treatment. If participant’s sputum sample is culture 
positive between the week 16 and week 26 treatment visits and their clinical condition suggests 
they may have an ongoing TB infection, Investigator may consider extending current treatment 
to 39 weeks. If the culture results between week 16 and week 26 are contaminated, missing or 
considered an isolated positive without clinical significance, available culture results should be 
used to make this decision. All decisions regarding treatment extension should be discussed with 
and approved by the Sponsor Medical Monitor  before implementation. Participants will be 
followed for 78 weeks after end of treatment. 
 
4.2 Treatment Plan: Schedule of Assessments 
• 
Screening Period- Screening Visit up to 14 days prior to Treatment 
• 
Treatment Period- Day 1 to Week 26. Additional visits every 3 weeks until last dose when 
dosing extended due to pauses or positive culture at Week 16 
• 
Follow-up Period- 4 Week post end of treatment follow-up Visit to 78 Week post end of 
treatment follow-up Visit 
Refer to: 
• 
Trial Flow Chart (Section 1.2) for the timing of all procedures and laboratory 
samples to done at each visit. 
• 
Trial  Procedures  (Section  7)  for  details  regarding  specific  procedures  or 
laboratory tests. 
Participants will receive oral daily dosing. They will be randomized to one of the following arms: 
 
 
Table 8:         Treatment Groups 
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Treatment Group 
No of Participants 
1 
Linezolid 1200 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus; 
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non- 
responsive 
2 
Linezolid 1200 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus; 
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non- 
responsive 
3 
Linezolid 600 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus; 
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non- 
responsive 
4 
Linezolid 600 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus; 
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non- 
responsive 
 
Figure 4: 
Trial Schematic 
 
 
Participants will be randomized to 1 of the 4 groups listed above. 
N = 45 Participants per group for a total of 180. 30 XDR-TB participants per group 
* Treatment will be extended to 39 weeks for participants who have a positive culture at week 16 
 
 
5 
Trial Population 
Participants must meet all inclusion and no exclusion criteria within the screening period. Re- 
testing for laboratory or ECG parameters is allowed within the 14-day screening period. Sponsor 
may consider replacement of late screen failure and un-assessable (as detailed in the statistical 
analysis plan) participants. 
26 Weeks of Treatment* 
Weeks 1-9 
Weeks 10-26 
1 
1200 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Primary Endpoint 
follow-up for relapse- 
free cure 26 weeks 
after end of treatment 
Full follow up 78 
weeks after end of 
treatment 
2 
1200 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100mg QD week 9 
Pretomanid 200 mg QD 
1200 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
3 
600 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
4 
600 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
600 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD
Pretomanid 200 mg QD
Bedaquiline 100 mg QD
Pretomanid 200 mg QD
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5.1 Inclusion Criteria 
Participants are required to meet all of the following inclusion criteria during the screening period 
in order to be randomized. 
1. Provide written, informed consent prior to all trial-related procedures (including any 
additional consent required for participants considered as minors per applicable regulatory 
authority or ethics committee). 
2. Willingness and ability to attend scheduled follow-up visits and undergo study 
assessments. 
3. HIV testing (if an HIV test was performed within 1 month prior to screening, it should not 
be repeated as long as a documented result can be provided [ELISA and/or Western Blot 
and/or Electro-Chemiluminescence]. If HIV status is a confirmed known positive, repeated 
HIV test is not needed if ELISA and/or Western Blot and/or Electro-Chemiluminescence 
documentation of presence of HIV infection is available. 
4. Male or female, aged 14 years or older. 
Disease Characteristics: 
5. Participants with one of the following pulmonary TB conditions: 
a. 
XDR-TB with 
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
documented resistance to rifamycins, a fluoroquinolone AND an injectable 
during the current TB diagnosis/disease course any time prior to or during 
screening period (may be sensitive or resistant to isoniazid); 
b. 
Pre-XDR-TB with 
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based molecular test within 3 months prior to or at 
screening and; 
ii. 
documented resistance to rifamycins, and to a fluoroquinolone OR an 
injectable during the current TB diagnosis/disease course any time prior to 
or during screening period (may be sensitive or resistant to isoniazid); 
c. 
MDR-TB with 
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected results within 3 months prior to screening or 
MTB confirmed in sputum based on molecular test within 3 months prior to 
or at screening and; 
ii. 
documented 
resistance 
to 
rifamycins 
during 
the 
current 
TB 
diagnosis/disease course any time prior to or during screening period (may 
be sensitive or resistant to isoniazid) and; 
iii. 
with documented non-response to treatment with the best available regimen 
for 6 months or more prior to enrolment who in the opinion of the Investigator 
have been adherent to treatment and will be adherent to study regimen. 
d. 
MDR-TB with 
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected within 3 months prior to screening or MTB 
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confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
documented 
resistance 
to 
rifamycins 
during 
the 
current 
TB 
diagnosis/disease course any time prior to or during screening period (may 
be sensitive or resistant to isoniazid) and; 
iii. 
who are unable to continue second line drug regimen due to a documented 
intolerance to: 
a. PAS, ethionamide, aminoglycosides or fluoroquinolones or ; 
b. Current treatment not listed above that renders participant eligible for 
the study in the Investigator’s opinion. 
6. Chest X-Ray within 6 months prior to or at screening, obtained and read locally by 
investigator or designee with results consistent with pulmonary TB in the opinion of the 
Investigator. 
 
Contraception: 
7. Be of non-childbearing potential or using effective methods of birth control, as defined 
below: 
 
Non-childbearing potential: 
a. Participant - not heterosexually active or practices sexual abstinence; or 
b. Female participant or male participant’s female sexual partner - bilateral 
oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months; 
or 
c. Male participant or female participant’s male sexual partner - vasectomised or 
has had a bilateral orchidectomy at least three months prior to screening. 
 
Effective birth control methods: 
a. Double barrier method which can include a male condom, diaphragm, cervical cap, 
or female condom; or 
b. Female participant: Barrier method combined with hormone-based contraceptives 
or an intra-uterine device for the female participant; 
c. Male participant’s female sexual partner: Double barrier method or hormone based 
contraceptives or an intra-uterine device for the female partner. 
 
And are willing to continue practicing birth control methods throughout treatment and for 6 
months (female participants) and 12 weeks (male participants) after the last dose of study 
medication. 
 
 
 
5.2 Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria during 
the screening period: 
Note: Hormone based contraception alone may not be reliable when taking IMP; 
therefore, hormone-based contraceptives alone cannot be used by female participants 
to prevent pregnancy. 
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Medical History and Concurrent Conditions 
1. Any condition in the Investigator’s opinion (i.e., an unstable disease such as 
uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended 
treatment, cancer that could affect survival through the protocol-specified follow up 
period), where participation in the trial would compromise the well-being of participant 
or prevent, limit or confound protocol specified assessments. 
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol- 
specified restrictions, visits and evaluations. 
3. In the judgment of the Investigator, the participant is not expected to survive for more 
than 6 months. 
4. Karnofsky score < 60 at screening. 
5. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal 
Products or related substances. 
6. Body mass index (BMI) < 17 kg/m2 
7. TB infection with historic DST or MIC results with values suggesting likely resistance 
to pretomanid, delamanid, linezolid or bedaquiline; the Sponsor Medical Monitor must 
be consulted to help interpret any available historic results. 
8. Participants who, upon the evaluation of their pulmonary disease, are expected to 
require a surgical procedure. 
9. Having participated in other clinical studies with dosing of investigational agents within 
8 weeks prior to screening or currently enrolled in an investigational study that includes 
treatment with medicinal agents. Participants who are participating in observational 
studies or who are in a follow up period of a trial that included drug therapy may be 
considered for inclusion. 
10. Participants with any of the following at Screening: 
• 
QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be 
discussed with and approved by the Sponsor Medical Monitor before enrolment. 
(Per measurements and reading done from screening central ECG.) 
• 
Heart failure 
• 
A personal or family history of congenital QT prolongation 
• 
A history of or known, untreated, ongoing hypothyroidism 
• 
A history of or ongoing bradyarrhythmia 
• 
A history of Torsade de Pointe 
11. Females who have a positive pregnancy test at Screening or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the study or within 6 
months of cessation of treatment. Males planning to conceive a child during the study 
or within 6 months of cessation of treatment. 
12. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, 
participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the 
course of the study, in the opinion of the Investigator. 
 
Previous and Concomitant Therapy 
13. Known (during screening) requirement for future Concomitant (during treatment) use 
of any prohibited and/or avoided medications noted in section 5.3. 
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14. Prior use of Monoamine Oxidase Inhibitors (MAOIs) within 2 weeks of randomization. 
15. Prior use of serotonergic antidepressants within 3 days of randomization if Investigator 
foresees potential risks for serotonin syndrome when combined with linezolid. 
16. Participants who have received more than 2 weeks of bedaquiline, linezolid or 
delamanid prior to first dose of IMP. 
17. Participants with newly diagnosed tuberculosis and HIV that require initiation of 
appropriate HIV therapy before participant has received at least 2 weeks of an anti- 
tuberculosis regimen. 
18. HIV infected participants with planned continued use of zidovudine, stavudine or 
didanosine. The antiretroviral therapy (ART) booster cobicistat should not be used. 
Please reference restrictions Section 5.3.3 Antiretroviral Therapy, for guidance on 
ART treatment during the treatment period. 
 
Diagnostic and Laboratory Abnormalities 
 
19. Participants with any of the following toxicities at Screening (labs may be repeated 
during screening period) as defined by the enhanced Division of Microbiology and 
Infectious Disease (DMID) adult toxicity table (November 2007): 
 
a. Viral load >1000 copies/mL (Unless newly diagnosed HIV and not yet on ART who 
otherwise qualify for participation); 
b. CD4+ count < 100 cells/µL (HIV positive participants); 
c. Serum potassium less than the lower limit of normal for the laboratory; 
d. Hemoglobin < 9.0 g/dL or < 90 g/L; 
e.  Platelets <100,000/mm3 or < 100 x 10^9/L; 
f. Absolute neutrophil count (ANC) < 1500/ mm3 or < 1.5 x 10^9/L; 
g. Aspartate aminotransferase (AST) 
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor Medical Monitor 
h. Alanine aminotransferase 
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor medical monitor; 
i. 
Total bilirubin 
• 
greater than 1.5 x ULN to be excluded; 
• 
1-1.5 x ULN must be discussed with and approved by the Sponsor Medical 
Monitor 
j. 
Direct bilirubin 
• 
Greater than ULN to be excluded 
k. Serum creatinine level greater than 1.5 times upper limit of normal 
l. 
Albumin <3.0 g/dl or < 30 g/L 
 
All inclusion and no exclusion criteria must be met. If no single variable/value is outside of the 
ranges of acceptability, but when multiple values are close to the limits and/or whenever the 
Investigator has reason to suspect that there might be a health problem (other than TB), enrolment 
should only be considered after discussing the case with the Sponsor Medical Monitor. 
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5.3 Restrictions 
5.3.1 Prior and Concomitant Medications and Other Treatments 
Concomitant medications should be kept to a minimum during the treatment period of the trial. 
However, if concomitant medications are necessary for the participant’s welfare and are unlikely 
to interfere with the IMP, they may be given at the discretion of the Investigator. For any 
concomitant medications given as a treatment for a new condition or a worsening of an existing 
condition occurring after signing of the Informed Consent Form, the condition must be 
documented on the Adverse Event pages of the electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be consulted and reviewed 
carefully. The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected to prevent any potentially serious and/or  life-threatening drug 
interactions. 
The following concomitant medications are prohibited during the treatment period and during the 
14 days after treatment completion: 
• 
Medicinal products used to treat pulmonary TB: including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and metronidazole. 
• 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). (e.g., phenelzine, 
isocarboxazid) 
The following concomitant medications should be avoided during the treatment period and during 
the 14 days after treatment completion to avoid possible drug interactions with the IMP. Use of 
any of the following must be discussed and approved by the Sponsor Medical Monitor prior to 
use: 
• 
Concomitant use of any drug known to prolong QTc interval (including but not limited to 
amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, 
clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, 
pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine). 
• 
Treatment with fluoroquinolones (as they are known prolong QTc), are strongly 
discouraged in the trial. They should only be used to treat intercurrent non-TB infections 
and if the benefit of treatment outweighs the risk of prolonged QTc. 
• 
Concomitant use of any drug known to induce significant myelosuppression 
• 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: ketoconazole, 
voriconazole, itraconazole, fluconazole; ketolids such as telithromycin; and macrolide 
antibiotics other than azithromycin) for more than 3 consecutive days; 
• 
The systemic use of CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, 
St. John’s wort, rifamycins and systemic dexamethasone. 
• 
Concomitant use of serotonergic antidepressants should be avoided if possible as 
participants on these agents and linezolid are at risk for serotonin syndrome. 
No protocol waivers will be granted by the TB Alliance. 
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• 
Caution should be used in treating diabetic patients receiving insulin or oral hypoglycemic 
agents as cases have been reported of hypoglycemic reactions when patients on these 
agents have been treated with linezolid. 
The following concomitant medications which are known to be hepatotoxic should be avoided as 
much as possible during screening and throughout the treatment period. If there are concerns 
about the co-administration of  hepatoxic drugs, discussion with the Sponsor Medical Monitor is 
encouraged (including but not limited to acetaminophen/paracetamol,  acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, augmentin/co- 
amoxiclav, azathioprine, baclofen, bumetanide, captopril, carbamazepine, celecoxib, 
chlorpromazine, chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-trimoxazole, 
darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, fosamprenavir, 
furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, 
loperamide, losartan, methotrexate, metolazone, mirtazepine, nitrofurantoin, omeprazole, other 
non-steroidal anti-inflammatory drugs, paroxetine, phenobarbital, phenothiazines, phenytoin, 
pravastatin, probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, simeprevir, 
simvastatin, sodium valproate, sotalol, sulfasalazine, sumatriptan, tamsulosin, terbinafine, 
tetracycline, theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, topiramate, trazodone, 
tricyclic antidepressants, trimethoprim, verapamil). 
5.3.2 Recommendations for Concomitant use of Anti-Malarials 
The following treatments for malaria are recommended for concomitant use with the IMP, should 
it be necessary: 
• 
Proguanil/atovaquone or 
• 
Artesunate plus sulfadoxine-pyrimethamine 
 
These recommendations are based on the potential for QT prolongation by bedaquiline and many 
anti-malarials. Due to the extended half-life of bedaquiline commencing anti-malarial treatment 
containing drugs that could prolong the QT interval, shortly after discontinuing bedaquiline, is not 
recommended. 
5.3.3 Antiretroviral Therapy 
For HIV infected participants, to avoid potentiating known key toxicities of linezolid (neuropathy 
and myelosuppression), the following antiretroviral therapies should not be used during the 
treatment period: zidovudine, stavudine, didanosine. 
The ART booster cobicistat should not be used. 
Only the following types of antiretroviral therapy (ART) are permissible during administration of 
regimens: 
• 
Nevirapine based regimen consisting of NVP in combination with any two NRTIs TDF/ABC 
and FTC/3TC. 
• 
Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any 
two NRTIs TDF/ABC and FTC/3TC. 
• 
Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC. 
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• 
In patients who have viral load suppressed on efavirenz at the time of screening, their 
ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. If possible, 
the same nucleoside backbone should be used. 
 
The investigator must assess the risks and benefits of these antiretroviral regimens in the 
context of co-infection with TB acknowledging the following caveats: 
• 
Triple NRTI is generally not considered optimal chronic ART; 
• 
Nevirapine based regimens are associated with higher ART failure in participants having 
or known to have previously had a viral load more than or equal to 100,000/ mL. 
5.3.4 Other Restrictions 
Large quantities of foods or beverages with high tyramine content should be avoided while taking 
linezolid. Quantities of tyramine consumed should be less than 100mg per meal. Foods high in 
tyramine content include those that may have undergone protein changes by aging, fermentation, 
pickling, or smoking to improve flavour, such as aged cheeses (0 to 15 mg tyramine per ounce); 
fermented or air-dried meats (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 
ounces); soy sauce (5mg tyramine per 1 teaspoon). The tyramine content of any protein-rich food 
may be increased if stored for long periods or improperly refrigerated. 
Alcohol should be avoided while on IMP, especially in participants with impaired hepatic function. 
5.4 Trial Discontinuation and Visits 
5.4.1 Treatment Discontinuation and Early Withdrawal 
A participant must be withdrawn from the trial due to the following; 
• 
Pregnancy (unless female post visit for end of treatment/early withdrawal from treatment); 
• 
Investigator considers it for safety reasons in the best interest of the participant that he/she 
be discontinued, including a concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB treatment. 
• 
At the specific request of the Sponsor or termination of the trial by Sponsor; 
• 
Lost to follow-up 
• 
In the opinion of the investigator, fails to comply with the protocol, including non- 
compliance to IMP. 
Participants may be withdrawn from the trial based on the following. The specific situation should 
be discussed with the Medical Monitor before withdrawing the patient. 
o Myco testing results from baseline (Screening through Week 4) indicate sensitivity 
to rifamycins; 
o Myco testing results from baseline (Screening through Week 4) with MICs that 
indicate likely resistance to bedaquiline, pretomanid or linezolid; 
All participants who discontinue trial treatment (but have not withdrawn consent) and received at 
least one dose of IMP will be requested to return for an early withdrawal visit and applicable safety 
Follow Up visits, as per flow chart (Section 1.2). 
A participant may discontinue from the trial at any time at his/her request (withdrawal of 
consent) or may be withdrawn at any time at the discretion of the investigator for safety, 
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behavioral compliance or administrative issues. When a participant withdraws consent from the 
trial, no additional follow-up visits will be performed. 
5.4.2 Early Withdrawal Follow-up 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made to 
complete the Early Withdrawal assessments. 
Once a participant has been withdrawn early from the trial, they will be requested to attend follow- 
up visits as described in Table 9: 
Table 9: Follow-up Visits Required for Early Withdrawal Participants 
 
Treatment 
Duration at 
EW visit 
Ophthalmology 
Examination at 
EWa 
Ophthalmology 
Examination 
12 week Post 
treatment follow- 
up visita 
26 Week 
Post 
Treatment 
Follow-up 
Visit 
78 Week Post 
Treatment 
Follow-up 
Visit 
≤ 14 days 
NA 
NA 
NA 
NA 
15 days to 
≤ 12 weeks 
NA 
Required 
Required 
Required 
> 12 weeks 
Required 
Required 
Required, if not 
already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 12 weeks after the 
EWD visit date. 
The 26 and 78 week post treatment follow-up visits will be performed to collect SAE information 
(including verification of survival) and participant reported TB outcome information. This visit may 
be telephonic, a home or a site visit. 
5.4.3 Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures, should be considered unscheduled regardless of the reason for the visit. The 
assessments which are undertaken as part of an Unscheduled visit should be as clinically 
indicated. 
The following situation/s require an unscheduled visit/s: 
• 
If cultures of both spot sputum samples are contaminated at the following visits, or if 
necessary, in order to help define a participant’s outcome status/assess culture status 
during follow-up, the participant should return for an unscheduled visit(s) to give additional 
samples or to document the participant is not able to produce sputum: 
 
• 
End of treatment visit 
• 
Week 26 post treatment follow-up visit 
• 
Post treatment follow-up visits from week 8 through week 65 (in addition to week 26 
follow-up) 
• 
End of Follow-up Period (week 78 post treatment completion visit) 
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• 
Early Withdrawal (if applicable). 
 
• 
At the end of 26 weeks and 78 weeks post treatment completion, to define outcome status, 
and to determine whether the participant has: 
• 
At least two sequential negative sputum culture results; or 
• 
At least two sequential positive sputum culture results; or 
• 
Has been unable to produce sputum after documentation of at least two negative 
sputum cultures with no intervening positive and are clinically asymptomatic. 
 
If they do not fall into one of the above categories, site should continue to collect sputum samples 
x 2 (one early morning and one spot at the research site or 2 spots samples at least 30 minutes 
apart, under the coaching and observation of the trial staff) at a minimum of 7 days or more apart 
until they fall into one of the above categories. 
 
5.4.4    Lost to Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants. A 
minimum of three contact attempts (telephonic/home visit) will be made for participants who do 
not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant will be 
considered LTFU. All attempts to contact the participant must be clearly documented in the 
participant’s source documents. 
5.4.5  Early Withdrawal due to TB 
Ultimately it is the investigator’s decision whether a participant should discontinue treatment due 
to a concern that the participant has symptomatic worsening TB and/or bacteriological 
failure/relapse. 
Discontinuation is usually not indicated by a single positive culture. Should a participant have a 
single positive culture result after being negative, the investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether it 
is in the participant’s best interest that he/she be discontinued. Prior to discontinuation of a 
participant due to TB, the investigator must discuss the participant with the Sponsor Medical 
Monitor, unless the investigator cannot contact the Sponsor Medical Monitor and considers that 
discontinuation must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the Investigator decides to discontinue trial treatment for a participant due to TB, additional 
sputum samples may need to be collected in order to ensure the participant’s outcome status may 
be determined, details noted in trial flowchart (Section 1.2). 
All Early Withdrawal participants who are confirmed sputum positive (at least two sequential 
sputum positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to specialists  who treat XDR-TB, pre-XDR TB or MDR-TB as 
applicable. 
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5.5 Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who is not randomized 
Completed 
Treatment / 
Completed FU* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued FU 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
FU** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
*   Note that this includes treatment failures who complete all applicable follow-up visits 
** Early Withdrawal 
5.6 Trial Stopping Rules 
There are no trial specific stopping rules. 
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data. In addition, the Sponsor 
has the right to stop the trial or a specific Investigational Site at any time, although this should 
only occur after consultation between involved parties. Should this occur, the local and central 
Ethics Committee/Institutional review Board (EC/IRB) and Regulatory Authorities will be informed. 
Should the Trial/Investigational Site be closed prematurely, all trial materials (except 
documentation that has to remain stored at the Investigational Site) will be returned to the Sponsor 
or vendor. The Investigator will retain all other documents until notification given by the Sponsor 
for destruction. Participants currently on treatment will receive an appropriate regimen and all 
participants will be referred to a unit specializing in the treatment of XDR-TB, Pre-XDR-TB or 
MDR-TB as applicable. 
 
6 
Treatment 
6.1 IMP Administration 
Treatment will be administered orally, once daily, with a full glass of water and a meal in the 
dosing schemes (treatment arms) outlined in Table 9. The study drug regimen should be 
initiated as specified below regardless of whether participant has received any of the allowed 
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prior exposure of bedaquiline or linezolid (up to 14 days), including a loading dose of 
bedaquiline. The Pharmacy Manual should be referenced for further details. 
Table 10: 
Investigational Medicinal Product Details 
 
Treatment Group 
Active and Placebo 
Linezolid 1200 mg 
daily for 26 weeks 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus; 
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 2 linezolid 600 mg active tablets once daily for 26 weeks 
• 1/2 (one half) placebo linezolid tablet once daily for 26 weeks 
Linezolid 1200 mg 
daily for 9 weeks 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus; 
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9 
• 2 linezolid 600 mg active tablets once daily for 9 weeks 
• ½ (one half) placebo linezolid  tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid tablets once daily for 17 weeks 
• ½ (one half) placebo linezolid tablet once daily for 17 weeks 
Linezolid 600 mg 
daily for 26 weeks 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus; 
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 1 linezolid 600 mg active tablet once daily for 26 weeks 
• 1 placebo linezolid tablet once daily for 26 weeks 
• ½ (one half) placebo linezolid tablet once daily for 26 weeks 
Linezolid 600 mg 
daily for 9 weeks 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus; 
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9 
• 1 linezolid 600 mg active tablet once daily for 9 weeks 
• 1 placebo linezolid tablet for 9 weeks 
• ½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolidtablets once daily for 17 weeks 
• ½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
6.2 Participant Compliance 
During site clinic visits or hospitalization, the IMP will be administered by the 
Investigator/designated site personnel. During the study, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully trained on how IMP is to be taken. When 
possible, participants will be checked for IMP compliance by the Investigators or trial 
personnel/National TB Treatment Program personnel via the hand-and-mouth procedure (both 
the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP). Additionally, participant cards/bottles will be checked for unused tablets at 
each visit during the treatment period 
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6.3 Treatment Modification(s) 
All treatment modifications should be discussed with the Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required urgently for a safety concern; the 
Medical Monitor should be informed within 24 hours of the change if not discussed prior to 
implementation. 
In the event of linezolid specific toxicities, the following should be considered and implemented 
per guidance in the monitoring and safety for specific toxicities section of protocol (8.3): 
 
• 
Blinded one step reductions (maximum 2 steps) in the dose of linezolid managed by the 
IXRS as per instructions in pharmacy manual and/or IXRS user manual 
o 1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or; 
o 600 mg QD to 300 mg QD, 300mg QD to placebo). 
• 
Temporary pause of linezolid 
• 
Permanent discontinuation of linezolid. 
• 
Participants who have a linezolid reduction can go back to a higher dose (1 step or 2 
steps) post discussion with and approval by the Sponsor Medical Monitor. 
Participants experiencing suspected drug related toxicities due to other drugs in the regimen (B- 
Pa), the full regimen may be halted for up to 35 consecutive days. 
Interruptions/pauses of the full regimen must not exceed 8 weeks (56 days) cumulatively. 
If participant’s sample is culture positive between the week 16 and week 26 treatment visits and 
their clinical condition suggests they may have an ongoing TB infection, Investigator may consider 
the option to extend the treatment to which the participant is randomized to 39 weeks. If the 
culture results between week 16 and week 26 are contaminated, missing or considered an 
isolated positive without clinical significance, available culture results should be used to make this 
decision. All decisions regarding treatment extension should be discussed with and approved by 
the Sponsor Medical Monitor before implementation. 
When treatment extended to 39 weeks, pauses of the full regimen must not exceed 13 weeks (91 
days) cumulatively. 
When the total of missed dosing days of the prescribed regimen and/or pauses is greater than 7 
days, the same number of missed doses should be dispensed/treatment extended to make up for 
the total missed doses. 
At no time should the participant be treated with a single agent. 
Every effort should be made for participants to receive a total of at least 9 weeks of linezolid, even 
if pauses are required. 
6.4 IMP Packaging and Labelling 
The complete formulations of the IMP bedaquiline and pretomanid are found in the respective 
Investigator Brochures(5,6). The complete formulations of linezolid are found in the Package 
Inserts(23,24,26). 
The IMP will be packaged as follows: 
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• 
Bedaquiline: Bottles containing: 
o 200 mg QD dose- 28 tablets- bedaquiline 100 mg 
o 100mg QD dose- 14 tablets- bedaquiline 100 mg 
• 
Pretomanid: Blister card containing 14 tablets- pretomanid 200 mg 
• 
Linezolid: Blister Card containing 7 days of dosing as follows: 
o 1200 mg QD Dose 
 
2 blister strips of 7 tablets each (14 tablets) containing active linezolid 600 
mg 
 
1 blister strip of 7 half tablets containing placebo linezolid 
o 600 mg QD Dose: 
 
1 blister strip of 7 tablets containing active linezolid 600 mg 
 
1 blister strip of 7 tablets containing placebo linezolid 
 
1 blister strip of 7 half tablets containing placebo linezolid 
o 300 mg Dose (for reductions): 
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid 
 
1 blister strip of 7 half tablets containing active linezolid 300 mg 
o Placebo Linezolid Dose: 
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid 
 
1 blister strip of 7 half tablets containing placebo linezolid 
 
 
The packaging of each bottle/blister card will be labelled with, at a minimum, the following 
information: 
• 
Name of Sponsor. 
• 
Name of medication. 
• 
Dosage,   quantity   and   method   of   administration   for   bedaquiline   and 
pretomanid. 
• 
Potential dosage, quantity and method of administration for linezolid. 
• 
Reference/Lot Number. 
• 
The statement “For Clinical Trial Use Only”. 
• 
Space for completion of Name of Investigator and Site Number. 
• 
MedID: medication identification number 
• 
Storage conditions. 
• 
Period of Use. 
• 
The statement “Keep out of reach of children”. 
• 
Expiry Date. 
• 
Directions for use. 
• 
Space for completion of participant number and visit/date dispensed. 
6.5 Method of Treatment Assignment 
Participants will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
web/voice response system (IXRS) which will utilize a randomization system using stratification 
with a random element to allocate participants evenly across the arms by HIV status and type of 
TB. Information & directions will be provided to each site via the IXRS user manual. 
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6.6 Blinding and Procedures for Breaking the Blind 
The blind must not be broken except in the case of a medical emergency, where treatment of the 
participant is influenced by the knowledge of what dose and duration of linezolid the participant is 
receiving. The investigator should discuss breaking the blind with the Sponsor Medical Monitor 
(or designee) prior to breaking the blind unless knowledge of treatment arm is required urgently 
for a safety concern. The Sponsor Medical Monitor should be informed of the blind break within 
24 hours if not discussed prior. IXRS will be programmed with blind-breaking instructions, 
described in the user manual. The Sponsor reserves the right to break the blind to fulfil any 
regulatory requirements regarding reporting of SAEs. If a participant is unblinded, they are not 
required to be withdrawn from the study. 
In the absence of any medical emergencies requiring a blind break, the blind for all participants 
will be broken once all clinical data and outcome parameters have been captured, no more data 
queries are pending and the statistical analysis plan has been finalized. 
6.7 Handling, Storage and Accountability 
The investigator or designee must confirm appropriate temperature conditions as per details on 
IMP labelling, have been maintained during transit for all trial treatment received and any 
discrepancies are reported and resolved before use of the trial treatment. 
Only participants enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Upon completion or termination of the trial, all unused 
and/or partially used IMPs must either be returned to Sponsor (or designated vendor) who will 
arrange for destruction or destroyed at site as agreed by Sponsor after final accountability has 
been confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising with 
respect to the trial medication. The Sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
 
7 
Trial Variables and Procedures 
The trial flowchart in Section (1.2) should be referenced for timing and sequence of 
assessments. 
7.1 Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written informed consent. 
• 
Visit dates 
• 
Participant disposition 
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• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and treatment history (including past and current TB 
diagnosis, alcohol use and smoking) 
• 
Screening coached spot sputum samples: 
o Smear microscopy for acid-fast bacilli. 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB 
complex and rifamycin resistance. 
• 
Urine pregnancy test: women of child-bearing potential only, whether they are 
sexually active or not. 
• 
Serology: HIV,CD4 count and viral load. 
o If an HIV test was performed within 1 month prior to trial start, it should not be 
repeated as long as documentation of results can be provided (ELISA and/or 
Western Blot and/or Electro-Chemiluminescence). 
o Where required by regulatory authorities or ethics committees: 
 
Separate approval for this to be performed will be obtained from 
participants in the written informed consent process. 
o prior to HIV testing and on receipt of the results, participants will be 
counselled on HIV by trained counsellors if they have indicated as such on 
the HIV consent form. If requested by the participant, HIV counselling 
provided to the participant by the study site should be clearly documented in 
the participant’s medical records/source.  Participants have the right to 
decline to know or receive their HIV test results. This decision should be 
clearly documented in the participant’s medical records/source. 
• 
Karnofsky score (Appendix 4). 
• 
Chest X-Ray: A Chest X-Ray digital image will be obtained and read locally by the 
Investigator or designee.  Digital images will be provided to the Sponsor; this process 
will be documented in the Radiology Manual.  The Investigator is responsible for 
review and analysis for participant inclusion. 
• 
Method of birth control: male and female participants and their partners. 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
7.2 Efficacy Variables and Procedures 
Two spot sputum samples are collected, one early morning brought from home or collected in the 
hospital ward and one spot collected at the research site under the coaching and observation of 
the trial staff or, if no early morning sample was provided, 2 samples collected on site at least 30 
minutes apart. The Mycobacteriology sampling methodology and requirements will be described 
in a separate document, the Laboratory Manual, which will be provided prior to the trial start. 
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the time to 
positivity (TTP) followed by a speciation test when applicable, to confirm MTB. 
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Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse; 
• 
Time to Sputum Culture Conversion; 
• 
Number of participants with Sputum Culture Conversion. 
Every effort is to be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favorable) result. A participant 
who never achieves culture negative status due to inability to produce sputum, but has completed 
26 week /78 week post treatment completion follow-up and is without clinical or biological 
evidence of relapse, will be considered to have a favorable outcome. 
TB Symptoms Profile: 
• 
The TB Symptoms Profile (found in the Subject Questionnaires Guideline) will record 
participants’ ratings of the severity of common TB symptoms. 
Patient Reported Health Status Variables and Procedures: 
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the trial flow chart. Patient Reported Health Status will be collected using the EQ-5D-5L 
Health Questionnaire (found in the Subject Questionnaires Guideline). This descriptive 
system consists of five health-related quality of life dimensions, each of which will be 
recorded using five levels of severity. Methodology: The Patient Reported Health Status 
methodology and requirements will be described in a separate document/guideline which 
will be provided prior to the trial start. 
 
7.3 Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
trial flow chart and assessed for evaluation of the safety endpoints: 
• 
Laboratory parameters. The Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, which will be provided prior to 
the trial start. The following analyses will be performed: 
o Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential, platelet count), 
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, 
calcium (corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2,  
creatine phosphokinase (CPK). 
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis. 
• 
12-lead Electrocardiogram (ECG): 
o Investigator assessment: normal, abnormal. 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected 
QT Interval (QTc) (QTcB and QTcF), QRS. 
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o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all 
participants and will be described in a separate document which will be 
provided prior to the trial start; 
 
Participants should be lying down (recumbent) for at least 5 minutes prior 
to each 12-lead ECG evaluation; 
 
ECGs are to be recorded for 10 seconds; 
 
All ECGs are to be performed in single. 
 
ECGs should be done before any labs when both included in a visit) 
 
For each participant, the ECGs should, to every extent possible, be 
collected at approximately the same time of day (+/- 1 hours) and in the 
same fed/fast state throughout the trial (e.g. 4 hours after lunch). 
• 
Vital signs: 
o Vital Signs, including weight (should be done before any labs) 
o Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 minutes of 
rest) using an appropriately sized cuff, and using the same type of sphygmomanometer, 
if possible by the same observer, at each relevant visit. 
o Heart rate (bpm). 
o Respiratory rate (breaths per minute) 
o Axillary body temperature (°C). 
• 
Physical examination: 
o Height is measured at screening only. 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and abdominal) 
examinations will be performed and any clinically significant findings will be recorded. 
o Weight (kg) (in light clothing and with no shoes). 
o Using the observed variables weight and height, calculated body mass index (BMI) will be 
derived. 
• 
Ophthalmology slit lamp examination. To be done by an Ophthalmologist trained on AREDS2 
assessment. The ophthalmology slit lamp methodology and requirements will be described in 
a separate document, the Ophthalmology Guideline. The following analyses will be 
performed: AREDS2 opacity typing and grading. 
• 
Ophthalmic examination. The ophthalmic examinations can be performed by any trained study 
staff. The screening exams must be done by the trained site study staff AND an 
Ophthalmologist. Methodology and requirements will be detailed in the Ophthalmology 
Guideline. 
• 
Ophthalmology History (Screening only); 
• 
Visual Acuity Test – Corrected. Distance Vision; 
• 
Color Vision Assessment. 
• 
Adverse events. 
• 
Brief peripheral neuropathy screen (found in the Subject Questionnaires Guideline) will record 
ratings. 
• 
Investigator assessment: 
Principal Investigator to review participant status at specified visits in flow chart including any 
time Investigator determines that participant fulfills criteria for primary outcome of treatment 
failure. Investigator to assess whether TB treatment is considered a “success” or “failure”. If 
considered a failure, should specify if based on bacteriology and/or clinical deterioration 
and/or radiological deterioration. 
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7.4 PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Synopsis Flowchart 1.2) will be used to update 
population PK models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this trial population. PK data from the 
current trial may be combined with prior data (e.g., from the NiX-TB trial) to enhance this 
population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ , Cmean, and T>MIC ) for subsequent analyses exploring relationships between 
drug exposure and efficacy and safety endpoints. 
 
7.5 Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between Screening through Week 4; 
• 
If consent granted, and when applicable, Pre-screening culture/isolate to be sub cultured 
and shipped and/or tested: 
o At the study lab if/when samples could support inclusion in the trial 
o To the study/central lab for relevant participants/with no baseline (positive cultures 
from screening through Week 4) 
• 
When applicable, 1st positive for MTB at/after week 16 for participant not responding to 
therapy and/or 1st positive during follow-up for potential new infection. 
 
The MTB isolates will be processed at the central lab(s) for: 
• 
MIC against bedaquiline, pretomanid and linezolid; 
• 
Drug Susceptibility Testing in liquid culture for rifampicin, isoniazid, streptomycin, 
ethambutol, pyrazinamide and second line TB drugs including but not limited to 
fluoroquinolones, and injectables; 
• 
Genotyping. 
 
The MTB isolates will be processed at the central lab(s) for: Positive MTB at/after end of 
treatment: Hain MTBDRplus and HainMTBRsl 
 
8 
Adverse Events 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe). 
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• 
Requires inpatient hospitalization or prolongation of existing hospitalization; In general, 
hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event. 
Note: Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalization, 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse. A “suspected 
transmission of infectious agent by a medicinal product” is also considered a serious adverse 
event under the SAE criterion “Other medically important condition”. 
8.1.3 Attribution/Causality 
• 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as  underlying disease(s), concomitant therapy, and other  risk 
factors, as well as the temporal relationship of the event to trial treatment administration will 
be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor/designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
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Table 11: 
Adverse Events Attribution/Causality Ratings 
 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive. The relationship in time is reasonable; 
therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event, which might be due to the use of the drug. The 
relationship in time is suggestive, e.g., confirmed by dechallenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s). 
 
8.1.4 Severity 
Table 12: 
Definitions for Adverse Event Severity Gradings 
 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
GRADE 4 
Potentially Life- 
Threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non- 
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected from the signing of the ICF until the 78-week post treatment follow-up 
visit at the time points specified in the Flowchart (Section 1.2) and recorded in the case report 
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from (CRF). The exception is early withdrawal participants who will only have SAEs collected from 
the time of their early withdrawal through the 78-week post treatment visit. 
Medical occurrences that begin after obtaining informed consent will be recorded as adverse 
events. If an adverse event started before signing of the informed consent, but is ongoing at trial 
start, it should be recorded as medical history. If the pre-existing medical occurrence worsens 
during the trial, and adverse event will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the investigator. 
The Sponsor/investigator/designee will inform Regulatory Authorities and/or IEC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the IEC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in participants who have 
completed the trial. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the trial, and he/she considers the event to be 
reasonably related to the trial treatment or trial participation, the investigator must promptly notify 
the Sponsor, IEC/IRB and regulatory authorities on an expedited basis in accordance with local 
requirements and ICH guidelines for GCP. 
8.2.1 Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
Until the end of the follow-up period; and 
• 
Until all queries on these AEs have been resolved. 
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the treating physician. If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor Medical Monitor. 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. Investigator should contact Sponsor/designee to discuss 
appropriate medical follow-up if consultation required. 
If a participant dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide Sponsor/representative with a copy of any post-mortem findings including 
histopathology. 
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New or updated information on an SAE will be recorded in the originally completed CRF and 
submitted to Sponsor within 24 hours of the information becoming known per SAE reporting 
guidelines. 
8.2.2 Clinical Laboratory Adverse Events 
Changes in the results of the Clinical Laboratory assessment results which the Investigator feels 
are clinically significant will be reported as adverse events. It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available. This review must be 
documented by the Investigators’ dated signature on the laboratory report. For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant. This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed. The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests. If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an adverse event. 
8.2.3 Disease under Study 
Symptoms of the disease under trial (Pulmonary Tuberculosis) experienced by the participant 
while on the trial will be assessed by the Investigator.  If the symptom has: 
• 
worsened while the participant is in the trial; and 
• 
the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event. 
If there is: 
• 
no change; and 
• 
the Investigator assesses the symptom as due to the participant’s TB; and 
• 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation. 
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 Overdose 
Overdose of IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an Adverse Event, including if the taking of 
the suspect medicine led to suicidal intention and subsequent overdose of the suspect medicine, 
or other medication. In this case it will be recorded as an adverse event. If it does not lead to an 
Adverse Event, it will not be recorded as an AE and this will be noted in the participant’s source 
documentation. 
8.2.5 Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration. Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
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Investigator will report to the Sponsor follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome. Infants will be followed for 6 months. 
All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following time- 
periods: 
• 
During the trial 
• 
Within 6 months after last dose of IMP 
If pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known. If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow up will be performed 
unless contraindicated by the pregnancy. 
Pregnancy reporting will follow the same time lines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly. This will follow the reporting procedures described above for SAE reporting. 
8.3 Monitoring for Specific Toxicities 
Monitoring for specific toxicities is based upon target organs as defined in preclinical toxicity 
studies Investigator’s Brochures(5,6) and Package Inserts.(23,24,25,26) Please reference section 6.3 
Treatment Modifications, which notes that all treatment modifications should be discussed with 
Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required 
urgently for a safety concern. The Medical Monitor should be informed within 24 hours of the 
change if not discussed prior to implementation. 
AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization or until the end of the follow-up period and until all queries on these AEs 
have been resolved. Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization. 
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases follow-up will be the responsibility of the treating physician. If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor Medical Monitor. 
 
 
8.3.1 Neurological 
Participants with co-administration of a serotonergic agent, including anti-depressants, should be 
monitored closely for signs of serotonin syndrome. The Investigator should determine whether 
the full regimen or the concomitant agent should be discontinued for those who experience signs 
or symptoms of serotonin syndrome such as cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours where possible. The recommendations for managing participants 
below assumes the laboratory abnormalities of concern have been confirmed. 
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Linezolid and/or the full regimen should be paused for participants experiencing a seizure. The 
Sponsor Medical Monitor should be contacted to review details and discuss whether linezolid or 
full regimen should be resumed. 
8.3.2 ALT, AST and Alkaline Phosphatase elevations: 
The Investigator should refer to Appendix 5 – Liver Toxicity Management and to the ZeNix 
Hepatotoxicity Management Guideline to appropriately manage the participant for  clinically 
significant elevations of AST, ALT or Alkaline Phosphatase. 
8.3.3 Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
Contact Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 4 elevations 
of lipase, Investigator should consider pausing the full regimen, pending further evaluation. 
8.3.4 Musculoskeletal System and Cardiac Muscle 
Myalgia 
Grade 2 (muscle tenderness at site other than sites of injection and/or venipuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
Participants with Grade 2 signs and symptoms should be followed closely. Participants with Grade 
3 or 4 signs and symptoms should be discussed with the Sponsor Medical Monitor to consider 
pausing trial medication, pending further evaluation. 
CPK 
For participants having elevations in CPK of potential clinical concern, the Investigator should 
check the CK-MB subunit, if high, consider pausing regimen and discuss with Sponsor Medical 
Monitor. 
8.3.5 Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
Participants should be monitored closely. The Investigator should discuss with the Sponsor 
Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation 
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artifacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator. If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
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per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen. 
8.3.6 Monitoring Linezolid Toxicities 
The following are guidelines for decisions to pause, reduce and to resume linezolid in response 
to the onset and resolution of known linezolid-specific toxicities. These are guidelines, and 
decisions must be made in the context of the entire clinical status of the participant. While the 
investigator may need to urgently interrupt dosing for potentially life threatening symptoms or 
laboratory findings, the Medical Monitor should be contacted and informed of any changes in 
dose within 24 hours.  Questions should be raised to the Sponsor’s Medical Monitor if the 
decision is not clear. 
8.3.6.1 Myelosuppression 
The hematologic parameters of hemoglobin and counts of Neutrophils and platelets are variable 
from measurement to measurement. While decreases in any of these may be caused by linezolid 
toxicity, decreases of concern should be evaluated in the context of the participant’s full clinical 
status and alternate explanations. Guidelines below are for situations of concern when it is 
considered likely that linezolid has caused the decrease. 
Anemia 
• 
Consider pausing linezolid if hemoglobin falls below 8 gm/dL or 80g/L (Grade 3) and 
significantly below baseline, or if hemoglobin falls > 25% of baseline. If it is clear that the 
anemia was caused by linezolid, consider resuming linezolid at half the dose when 
hemoglobin improves and linezolid is resumed. 
Leukopenia 
• 
Consider pausing linezolid if the Absolute Neutrophil Count (ANC) falls below 750/mm3 
or 0.75 x 10^9/L (Grade 3) and significantly below baseline. Ideally confirm with a repeat 
test before making further decisions as ANCs can have diurnal and other variability. If it is 
clear that the leukopenia was caused by linezolid, consider resuming linezolid at half the 
dose when ANC improves and linezolid is resumed. 
Thrombocytopenia 
• 
Consider pausing linezolid if platelets fall below 50,000/mm3 or 50 x 10^9/L (Grade 3) and 
significantly below baseline. Ideally confirm with a repeat test before making further 
decisions. If it is clear that the thrombocytopenia was caused by linezolid, consider 
resuming linezolid at half the dose when platelets improves and linezolid is resumed. 
8.3.6.2 Peripheral Neuropathy 
The decision to reduce the dose, or to pause linezolid until symptoms improve is a judgment 
based on changes in signs and symptoms identified by the investigator and informed by 
discussion with the trial participant. As general guidance, consider pausing and/or reducing 
linezolid when the grade of a neuropathy sign or symptom increases by a grade to grade two or 
greater. If it is clear that linezolid caused the neuropathy, consider resuming linezolid at half the 
dose, when the neuropathy improves. 
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8.3.6.3 Optic Neuropathy 
A participant with visual symptoms of concern or change in visual acuity of 2 lines or more or 
change in color vision of more than one plate should be referred to the site ophthalmologist for 
evaluation with a retinal examination. Any changes as assessed by the ophthalmologist that raise 
concern that an optic neuropathy may be developing should be discussed with the medical 
monitor and linezolid should be paused. If a likely or definite optic neuropathy is confirmed, 
linezolid should be permanently discontinued. 
8.3.6.4 Lactic Acidosis 
Lactic acidosis as a toxicity of linezolid should be considered if participants have gastrointestinal 
symptoms that are not explained by other more common causes of their symptoms. Such 
participants should have lactate measured and, as indicated, a full evaluation of pH and 
bicarbonate. Note that lactate should not be measured in participants who have no symptoms of 
concern, as elevated asymptomatic lactate may be common and it is difficult to interpret the 
clinical relevance of this. Also evaluate whether any concomitant medications, such as anti- 
retroviral therapies, may be associated with lactic acidosis and consider pausing them until the 
acidosis resolves. Consider pausing linezolid if a patient has GI symptoms and acidosis likely to 
be secondary to linezolid toxicity that is not otherwise explained. 
8.4 Safety Monitoring by Data Monitoring Committee 
A DSMC will be appointed for the trial. The primary responsibility of the DSMC will be to act in an 
advisory capacity to the Sponsor to safeguard the interests of trial participants by monitoring 
participant safety, assess participant risk versus benefit, and assess data quality and general 
evaluation of the trial progress. Its activities will be delineated in a DSMC charter that will define 
the membership, responsibilities and the scope and frequency of data reviews. The DSMC will 
operate on a conflict-free basis independently of the Sponsor and the trial team. It will comprise 
at least 3 voting members that include at least 2 clinicians and one statistician. The DSMC may 
have an organizational meeting prior to commencement of the trial. The DSMC will have meetings 
where it will review unblinded data during a closed session. These meetings will be planned at 
regular intervals. The Sponsor or the DSMC may convene ad hoc meetings based on rates of 
SAEs and/or to review results of the futility analysis or if safety concerns arise during the trial. 
After its assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial. 
 
9 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 Analysis Population 
The primary  analysis population will include both XDR and non-XDR (pre-XDR and MDR 
intolerant and non-responsive TB) participants (up to 45 per arm). A secondary analysis will be 
restricted to the XDR participants only (30 per arm). 
A modified intent-to-treat (mITT) and a per-protocol (PP) analysis for each arm and analysis 
population will be conducted. The mITT will be considered the primary analysis and will include 
all those in the ITT analysis with additional specific exclusions detailed in the statistical analysis 
plan (SAP). 
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Other analyses will be performed (for sensitivity) including a full intent-to-treat (ITT) analysis with 
no exclusions, and an analysis excluding only those who were later found to be ineligible at 
baseline (based on data collected prior to randomization). 
The Safety analysis population will include data from all randomized participants who received at 
least one dose of IMP. 
Full details of all the analysis populations will be defined in the SAP. 
9.2 Sample Size 
The objective of this trial is to evaluate the efficacy, safety and tolerability of various doses and 
durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants 
with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
In order to fulfil this objective, it is planned to randomize 30 XDR-TB participants per treatment 
group and up to 15 pre-XDR and/or MDR intolerant/non-responsive -TB participants per group. A 
sample size of 30-45 per arm will provide more than 90% power to demonstrate that the lower 
bound of the 95% confidence interval of this estimate is greater than 50%, using a 2-sided 5% 
significance level. This assumes that the true cure rate is 80 percent. 
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as 
the target, because it is above the entire range of the historical control for cure of XDR-TB and 
because a cure rate of 50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a 
shortened, simplified, all oral, inexpensive and safer regimen would clearly represent an important 
therapeutic advancement. A standard-of-care control group cannot reasonably be included in the 
trial for several reasons. 1) Given that the regimens being tested contain B and L, these drugs 
would need to be excluded from the control group. However, they are beginning to be used 
increasingly in XDR-TB, despite lack of firm evidence, but with positive anecdotal reports. Asking 
patients in the control group to avoid these medications could present an ethical issue. 2) The 
success rate of standard-of-care treatment for XDR-TB, particularly without B and L (see below), 
and the risk and difficulty of its administration contrast markedly with the early findings of B-L-Pa 
in the Nix-TB trial. It is unlikely that patients would sign informed consent to receive standard-of- 
care treatment if there is an alternative, but even if they do there remains an ethical issue of 
comparing such a disadvantaged treatment with such an advantaged treatment. 3) The scientific 
validity of comparing a 12-month endpoint (B-L-Pa) with a 30- or 36-month endpoint (standard of 
care) would represent a significant challenge. 
9.3 Interim Analyses 
No formal interim analyses are planned.  Primary analysis will be performed on the 26 week 
follow-up data (after end of treatment when the last randomized participant has completed 26 
weeks of follow-up after end of treatment). 
There will be two database locks, data analyses and trial reports generated for this trial: 
1. 
When all participants have completed 26 weeks of follow-up after end of treatment. 
2. 
When all participants have completed 78 weeks of follow-up from after end of treatment. 
9.4 Primary and Secondary Endpoint Analysis 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT). 
A secondary analysis will be restricted to the XDR participants only (30 per arm). We will 
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evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that  
the incidence of bacteriologic failure or relapse or clinical failure (including mortality) at 6 months 
(26 weeks) after the end of therapy is less than 50%. 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and 
safety and to control the overall type I error rate the following analysis strategy will be adopted 
for both the primary and secondary analysis populations: 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 
weeks) with the L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a 
success.  Similarly, L600 9 weeks will only be tested if L600 26 weeks is a success.  A 
Bonferroni adjustment will be made for comparing the L1200 9 weeks and L600 26 weeks arms 
simultaneously, using p<0.025.  For these comparisons the lower bound of the 97.5% 
confidence interval will need to exceed 50% for success. 
No formal statistical pairwise comparisons between the arms will be performed. 
9.5 Safety and Tolerability Analysis 
• 
The incidence of all-cause mortality will be summarized. 
• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake. Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
• 
Cardiovascular Safety: QT intervals will be adjusted using Fridericia’s correction and Bazett’s 
correction. QT/QTc values and changes from pre-dose (average of Screening and Day 1 
values) at each time point will be summarized using descriptive statistics by group and time 
of collection. These will be presented as descriptive analyses, and no inferential tests will be 
carried out. 
o Post-baseline QT/QTc intervals will be classified into the following categories: 
 
QT/QTc < 450 msec 
 
450 msec < QT/QTc < 480 msec 
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 
480 msec < QT/QTc < 500 msec 
 
QT/QTc > 500 msec 
o QTc changes from baseline will be classified into the following categories: 
 
increase < 30 msec, 
 
30 msec and < 60 msec, and 
 
increase > 60 msec. 
o Frequency counts will be used to summarize the number of participants at each 
time point according to the above categories. 
o ECG results will be classified as normal or abnormal (investigator assessment) 
and summarized using frequency counts by dose group and time of collection. 
• 
Ophthalmology: Descriptive statistics, including changes from baseline, will be summarized 
and listed by participant for ophthalmology slit lamp examination (age related eye disease 
study 2 [AREDS2] lens opacity classification and grading). Categorical data for lens opacity 
will be summarized in a frequency table for the right and left eye, respectively. 
• 
Visual acuity and color vision: Descriptive statistics, including changes from baseline, will be 
summarized and listed by participant for both Visual Acuity and Color Assessments. 
Categorical data for changes in visual acuity and color vision from baseline will be summarized 
in a frequency table for the right and left eye, respectively. 
• 
Descriptive statistics of neuropathy data derived from Brief Peripheral Neuropathy Screen. 
Categorical data for observed signs and symptoms of neuropathy will be summarized in 
frequency tables, including changes in signs and symptoms from baseline. 
• 
Other safety variables: Laboratory Parameters, Physical Examination, Vital signs (see  
Appendix 3), Concomitant medication, ophthalmic examination and peripheral neuropathy. 
Descriptive summary statistics will be presented. The incidence of liver related laboratory 
abnormalities will be explored. 
9.6 Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update population pharmacokinetic 
(PopPK) models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study trial population, and to derive 
individual exposure metrics for use in exposure-response analyses. PK data from the current trial 
may be combined with prior data (e.g., from the NiX-TB trial) to enhance this population PK 
analysis. Detailed plans for the PopPK analysis will be outlined in a separate modeling plan, and 
results will be reported in separate modeling report. 
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9.7 Pharmacokinetics/Pharmacodynamics 
For each analyte, the PopPK model will be used to derive individual exposure metrics such as 
steady-state Ctrough, Cmax, AUCτ, and time-above-minimum-inhibitory-concentration (T>MIC), 
or alternative individual summaries of these metrics over the treatment period to account for dose 
adjustments and interruptions as appropriate. Relationships between such exposure metrics and 
efficacy and safety endpoints will be explored graphically and by model-based analyses as 
appropriate. Planning details and results will be included in the separate modeling plan and report. 
 
10 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended. For screening failure participants specific eCRF pages will be 
completed as described in the eCRF Completion Guidelines. For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source documents will include, but are not limited to, 
progress notes, in-Patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators. The 
Investigator 
has 
to 
permit 
trial 
related 
monitoring, 
audits, 
Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-Patient records while participants is on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial center files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection subsequent to trial completion. The essential documents should be retained for 
not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP. Investigator should notify Sponsor/designees 
prior to destroying any records pertaining to the trial. 
 
11 Quality Control and Assurance 
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, ICH GCP, and the ethical principles that have their origin in the Declaration of 
Helsinki. 
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The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures, where available will be adhered to for all clinical and 
bioanalytical activities relevant to the quality of the trial. Participant compliance will be monitored 
throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-investigators. Written 
IEC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor. The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, ICH GCP, the ethical principles that have their origin in the Declaration of 
Helsinki and the applicable regulatory requirements. 
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for the purpose of monitoring various aspects of the trial, and to assure appropriate conduct of 
the trial in accordance with ICH GCP. Visits will take place usually within a predetermined interval, 
but this may vary during the course of the trial. The Investigator and site staff will allow the trial 
monitor and authorized representatives of the Sponsor to (1) inspect all CRFs, written informed 
consent documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs (where applicable), training records, facilities and 
other trial related systems/processes, and (2) access clinical supplies, dispensing and storage 
areas. The Investigator and site staff should also (1) agree to assist with monitoring activities if 
requested and (2) provide adequate time and space for monitoring visits. 
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator. All queries should be resolved in a timely manner. A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Monitoring 
Plan requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly. 
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It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB and Health Authority, per their guidelines. The 
site PI/all study staff is responsible for knowing and adhering to their IRB and Health Authority (as 
required) requirements. 
11.4 Auditing 
For the purpose of compliance with ICH GCP and regulatory agency guidelines, it may be 
necessary for Sponsor-authorized Quality Assurance personnel and/or authorized personnel from 
an external regulatory agency to conduct an audit or inspection of the investigational site. The 
purpose of an audit is to assess the quality of data with regard to accuracy, adequacy and 
consistency, and to assure that studies are in accordance with the guidelines. Having the highest 
quality data from studies is an essential aspect of drug development. 
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial. The 
audit will involve the review of all trial-related documentation required by ICH GCP to be 
maintained by each site; drug storage, dispensing and return; all trial-related supplies; and source 
documents against the CRFs to assure the adequacy and accuracy of the information which has 
been recorded, including the verification of any AEs which have occurred. The auditors or 
inspectors may also review site SOPs (where applicable), training records, site facilities and other 
trial related systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
 
12 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with ICH GCP, the ethical principles that have 
their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
Review 
The protocol and required trial related documents will be reviewed by the sites respective 
IEC/IRB. The trial will not start until the IEC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, plus 
any other trial related documents required for review. The IEC/IRB shall be constituted and shall 
operate in accordance with International ICH GCP, the ethical principles that have their origin in 
the Declaration of Helsinki. The Investigator will maintain an accurate and complete record of all 
submissions made to, and responses from the IRB/IEC. The records should be filed in the 
Investigator’s Trial File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations. As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
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12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed. Investigators may discuss  the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent. However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for the purpose of determining eligibility for research, including withdrawal from current 
medication(s). When this is done in anticipation of, or in preparation for, the research, it is 
considered to be part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol. Participants must 
be informed that their participation is voluntary. The investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same IEC/IRB responsible for approval of this protocol. Each 
informed consent form shall include the elements required by the ICH GCP and must adhere to 
the ethical principles that have their origin in the Declaration of Helsinki. 
The trial will be included and updated in the appropriate Country registry and referenced in the 
ICF. 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the IEC/IRB approved written informed consent form 
will be signed and dated by both the participant and the person obtaining consent (Investigators 
or designees), and by any other parties required by the IEC/IRB. Ongoing participants must be 
re-consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative. Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s 
medical record. 
The monitor will inspect the original completed consent form(s) for all participants 
12.5 Confidentiality 
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with ICH GCP, applicable local 
legislation/regulations. Subject to the requirement for source data verification by  the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained. Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted. No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the Sponsor or designees. 
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13 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial. 
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible IEC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors. (30) 
Because the Study is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Study must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Study must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
 
14 Protocol Amendment Policy 
Any change to the protocol will be effected by means of a protocol amendment. Any changes 
which affect participant safety or welfare will be submitted to the IEC/IRB and Regulatory 
Authorities prior to implementation. The Investigator, IEC/IRB, and Sponsor must agree on all 
amendments. No amendment will be implemented until approved by the relevant Authorities 
and/or IEC/IRB and signed by all required parties. Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised. 
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the IEC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
 
15 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the Global Alliance for TB Drug Development (TB Alliance). The TB Alliance 
is a not for profit, product development partnership accelerating the discovery and development 
of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, 
be compatible with antiretroviral therapies for  those HIV-TB participants  currently  on such 
therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide. It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
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The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial. The Sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability  insurance coverage for  itself and will provide an 
associated certificate upon request. The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses. 
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16 References 
 
1. “A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis”. ClinicalTrials.gov, 25 
January 2017. https://www.clinicaltrials.gov/ct2/show/NCT02333799 
2. Bonilla CA, Crossa A, Jave HO, Mitnick CD, Jamanca RB, Herrera C, Ascencios L, 
Mendoza A, Bayona J, Zignol M and Jaramillo E (2008). “Management of Extensively 
Drug-Resistant Tuberculosis in Peru: Cure Is Possible”. PLoS One 3(8): e2957. 
3. Cox H, Ford, N. “Linezolid for the treatment of complicated drug-resistant tuberculosis: a 
systematic review and meta-analysis” INT J TUBERC LUNG DIS 16(4):447–454, 2012. 
4. Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, van Niekerk C, 
Erondu N, Ginsberg AM, Becker P and Spigelman MK (2012). “Phase II Dose-Ranging 
Trial of the Early Bactericidal Activity of PA-824”. Antimicrobial Agents and Chemotherapy; 
56(6): 3027-3031. 
5. Bedaquiline (TMC207) Investigator’s Brochure, Janssen Research and Development., 
Edition 9, 09 October 2015. 
6. Investigator’s Brochure Pretomanid (PA-824), Global Alliance for TB Drug Development., 
Version 17, 22 December 2016. 
7. Keshavjee S, Gelmanova IY, Shin SS, Mishushtin SP, Andreev YG, Atwood S, Furin JJ 
and Miller A (2012). “Hepatotoxicity during treatment for multidrug-resistant tuberculosis: 
occurrence, management and outcome”. Int J Tuberc Lung Dis 16(5):596-603. 
8. Leach KL, Brickner SJ, Noe MC, Miller PF. "Linezolid, the first oxazolidinone antibacterial 
agent" Ann NY Acad Sci. 2011 Mar; 1222:49-54. 2011. 
9. Lee, et al. "Linezolid for treatment of chronic extensively drug-resistant tuberculosis" N 
Engl J Med. 2012 Oct 18; 367(16):1508-18. 
10. Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, 
Reynolds RC, and Orme IM. “Preclinical Testing of the Nitroimidazopyran PA-824 for 
Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models” 
Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301. 
11. Lytvynenko N, Cherenko S, Feschenko Y, Pogrebna M, Senko Y, Barbova A, Manzi M, 
Denisiuk O, Ramsay A and Zachariah R (2014). “Management of multi and extensively 
drug resistant tuberculosis in Ukraine: how well are we doing?” IUALTD Public Health 
Action 4(3): S67-S72. 
12. Manjunatha U, Boshoff HI, Berry CE. The mechanism of action of PA-824: novel insights 
from transcriptional profiling. Commun Integr Biol. 2009; 2(3):215-218. 
13. Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton, JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci USA. 2006; 103(2):431-436. 
14. McLeay SC, Vis P, van Heeswijk RPG and Green B (2014). “Population Pharmacokinetics 
of Bedaquiline (TMC207), a Novel Antituberculosis  Drug”. Antimicrobial Agents and 
Chemotherapy 58(9): 5315-5324. 
15. Mdluli K, Nuermberger, E. “Pre-Clinical Drug Combination Studies to Identify Novel 
Regimens for TB”. In: Recent Advances in TB Drug Development symposium, 40th Union 
World Conference, International Union Against TB and Lung Disease, Cancun, Mexico, 
2009. 
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16. Mdluli K, Nuermberger E, Taylor K, Williams N, Koen A, Khisimuzi E, Rokeya T, Si-Yang 
L, Peloquin C, Dinesh C. “Sterilizing activity of novel TMC207- and PA-824-containing 
regimens in a murine model of tuberculosis” Antimicrobial Agents and Chemotherapy 
2011; 55: 5485-5492. 
17. Migliori GB, Sotgiu G, Gandhi NR, Falzon D, DeRiemer K, Centis R, Hollm-Delgado MG, 
Palmero D, Perez-Guzman C, Vargas MH, D’Ambrosio L, Spanevello A, Bauer M, Chan 
ED, Schaaf HS, Keshavjee S, Holtz TH, Menzies D and “The Collaborative Group for 
Meta-Analysis of Individual Patient Data in MDR-TB” (2013). “Drug resistance beyond 
XDR-TB: results from a large individual patient data meta-analysis”. Eur Respir J. 42(1): 
169-179. 
18. Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006; 50(8):2621-2625. 
19. Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal, I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 2008; 
52(4):1522-1524. 
20. Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005; 172(11):1452-1456. 
21. O’Donnell MR, Padayatchi N, Master I, Osburn G and Horsbaugh CR. “Improved Early 
Results for Patients with Extensively Drug Resistant Tuberculosis and HIV in South 
Africa”. Int J Tuberc Lung Dis. 13(7): 855-861. 
22. Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
23. Package Insert for South Africa, ZYVOXID® (linezolid), Pfizer Pharmaceuticals, May 
2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=1045. Date last accessed: 15 April 
15 2016. 
24. Package Insert, Lizomac™ 600 (linezolid), MacLeods Pharmaceutical, 2014. 
25. Package 
Insert, 
SIRTURO®, 
Janssen 
Therapeutics, 
December 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204384s006lbl.pdf. Date last 
accessed: 15 April 2016. 
26. Package 
Insert, 
ZYVOX®, 
Pfizer 
Pharmaceuticals, 
June 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021130s030,021131s029,02 
1132s034lbl.pdf. Date last accessed: 15 April 2016. 
27. Park IN, et al. “Efficacy and tolerability  of daily-half dose linezolid in patients with 
intractable multidrug-resistant tuberculosis.” B Antimicrobial Chemotherapy 2006; 58:701- 
704. 
28. Pietersen E, et al. "Long-term outcomes of patients with extensively drug-resistant 
tuberculosis in South Africa: a cohort study" Lancet, 2014 Jan 16. pii: S0140- 
6736(13)62675-6. 
29. Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, Vasilyeca I, 
Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, Van 
Baelen B, van Heeswijk RPG and Dannemann B (2016). “Bedaquiline safety data in a 
broad patient population treated for drug-resistant TB including XDR-TB (C209 study)”. 
Tuberculosis 47: 394-402. 
30. “Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in 
Medical Journals”, December 2016 update.  http://www.icmje.org/icmje-recommendations.pdf, 
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31. Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578. 
32. Schecter GF, et al. “Linezolid Treatment for MDR-TB”. Clinical Infectious Diseases 2010; 
50:49-55. 
33. Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008; 
322(5906):1392-1395. 
34. Singla R. "Linezolid: an Effective, Safe and Cheap Drug for Patients Failing Multidrug- 
resistant Tuberculosis Treatment in India" Eur Respir J. 2012 Apr; 39(4):956-62. doi: 
10.1183/09031936.00076811. Epub 2011 Sep 29. 
35. Stover, C. K., P. Warrener, D. R. VanDevanter, et al. 2000. “A small-molecule 
nitroimidazopyran drug candidate for the treatment of tuberculosis”. Nature 405:962–966. 
36. Tasneen R, Betoudji F, Tyagi S, et al. Contributions of oxazolidinones to the efficacy of 
novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis. 
Antimicrob. Agents Chemother Posted Online 26 October 2015. Dol:10.1128/AAC.01691- 
15. 
37. Tasneen R, Tyagi S, Williams K, Grosset J, Nuermberger E. “Enhanced bactericidal 
activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of 
tuberculosis”. Antimicrob Agents Chemother. 2008; 52(10):3664-3668. 
38. Tato M, et al. "In vitro activity of linezolid against Mycobacterium tuberculosis complex, 
including multidrug-resistant Mycobacterium bovis isolates". Int. J. Antimicrob Agents 
2006 Jul; 28(1)75-8. 
39. Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”. 
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
40. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. Bactericidal 
activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2005; 49(6): 2289-2293. 
41. WHO Treatment of Tuberculosis Guidelines, 4th Edition. 2010. 
42. World Health Organization. Global Tuberculosis Report 2014, 19th ed. 2014. 
43. World Health Organization. Global Tuberculosis Report 2015, 20th ed. 2015. 
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Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
exact figure/100/scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at 
least 20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life- 
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization 
or hospice care probable. 
 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common Toxicity 
Criteria (CTC), and World Health Organization (WHO)) have been adapted for use by the 
Division of Microbiology and Infectious Diseases (DMID) and modified to better meet the 
needs of Patients in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
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HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000- 
99,999/mm3 
50,000- 
74,999/mm3 
20,000- 
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000- 
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low : 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low : 
<100 mg/dL 
High: 
>600 mg/dL 
Low : 
< 50 mg/dL 
---------- 
Fibrinogen 
associated w ith 
gross bleeding or 
w ith disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
 
 
CHEMISTRIES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life- 
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 88 of 97 
 
 
 
Hypocalcemia 
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life- 
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life- 
threatening arrhythmia 
Hyperbilirubinemia 
(w hen accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(w hen other liver 
function are in the 
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
 
ENZYMES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
 
URINALYSIS 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 89 of 97 
 
 
 
Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, w ith or 
w ithout clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent 
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment required 
acute treatment 
required; 
outpatienttreatm 
ent or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension w ith 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable w ith oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled w ith 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow  
requires treatment; 
normalizes w ith 
bronchodilator; FEV1 
50% - 70% (of peak 
flow ) 
no normalization w ith 
bronchodilator;FEV1 
25% - 50% of peak 
flow ; or retractions 
present 
cyanosis: FEV1 < 
25% of peak flow  
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea w ith normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 90 of 97 
 
 
 
GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3- 
4 loose stools/day 
or mild diarrhea 
last < 1 w eek 
moderate or 
persistent; 5-7 loose 
stools/day or 
diarrhea lasting >1 
w eek 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required 
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization 
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
sw allow ing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
sw allow  solid foods 
unable to drink 
fluids; requires IV 
fluids 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 91 of 97 
 
 
 
NEUROLOGICAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe mood 
changes requiring 
therapy; or suicidal 
ideation; or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
w eakness no 
objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function 
objective 
w eakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate 
discomfort; non- 
narcotic analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
w ith symptomatic 
improvement 
incapacitating; 
or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment (mod 
decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or w rists) or 
loss of sensation of 
at least mod 
degree in multiple 
different body 
areas (i.e., upper 
and low er 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis;  or 
seizures 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 92 of 97 
 
 
 
MUSCULOSKELETAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering w ith 
function 
moderate pain, 
analgesics and/or 
pain interfering w ith 
function but not w ith 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering w ith 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain w ith 
inflammation, 
erythema or joint 
sw elling – but not 
interfering w ith 
function 
moderate pain w ith 
inflammation, 
erythema or joint 
sw elling – interfering 
w ith function, but not 
w ith activities of 
daily living 
severe pain w ith 
inflammation, 
erythema or joint 
sw elling –and 
interfering w ith 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia w ith no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or w ith 
moderate 
impairment of 
activity 
severe muscle 
tenderness w ith 
marked impairment 
of activity 
frank 
myonecrosis 
 
 
SKIN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected Stevens- 
Johnson or 
necrosis requiring 
surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
Erythema 
< 15mm 
15-30 mm 
>30mm 
Edema 
< 15mm 
15-30 mm 
>30mm 
Rash at Injection 
Site 
< 15mm 
15-30 mm 
>30mm 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 93 of 97 
 
 
 
SYSTEMIC 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus w ithout rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial narcotic 
therapy 
intractable; requires 
repeated narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
normal activity 
decreased 25- 50% 
> 48 hours 
normal activity 
decreased > 50% 
can’t w ork 
unable to care for 
self 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 94 of 97 
 
 
Appendix 3: Cardiovascular Safety 
 
Vital Signs 
The following abnormalities will be defined for vital signs: 
 
Abnormality Code 
Vital Signs Parameter 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 90 mmHg- 
<100 mmHg 
> 140 mmHg- 
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg- 
<110 mmHg 
≥ 160 mmHg- 
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or 
Grade 4” 
≥ 120 bpm 
- 
- 
Intubation 
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CONFIDENTIAL 
Page 95 of 97 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
 
 
Appendix 4: Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms of 
disease. 
80 
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
Cares for self; unable to carry on normal activity or to 
do active work. 
70 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
60 
Requires considerable assistance and frequent medical 
care. 
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109(22). 
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CONFIDENTIAL 
Page 96 of 97 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
 
 
 
 
Appendix 5: Liver Toxicity Management 
Standard anti-TB chemotherapy is known to cause derangement of liver function tests in a 
substantial number of patients. In many cases this will be asymptomatic and self-limiting. In some 
cases, severe hepatitis and even fulminant liver failure and death can occur. 
In pre-marketing clinical trials of new drugs and regimens it is especially important to identify and 
carefully manage any trial participants who are at risk of progression to serious liver injury. The 
observation of altered liver function to a degree that has a high risk of progressing to liver failure 
has been referred to informally as Hy’s Law;(31,39); this reflects that pure hepatocellular injury 
sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, Hy’s Law cases have the following three components: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo. 
2. Among trial participants showing such aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show elevation of serum total bilirubin (TBL) 
to >2x ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase 
(ALP)). 
3. No other reason can be found to explain the combination of increased AT and total bilirubin 
level (TBL), such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury. 
During the trial, liver function will be monitored regularly with clinical assessment and blood tests 
in study participants and this will assist in follow up laboratory measurements that can document 
either resolution of abnormalities or signal the potential for drug-induced liver injury (DILI). In a 
clinical trial of new drugs and combinations it is especially important for investigators to follow 
closely any participants who have evidence of hepatic inflammation or potential toxicity. The 
following procedure describes the management of deranged liver function tests in study 
participants. 
Procedure 
Blood tests for liver function will be taken routinely at screening (Day -14 to -1) and at the specific 
time points designated in the protocol, and at Early Withdrawal. If at any other visit the clinician 
suspects derangement of liver function, e.g. the participant describes nausea and vomiting, right 
upper abdominal pain or is jaundiced, blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of hepatitis or hepatic impairment and any 
potentially contributing causes. 
Suspected liver toxicity (or elevated liver enzymes detected in the absence of symptoms) must 
be taken seriously and detailed guidance will be provided in a separate document “ZeNix 
Hepatotoxicity Management Guideline”. Investigators should refer to this document as a guide to 
management in cases of suspected or proven liver toxicity. Importantly, the trial Medical Monitor 
is available to provide further assistance if there is any uncertainty or additional questions. 
403 of 784


CONFIDENTIAL 
Page 97 of 97 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 13 JUNE 2018 
Protocol Name: ZeNix 
 
 
The laboratory source (print-out of any results) should be stored alongside or transcribed into the 
clinical source document. Each abnormal value should be marked as clinically significant (CS) or 
non-clinically significant (NCS); the assessment of significance is at the discretion of the 
investigator. All clinically significant abnormal results must be recorded as Adverse Events in the 
eCRF and graded clinically as per the DMID adult toxicity table grading, (Appendix 2). 
Assessments and decision making for elevations in aminotransferase values or bilirubin of various 
levels of concern are detailed below: 
Elevated liver enzymes considered of clinical significance, but not accompanied by other signs 
and symptoms, should be reported as an adverse event and should usually be recorded as 
elevated liver enzymes. If the term "hepatitis" is used, the Safety Data Manager will question the 
site for additional evidence to support the diagnosis, such as clinical signs and serological or 
biopsy data. While a liver biopsy is not required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for cases where there is supportive evidence 
beyond a liver enzyme abnormality. However, if the investigator will confirm the diagnosis of 
hepatitis just on the basis of clinical signs and laboratory values the diagnosis will be accepted. 
Should other symptoms or signs be present, these should also be recorded as adverse events. 
Restarting Medication 
Liver function tests that are improving should be repeated regularly, such as every 3 days for the 
first week then once a week until they return to near baseline values for the participant. Manage 
the participant symptomatically as required using medications that are not potentially hepatotoxic. 
Infection control issues must be carefully managed whilst TB medications are being withheld, 
especially if the participant is still culture positive for acid fast bacilli. 
If medication has been temporarily stopped, once the liver function values have decreased 
substantially a decision must be made about further TB management. This will be dependent on 
the clinical context and a decision must be made in discussion with the Sponsor Medical Monitor. 
Treatment can only be restarted if the trial Medical Monitor is in agreement with the plan. In all 
cases treatment should be recommenced under close supervision for any evidence of recurrent 
liver function abnormalities. 
If there is a further significant elevation of hepatic enzymes or bilirubin or symptoms of clinical 
concern after resumption of study medication, the study medication should be withdrawn 
permanently. Participants who permanently discontinue study medication should be managed as 
clinically indicated according to local National TB Programme guidelines. The Sponsor Medical 
Monitor can be contacted for further advice when referring to the National Treatment Program. 
The trial Medical Monitor is available to assist the Investigators in both the management of liver 
toxicity and decisions regarding the holding or re-introduction of trial medication. Investigators 
must involve the Medical Monitor in any decisions regarding medication hold or re-start, and there 
should always be a low threshold for contacting the Medical Monitor in cases of elevated liver 
enzymes. 
Refer to ZeNix Hepatotoxicity Management Guideline for further details. 
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409 of 784


 
 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version:  Version 2.0, dated 13 June 2018 
Protocol Name:     ZeNix 
 
 
Protocol Amendment Template 
 
 
TMP02-C V3.0 dated 06Dec2017 
 
 
 
 
 
 
 
 
 
Page 1 of 36 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
Protocol Name / Number: 
ZeNix/ NC-007-(B-Pa-L) 
Protocol Title: 
A Phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various doses and 
treatment durations of linezolid plus bedaquiline and pretomanid in participants with pulmonary infection 
of either extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-
responsive multi-drug resistant tuberculosis (MDR-TB). 
 
 
Reasons for Protocol Amendment: 
1  Change of screening period from up to 9 to up to 14 days to provide sites with adequate time for assessments (In section 1.1 
Synopsis Summary, 1.2 Synopsis Flowchart and 4.2 Treatment Plan: Schedule of Assessments, 5. Trial Population.) 
2  Removed limitation of 60 non-XDR participants/requirement for 120 XDR participants. Enrollment to include 180 participants 
who are either XDR, pre-XDR or MDR intolerant or non-responsive. (In section 1.1 Synopsis summary and 4.1 Summary of 
Trial Design) 
3  Updated randomization details, specifically abbreviation of phone/web system utilized (changed IWRS to IXRS) and 
“minimization” to “stratification”.  (In section 1.1 Synopsis Summary, 4.1 Summary of Trial Design, and 6.5 Method of 
Treatment Assignment) 
4  Clarified scenarios and timing of culture positive results for consideration of treatment extensions from “week 16” to 
“between week 16 and week 26” (In section 1.1 Synopsis Summary, 1.2 of Synopsis Flowchart, and 4.1 Summary of Trial 
Design) 
5  Clarified language throughout the protocol to specify when Sponsor Medical Monitor’s approval vs. notification required (In 
section 1.1 Synopsis, 4.1 Summary of Trial Design, 5.2 Exclusion Criteria, 5.4 Trial Discontinuation and Visits, 5.3.1 Prior and 
Concomitant Medications and Other Treatments, 6.3 Treatment Modification(s), 6.6 Blinding and Procedures for Breaking the 
Blind, 8.2.1 Follow up of AE, and 8.3 Monitoring for Specific Toxicities) 
6  Clarified descriptions of regimen and dosing instructions to note linezolid 600 mg full or half tablets and placebo full or half 
tablets vs. 300 mg half tablet or linezolid 300 or 600 mg placebo. (In section 1.1 Synopsis Summary, 6.1 IMP Administration, 
and 6.4 IMP Packaging and Labelling) 
7  Clarified treatment modifications to note 2 step (vs. 3 step) blinded decreases, and ability to raise linezolid dose back up to 
starting level, specifics on when for make-up dosing required (when missed more than 7 days) and deleted (when repetitive) 
or moved wording.  (In section 1.1 Synopsis Summary and 6.3 Treatment Modification[s])  
410 of 784


 
 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version:  Version 2.0, dated 13 June 2018 
Protocol Name:     ZeNix 
 
 
Protocol Amendment Template 
 
 
TMP02-C V3.0 dated 06Dec2017 
 
 
 
 
 
 
 
 
 
Page 2 of 36 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
8  Clarified primary endpoint timing in definition, from “through follow up until 26 weeks” to “at 26 weeks” after the end of 
treatment (In section 1.1 Synopsis Summary) 
9  Updated Safety endpoint for ophthalmology slit lamp exams to include “observed” (In section 1.1 Synopsis Summary) 
10  Addition of ophthalmology exams at treatment week 23 and follow-up week 12 to ensure appropriate safety monitoring (In 
section 1.2 Synopsis Flowchart, and section 5.4 Trial Discontinuation and Visits) 
11  Addition of assessments required when patients withdraw during post treatment follow-up, which will be the same 
assessments required for week 78 post treatment follow-up visit. (In section 1.2 Synopsis Flowchart, and 5.4.2 Early 
Withdrawal Follow-up) 
12  Clarified visit scheduling for understanding.  Referenced treatment modification for treatment extension scenarios, removed 
repeated text, and provided clear examples. (In section 6.3 Treatment Modification[s]) 
13  Updated and added details on HIV testing to clarify that historical documented results must be from ELISA, Western blot or 
electrochemiluminescence (added). Added allowance for repeated HIV testing when results indeterminate. (In section 1.2 
Synopsis Flowchart, and 5.1 Inclusion Criteria) 
14  Clarified requirement for CD4 and viral load testing for HIV positive participants, noted that CD4 testing should be done if 
patient is an early withdrawal during treatment period. 
15  Change of acceptable chest x-ray results from 1 month prior to screening to 6 months prior to or at screening (In section 1.2 
Synopsis Flowchart, and 5.1 Inclusion Criteria) 
16  Clarified ECG testing to note that central reading of screening to be used for eligibility. (In section 1.2 Synopsis Flowchart) 
17  Added sentence to note that height is only collected as part of full physical exam at screening (In section 1.2 Synopsis 
Flowchart) 
18  Addition of Gamma Glutamyl Transferase (GGT) test to screening labs and instructions on additional testing for liver toxicity 
management to safety laboratory section.  Removed note that follow-up microscopy will be done at discretion of Investigator 
as will be done automatically for all abnormal results.   (In section 1.2 Synopsis Flowchart) 
19  Clarified language regarding PK sampling timing, including instructions for sampling when full regimen or linezolid paused or 
when linezolid is reduced. Included language regarding recoding of dates and times of previous 2 doses of IMP. (In section 
1.2 Synopsis Flowchart) 
20  Updated Sputum Sampling details: 
Clarified and detailed testing on sputum vs. isolate in table (In section 1.2 Synopsis Flowchart) 
Addition of details on extended DST to inform patient treatment at appropriate labs (In section 1.2 Synopsis Flowchart) 
411 of 784


 
 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version:  Version 2.0, dated 13 June 2018 
Protocol Name:     ZeNix 
 
 
Protocol Amendment Template 
 
 
TMP02-C V3.0 dated 06Dec2017 
 
 
 
 
 
 
 
 
 
Page 3 of 36 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
Clarified timing of tests, detailing requirements for testing on first positive samples at/after week 16 (addition) for extension 
or at/after end of treatment for potential new infections (In section 1.2 Synopsis Flowchart and 7.5 Mycobacteriology 
Characterization and Variable and Procedures) 
Clarified use of pre-screening, adding scenario to support testing for inclusion into the trial. (In section 1.2 Synopsis 
Flowchart) 
Removed details on handling of pre-screening samples. (In section 1.2 Synopsis Flowchart and 7.5 Mycobacteriology 
Characterization and Variable and Procedures) 
Moved wording on isolate testing (EMS preference and scenarios for requesting second isolate) to footnote under table (In 
section 1.2 Synopsis Flowchart) 
Clarified that cultures should be stored (In section 1.2 Synopsis Flowchart) 
Clarified testing done at Central lab to describe scenarios for paired genotyping to determine relapse/reinfection (In section 
1.2 Synopsis Flowchart) 
Moved details on unscheduled visits to section 5.4.3 
 
21  Removal of Isoniazid (INH) resistance as an inclusion criteria (In section 5.1 Inclusion Criteria, section 5.4 Discontinuation 
from Treatment/Trial) 
Clarified requirements for documented resistance to make it clear that testing done at screening can be used for inclusion 
into trial (In section 5.1 Inclusion Criteria) 
22  Updated Contraception inclusion criteria to align clarify differences between female participants and male participant’s 
female partners (In section 5.1 Inclusion Criteria) 
Changed required period for male participants to practice birth control methods from 6 months to 12 weeks to align with 
guidance in IB (In section 5.1 Inclusion Criteria) 
Removed “female partners of male participants” in note about hormone based contraception as female partners not taking 
IMP (In section 5.1 Inclusion Criteria) 
23  Clarified exclusion based on resistance to study IMP to specific historic DST or MIC results and added wording to consult 
Sponsor Medical Monitor (In section 5.2 Exclusion Criteria) 
24  Updated Previous and Concomitant Therapy exclusion section to: 
Reference restriction section (and removal of the detailed examples) for exclusion of patients who have planned use of those 
medications  (In section 5.2 Exclusion Criteria and section 5.3 Restrictions) 
412 of 784


 
 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version:  Version 2.0, dated 13 June 2018 
Protocol Name:     ZeNix 
 
 
Protocol Amendment Template 
 
 
TMP02-C V3.0 dated 06Dec2017 
 
 
 
 
 
 
 
 
 
Page 4 of 36 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
Removed exclusion criteria for participants with existing TB diagnosis and HIV coinfection to have been on ARTs for at least 
4 weeks prior to screening as not necessary, as suppressed viral load and minimum CD4 count indicates that the 
participant’s HIV is controlled (In section 5.2 Exclusion Criteria) 
Changed requirement for participants with newly diagnosed TB and HIV for receipt of at least 2 weeks of an anti-tuberculosis 
regimen instead of study medication as many participants are already on TB medications when screened for trial (In section 
5.2 Exclusion Criteria) 
25  Addition of laboratory units utilized by the central lab and correction of units for viral load and Albumin (In section 5.2 
Exclusion Criteria) 
26  Addition of wording to note that no protocol waivers will be granted by the TB Alliance (In section 5.2 Exclusion Criteria) 
27  Updated Concomitant therapy restrictions to distinguish medications that are strictly prohibited, must be discussed and 
approved prior to use or should be avoided with option to contact the Sponsor Medical Monitor to discuss.  (Section 5.3 
Restrictions) 
28  Updated Discontinuation from Treatment/Trial section:  
Clarified when participant “must” be withdrawn vs. “may” be withdrawn post discussion with Sponsor Medical Monitor (In 
section 5.4.1 Treatment Discontinuation and Early Withdrawal) 
Clarified that withdrawal for pregnancy not relevant post treatment completion trial (In section 5.4.1 Treatment 
Discontinuation and Early Withdrawal) 
Clarified withdrawal for safety reasons to include concerns of symptomatic TB (failure/relapse) (In section 5.4.1 Treatment 
Discontinuation and Early Withdrawal) 
Clarified withdraw at anytime at discretion of Investigator for safety, administrative, or compliance reasons 
(In section 5.4.1 Treatment Discontinuation and Early Withdrawal) 
Added wording that clarified no follow-up visits will be performed when a participant withdraws consent (In section 5.4.1 
Treatment Discontinuation and Early Withdrawal) 
Added section to clarify what visits/assessments are done post early withdrawal (In section 5.4.2 Early Withdrawal Follow-
up) 
Moved section on unscheduled visits/assessments are done post early withdrawal (In section 5.4.3 Unscheduled Visits) 
Removed wording from unscheduled visit section that instructed investigator to contact medical monitor to discuss outcome 
status scenarios (In section 5.4.4 Early Withdrawal due to TB)  
29  Clarified that cards and bottles will be checked for unused tablets at each treatment visit (In section 6.2 Participant 
Compliance) 
413 of 784


 
 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version:  Version 2.0, dated 13 June 2018 
Protocol Name:     ZeNix 
 
 
Protocol Amendment Template 
 
 
TMP02-C V3.0 dated 06Dec2017 
 
 
 
 
 
 
 
 
 
Page 5 of 36 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
30  Updated IMP package labeling requirements to reflect the same information as the updated label, removal of sponsor 
address and phone number (In section 6.4 IMP Packaging and Labelling) 
31  Addition of wording to note that patients are not required to be withdrawn if their treatment blind is broken (In section 6.6 
Blinding and Procedures for Breaking the Blind) 
32  Addition of alcohol use to clinically significant medical and treatment history (In section 7.1 Demographic and Background 
Variables and Procedures)  
33  Addition of viral load and electrochemiluminescence as example of HIV test (In section 7.1 Demographic and Background 
Variables and Procedures) 
34  Addition of concomitant medications (In section 7.1 Demographic and Background Variables and Procedures) 
35  Removed appendices and references to appendices for EQ-5D-5L, BPNS and TB Symptoms profiles and referenced the 
ZeNix Subject Questionnaires Guideline, for the current forms. (In section 7.2 Efficacy Variable and Procedures, 7.3 Safety 
and Tolerability of Assessments, 7.5 Mycobacteriology Characterization Variable and Procedures) 
36  Addition of reference to Liver Toxicity Management Guideline (In section 8.3.2 ALT, AST, and Alkaline Phosphatase 
Elevation) 
37  Addition of reference to health authority, where applicable for protocol deviation reporting (In Section 11.3 Protocol 
Deviations) 
38  Administrative changes, including spelling, grammar and format changes have been applied to the entire document. Refer to 
the ‘tracked changes’ for details of changes made 
 
 
# 
Section 
Previous Text 
Version 1.0, dated 23-Feb-17 
 
Amended Text 
Version 2.0, dated 13-Jun-18 
Additional text - bold font. Deleted text – strike-through. 
Reason 
for 
Change 
Insert reason # 
from table above 
1 
1.1  Synopsis 
Summary  
Participants will have a screening period of up to 9 days and will be 
randomized to receive one of the 4 active treatment arms. Participants 
will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an 
interactive web response system (IWRS) which will utilize a dynamic 
randomization system using minimization with a random element to 
allocate participants evenly across the arms by HIV status and type of 
TB.   
 
Participants will have a screening period of up to 14 days and will be 
randomized to receive one of the 4 active treatment arms. 
Participants will be randomized to one of the four regimens in a 
1:1:1:1 ratio, using an interactive voice and web response system 
(IXRS) which will utilize a randomization system using stratification 
with a random element to allocate participants evenly across the 
arms by HIV status and type of TB.   
 
1,3,4, 
and 5 
414 of 784


 
 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version:  Version 2.0, dated 13 June 2018 
Protocol Name:     ZeNix 
 
 
Protocol Amendment Template 
 
 
TMP02-C V3.0 dated 06Dec2017 
 
 
 
 
 
 
 
 
 
Page 6 of 36 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
Each participant will receive 26 weeks of treatment.  If participant’s week 
16 sample remains culture positive, Investigator may consider extending 
current treatment to 39 weeks, in consultation with the Sponsor Medical 
Monitor 
 
Participants will be followed for 78 weeks after end of treatment. 
Each participant will receive 26 weeks of treatment   they may have 
an ongoing TB infection, Investigator may consider extending 
current treatment to 39 weeks.   If the culture results between week 
16 and week 26 are contaminated, missing or considered an 
isolated positive without clinical significance, available culture 
results should be used to make this decision. All decisions regarding 
treatment extension should be discussed with and approved by the 
Sponsor Medical Monitor before implementation. 
 
Participants will be followed for 78 weeks after end of treatment. 
2 
1.1  Synopsis 
Summary 
A total of up to 180 participants: 
120 (30 per treatment arm) XDR-TB participants, and up to 60 (15 per 
arm) pre-XDR or treatment intolerant/non-responsive MDR pulmonary 
tuberculosis Participants, male and female, aged 14 and over. 
Enrollment will stop when 120 XDR-TB participants are randomized. 
Sponsor may consider replacement of late screen failure and un-
assessable (as detailed in the statistical analysis plan) participants. 
A total of up to 180 participants male and female, aged 14 and over. 
Sponsor may consider replacement of late screen failure and un-
assessable (as detailed in the statistical analysis plan) participants. 
2 
3 
1.1  Synopsis 
Summary  
The test product will be supplied as: 
• 
bedaquiline 100 mg tablets 
• 
pretomanid 200 mg tablets 
• 
linezolid (scored) 600 mg tablets 
• 
placebo linezolid (scored) 600 mg tablets 
• 
linezolid half tablet (pre-cut) 300 mg  
• 
placebo linezolid half tablet (pre-cut) 300 mg 
 
Linezolid treatment will be supplied as 2 rows of full tablets and one row 
of half-tablets to allow for all possible dosing options while maintaining 
the blind.  
 
Treatment will be administered orally, once daily, with a full glass of 
water and a meal in the following dosing schemes (treatment arms): 
Participants will receive the following: 
• 
bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily 
for 18 weeks plus;  
• 
pretomanid 200 mg once daily for 26 weeks plus; 
• 
Linezolid- participants will be randomly assigned to receive one of 
the following four linezolid treatment doses and durations:  
The regimen will be supplied as the following: 
 
Product 
Tablet Strength 
Abbreviation  
Bedaquiline 
100 mg  
(B) 
Pretomanid 
200 mg  
(Pa) 
Linezolid (scored) 
600 mg 
(L) 
Placebo Linezolid 
(scored) 
placebo 
(L) 
Linezolid 600 mg 
half tablet (pre-
cut) 
300 mg 
(L) 
 
Placebo linezolid 
600 mg half tablet 
(pre-cut) 
placebo 
(L) 
 
Linezolid treatment will be supplied as 2 rows of full tablets (active 
or placebo) and one row of half-tablets (active or placebo) to allow 
for all possible dosing options while maintaining the blind.  
 
Instructions for Dosing: 
6 
415 of 784


 
 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version:  Version 2.0, dated 13 June 2018 
Protocol Name:     ZeNix 
 
 
Protocol Amendment Template 
 
 
TMP02-C V3.0 dated 06Dec2017 
 
 
 
 
 
 
 
 
 
Page 7 of 36 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
Linezolid 1200 mg daily for 26 weeks 
• 
2 linezolid 600 mg active tablets once daily for 26 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
• 
2 linezolid 600 mg active tablets once daily for 9 weeks  
• 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
Linezolid 600 mg daily for 26 weeks 
• 
1 linezolid 600 mg active tablet once daily for 26 weeks 
• 
1 placebo linezolid 600 mg tablet once daily for 26 weeks  
• 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid 600 mg tablet for 9 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
 
Treatment will be administered orally, once daily, with a full glass of 
water and a meal in the following dosing schemes (treatment arms): 
 
Participants will receive the following: 
• 
bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• 
pretomanid 200 mg once daily for 26 weeks plus; 
• 
Linezolid- participants will be randomly assigned to receive 
one of the following four blinded linezolid treatment doses and 
durations:  
Linezolid 1200 mg daily for 26 weeks 
• 
2 linezolid 600 mg active tablets once daily for 26 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
 
Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
• 
2 linezolid 600 mg active tablets once daily for 9 weeks  
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
Linezolid 600 mg daily for 26 weeks 
• 
1 linezolid 600 mg active tablet once daily for 26 weeks 
• 
1 placebo linezolid tablet once daily for 26 weeks  
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
 
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid tablet for 9 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
416 of 784


 
 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version:  Version 2.0, dated 13 June 2018 
Protocol Name:     ZeNix 
 
 
Protocol Amendment Template 
 
 
TMP02-C V3.0 dated 06Dec2017 
 
 
 
 
 
 
 
 
 
Page 8 of 36 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid tablet for 9 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
4 
1.1  Synopsis 
Summary  
Treatment Modifications: 
 
The above treatment schemes may require modification due to toxicities 
as noted below. All dose modifications should be discussed with the 
Sponsor Medical Monitor prior to implementation, unless a pause or 
dose reduction is required urgently for a safety concern; the Medical 
Monitor should be informed within 24 hours of the change if not 
discussed prior to implementation 
 
In the event of linezolid specific toxicities, the following should be 
considered and implemented per guidance in the monitoring and safety 
for specific toxicities section of protocol.  Every effort should be made for 
participants to receive a total of 9 weeks of linezolid, even if pauses are 
required: 
• 
Blinded one step reductions (maximum 3 steps) in the dose of 
linezolid (1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or 
300mg QD to placebo) managed by the IWRS as per instructions 
in pharmacy manual and/or IWRS user manual.  
• 
Temporary pause of linezolid due to a linezolid-specific toxicity 
should be considered and implemented per guidance in the 
monitoring and safety for specific toxicities section of protocol. 
• 
Permanent discontinuation of linezolid. 
 
For participants experiencing suspected drug related toxicities due to 
other drugs in the regimen (B-Pa), the full regimen may be halted for up 
to 35 consecutive days.  
Treatment Modifications: 
 
The above treatment schemes may require modification due to 
toxicities as noted below. All dose modifications should be 
discussed with the Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required 
urgently for a safety concern; the Medical Monitor should be 
informed within 24 hours of the change if not discussed prior to 
implementation 
 
In the event of linezolid specific toxicities, the following should be 
considered and implemented per guidance in the monitoring and 
safety for specific toxicities section (8.3) of protocol:   
 
• 
Blinded one step reductions (maximum 2 steps) in the dose 
of linezolid managed by the IXRS as per instructions in 
pharmacy manual and/or IXRS user manual.  
o 1200 mg QD to 600 mg QD, 600 mg QD to 300 mg 
QD or   
o 600 mg QD to 300 mg QD, 300mg QD to placebo  
• 
Temporary pause of linezolid. 
• 
Permanent discontinuation of linezolid. 
• 
Participants who have a linezolid reduction can go back to a 
higher dose (1 step or 2 steps) post discussion with and 
approval by Sponsor Medical Monitor. 
 
 
7 
417 of 784


 
 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version:  Version 2.0, dated 13 June 2018 
Protocol Name:     ZeNix 
 
 
Protocol Amendment Template 
 
 
TMP02-C V3.0 dated 06Dec2017 
 
 
 
 
 
 
 
 
 
Page 9 of 36 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
Interruptions/pauses of all Investigational Medicinal Product (IMP) must 
not exceed 8 weeks (56 days) cumulatively.  
 
If participant’s week 16 sample remains culture positive, Investigator 
may consider option to extend current treatment to 39 weeks, in 
consultation with the Sponsor Medical Monitor. When treatment is 
extended due to a positive culture at week 16, interruptions/pauses of all 
IMP must not exceed 13 weeks (91 days) cumulatively. 
 
At no time should the participant be treated with a single agent. 
For participants experiencing suspected drug related toxicities due 
to other drugs in the regimen (B-Pa), the full regimen may be halted 
for up to 35 consecutive days.  
 
Interruptions/pauses of all Investigational Medicinal Product (IMP) 
must not exceed 8 weeks (56 days) cumulatively.  
 
When treatment is extended to 39 weeks, interruptions/pauses of all 
IMP must not exceed 13 weeks (91 days) cumulatively. 
 
When the total of missed dosing days of the prescribed regimen 
and/or pauses is greater than 7 days, the same number of missed 
doses should be dispensed/treatment extended to make up for the 
total missed doses. 
 
At no time should the participant be treated with a single agent. 
 
Every effort should be made for participants to receive a total of 9 
weeks of linezolid, even if pauses are required 
5 
1.1  Synopsis 
Summary  
Primary Endpoint: 
Incidence of bacteriologic failure or relapse or clinical failure through 
follow up until 26 weeks after the end of treatment. 
 
Primary Endpoint: 
Incidence of bacteriologic failure or relapse, or clinical failure at 26 
weeks after the end of treatment. 
 
 
 
8 
6 
1.1  Synopsis 
Summary  
• 
Descriptive statistics of ophthalmology slit lamp examination data 
(age related eye disease study 2 [AREDS2]) lens opacity 
classification and grading). Categorical data for lens opacity will 
be summarized in a frequency table for the right and left eye, 
respectively, including change from baseline. 
 
• 
Descriptive statistics of ophthalmology slit lamp examination 
data (age related eye disease study 2 [AREDS2]) lens 
opacity classification and grading). Categorical data for lens 
opacity will be summarized in a frequency table for the right 
and left eye, respectively, including observed and change 
from baseline 
 
9 
7 
1.1  Synopsis 
Summary  
Trial Duration: 
~3.5 Years (An enrolment period of at least 18 months plus 9 days pre-
treatment plus 6 month treatment period plus 18 months post treatment 
follow-up). 
Trial Duration: 
~3.5 Years (An enrolment period of at least 18 months plus 14 days 
pre-treatment plus 6 months treatment period plus 18 months post 
treatment follow-up). 
1 
8 
1.2 Synopsis 
Flowchart 
Captured in synopsis flowchart/table under time of visits, screening:  Up to 
9 days prior to Treatment 
Captured in synopsis flowchart/table under time of visits, screening:   
Up to 14 days prior to first dose 
1 
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9 
1.2 Synopsis 
Flowchart 
 
Captured in synopsis flowchart/table (after week 23 treatment): Visits 
every 3 weeks   if extended due to IMP pause or culture (+) at week 16 
 
Captured in synopsis flowchart/table (after week 23 treatment): 
Visits every 3 weeks if extended. 
   
12 
10 
1.2 Synopsis 
Flowchart 
 
Captured in flowchart/table: Ophthalmic exams are performed during 
screening, treatment week 4, week 8, week 12, week 16m week 20 visits 
every 3 weeks if extended, end of OR Early withdrawal from treatment, 
and post treatment follow-up week 4. 
Captured in flowchart/table: Ophthalmic exams are marked as 
performed during screening, treatment week 4, week 8, week 12, 
week 16, week 20, week 23, visits every 3 weeks if extended, end of 
OR Early withdrawal from treatment, post treatment follow-up week 
4, and follow-up week 12. 
10 
11 
1.2 Synopsis 
Flowchart 
 
1.2 Synopsis Flowchart: 
 
Captured in flowchart/table: Post Treatment Follow-up 78 weeks 
 
1.2 Synopsis Flowchart: 
 
Captured in flowchart/table: Post Treatment Follow-up 78 weeks/EW 
 
11 
12 
1.2 Synopsis  
Flowchart 
 
a. 
Screening: Screening assessments can occur on different days 
within nine days prior to Day 1 dosing. If a participant fails screening, 
a full re-screen may occur at a later date post discussion with Medical 
Monitor.  All screening procedures must be repeated at re-screen visit, 
with the exception of the slit lamp examination, which can be used 
from a previous screening if within 8 weeks of anticipated 
randomization. 
 
a.    Screening: Screening assessments can occur on different days 
within 14 days prior to Day 1 dosing (randomization). If a 
participant fails screening, a full re-screen may occur at a later 
date.  All screening procedures must be repeated at re-screen 
visit, with the exception of the slit lamp examination, which can 
be used from a previous screening if within 8 weeks of 
anticipated randomization. 
 
1 and 5 
13 
1.2 Synopsis  
Flowchart 
 
b.  Visit Schedule: If the duration of treatment is extended due to dose  
pauses (e.g., takes participant 35 weeks to complete 26 weeks of 
treatment) or positive week 16 culture, unscheduled visits should be 
added every 3 weeks (+/- 7 days).  End of treatment visit (final 
treatment visit) should be done within 7 days AFTER the last dose of 
IMP.  
1. If participant completes treatment at week 26, end of 
treatment visit should be done within 7 days after last dose of 
week 26. 
2. If participant completes 26 weeks of therapy at week 33 due 
to pauses, visits can be done at weeks 26, 29 and 33 (3 weeks 
from week 29 plus 7-day window). The week 33 visit would be 
the end of treatment visit and should be completed within 7 
days after last dose. 
3. If participant completes treatment at week 39 due to post 
treatment extension related to positive culture at week 16, 
visits can be completed at weeks 26, 29, 32, 35 and 39 (3 
b. 
Visit Schedule: If the duration of treatment is extended (see 
section 6.3, Treatment Modifications for details), unscheduled 
visits should be added every 3 weeks (+/- 7 days).   
1. End of treatment visit (final treatment visit) should 
be done within 7 days AFTER the last dose of IMP.  
2. If participant completes 26 weeks of therapy at 
week 33 due to full regimen pauses, an EXAMPLE 
of visit scheduling would be weeks 26, 29 and 33 (3 
weeks from week 29 plus 7-day window). In this 
scenario, the week 33 visit would be the end of 
treatment visit and should be completed within 7 
days after last dose. 
3. If participant completes treatment at week 39 due to 
treatment extension, an example of visit scheduling 
would be visits at weeks 26, 29, 32, 35 and 39/End 
of treatment (3 weeks plus 7-day window).  
4. Follow-up visits should be scheduled based on 
timing of end of last dose of IMP (e.g., 4-week 
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weeks plus 7-day window), visit at week 39 would be the end 
of treatment visit. 
4. Follow-up visits should be scheduled based on timing of end 
of treatment/early withdrawal from treatment (e.g., 4-week 
follow-up to be scheduled 4 weeks after last dose of IMP). 
 
follow-up to be scheduled 4 weeks after last dose of 
IMP). 
 
14 
1.2 Synopsis  
Flowchart 
 
c. 
Follow-up Visits Early Withdrawal Participants: Once a participant 
has been discontinued from treatment, they will be required to attend 
an Early Withdrawal visit. If participant: 
 
1. Received/took < 14 doses, no additional follow-up visits are 
required.   
2. Received 15 or more doses, follow-up after end of treatment 
at week 12, week 26 (if not already performed) and week 78 
are required. The week 12 visit will only require the 
ophthalmologic exams. The week 26 and 78 follow-up visits 
will be to collect Serious Adverse Event (SAE) information 
(including verification of survival) and patient reported TB 
outcome information only and may be telephonic, a home or 
a site visit. This includes participants who are withdrawn from 
the trial due to meeting the treatment failure endpoint. 
Participant may need to return for visits to collect sputum 
samples to determine outcome status as per section “r”. 
 
c. Follow-up Visits Early Withdrawal Participants: Once a 
participant has been discontinued, they will be required to 
attend an Early Withdrawal visit. If participant: 
1. Received/took < 14 doses, no additional follow-up visits 
are required.   
2. Received 15 or more doses and is withdrawn during 
treatment, follow-up after end of treatment/EW visit at 
week 12, week 26 (if not already performed) and week 
78 are required. The follow-up week 12 visit will only 
require the ophthalmologic exams. The week 26 and 78 
follow-up visits will be to collect Serious Adverse Event 
(SAE) information (including verification of survival) and 
patient reported TB outcome information only and may 
be telephonic, a home or a site visit. This includes 
participants who are withdrawn from the trial due to 
meeting the treatment failure endpoint. Participant may 
need to return for visits to collect sputum samples to 
determine outcome status. 
3. For participants who are withdrawn during post treatment 
follow-up, site should perform study procedures required 
for week 78 post treatment follow-up visit. If participant 
will not return for visit, site should obtain information on 
SAE and patient reported TB outcome as noted above in 
no 2. 
 
11 
15 
1.2 Synopsis 
Flowchart 
 
e. 
HIV testing: If HIV status is a confirmed known positive, repeated 
HIV test is not needed provided that a documented HIV test result 
(ELISA, Western Blot or Electro-Chemiluminescence) is available. If 
HIV status is unknown or suspected negative, HIV test will be 
requested. If an ELISA and/or Western Blot and/or Electro-
Chemiluminescence based HIV test was performed within 4 weeks 
prior to screening, it should not be repeated if documentation of 
testing method and negative HIV results can be provided. Repeated 
e. 
HIV testing: If HIV status is a confirmed known positive, 
repeated HIV test is not needed provided that a documented 
HIV 
test result (ELISA, Western Blot or 
Electro-
Chemiluminescence) is available. If HIV status is unknown or 
suspected negative, HIV test will be requested. If an ELISA 
and/or Western Blot and/or Electro-Chemiluminescence based 
HIV test was performed within 4 weeks prior to screening, it 
should not be repeated if documentation of testing method and 
negative HIV results can be provided. Repeated HIV testing, 
13 
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HIV testing, during the Screening period is permitted for 
indeterminate HIV results. 
 
during the Screening period is permitted for indeterminate HIV 
results. 
16 
1.2 Synopsis 
Flowchart 
f. CD4 count and viral load: For all HIV-positive participants, viral load 
and CD4 at screening, CD4 only tested at end of treatment or early 
withdrawal. 
f. 
CD4 count and viral load:  Required for all HIV-positive 
participants. Viral load and CD4 required at screening, CD4 
will be tested at end of treatment or early withdrawal from 
treatment visit. 
14 
17 
1.2 Synopsis  
Flowchart 
 
g. Chest X-Ray: A chest x-ray (digital image) within one month prior to 
screening, will be obtained and read locally by Investigator or 
designee. Digital images will be provided to Sponsor, this process will 
be described in a separate document, the Radiology Manual. 
g. 
Chest X-Ray: A chest x-ray (digital image) within 6 months 
one month prior to or at screening, will be obtained and read 
locally by Investigator or designee. Digital images will be 
provided to Sponsor, this process will be described in a 
separate document, the Radiology Manual 
15 
18 
1.2 Synopsis  
Flowchart 
 
k. Single 12-Lead ECG: To every extent possible, should be performed 
at approximately the same time of day (+/- 1 hours) and in the same 
fed/fasted state throughout the trial (e.g. 4 hours after lunch). Central 
ECG analysis will be performed. 
k. 
Single 12-Lead ECG: When possible, should be performed 
at approximately the same time of day (+/- 1 hours) and in the 
same fed/fasted state throughout the trial (e.g. 4 hours after 
lunch). Central ECG analysis will be performed. Central 
reading of screening results will be used to determine 
eligibility. 
16 
19 
1. 2 Synopsis 
Flowchart 
 
l.    Physical Exam:  Limited Physical exams should include weight and 
a gross neurological, pulmonary, cardiovascular and abdominal 
exam. 
l.        Physical Exam:  Limited Physical exams should include 
weight and a gross neurological, pulmonary, cardiovascular 
and abdominal exam. Height will only be collected as part of 
full exam at screening. 
17 
20 
1.2 Synopsis 
Flowchart 
 
m. Safety Laboratory Assessments: The Safety Laboratory sampling 
methodology and requirements will be described in a separate 
document, the Laboratory Manual, which will be provided prior to the 
trial start. The following analyses will be performed: 
1. Full Blood Count (hemoglobin, hematocrit, red blood cell 
count, white blood cell count with differential, platelet 
count).  
2. Clinical Chemistry (albumin, serum urea, creatinine, 
direct, indirect and total bilirubin, uric acid, total protein, 
alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), lipase, phosphate, 
sodium, potassium, calcium (corrected for albumin), 
chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK). 
3. Urinalysis (pH, specific gravity, protein, glucose, micro-
albumin, ketones, bilirubin, creatinine, nitrite, sodium, 
m. 
Safety Laboratory Assessments/Urine Drug Screen: The 
Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, 
which will be provided prior to the trial start. The following 
analyses will be performed: 
• 
Full Blood Count (hemoglobin, hematocrit, red blood cell 
count, white blood cell count with differential, platelet 
count).  
• 
Clinical Chemistry (albumin, serum urea, creatinine, 
direct, indirect and total bilirubin, uric acid, total protein, 
alkaline phosphatase, aspartate aminotransferase 
(AST), 
alanine 
aminotransferase 
(ALT), 
lipase, 
phosphate, sodium, potassium, calcium (corrected for 
albumin), 
chloride, 
magnesium, 
glucose, 
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urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per 
discretion of Investigator. 
4. Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, opiates, benzodiazepines, barbiturates, 
at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 5. Positive 
results will not automatically exclude participant from the 
trial. 
 
bicarbonate/CO2, creatine phosphokinase (CPK).  GGT 
will be done at screening. 
• 
When managing participants with elevated liver enzymes 
at an unscheduled visit, the Investigator can request 
additional tests, in addition to the repeated LFT [e.g. 
Gamma Glutamyl Transferase, screening for hepatitis A, 
B, C; to assist in ruling out other causes of abnormal liver 
test (e.g. alcohol induced hepatic cell injury, hepatobiliary 
disease, hepatic viral infection). 
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-
albumin, ketones, bilirubin, creatinine, nitrite, sodium, 
urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis. 
• 
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, opiates, benzodiazepines, barbiturates, 
at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 2.  Positive 
results will not automatically exclude participant from the 
trial. 
21 
1.2 Synopsis  
Flowchart 
 
o. PK Sampling:  Specific PK blood draws as follows: 
1. Day 1; pre-dose (within 2 hours prior to dosing) 
2. Week 2: pre-dose (within 2 hours prior to dosing), 2–3 
hours post-dose and 6–8 hours post-dose 
3. Week 8: pre-dose (within 2 hours prior to dosing), 2–3 
hours post-dose and 6–8 hours post-dose 
4. Week 12: pre-dose (within 2 hours prior to dosing)  
5. Week 20 or at early withdrawal if prior to week 20: pre-
dose (within 2 hours prior to dosing) and 2–3 hours post-
dose. 
When participant is discharged and seen as an outpatient, site should 
make every effort to collect 6-8 hour samples at weeks 8 and when 
operationally and logistically feasible. 
If dosing of any component of the regimen has been paused, and no 
dose of some component is given on the scheduled day of sampling, 
then defer the sampling until the dosing of all components has been 
resumed, even if some component is at a different dose level, and bring 
the patient back for sampling on an unscheduled visit when all 
o. PK Sampling:  The dates and times of the two doses of IMP taken 
prior to all pre-dose PK samples will be collected in the eCRF.    
 
Specific PK blood draws will be obtained as follows (pre-dose to 
be done after ECGs): 
1. Day 1; pre-dose (within 2 hours prior to dosing) 
2. Week 2: pre-dose (within 2 hours prior to dosing), 2–3 
hours post-dose and 6–8 hours post-dose 
3. Week 8: pre-dose (within 2 hours prior to dosing), 2–3 
hours post-dose and 6–8 hours post-dose 
4. Week 12: pre-dose (within 2 hours prior to dosing)  
5. Week 20 or at early withdrawal if prior to week 20: pre-
dose (within 2 hours prior to dosing) and 2–3 hours post-
dose 
• 
When participant is discharged and seen as an 
outpatient, site should make every effort to collect 6-8 
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components are administered. If the site has permanently discontinued 
linezolid due to toxicity, sampling should be done on a day when the 
bedaquiline and pretomanid are dosed. 
hour sample at week 8 when operationally and 
logistically feasible.  
• 
Hospitalization information (e.g. discharge date) will be 
collected in the eCRF. 
• 
If the full regimen or linezolid is paused, PK sampling 
should be delayed until full regimen or linezolid are 
resumed. 
• 
PK sampling should be completed even if the 
participant’s linezolid dose has been lowered or 
Linezolid has been permanently discontinued.  
• 
Sites may bring participant back at a scheduled or 
unscheduled visit (can occur outside of visit windows) to 
collect PKs to ensure draw is done when IMP is 
administered.  
 
22 
 
1.2 Synopsis 
Flowchart 
 
 
 
SPUTUM SAMPLES GENERAL: If EMS is not available, site should make 
every attempt to collect two spot samples at least 30 minutes apart.  
 
BASELINE: If available, site will request pre-screening culture that was 
used for the tests that qualified the participant for inclusion into the trial to 
 
5 and 20 
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be subcultured and shipped to the study lab from the applicable lab for 
relevant participants with no positive cultures from screening through week 
4 (with consent). Samples should be stored according to the applicable lab 
procedures until shipment to the designated study lab. Included with each 
shipment will be a copy of the applicable lab reports and all participant 
identifying information redacted and a completed shipment inventory form 
with appropriate participant trial identifiers. Details on how samples will be 
packed and shipped will be provided in the lab manual. 
 
POSITIVE MTB AT/AFTER END OF TREATMENT: Only one isolate 
(preferably from EMS) should be shipped. Second isolate may be 
requested if first is contaminated.  
 
MOLECULAR TESTING:  
• 
At Screening: GeneXpert, Hain MTBDRplus or equivalent to 
determine MTB complex and R resistance. 
• 
Positive MTB at/after end of treatment: Hain MTBDRplus and 
HainMTBRsl 
 
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including but not 
limited to FQ and injectables. 
 
STORAGE: MTB isolates from all positive cultures to be stored at the 
study laboratory until trial closure for the applicable study tests. The 
extracted MTB DNA from the applicable baseline and follow-up isolates 
will also be stored at the central lab for potential further work to validate 
new assay tools for 5 years after trial closure. 
 
CENTRAL LAB: Results from testing at Central myco lab (MIC, DST and 
genotyping) will not routinely be provided to sites.  In the event of 
participant relapse/failure, Sponsor will provide available results to the site 
in order to inform appropriate participant treatment. 
 
UNSCHEDULED VISITS: If cultures of both spot sputum samples are 
contaminated at the following visits, or if necessary in order to help define 
a participant’s outcome status/assess culture status during follow-up, the 
participant should return for an unscheduled visit(s) to give additional 
samples or to document the participant is not able to produce sputum: 
  
 
SPUTUM SAMPLES GENERAL: If EMS (early morning sputum) is 
not available, site should make every attempt to collect two spot 
samples at least 30 minutes apart.  
 
PRE-SCREENING SAMPLES: If consent granted by participant, and 
when applicable, site can request pre-screening culture/isolate/DNA 
from current TB diagnosis/disease course to be sub-cultured and 
shipped and/or tested: 
• 
at the study lab if/when those samples could support 
inclusion in trial.  
• 
at the study/central lab for relevant participants with no 
baseline (no positive cultures from screening through week 
4). 
 
MOLECULAR TESTING:  
• 
At Screening: GeneXpert, Hain MTBDRplus or equivalent to 
determine MTB complex and Rifampicin resistance. 
• 
Positive MTB at/after week 16: Hain MTBDRplus and 
HainMTBRsl 
 
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including 
but not limited to fluoroquinolones and injectables. 
 
STORAGE: MTB isolates from all positive cultures to be stored at the 
study laboratory until trial closure for the applicable study tests. The 
cultures as well as the extracted MTB DNA from the applicable 
baseline and follow-up isolates will also be stored at the central lab 
for potential further work to validate new assay tools for 5 years after 
trial closure. 
 
CENTRAL LAB: Results from testing at central lab (MIC, DST and 
genotyping) will not routinely be provided to sites.  In the event that 
results are necessary to determine appropriate participant treatment, 
Sponsor will provide available drug susceptibility results to the site. 
Genotyping will be performed on paired DNA extracts to determine if 
the participant was a relapse or reinfection (See SAP for details). 
 
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• 
End of treatment visit; 
• 
Week 26 post treatment follow-up visit; 
• 
Post treatment follow-up visits from week 8 through week 65 
(in addition to week 26 follow-up); 
• 
End of Follow-up Period (week 78 post treatment completion 
visit); 
• 
Early Withdrawal (if applicable). 
 
At the end of 26 weeks and 78 weeks post treatment completion, to define 
outcome status, need to confirm whether the participant has: 
• 
At least two sequential negative sputum culture results; or  
• 
At least two sequential positive sputum culture results; or  
• 
Has been unable to produce sputum after documentation of 
at least two negative sputum cultures with no intervening 
positive and are clinically asymptomatic. 
 
If they do not fall into one of these categories, site should continue to 
collect sputum samples x 2 (one Early Morning and one Spot at the 
research site or 2 spots samples at least 30 minutes apart, under the 
coaching and observation of the trial staff) at a minimum of 7 days or 
more apart until they fall into one of the above categories. 
 
If in any of the above scenarios the Investigator is unsure of the 
outcome, the Investigator must contact the Sponsor Medical Monitor to 
discuss and agree on how the patient is to be handled. 
EXTENDED DST TESTING: Paired isolates from baseline and 
at/after week 16 should be shipped to a relevant lab (as 
applicable/available per Country) for DST extending beyond the 
panel of drugs tested at the central lab.  Extended results will be 
provided to the site to inform appropriate participant treatment.   
 
 
23 
4.1 Summary of 
Trial Design 
Enrolment will stop when 120 XDR-TB participants are randomized. 
Participants will be randomized to one of the four regimens in a 1:1:1:1 
ratio, using an interactive web response system (IXRS) which will utilize a 
dynamic randomization system using minimization with a random element 
to allocate participants evenly across the arms by HIV status and type of 
TB after they have given written, informed consent and met all eligibility 
criteria.  
Participants will be randomized to one of the four regimens in a 
1:1:1:1 ratio, using an interactive voice and web response system 
(IXRS) which will utilize a randomization system using stratification 
with a random element to allocate participants evenly across the arms 
by HIV status and type of TB after they have given written, informed 
consent and met all eligibility criteria.  
2 
24 
4.1 Summary of 
Trial Design 
Each participant will receive 26 weeks of treatment.  If participant’s week 
16 sample remains culture positive, Investigator may consider option to 
extend current treatment to 39 weeks, in consultation with the Sponsor 
Each participant will receive 26 weeks of treatment. If participant’s 
sputum sample is culture positive between the week 16 and week 26 
treatment visits and their clinical condition suggests they may have 
4 and 5 
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Medical Monitor. Participants will be followed for 78 weeks after end of 
treatment. 
an ongoing TB infection, Investigator may consider extending current 
treatment to 39 weeks.   If the culture results between week 16 and 
week 26 are contaminated, missing or considered an isolated positive 
without clinical significance, available culture results should be used 
to make this decision. All decisions regarding treatment extension 
should be discussed with and approved by the Sponsor Medical 
Monitor before implementation. Participants will be followed for 78 
weeks after end of treatment. 
25 
5.1 Inclusion 
Criteria 
3. HIV testing (if an HIV test was performed within 1 month prior to 
screening, it should not be repeated as long as documentation can 
be provided [ELISA and/or Western Blot].  If HIV status is a 
confirmed known positive, repeated HIV test is not needed provided 
documentation is available 
3. HIV testing (if an HIV test was performed within 1 month prior to 
screening, it should not be repeated as long as a documented 
result can be provided [ELISA and/or Western Blot and/or 
Electro-Chemiluminescence].  If HIV status is a confirmed known 
positive, repeated HIV test is not needed if ELISA and/or Western 
Blot and/or Electro-Chemiluminescence documentation of 
positive is available. 
13 
26 
5.1 Inclusion 
Criteria 
5. Participants with one of the following pulmonary TB conditions: 
a.  XDR-TB with  
i. 
A documented culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 
months prior to screening or MTB confirmed in sputum 
based on molecular test within 3 months prior to or at 
screening and: 
ii. 
historical documented resistance to isoniazid, rifamycins, a 
fluoroquinolone AND an injectable during the current TB 
diagnosis/disease course;  
b. 
Pre-XDR-TB with 
i. 
A documented culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 
months prior to screening or MTB confirmed in sputum 
based molecular test within 3 months prior to or at 
screening and; 
ii. 
historical documented resistance to isoniazid, rifamycins, 
and to a fluoroquinolone OR an injectable during the 
current TB diagnosis/disease course. 
c. 
MDR-TB with 
i. 
documented by culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected results within 
5. Participants with one of the following pulmonary TB conditions: 
a. 
 XDR-TB with  
i. A documented culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 months 
prior to screening or MTB confirmed in sputum based on 
molecular test within 3 months prior to or at screening and: 
ii. documented resistance to rifamycins, a fluoroquinolone 
AND an injectable during the current TB diagnosis/disease 
course any time prior to or during screening period (may be 
sensitive or resistant to isoniazid);  
b. 
Pre-XDR-TB with 
i. A documented culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 months 
prior to screening or MTB confirmed in sputum based 
molecular test within 3 months prior to or at screening and; 
ii. documented resistance to 
rifamycins, and 
to 
a 
fluoroquinolone OR an injectable during the current TB 
diagnosis/disease course any time prior to or during 
screening period (may be sensitive or resistant to isoniazid); 
c. 
MDR-TB with 
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3 months prior to screening or MTB confirmed in sputum 
based on molecular test within 3 months prior to or at 
screening and; 
ii. 
historical documented resistance to isoniazid and 
rifamycins during the current TB diagnosis/disease course; 
iii. 
with documented non-response to treatment with the best 
available regimen for 6 months or more prior to enrolment 
who in the opinion of the Investigator have been adherent 
to treatment and will be adherent to study regimen.   
d. 
MDR-TB with  
i. 
documented by culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 
months prior to screening or MTB confirmed in sputum 
based on molecular test within 3 months prior to or at 
screening and: 
ii. 
historical documented resistance to isoniazid and 
rifamycins during the current TB diagnosis/disease course 
and; 
iii. 
who are unable to continue second line drug regimen due 
to a documented intolerance to: 
a. PAS, ethionamide, aminoglycosides or 
fluoroquinolones or ; 
b. Current treatment not listed above that renders 
participant eligible for the study in the Investigator’s 
opinion. 
i. documented by culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected results within 3 
months prior to screening or MTB confirmed in sputum 
based on molecular test within 3 months prior to or at 
screening and; 
ii. documented resistance to rifamycins during the current TB 
diagnosis/disease course any time prior to or during 
screening period (may be sensitive or resistant to isoniazid) 
and; 
iii. with documented non-response to treatment with the best 
available regimen for 6 months or more prior to enrolment 
who in the opinion of the Investigator have been adherent to 
treatment and will be adherent to study regimen.   
d. 
MDR-TB with  
i. documented by culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 months 
prior to screening or MTB confirmed in sputum based on 
molecular test within 3 months prior to or at screening and: 
ii. documented resistance rifamycins during the current TB 
diagnosis/disease course any time prior to or during 
screening period (may be sensitive or resistant to isoniazid) 
and; 
iii. who are unable to continue second line drug regimen due to 
a documented intolerance to: 
a. PAS, ethionamide, aminoglycosides or fluoroquinolones 
or ; 
b. Current treatment not listed above that renders 
participant eligible for the study in the Investigator’s 
opinion.  
27 
5.1 Inclusion 
Criteria 
Chest X-Ray within 1 months prior at screening, obtained and read locally 
by investigator or designee with results consistent with pulmonary TB in 
the opinion of the Investigator. 
Chest X-Ray within 6 months prior to or at screening, obtained and 
read locally by investigator or designee with results consistent with 
pulmonary TB in the opinion of the Investigator. 
15 
28 
5.1 Inclusion 
Criteria 
Contraception: 
7. Be of non-childbearing potential or using effective methods of birth 
control, as defined below: 
 
Contraception: 
7. Be of non-childbearing potential or using effective methods 
of birth control, as defined below: 
 
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Non-childbearing potential: 
a. Participant - not heterosexually active or practices sexual 
abstinence; or  
b. Female 
participant/sexual 
partner 
- 
bilateral 
oophorectomy, 
bilateral 
tubal 
ligation 
and/or 
hysterectomy or has been postmenopausal with a history 
of no menses for at least 12 consecutive months; or  
c. Male participant/sexual partner - vasectomised or has 
had a bilateral orchidectomy at least three months prior 
to Screening. 
 
Effective birth control methods:                                            
A double contraceptive method should be used as follows: 
a. Double barrier method which can include any 2 of the 
following: a male condom, diaphragm, cervical cap, or 
female condom (male and female condoms should not be 
used together); or  
b. Barrier method (one of the above) combined with 
hormone-based contraceptives or an intra-uterine device 
for the female participant/partner; 
 
And are willing to continue practicing birth control methods throughout 
treatment and for 6 months (both male and female participants) after the 
last dose of study medication. 
 
Note: Hormone based contraception alone may not be reliable when 
taking IMP; therefore, hormone based contraceptives alone cannot be 
used by female participants or female partners of male participants to 
prevent pregnancy. 
 
Non-childbearing potential: 
a. Participant - not heterosexually active or practices 
sexual abstinence; or  
b. Female participant or male participant’s female 
sexual partner - bilateral oophorectomy, bilateral 
tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at 
least 12 consecutive months; or  
c. Male participant or female participant’s male sexual 
partner - vasectomised or has had a bilateral 
orchidectomy at least three months prior to 
screening. 
 
Effective birth control methods:                                     
a. Double barrier method which can include a male 
condom, diaphragm, cervical cap, or female condom; 
or  
b. Female participant: Barrier method combined with 
hormone-based contraceptives or an intra-uterine 
device for the female participant; 
c. Male participant’s female sexual partner: Double 
barrier method or hormone based contraceptives or 
an intra-uterine device for the female partner. 
 
And are willing to continue practicing birth control methods 
throughout treatment and for 6 months female participants and 12 
weeks (male participants) after the last dose of study medication. 
 
Note: Hormone based contraception alone may not be reliable 
when taking IMP; therefore, hormone-based contraceptives alone 
cannot be used by female participants to prevent pregnancy. 
 
29 
5.2 Exclusion 
Criteria 
7. TB infection with known resistance to pretomanid, delamanid, 
linezolid or bedaquiline. 
7. TB infection with historic DST or MIC results with values 
suggesting likely known resistance to pretomanid, 
delamanid, linezolid or bedaquiline; the Sponsor Medical 
Monitor should be consulted to help interpret any available 
historic results. 
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30 
5.2 Exclusion 
Criteria 
10. Participants with any of the following at Screening: 
• QTcF interval on ECG >500 msec. Participants with QTcF > 450 
must be discussed with the Sponsor Medical Monitor before 
enrolment. 
• Heart failure 
• A personal or family history of congenital QT prolongation 
• A history of or known, untreated, ongoing hypothyroidism 
• A history of or ongoing bradyarrhythmia 
• A history of Torsade de Pointe 
10. Participants with any of the following at Screening: 
• 
QTcF interval on ECG >500 msec. Participants with QTcF 
> 450 must be discussed with and approved by the 
Sponsor Medical Monitor before enrolment. (Per 
measurements and reading done from screening central 
ECG.) 
• 
Heart failure 
• 
A personal or family history of congenital QT prolongation 
• 
A history of or known, untreated, ongoing hypothyroidism 
• 
A history of or ongoing bradyarrhythmia 
• 
A history of Torsade de Pointe 
5 and 16 
31 
5.2 Exclusion 
Criteria 
Previous and Concomitant Therapy 
13. 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or 
prior use within 2 weeks of randomization.  
14. 
Concomitant use of serotonergic antidepressants or prior use 
within 3 days of randomization if Investigator foresees potential 
risks for serotonin syndrome when combined with linezolid.  
15. 
Concomitant use of any drug known to prolong QTc interval 
(including, but not limited to, amiodarone, bepridil, chloroquine, 
chlorpromazine, cisapride, cyclobenzaprine, clarithromycin, 
disopyramide, dofetilide, domperidone, droperidol, erythromycin, 
fluoroquinolones, halofantrine, haloperidol, ibutilide, levomethadyl, 
mesoridazine, methadone, pentamidine, pimozide, procainamide, 
quinidine, sotalol, sparfloxacin, thioridazine).  
16. 
Concomitant use of any drug known to induce myelosuppression.  
17. 
Concomitant use of any drugs or substances known to be strong 
inhibitors or inducers of cytochrome P450 enzymes (including but 
not limited to efavirenz, quinidine, tyramine, ketoconazole, 
fluconazole, testosterone, quinine, gestodene, metyrapone, 
phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, 
erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). 
Exceptions may include use of lopinavir/ritonavir regimen as noted 
in section 5.3.3. 
18. 
Participants who have received more than 2 weeks of bedaquiline, 
linezolid or delamanid prior to first dose of IMP. 
19. 
 Participants with an existing TB diagnosis (a diagnosis made > 4 
weeks prior to screening) and HIV co-infection, must have been on 
an ART for at least 4 weeks prior to screening.  
Previous and Concomitant Therapy 
13. Known (during screening) requirement for future Concomitant 
(during treatment) use of any prohibited and/or avoided 
medications noted in section 5.3. 
14. Prior use of Monoamine Oxidase Inhibitors (MAOIs) within 2 
weeks of randomization.  
15. Prior use of serotonergic antidepressants within 3 days of 
randomization if Investigator foresees potential risks for 
serotonin syndrome when combined with linezolid.  
16. Participants who have received more than 2 weeks of 
bedaquiline, linezolid or delamanid prior to first dose of IMP. 
17. Participants with newly diagnosed tuberculosis and HIV that 
require initiation of appropriate HIV therapy before participant 
has received at least 2 weeks of an anti-tuberculosis regimen.  
18. HIV infected participants with planned continued use of 
zidovudine, stavudine or didanosine. The antiretroviral therapy 
(ART) booster cobicistat should not be used. Please reference 
restrictions Section 5.3.3 Antiretroviral Therapy, for guidance 
on ART treatment during the treatment period. 
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20. 
Participants with newly diagnosed tuberculosis and HIV may be 
enrolled provided that appropriate HIV therapy will not be initiated 
until participant has received at least 2 weeks of study medication.  
21. 
HIV infected participants: the following antiretroviral therapies 
should not be used: zidovudine, stavudine, didanosine. The 
antiretroviral therapy (ART) booster cobicistat should not be used. 
Please reference restrictions Section 5.3.3 Antiretroviral Therapy, 
for guidance on ART treatment during the treatment period. 
32 
5.2 Exclusion 
Criteria 
Diagnostic and Laboratory Abnormalities 
 
22. 
Participants with any of the following toxicities at Screening (labs 
may be repeated during screening period) as defined by the 
enhanced Division of Microbiology and Infectious Disease (DMID) 
adult toxicity table (November 2007): 
 
a. 
Viral load >1000 IU/ml (Unless newly diagnosed HIV and not yet 
on ART who otherwise qualify for participation); 
b. 
CD4+ count < 100 cells/µL (HIV positive participants); 
c. 
Serum potassium less than the lower limit of normal for the 
laboratory; 
d. 
Hemoglobin < 9.0 g/dL; 
e. 
Platelets <100,000/mm3; 
f. 
Absolute neutrophil count (ANC) < 1500/ mm3; 
g. 
Aspartate aminotransferase (AST)  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with 
and approved by the Sponsor Medical Monitor 
h. 
Alanine aminotransferase  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with 
and approved by the Sponsor medical monitor; 
i. 
Total bilirubin 
• 
greater than 1.5 x ULN to be excluded; 
• 
1-1.5 x ULN must be discussed with and approved by the 
Sponsor Medical Monitor  
j. 
Direct bilirubin 
• 
Greater than ULN to be excluded 
Diagnostic and Laboratory Abnormalities 
 
19. 
Participants with any of the following toxicities at Screening 
(labs may be repeated during screening period) as defined by 
the enhanced Division of Microbiology and Infectious Disease 
(DMID) adult toxicity table (November 2007): 
 
a. 
Viral load >1000 copies/mL (Unless newly diagnosed HIV 
and not yet on ART who otherwise qualify for participation); 
b. 
CD4+ count < 100 cells/µL (HIV positive participants); 
c. 
Serum potassium less than the lower limit of normal for the 
laboratory; 
d. 
Hemoglobin < 9.0 g/dL or < 90 g/L; 
e. 
Platelets <100,000/mm3 or < 100 x 10^9/L; 
f. 
Absolute neutrophil count (ANC) < 1500/ mm3 or < 1.5 x 
10^9/L; 
g. 
Aspartate aminotransferase (AST)  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed 
with and approved by the Sponsor Medical Monitor 
h. 
Alanine aminotransferase  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed 
with and approved by the Sponsor medical monitor; 
i. 
Total bilirubin 
• 
greater than 1.5 x ULN to be excluded; 
• 
1-1.5 x ULN must be discussed with and approved by the 
Sponsor Medical Monitor  
j. 
Direct bilirubin 
• 
Greater than ULN to be excluded 
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k. 
Serum creatinine level greater than 1.5 times upper limit of 
normal 
l. 
Albumin <3.0 mg/dl 
k. 
Serum creatinine level greater than 1.5 times upper limit of 
normal 
l. 
Albumin <3.0 g/dl or < 30 g/L 
33 
5.2 Exclusion 
Criteria 
 
 
 
26 
34 
5.3.1 Prior and 
Concomitant 
Medications and 
Other 
Treatments 
The following concomitant medications are prohibited during the treatment 
period to avoid possible drug interactions with the IMP: 
• 
Medicinal products used to treat pulmonary TB:  including but not 
limited to gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, 
para-aminosalicylic 
acid, 
rifapentine, 
thioacetazone, 
capreomycin, quinolones, thioamides, and metronidazole. 
• 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). (e.g., 
phenelzine, isocarboxazid) 
• 
Concomitant use of any drug known to prolong QTc interval 
(including but not limited to amiodarone, bepridil, chloroquine, 
chlorpromazine, cisapride, cyclobenzaprine, clarithromycin, 
disopyramide dofetilide, domperidone, droperidol, erythromycin, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozide, procainamide, quinidine, 
sotalol, sparfloxacin, thioridazine).  
• 
Treatment with fluoroquinolones (as they are known prolong QTc), 
are strongly discouraged in the trial. They should only be used to 
treat intercurrent non-TB infections and if the benefit of treatment 
outweighs the risk of prolonged QTc.   
• 
Concomitant use of any drug known to induce myelosuppression.  
• 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: 
ketoconazole, voriconazole, itraconazole, fluconazole; ketolids 
such as telithromycin; and macrolide antibiotics other than 
azithromycin) for more than 3 consecutive days; 
• 
The systemic use of CYP3A4 inducers (e.g., phenytoin, 
carbamazepine, phenobarbital, St. John’s wort, rifamycins and 
systemic dexamethasone. 
 
The following concomitant medications are prohibited during the 
treatment period and during the 14 days after treatment completion: 
• 
Medicinal products used to treat pulmonary TB:  including but 
not limited to gatifloxacin, amikacin, cycloserine, rifabutin, 
kanamycin, 
para-aminosalicylic 
acid, 
rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and 
metronidazole. 
• 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). 
(e.g., phenelzine, isocarboxazid) 
The following concomitant medications should be avoided during the 
treatment period and during the 14 days after treatment completion 
to avoid possible drug interactions with the IMP. Use of any of the 
following must be discussed and approved by the Sponsor Medical 
Monitor prior to use: 
• 
Concomitant /use of any drug known to prolong QTc interval 
(including but not limited to amiodarone, bepridil, 
chloroquine, chlorpromazine, cisapride, cyclobenzaprine, 
clarithromycin, disopyramide dofetilide, domperidone, 
droperidol, erythromycin, halofantrine, haloperidol, ibutilide, 
levomethadyl, mesoridazine, methadone, pentamidine, 
pimozide, procainamide, quinidine, sotalol, sparfloxacin, 
thioridazine).  
• 
Treatment with fluoroquinolones (as they are known prolong 
QTc), are strongly discouraged in the trial. They should only 
be used to treat intercurrent non-TB infections and if the 
benefit of treatment outweighs the risk of prolonged QTc.   
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Concomitant use of serotonergic antidepressants should be avoided if 
possible as participants on these agents and linezolid are at risk for 
serotonin syndrome.  
Caution should be used in treating diabetic patients receiving insulin or 
oral hypoglycemic agents as cases have been reported of hypoglycemic 
reactions when patients on these agents have been treated with linezolid. 
Any drug known to be hepatotoxic should be avoided as much as 
possible during screening and throughout the treatment period (including 
but not limited to acetaminophen/paracetamol,  acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, 
atorvastatin, augmentin/co-amoxiclav, azathioprine, baclofen, 
bumetanide, captopril, carbamazepine, celecoxib, chlorpromazine, 
chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-
trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, 
fluconazole, fluoxetine, fosamprenavir, furosemide, gliclazide, 
glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, 
loperamide, losartan, methotrexate, metolazone, mirtazepine, 
nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory drugs, 
paroxetine, phenobarbital, phenothiazines, phenytoin, pravastatin, 
probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, 
simeprevir, simvastatin, sodium valproate, sotalol, sulfasalazine, 
sumatriptan, tamsulosin, terbinafine, tetracycline, theophyllin/uniphyllin, 
tipranavir, tolazamide, tolbutamide, topiramate, trazodone, tricyclic 
antidepressants, trimethoprim, verapamil). 
 
• 
Concomitant use of any drug known to induce significant 
myelosuppression 
• 
The systemic use of CYP3A4 inhibitors (e.g., azole 
antifungals: ketoconazole, voriconazole, 
itraconazole, 
fluconazole; ketolids such as telithromycin; and macrolide 
antibiotics other than azithromycin) for more than 3 
consecutive days; 
• 
The systemic use of CYP3A4 inducers (e.g., phenytoin, 
carbamazepine, phenobarbital, St. John’s wort, rifamycins 
and systemic dexamethasone.  
• 
Concomitant use of serotonergic antidepressants should be 
avoided if possible as participants on these agents and 
linezolid are at risk for serotonin syndrome.  
• 
Caution should be used in treating diabetic patients receiving 
insulin or oral hypoglycemic agents as cases have been 
reported of hypoglycemic reactions when patients on these 
agents have been treated with linezolid. 
The following concomitant medications which are known to be 
hepatotoxic should be avoided as much as possible during screening 
and throughout the treatment period.  If there are concerns about the 
co-administration of  hepatoxic drugs, discussion with the Sponsor 
Medical Monitor is encouraged (including but not limited to 
acetaminophen/paracetamol, 
 
acetazolamide, 
allopurinol, 
amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, 
augmentin/co-amoxiclav, azathioprine, baclofen, 
bumetanide, 
captopril, 
carbamazepine, 
celecoxib, 
chlorpromazine, 
chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-
trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, 
fluconazole, fluoxetine, fosamprenavir, furosemide, gliclazide, 
glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, 
loperamide, losartan, methotrexate, metolazone, mirtazepine, 
nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory 
drugs, paroxetine, phenobarbital, phenothiazines, phenytoin, 
pravastatin, probenecid, prochlorperazine, risperidone, rosuvastatin, 
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sertraline, simeprevir, simvastatin, sodium valproate, sotalol, 
sulfasalazine, sumatriptan, tamsulosin, terbinafine, tetracycline, 
theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, topiramate, 
trazodone, tricyclic antidepressants, trimethoprim, verapamil). 
 
35 
5.4 Trial 
Discontinuation 
and Visits 
5.4  Discontinuation from Treatment/Trial  
The following may result in the discontinuation of trial treatment;  
 
• 
Pregnancy; 
• 
Investigator considers it for safety reasons in the best interest of 
the participant that he/she be discontinued. This could include, but 
is not limited to: 
o Adverse event(s); 
o Myco testing results from baseline (Screening through 
Week 4) indicate sensitivity to isoniazid and/or rifamycins; 
o Myco testing results from baseline (Screening through 
Week 4) indicate resistance to bedaquiline, pretomanid or 
linezolid; 
o In the opinion of the investigator, fails to comply with the 
protocol, including non-compliance to IMP. 
All participants who discontinue trial treatment (but have not withdrawn 
consent) and received at least one dose of IMP will be requested to 
return for an early withdrawal visit and applicable safety Follow Up visits, 
as per flow chart (Section 1.2). 
In the event of the following, participants will be and/or are considered 
discontinued from the trial and no additional follow-up visits are required: 
• 
Withdrawal of informed consent; 
• 
Lost to follow-up; 
• 
Termination of the trial by the sponsor. 
5.4  Trial Discontinuation and Visits 
 
5.4.1 
Treatment Discontinuation and Early Withdrawal 
 
A participant must be withdrawn from the trial due to the following;  
• 
Pregnancy;(unless female post visit for end of treatment/early 
withdrawal from treatment); 
• 
Investigator considers it for safety reasons in the best interest 
of the participant that he/she be discontinued, including a 
concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB 
treatment.  
• 
At the specific request of the sponsor or termination of the 
trial by Sponsor; 
• 
Lost to follow-up 
• 
In the opinion of the investigator, fails to comply with the 
protocol, including non-compliance to IMP. 
Participants may be withdrawn from the trial based on the following. 
The specific situation should be discussed with the Medical Monitor 
before withdrawing the patient. 
o Myco testing results from baseline (Screening 
through Week 4) indicate sensitivity to rifamycins; 
o Myco testing results from baseline (Screening 
through Week 4) with MICs that indicate likely 
resistance to bedaquiline, pretomanid or linezolid; 
21 and 
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A participant may discontinue from the trial at any time at his/her request 
(withdrawal of consent). 
 
All participants who discontinue trial treatment (but have not 
withdrawn consent) and received at least one dose of IMP will be 
requested to return for an early withdrawal visit and applicable safety 
Follow Up visits, as per flow chart (Section 1.2). 
A participant may discontinue from the trial at any time at his/her 
request (withdrawal of consent) or may be withdrawn at any time at 
the discretion of the investigator for safety, behavioral compliance or 
administrative issues. When a participant withdraws consent from 
the trial, no additional follow-up visits will be performed.  
36 
5.4.2 Early 
Withdrawal 
Follow-up 
 
  
  
5.4.2 
Early Withdrawal Follow-up 
In case of early withdrawal during the treatment or follow-up period, 
all efforts shall be made to complete the Early Withdrawal 
assessments.   
Once a participant has been withdrawn early from the trial, they will 
be requested to attend follow-up visits as described in Table 9: 
 
 
The 26 and 78 week post treatment follow-up visits will be performed 
to collect SAE information (including verification of survival) and 
participant reported TB outcome information.  This visit may be 
telephonic, a home or a site visit.  
 
 
10 and 
28 
Table X: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EW visit 
Ophthalmology 
Examination at 
EWa 
Ophthalmology 
Examination  
 
12 week Post 
treatment follow-
up visita 
26 Week  
Post 
Treatment  
Follow-up 
Visit 
78 Week Post 
Treatment 
Follow-up 
Visit 
≤ 14 days 
NA 
NA 
NA 
NA 
15 days to      
≤ 12 weeks 
NA 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if not 
already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 12 weeks after the 
EWD visit date. 
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37 
5.4.3 
Unscheduled 
Visits 
 
5.4.3 Unscheduled Visits 
 
Any visit which is conducted in addition to those required by the 
Synopsis Flow Chart and Procedures, should be considered 
unscheduled regardless of the reason for the visit. The assessments 
which are undertaken as part of an Unscheduled visit should be as 
clinically indicated.  
The following situation/s require an unscheduled visit/s: 
• If cultures of both spot sputum samples are contaminated at the 
following visits, or if necessary in order to help define a 
participant’s outcome status/assess culture status during follow-
up, the participant should return for an unscheduled visit(s) to give 
additional samples or to document the participant is not able to 
produce sputum: 
  
• End of treatment visit; 
• Week 26 post treatment follow-up visit; 
• Post treatment follow-up visits from week 8 through week 
65 (in addition to week 26 follow-up); 
• End of Follow-up Period (week 78 post treatment 
completion visit); 
• Early Withdrawal (if applicable). 
 
•  At the end of 26 weeks and 78 weeks post treatment completion, 
to define outcome status, and to determine whether the 
participant has: 
• At least two sequential negative sputum culture results; or  
• At least two sequential positive sputum culture results; or  
• Has been unable to produce sputum after documentation of 
at least two negative sputum cultures with no intervening 
positive and are clinically asymptomatic. 
 
If they do not fall into one of the above categories, site should 
continue to collect sputum samples x 2 (one early morning and one 
spot at the research site or 2 spots samples at least 30 minutes 
apart, under the coaching and observation of the trial staff) at a 
28 
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minimum of 7 days or more apart until they fall into one of the above 
categories. 
 
5.4.4 Lost to Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-
up (LTFU) participants.  A minimum of three contact attempts 
(telephonic/home visit) will be made for participants who do not 
arrive for their scheduled trial visits. If these attempts are 
unsuccessful the participant will be considered LTFU.  All attempts 
to contact the participant must be clearly documented in the 
participant’s source documents 
38 
5.4.4 Early 
Withdrawal due 
to TB 
Discontinuation from treatment due to TB 
5.4.5 Early Withdrawal due to TB 
28 
39 
6.1 IMP 
Administration 
Table 9: Investigational Medicinal Product Details  
Table 10: 
 Investigational Medicinal Product Details  
6 
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Treatment 
Group 
Active and Placebo 
Linezolid 
1200 mg 
daily for 26 
weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 
weeks then 1 bedaquiline 100 mg active tablet 
once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 
weeks. 
• 2 linezolid 600 mg active tablets once daily for 26 
weeks 
• 1 placebo linezolid 600 mg tablet once daily for 26 
weeks  
Linezolid 
1200 mg 
daily for 9 
weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 
weeks then 1 bedaquiline 100 mg active tablet 
once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 
weeks. 
Weeks 1-9  
• 2 linezolid 600 mg active tablets once daily for 9 
weeks  
• 1 placebo linezolid 300 mg half tablet once daily for 
9 weeks 
Weeks 10-26 
• 2 placebo linezolid 600 mg tablets once daily for 17 
weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 
17 weeks 
Linezolid 600 
mg daily for 
26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 
weeks then 1 bedaquiline 100 mg active tablet 
once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 
weeks. 
• 1 linezolid 600 mg active tablet once daily for 26 
weeks 
• 1 placebo linezolid 600 mg tablet once daily for 26 
weeks  
Treatment 
Group 
Active and Placebo 
Linezolid 
1200 mg 
daily for 26 
weeks 
 
• 2 bedaquiline 100 mg active tablets once daily 
for 8 weeks then 1 bedaquiline 100 mg active 
tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily 
for 26 weeks. 
• 2 linezolid 600 mg active tablets once daily for 
26 weeks 
• ½ (one half) placebo linezolid tablet once daily 
for 26 weeks  
Linezolid 
1200 mg 
daily for 9 
weeks 
 
• 2 bedaquiline 100 mg active tablets once daily 
for 8 weeks then 1 bedaquiline 100 mg active 
tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily 
for 26 weeks. 
Weeks 1-9  
• 2 linezolid 600 mg active tablets once daily for 
9 weeks  
• ½ (one half) placebo linezolid tablet once daily 
for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid tablets once daily for 17 
weeks 
• ½ (one half) placebo linezolid tablet once daily 
for 17 weeks 
Linezolid 
600 mg 
daily for 26 
weeks 
 
• 2 bedaquiline 100 mg active tablets once daily 
for 8 weeks then 1 bedaquiline 100 mg active 
tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily 
for 26 weeks. 
• 1 linezolid 600 mg active tablet once daily for 
26 weeks 
• 1 placebo linezolid tablet once daily for 26 
weeks  
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• 1 placebo linezolid 300 mg half tablet once daily for 
26 weeks 
Linezolid 600 
mg daily for 
9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 
weeks then 1 bedaquiline 100 mg active tablet 
once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 
weeks. 
Weeks 1-9 
• 1 linezolid 600 mg active tablet once daily for 9 
weeks 
• 1 placebo linezolid 600 mg tablet for 9 weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 
9 weeks 
Weeks 10-26 
• 2 placebo linezolid 600 mg tablets once daily for 17 
weeks 
• 1 placebo linezolid 300 mg half tablet once daily for 
17 weeks 
 
• ½ (one half) placebo linezolid tablet once daily 
for 26 weeks 
Linezolid 
600 mg 
daily for 9 
weeks 
 
• 2 bedaquiline 100 mg active tablets once daily 
for 8 weeks then 1 bedaquiline 100 mg active 
tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily 
for 26 weeks. 
Weeks 1-9 
• 1 linezolid 600 mg active tablet once daily for 9 
weeks 
• 1 placebo linezolid tablet for 9 weeks 
• ½ (one half) placebo linezolid tablet once daily 
for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid tablets once daily for 17 
weeks 
• ½ (one half) placebo linezolid tablet once daily 
for 17 weeks 
 
40 
6.2 Participant 
Compliance 
Additionally, participant cards will be checked for unused tablets in the 
blisters. 
 
Additionally, participant cards/bottles will be checked for unused 
tablets at each visit during the treatment period.  
 
29 
41 
6.3 Treatment 
Modification(s) 
All dose modifications should be discussed with the Sponsor Medical 
Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be 
informed within 24 hours of the change if not discussed prior to 
implementation. 
All dose modifications should be discussed with the Sponsor Medical 
Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be 
informed within 24 hours of the change if not discussed prior to 
implementation. 
In the event of linezolid specific toxicities, the following should be 
considered and implemented per guidance in the monitoring and safety for 
specific toxicities section of protocol: 
All treatment modifications should be discussed with the Sponsor 
Medical Monitor prior to implementation, unless a pause or dose 
reduction is required urgently for a safety concern; the Medical 
Monitor should be informed within 24 hours of the change if not 
discussed prior to implementation.  
 
In the event of linezolid specific toxicities, the following should be 
considered and implemented per guidance in the monitoring and 
safety for specific toxicities section of protocol (8.3): 
• 
Blinded one step reductions (maximum 2 steps) in the dose 
of linezolid managed by the IXRS as per instructions in 
pharmacy manual and/or IXRS user manual 
4, 5, and 
7  
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• 
Blinded one step reductions (maximum 3 steps) in the dose of 
linezolid (1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD 
or 300mg QD to placebo) managed by the IWRS as per 
instructions in pharmacy manual and/or IWRS user manual.  
• 
Temporary pause of linezolid due to a linezolid-specific toxicity 
should be considered and implemented per guidance in the 
monitoring and safety for specific toxicities section of protocol. 
• 
Permanent discontinuation of linezolid. 
Participants experiencing suspected drug related toxicities due to other 
drugs in the regimen (B-Pa), the full regimen may be halted for up to 35 
consecutive days.  
Pauses of the full regimen must not exceed 8 weeks (56 days) 
cumulatively.   
If participant’s week 16 sample remains culture positive, Investigator may 
consider option to extend current treatment to 39 weeks, in consultation 
with the Sponsor Medical Monitor. When treatment extended due to a 
positive culture at week 16, pauses of the full regimen must not exceed 13 
weeks (91 days) cumulatively. 
When total of missed dosing days and/or pauses is greater than 7 days, 
additional make-up doses should be dispensed/treatment extended. 
At no time should the participant be treated with a single agent. 
 
o 1200 mg QD to 600 mg QD, 600 mg QD to 300 mg 
QD or;  
o 600 mg QD to 300 mg QD, 300mg QD to placebo).  
• 
Temporary pause of linezolid  
• 
Permanent discontinuation of linezolid. 
• 
Participants who have a linezolid reduction can go back to a 
higher dose (1 step or 2 steps) post discussion with and 
approval by the Sponsor Medical Monitor. 
Participants experiencing suspected drug related toxicities due to 
other drugs in the regimen (B-Pa), the full regimen may be halted for 
up to 35 consecutive days.  
Interruptions/pauses of the full regimen must not exceed 8 weeks (56 
days) cumulatively.   
If participant’s sample is culture positive between the week 16 and 
week 26 treatment visits and their clinical condition suggests they 
may have an ingoing TB infection, Investigator may consider the 
option to extend treatment to which the participant is randomized to 
39 weeks. If the culture results between week 16 and week 26 are 
contaminated, missing or considered an isolated positive without 
clinical significance, available culture results should be used to make 
this decision. All decisions regarding treatment extension should be 
discussed with and approved by the Sponsor Medical Monitor before 
implementation.  
When treatment extended to 39 weeks, pauses of the full regimen 
must not exceed 13 weeks (91 days) cumulatively. 
When the total of missed dosing days of the prescribed regimen 
and/or pauses is greater than 7 days, the same number of missed 
doses should be dispensed/treatment extended to make up for the 
total missed doses. 
At no time should the participant be treated with a single agent. 
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Every effort should be made for participants to receive a total of at 
least 9 weeks of linezolid, even if pauses are required. 
42 
6.4 IMP 
Packaging and 
Labelling 
The complete formulations of the IMP bedaquiline and pretomanid are 
found in the respective Investigator Brochures. The complete formulations 
of linezolid are found in the Package Inserts  
The IMP will be packaged as follows: 
• 
Bedaquiline: Bottles containing: 
o 200 mg QD dose- 28 tablets- bedaquiline 100 mg 
o 100mg QD dose- 14 tablets- bedaquiline 100 mg  
• 
Pretomanid: Blister card containing 14 tablets- pretomanid 200 mg  
• 
Linezolid: Blister Card containing 7 days of dosing as follows: 
o 1200 mg QD Dose  
 
2 blister strips of 7 tablets each (14 tablets) 
containing active linezolid 600 mg   
 
1 blister strip of 7 half tablets containing placebo 
linezolid 300 mg  
o 600 mg QD Dose:  
 
1 blister strip of 7 tablets containing active 
linezolid 600 mg   
 
1 blister strip of 7 tablets containing placebo 
linezolid 600 mg 
 
1 blister strip of 7 half tablets containing placebo 
linezolid 300 mg  
o 300 mg Dose (for reductions): 1 row of 7 active 600 mg 
tablets for 7 days of dosing 
 
2 blister strips of 7 tablets each (14 tablets) 
containing placebo linezolid 600 mg   
 
1 blister strip of 7 half tablets containing active 
linezolid 300 mg  
o Placebo Linezolid Dose: 2 rows of 7 placebo 600 mg 
tablets for 7 days of dosing 
 
2 blister strips of 7 tablets each (14 tablets) 
containing placebo linezolid 600 mg   
The complete formulations of the IMP bedaquiline and pretomanid 
are found in the respective Investigator Brochures. The complete 
formulations of linezolid are found in the Package Inserts.  
The IMP will be packaged as follows: 
• 
Bedaquiline: Bottles containing: 
o 200 mg QD dose- 28 tablets- bedaquiline 100 mg 
o 100mg QD dose- 14 tablets- bedaquiline 100 mg  
• 
Pretomanid: Blister card containing 14 tablets- pretomanid 
200 mg  
• 
Linezolid: Blister Card containing 7 days of dosing as follows: 
o 1200 mg QD Dose  
 
2 blister strips of 7 tablets each (14 tablets) 
containing active linezolid 600 mg   
 
1 blister strip of 7 half tablets containing 
placebo linezolid   
o 600 mg QD Dose:  
 
1 blister strip of 7 tablets containing active 
linezolid 600 mg   
 
1 blister strip of 7 tablets containing placebo 
linezolid  
 
1 blister strip of 7 half tablets containing 
placebo linezolid  
o 300 mg Dose (for reductions):  
 
2 blister strips of 7 tablets each (14 tablets) 
containing placebo linezolid  
 
1 blister strip of 7 half tablets containing 
active linezolid 300 mg  
o Placebo Linezolid Dose:  
 
2 blister strips of 7 tablets each (14 tablets) 
containing placebo linezolid    
6 
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 
1 blister strip of 7 half tablets containing placebo 
linezolid 300 mg  
 
 
1 blister strip of 7 half tablets containing 
placebo linezolid   
 
 
43 
6.4 IMP 
Packaging and 
Labelling 
The packaging of each bottle/blister card will be labelled with, at a 
minimum, the following information: 
• 
Name, address and telephone number of Sponsor. 
The packaging of each bottle/blister card will be labelled with, at a 
minimum, the following information: 
• 
Name of Sponsor. 
30 
44 
6.5 Method of 
Treatment 
Assignment 
Participants will be randomized to one of the four regimens in a 1:1:1:1 
ratio, using an interactive web response system (IWRS) which will utilize 
a dynamic randomization system using minimization with a random 
element to allocate participants evenly across the arms by HIV status and 
type of TB.  Information & directions will be provided to each site via the 
IWRS user manual. 
 
Participants will be randomized to one of the four regimens in a 
1:1:1:1 ratio, using an interactive web/voice response system (IXRS) 
which will utilize a randomization system using stratification with a 
random element to allocate participants evenly across the arms by 
HIV status and type of TB.  Information & directions will be provided 
to each site via the IXRS user manual. 
3 
45 
6.6 Blinding and 
Procedures for 
Breaking the 
Blind 
The blind must not be broken except in the case of a medical emergency, 
where treatment of the participant is influenced by the knowledge of what 
dose and duration of linezolid the participant is receiving. It is requested 
that the Investigator make every effort to contact the Sponsors medical 
monitor (or designee) prior to breaking the blind. IWRS will be 
programmed with blind-breaking instructions, described in the user 
manual. The sponsor reserves the right to break the blind in order to fulfil 
any regulatory requirements regarding reporting of SAEs. 
 
The blind must not be broken except in the case of a medical 
emergency, where treatment of the participant is influenced by the 
knowledge of what dose and duration of linezolid the participant is 
receiving. The investigator should discuss breaking the blind with the 
Sponsor Medical Monitor (or designee) prior to breaking the blind 
unless knowledge of treatment arm is required urgently for a safety 
concern. The Sponsor Medical Monitor should be informed of the 
blind break within 24 hours if not discussed prior. IXRS will be 
programmed with blind-breaking instructions, described in the user 
manual. The Sponsor reserves the right to break the blind to fulfil any 
regulatory requirements regarding reporting of SAEs. If a participant 
is unblinded they are not required to be withdrawn from the study. 
31 
46 
7.1 Demographic 
and Background 
Variables 
• 
Clinically significant medical and treatment history (including 
past and current TB diagnosis and smoking) 
 
• 
Clinically significant medical and treatment history 
(including past and current TB diagnosis, alcohol use 
and smoking) 
32 
47 
7.1 Demographic 
and Background 
Variables 
• 
Serology: HIV and CD4 count.  
• 
Serology: HIV, CD4 count and viral load.  
• 
If an HIV test was performed within 1 month prior to 
trial start, it should not be repeated as long as 
33 
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• 
If an HIV test was performed within 1 month prior to trial start, it 
should not be repeated as long as documentation of results can 
be provided (ELISA and/or Western Blot). 
documentation of results can be provided (ELISA 
and/or 
Western 
Blot 
and/or 
Electro-
Chemiluminescence). 
 
48 
7.1 Demographic 
and Background 
Variables 
N/A- bullet point did not exist in version 1.0 
• 
Concomitant medications 
 
34 
49 
7.2 Efficacy 
Variables and 
procedures 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (Appendix 7) will record participants’ 
ratings of the severity of common TB symptoms.  
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at 
the time points described in the trial flow chart. Patient Reported 
Health Status will be collected using the EQ-5D-5L Health 
Questionnaire (Appendix 5). This descriptive system consists of five 
health-related quality of life dimensions, each of which will be 
recorded using five levels of severity. Methodology: The Patient 
Reported Health Status methodology and requirements will be 
described in a separate document/guideline which will be provided 
prior to the trial start. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (found in the Subject 
Questionnaires Guideline) will record participants’ ratings of 
the severity of common TB symptoms.  
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be 
collected at the time points described in the trial flow chart. 
Patient Reported Health Status will be collected using the 
EQ-5D-5L Health Questionnaire (found in the Subject 
Questionnaires Guideline). This descriptive system consists 
of five health-related quality of life dimensions, each of 
which will be recorded using five levels of severity. 
Methodology: The Patient Reported Health Status 
methodology and requirements will be described in a 
separate document/guideline which will be provided prior to 
the trial start. 
35 
50 
7.3 Safety and 
Tolerability 
Assessments 
• 
Brief Peripheral Neuropathy Screen (Appendix 6) will record ratings. 
 
• 
Brief peripheral neuropathy screen (found in the Subject 
Questionnaires Guideline) will record ratings. 
35 
51 
 
7.5 
Mycobacteriology 
Characterization 
Variable and 
Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between screening 
through Week 4; 
• 
Pre-screening culture that was used for the tests that qualified the 
participant for inclusion into the trial to be subcultured and shipped 
to the central from the applicable lab for relevant participants/with 
no positive cultures from screening through week 4 and appropriate 
consent 
The following Mycobacterial Characterization variables will be 
collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between 
Screening through Week 4; 
• 
If consent granted, and when applicable, Pre-screening 
culture/isolate to be sub cultured and shipped and/or tested: 
o At the study lab if/when samples could support 
inclusion in the trial 
35 
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• 
When applicable, end of treatment or visits with positive cultures 
during post-treatment follow-up. 
 
o To the study/central lab for relevant participants/with 
no baseline (positive cultures from screening through 
Week 4)  
• 
When applicable, 1st positive for MTB at/after week 16 for 
participant not responding to therapy and/or 1st positive 
during follow-up for potential new infection. 
52 
8.2.1 Follow up 
of Adverse 
Events 
Certain long-term AEs cannot be followed until resolution within the setting 
of this protocol. In these cases follow-up will be the responsibility of the 
treating physician.  However, this will have to be agreed upon with the 
Sponsor Medical Monitor. 
Certain long-term AEs cannot be followed until resolution within the 
setting of this protocol. In these cases, follow-up will be the 
responsibility of the treating physician.  If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor 
Medical Monitor. 
5 
53 
8.3 Monitoring for 
Specific 
Toxicities 
Monitoring for specific toxicities is based upon target organs as defined in 
preclinical toxicity studies Investigator’s Brochures and Package Inserts. 
AEs still ongoing at the end of treatment in the trial will be followed until 
satisfactory clinical resolution or stabilization or until the end of the follow-
up period and until all queries on these AEs have been resolved.  Grade 
3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory 
resolution or stabilization.  
Monitoring for specific toxicities is based upon target organs as 
defined in preclinical toxicity studies Investigator’s Brochures(5,6) 
and Package Inserts.(24,25,26,27) Please reference section 6.3. 
Treatment Modifications, which notes that all treatment modifications 
should be discussed with Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required urgently 
for a safety concern.  The Medical Monitor should be informed within 
24 hours of the change if not discussed prior to implementation.   
AEs still ongoing at the end of treatment in the trial will be followed 
until satisfactory clinical resolution or stabilization or until the end of 
the follow-up period and until all queries on these AEs have been 
resolved.  Grade 3 and grade 4 laboratory abnormalities and 
laboratory abnormalities considered clinically significant should be 
followed until satisfactory resolution or stabilization. Certain long-term 
AEs cannot be followed until resolution within the setting of this 
protocol. In these cases follow-up will be the responsibility of the 
treating physician. If there is uncertainty, Investigator can discuss 
appropriate follow-up with the Sponsor Medical Monitor. 
5 
54 
8.3.2 ALT, AST 
and Alkaline 
Phosphatase 
elevations 
The Investigator should refer to Appendix 8 – Liver Toxicity Management 
to appropriately manage the participant for clinically significant elevations 
of AST, ALT or Alkaline Phosphatase. 
The Investigator should refer to Appendix 6 – Liver Toxicity 
Management and to the ZeNix Hepatotoxicity Management Guideline 
36 
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to appropriately manage the participant for clinically significant 
elevations of AST, ALT or Alkaline Phosphatase. 
55 
11.3 Protocol 
Deviations 
It is the responsibility of the site to use continuous vigilance to identify and 
report deviations. All deviations must be addressed in study source 
documents and reported to Sponsor/designee. Protocol deviations must 
be sent to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. 
 
It is the responsibility of the site to use continuous vigilance to 
identify and report deviations. All deviations must be addressed in 
study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB and Health 
Authority per their guidelines. The site PI/all study staff is 
responsible for knowing and adhering to their IRB and Health 
Authority (as required) requirements 
37 
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Sponsor 
 
I agree to the terms of this protocol amendment 
 
 
 
 
 
 
Signature of Senior Medical Officer 
 
Printed name 
 
Date 
 
 
Principal Investigator 
 
I hereby confirm I have read the above Protocol Amendment and agree to conduct this clinical trial as outlined in the above 
Protocol Amendment. I will provide copies of the Protocol Amendment and access to all of the information required to conduct the 
clinical trial according to the above Protocol Amendment to the site personnel under my supervision. I will discuss this material with 
them and ensure they are fully informed on all trial requirements.  
 
 
 
 
 
 
Signature of Principal Investigator 
 
Printed name 
 
Date 
 
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Protocol Name / Number:
ZeNix/ NC-007-(B-Pa-L)
Protocol Title:
A Phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various doses and 
treatment durations of linezolid plus bedaquiline and pretomanid in participants with pulmonary infection 
of either extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-
responsive multi-drug resistant tuberculosis (MDR-TB).
Reasons for Protocol Amendment:
1
Change of screening period from up to 9 to up to 14 days to provide sites with adequate time for assessments (In section 1.1 
Synopsis Summary, 1.2 Synopsis Flowchart and 4.2 Treatment Plan: Schedule of Assessments, 5. Trial Population.)
2
Removed limitation of 60 non-XDR participants/requirement for 120 XDR participants. Enrollment to include 180 participants 
who are either XDR, pre-XDR or MDR intolerant or non-responsive. (In section 1.1 Synopsis summary and 4.1 Summary of 
Trial Design)
3
Updated randomization details, specifically abbreviation of phone/web system utilized (changed IWRS to IXRS) and
“minimization” to “stratification”.  (In section 1.1 Synopsis Summary, 4.1 Summary of Trial Design, and 6.5 Method of 
Treatment Assignment)
4
Clarified scenarios and timing of culture positive results for consideration of treatment extensions from “week 16” to 
“between week 16 and week 26” (In section 1.1 Synopsis Summary, 1.2 of Synopsis Flowchart, and 4.1 Summary of Trial 
Design)
5
Clarified language throughout the protocol to specify when Sponsor Medical Monitor’s approval vs. notification required (In 
section 1.1 Synopsis, 4.1 Summary of Trial Design, 5.2 Exclusion Criteria, 5.4 Trial Discontinuation and Visits, 5.3.1 Prior and 
Concomitant Medications and Other Treatments, 6.3 Treatment Modification(s), 6.6 Blinding and Procedures for Breaking the 
Blind, 8.2.1 Follow up of AE, and 8.3 Monitoring for Specific Toxicities)
6
Clarified descriptions of regimen and dosing instructions to note linezolid 600 mg full or half tablets and placebo full or half 
tablets vs. 300 mg half tablet or linezolid 300 or 600 mg placebo. (In section 1.1 Synopsis Summary, 6.1 IMP Administration, 
and 6.4 IMP Packaging and Labelling)
7
Clarified treatment modifications to note 2 step (vs. 3 step) blinded decreases, and ability to raise linezolid dose back up to 
starting level, specifics on when for make-up dosing required (when missed more than 7 days) and deleted (when repetitive) 
or moved wording.  (In section 1.1 Synopsis Summary and 6.3 Treatment Modification[s])
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Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 2 of 37
CONFIDENTIAL
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8
Clarified primary endpoint timing in definition, from “through follow up until 26 weeks” to “at 26 weeks” after the end of 
treatment (In section 1.1 Synopsis Summary)
9
Updated Safety endpoint for ophthalmology slit lamp exams to include “observed” (In section 1.1 Synopsis Summary)
10
Addition of ophthalmology exams at treatment week 23 and follow-up week 12 to ensure appropriate safety monitoring (In 
section 1.2 Synopsis Flowchart, and section 5.4 Trial Discontinuation and Visits)
11
Addition of assessments required when patients withdraw during post treatment follow-up, which will be the same 
assessments required for week 78 post treatment follow-up visit. (In section 1.2 Synopsis Flowchart, and 5.4.2 Early 
Withdrawal Follow-up)
12
Clarified visit scheduling for understanding.  Referenced treatment modification for treatment extension scenarios, removed 
repeated text, and provided clear examples. (In section 6.3 Treatment Modification[s])
13
Updated and added details on HIV testing to clarify that historical documented results must be from ELISA, Western blot or 
electrochemiluminescence (added). Added allowance for repeated HIV testing when results indeterminate. (In section 1.2 
Synopsis Flowchart, and 5.1 Inclusion Criteria)
14
Clarified requirement for CD4 and viral load testing for HIV positive participants, noted that CD4 testing should be done if 
patient is an early withdrawal during treatment period.
15
Change of acceptable chest x-ray results from 1 month prior to screening to 6 months prior to or at screening (In section 1.2 
Synopsis Flowchart, and 5.1 Inclusion Criteria)
16
Clarified ECG testing to note that central reading of screening to be used for eligibility. (In section 1.2 Synopsis Flowchart)
17
Added sentence to note that height is only collected as part of full physical exam at screening (In section 1.2 Synopsis 
Flowchart)
18
Addition of Gamma Glutamyl Transferase (GGT) test to screening labs and instructions on additional testing for liver toxicity 
management to safety laboratory section.  Removed note that follow-up microscopy will be done at discretion of Investigator 
as will be done automatically for all abnormal results.  (In section 1.2 Synopsis Flowchart)
19
Clarified language regarding PK sampling timing, including instructions for sampling when full regimen or linezolid paused or 
when linezolid is reduced. Included language regarding recoding of dates and times of previous 2 doses of IMP. (In section 
1.2 Synopsis Flowchart)
20
Updated Sputum Sampling details:
Clarified and detailed testing on sputum vs. isolate in table (In section 1.2 Synopsis Flowchart)
Addition of details on extended DST to inform patient treatment at appropriate labs (In section 1.2 Synopsis Flowchart)
447 of 784


Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 3 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
Clarified timing of tests, detailing requirements for testing on first positive samples at/after week 16 (addition) for extension 
or at/after end of treatment for potential new infections (In section 1.2 Synopsis Flowchart and 7.5 Mycobacteriology 
Characterization and Variable and Procedures)
Clarified use of pre-screening, adding scenario to support testing for inclusion into the trial. (In section 1.2 Synopsis 
Flowchart)
Removed details on handling of pre-screening samples. (In section 1.2 Synopsis Flowchart and 7.5 Mycobacteriology 
Characterization and Variable and Procedures)
Moved wording on isolate testing (EMS preference and scenarios for requesting second isolate) to footnote under table (In 
section 1.2 Synopsis Flowchart)
Clarified that cultures should be stored (In section 1.2 Synopsis Flowchart)
Clarified testing done at Central lab to describe scenarios for paired genotyping to determine relapse/reinfection (In section 
1.2 Synopsis Flowchart)
Moved details on unscheduled visits to section 5.4.3
21
Removal of Isoniazid (INH) resistance as an inclusion criteria (In section 5.1 Inclusion Criteria, section 5.4 Discontinuation 
from Treatment/Trial)
Clarified requirements for documented resistance to make it clear that testing done at screening can be used for inclusion 
into trial (In section 5.1 Inclusion Criteria)
22
Updated Contraception inclusion criteria to align clarify differences between female participants and male participant’s 
female partners (In section 5.1 Inclusion Criteria)
Changed required period for male participants to practice birth control methods from 6 months to 12 weeks to align with 
guidance in IB (In section 5.1 Inclusion Criteria)
Removed “female partners of male participants” in note about hormone based contraception as female partners not taking 
IMP (In section 5.1 Inclusion Criteria)
23
Clarified exclusion based on resistance to study IMP to specific historic DST or MIC results and added wording to consult 
Sponsor Medical Monitor (In section 5.2 Exclusion Criteria)
24
Updated Previous and Concomitant Therapy exclusion section to:
Reference restriction section (and removal of the detailed examples) for exclusion of patients who have planned use of those 
medications (In section 5.2 Exclusion Criteria and section 5.3 Restrictions)
448 of 784


Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 4 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
Removed exclusion criteria for participants with existing TB diagnosis and HIV coinfection to have been on ARTs for at least 
4 weeks prior to screening as not necessary, as suppressed viral load and minimum CD4 count indicates that the 
participant’s HIV is controlled (In section 5.2 Exclusion Criteria)
Changed requirement for participants with newly diagnosed TB and HIV for receipt of at least 2 weeks of an anti-tuberculosis 
regimen instead of study medication as many participants are already on TB medications when screened for trial (In section 
5.2 Exclusion Criteria)
25
Addition of laboratory units utilized by the central lab and correction of units for viral load and Albumin (In section 5.2 
Exclusion Criteria)
26
Addition of wording to note that no protocol waivers will be granted by the TB Alliance (In section 5.2 Exclusion Criteria)
27
Updated Concomitant therapy restrictions to distinguish medications that are strictly prohibited, must be discussed and 
approved prior to use or should be avoided with option to contact the Sponsor Medical Monitor to discuss. (Section 5.3 
Restrictions)
28
Updated Discontinuation from Treatment/Trial section:
Clarified when participant “must” be withdrawn vs. “may” be withdrawn post discussion with Sponsor Medical Monitor (In 
section 5.4.1 Treatment Discontinuation and Early Withdrawal)
Clarified that withdrawal for pregnancy not relevant post treatment completion trial (In section 5.4.1 Treatment 
Discontinuation and Early Withdrawal)
Clarified withdrawal for safety reasons to include concerns of symptomatic TB (failure/relapse) (In section 5.4.1 Treatment 
Discontinuation and Early Withdrawal)
Clarified withdraw at anytime at discretion of Investigator for safety, administrative, or compliance reasons
(In section 5.4.1 Treatment Discontinuation and Early Withdrawal)
Added wording that clarified no follow-up visits will be performed when a participant withdraws consent (In section 5.4.1 
Treatment Discontinuation and Early Withdrawal)
Added section to clarify what visits/assessments are done post early withdrawal (In section 5.4.2 Early Withdrawal Follow-
up)
Moved section on unscheduled visits/assessments are done post early withdrawal (In section 5.4.3 Unscheduled Visits)
Removed wording from unscheduled visit section that instructed investigator to contact medical monitor to discuss outcome 
status scenarios (In section 5.4.4 Early Withdrawal due to TB)
29
Clarified that cards and bottles will be checked for unused tablets at each treatment visit (In section 6.2 Participant 
Compliance)
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Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 5 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
30
Updated IMP package labeling requirements to reflect the same information as the updated label, removal of sponsor 
address and phone number (In section 6.4 IMP Packaging and Labelling)
31
Addition of wording to note that patients are not required to be withdrawn if their treatment blind is broken (In section 6.6 
Blinding and Procedures for Breaking the Blind)
32
Addition of alcohol use to clinically significant medical and treatment history (In section 7.1 Demographic and Background 
Variables and Procedures) 
33
Addition of viral load and electrochemiluminescence as example of HIV test (In section 7.1 Demographic and Background 
Variables and Procedures)
34
Addition of concomitant medications (In section 7.1 Demographic and Background Variables and Procedures)
35
Removed appendices and references to appendices for EQ-5D-5L, BPNS and TB Symptoms profiles and referenced the 
ZeNix Subject Questionnaires Guideline, for the current forms. (In section 7.2 Efficacy Variable and Procedures, 7.3 Safety 
and Tolerability of Assessments, 7.5 Mycobacteriology Characterization Variable and Procedures)
36
Addition of reference to Liver Toxicity Management Guideline (In section 8.3.2 ALT, AST, and Alkaline Phosphatase 
Elevation)
37
Addition of reference to health authority, where applicable for protocol deviation reporting (In Section 11.3 Protocol 
Deviations)
38
Administrative changes, including spelling, grammar and format changes have been applied to the entire document. Refer to 
the ‘tracked changes’ for details of changes made
#
Section
Previous Text
RUS Protocol Version 1.0, dated 15-Nov-17
Amended Text
RUS Protocol Version 2.0, dated 13-Jun-18
Additional text - bold font. Deleted text – strike-through.
Reason 
for 
Change
Insert reason # 
from table above
1
1.1  Synopsis
Summary
Participants will have a screening period of up to 9 days and will be 
randomized to receive one of the 4 active treatment arms. Participants 
will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an 
interactive web response system (IWRS) which will utilize a dynamic 
randomization system using minimization with a random element to 
allocate participants evenly across the arms by HIV status and type of 
TB.  
Participants will have a screening period of up to 14 days and will be 
randomized to receive one of the 4 active treatment arms. 
Participants will be randomized to one of the four regimens in a 
1:1:1:1 ratio, using an interactive voice and web response system 
(IXRS) which will utilize a randomization system using stratification 
with a random element to allocate participants evenly across the 
arms by HIV status and type of TB.  
1,3,4,
and 5
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Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 6 of 37
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Each participant will receive 26 weeks of treatment.  If participant’s week 
16 sample remains culture positive, Investigator may consider extending 
current treatment to 39 weeks, in consultation with the Sponsor Medical 
Monitor
Participants will be followed for 78 weeks after end of treatment.
Each participant will receive 26 weeks of treatment
they may have 
an ongoing TB infection, Investigator may consider extending 
current treatment to 39 weeks.   If the culture results between week 
16 and week 26 are contaminated, missing or considered an 
isolated positive without clinical significance, available culture 
results should be used to make this decision. All decisions regarding 
treatment extension should be discussed with and approved by the 
Sponsor Medical Monitor before implementation.
Participants will be followed for 78 weeks after end of treatment.
2
1.1  Synopsis 
Summary
A total of up to 180 participants:
120 (30 per treatment arm) XDR-TB participants, and up to 60 (15 per 
arm) pre-XDR or treatment intolerant/non-responsive MDR pulmonary 
tuberculosis Participants, male and female, aged 18 and over. 
Enrollment will stop when 120 XDR-TB participants are randomized. 
Sponsor may consider replacement of late screen failure and un-
assessable (as detailed in the statistical analysis plan) participants.
A total of up to 180 participants male and female, aged 18 and over. 
Sponsor may consider replacement of late screen failure and un-
assessable (as detailed in the statistical analysis plan) participants.
2
3
1.1  Synopsis
Summary
The test product will be supplied as:
bedaquiline 100 mg tablets
pretomanid 200 mg tablets
linezolid (scored) 600 mg tablets
placebo linezolid (scored) 600 mg tablets
linezolid half tablet (pre-cut) 300 mg 
placebo linezolid half tablet (pre-cut) 300 mg
Linezolid treatment will be supplied as 2 rows of full tablets and one row 
of half-tablets to allow for all possible dosing options while maintaining 
the blind. 
Treatment will be administered orally, once daily, with a full glass of 
water and a meal in the following dosing schemes (treatment arms):
Participants will receive the following:
bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily 
for 18 weeks plus; 
pretomanid 200 mg once daily for 26 weeks plus;
Linezolid- participants will be randomly assigned to receive one of 
the following four linezolid treatment doses and durations: 
The regimen will be supplied as the following:
Product
Tablet Strength
Abbreviation 
Bedaquiline
100 mg 
(B)
Pretomanid
200 mg 
(Pa)
Linezolid (scored)
600 mg
(L)
Placebo Linezolid 
(scored)
placebo
(L)
Linezolid 600 mg 
half tablet (pre-
cut)
300 mg
(L)
Placebo linezolid 
600 mg half tablet 
(pre-cut)
placebo
(L)
Linezolid treatment will be supplied as 2 rows of full tablets (active 
or placebo) and one row of half-tablets (active or placebo) to allow 
for all possible dosing options while maintaining the blind. 
Instructions for Dosing:
6
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Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 7 of 37
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Linezolid 1200 mg daily for 26 weeks
2 linezolid 600 mg active tablets once daily for 26 weeks
1 placebo linezolid 300 mg half tablet once daily for 26 weeks
Linezolid 1200 mg daily for 9 weeks
Weeks 1-9
2 linezolid 600 mg active tablets once daily for 9 weeks 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks
Weeks 10-26
2 placebo linezolid 600 mg tablets once daily for 17 weeks
1 placebo linezolid 300 mg half tablet once daily for 17 weeks
Linezolid 600 mg daily for 26 weeks
1 linezolid 600 mg active tablet once daily for 26 weeks
1 placebo linezolid 600 mg tablet once daily for 26 weeks 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks
Linezolid 600 mg daily for 9 weeks
Weeks 1-9
1 linezolid 600 mg active tablet once daily for 9 weeks
1 placebo linezolid 600 mg tablet for 9 weeks
1 placebo linezolid 300 mg half tablet once daily for 9 weeks
Weeks 10-26
2 placebo linezolid 600 mg tablets once daily for 17 weeks
1 placebo linezolid 300 mg half tablet once daily for 17 weeks
Treatment will be administered orally, once daily, with a full glass of 
water and a meal in the following dosing schemes (treatment arms):
Participants will receive the following:
bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus; 
pretomanid 200 mg once daily for 26 weeks plus;
Linezolid- participants will be randomly assigned to receive 
one of the following four blinded linezolid treatment doses and 
durations: 
Linezolid 1200 mg daily for 26 weeks
2 linezolid 600 mg active tablets once daily for 26 weeks
½ (one half) placebo linezolid tablet once daily for 26 weeks
Linezolid 1200 mg daily for 9 weeks
Weeks 1-9
2 linezolid 600 mg active tablets once daily for 9 weeks 
½ (one half) placebo linezolid tablet once daily for 9 weeks
Weeks 10-26
2 placebo linezolid tablets once daily for 17 weeks
½ (one half) placebo linezolid tablet once daily for 17 weeks
Linezolid 600 mg daily for 26 weeks
1 linezolid 600 mg active tablet once daily for 26 weeks
1 placebo linezolid tablet once daily for 26 weeks 
½ (one half) placebo linezolid tablet once daily for 26 weeks
Linezolid 600 mg daily for 9 weeks
Weeks 1-9
1 linezolid 600 mg active tablet once daily for 9 weeks
1 placebo linezolid tablet for 9 weeks
½ (one half) placebo linezolid tablet once daily for 9 weeks
Weeks 10-26
2 placebo linezolid tablets once daily for 17 weeks
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Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
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½ (one half) placebo linezolid tablet once daily for 17 weeks
Linezolid 600 mg daily for 9 weeks
Weeks 1-9
1 linezolid 600 mg active tablet once daily for 9 weeks
1 placebo linezolid tablet for 9 weeks
½ (one half) placebo linezolid tablet once daily for 9 weeks
Weeks 10-26
2 placebo linezolid tablets once daily for 17 weeks
½ (one half) placebo linezolid tablet once daily for 17 weeks
4
1.1  Synopsis
Summary
Treatment Modifications:
The above treatment schemes may require modification due to toxicities 
as noted below. All dose modifications should be discussed with the 
Sponsor Medical Monitor prior to implementation, unless a pause or 
dose reduction is required urgently for a safety concern; the Medical 
Monitor should be informed within 24 hours of the change if not 
discussed prior to implementation
In the event of linezolid specific toxicities, the following should be 
considered and implemented per guidance in the monitoring and safety 
for specific toxicities section of protocol.  Every effort should be made for 
participants to receive a total of 9 weeks of linezolid, even if pauses are 
required:
Blinded one step reductions (maximum 3 steps) in the dose of 
linezolid (1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or 
300mg QD to placebo) managed by the IWRS as per instructions 
in pharmacy manual and/or IWRS user manual. 
Temporary pause of linezolid due to a linezolid-specific toxicity 
should be considered and implemented per guidance in the 
monitoring and safety for specific toxicities section of protocol.
Permanent discontinuation of linezolid.
For participants experiencing suspected drug related toxicities due to 
other drugs in the regimen (B-Pa), the full regimen may be halted for up 
to 35 consecutive days. 
Treatment Modifications:
The above treatment schemes may require modification due to 
toxicities as noted below. All dose modifications should be 
discussed with the Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required 
urgently for a safety concern; the Medical Monitor should be 
informed within 24 hours of the change if not discussed prior to 
implementation
In the event of linezolid specific toxicities, the following should be 
considered and implemented per guidance in the monitoring and 
safety for specific toxicities section (8.3) of protocol:  
Blinded one step reductions (maximum 2 steps) in the dose 
of linezolid managed by the IXRS as per instructions in 
pharmacy manual and/or IXRS user manual. 
o
1200 mg QD to 600 mg QD, 600 mg QD to 300 mg 
QD or  
o
600 mg QD to 300 mg QD, 300mg QD to placebo 
Temporary pause of linezolid.
Permanent discontinuation of linezolid.
Participants who have a linezolid reduction can go back to a 
higher dose (1 step or 2 steps) post discussion with and 
approval by Sponsor Medical Monitor.
7
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Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
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Interruptions/pauses of all Investigational Medicinal Product (IMP) must 
not exceed 8 weeks (56 days) cumulatively. 
If participant’s week 16 sample remains culture positive, Investigator 
may consider option to extend current treatment to 39 weeks, in 
consultation with the Sponsor Medical Monitor. When treatment is 
extended due to a positive culture at week 16, interruptions/pauses of all 
IMP must not exceed 13 weeks (91 days) cumulatively.
At no time should the participant be treated with a single agent.
For participants experiencing suspected drug related toxicities due 
to other drugs in the regimen (B-Pa), the full regimen may be halted 
for up to 35 consecutive days. 
Interruptions/pauses of all Investigational Medicinal Product (IMP) 
must not exceed 8 weeks (56 days) cumulatively. 
When treatment is extended to 39 weeks, interruptions/pauses of all 
IMP must not exceed 13 weeks (91 days) cumulatively.
When the total of missed dosing days of the prescribed regimen 
and/or pauses is greater than 7 days, the same number of missed 
doses should be dispensed/treatment extended to make up for the 
total missed doses.
At no time should the participant be treated with a single agent.
Every effort should be made for participants to receive a total of 9 
weeks of linezolid, even if pauses are required
5
1.1  Synopsis 
Summary 
Primary Endpoint:
Incidence of bacteriologic failure or relapse or clinical failure through 
follow up until 26 weeks after the end of treatment.
Primary Endpoint:
Incidence of bacteriologic failure or relapse, or clinical failure at 26 
weeks after the end of treatment.
8
6
1.1  Synopsis 
Summary 
Descriptive statistics of ophthalmology slit lamp examination data 
(age related eye disease study 2 [AREDS2]) lens opacity 
classification and grading). Categorical data for lens opacity will 
be summarized in a frequency table for the right and left eye, 
respectively, including change from baseline.
Descriptive statistics of ophthalmology slit lamp examination 
data (age related eye disease study 2 [AREDS2]) lens 
opacity classification and grading). Categorical data for lens 
opacity will be summarized in a frequency table for the right 
and left eye, respectively, including observed and change 
from baseline
9
7
1.1  Synopsis 
Summary 
Trial Duration:
~3.5 Years (An enrolment period of at least 18 months plus 9 days pre-
treatment plus 6 month treatment period plus 18 months post treatment 
follow-up).
Trial Duration:
~3.5 Years (An enrolment period of at least 18 months plus 14 days 
pre-treatment plus 6 months treatment period plus 18 months post 
treatment follow-up).
1
8
1.2 Synopsis
Flowchart
Captured in synopsis flowchart/table under time of visits, screening: Up to 
9 days prior to Treatment
Captured in synopsis flowchart/table under time of visits, screening:
Up to 14 days prior to first dose
1
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Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
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Page 10 of 37
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9
1.2 Synopsis 
Flowchart
Captured in synopsis flowchart/table (after week 23 treatment): Visits 
every 3 weeks   if extended due to IMP pause or culture (+) at week 16
Captured in synopsis flowchart/table (after week 23 treatment):
Visits every 3 weeks if extended.
12
10
1.2 Synopsis 
Flowchart
Captured in flowchart/table: Ophthalmic exams are performed during 
screening, treatment week 4, week 8, week 12, week 16m week 20 visits 
every 3 weeks if extended, end of OR Early withdrawal from treatment, 
and post treatment follow-up week 4.
Captured in flowchart/table: Ophthalmic exams are marked as
performed during screening, treatment week 4, week 8, week 12, 
week 16, week 20, week 23, visits every 3 weeks if extended, end of 
OR Early withdrawal from treatment, post treatment follow-up week 
4, and follow-up week 12.
10
11
1.2 Synopsis 
Flowchart
1.2 Synopsis Flowchart:
Captured in flowchart/table: Post Treatment Follow-up 78 weeks
1.2 Synopsis Flowchart:
Captured in flowchart/table: Post Treatment Follow-up 78 weeks/EW
11
12
1.2 Synopsis
Flowchart
a.
Screening: Screening assessments can occur on different days 
within nine days prior to Day 1 dosing. If a participant fails screening, 
a full re-screen may occur at a later date post discussion with Medical 
Monitor. All screening procedures must be repeated at re-screen visit, 
with the exception of the slit lamp examination, which can be used 
from a previous screening if within 8 weeks of anticipated 
randomization.
a.
Screening: Screening assessments can occur on different days 
within 14 days prior to Day 1 dosing (randomization). If a 
participant fails screening, a full re-screen may occur at a later 
date.  All screening procedures must be repeated at re-screen 
visit, with the exception of the slit lamp examination, which can 
be used from a previous screening if within 8 weeks of 
anticipated randomization.
1 and 5
13
1.2 Synopsis
Flowchart
b. Visit Schedule: If the duration of treatment is extended due to dose 
pauses (e.g., takes participant 35 weeks to complete 26 weeks of 
treatment) or positive week 16 culture, unscheduled visits should be 
added every 3 weeks (+/- 7 days).  End of treatment visit (final 
treatment visit) should be done within 7 days AFTER the last dose of 
IMP. 
1.
If participant completes treatment at week 26, end of 
treatment visit should be done within 7 days after last dose of 
week 26.
2.
If participant completes 26 weeks of therapy at week 33 due 
to pauses, visits can be done at weeks 26, 29 and 33 (3 weeks 
from week 29 plus 7-day window). The week 33 visit would be 
the end of treatment visit and should be completed within 7 
days after last dose.
3.
If participant completes treatment at week 39 due to post 
treatment extension related to positive culture at week 16, 
visits can be completed at weeks 26, 29, 32, 35 and 39 (3 
b.
Visit Schedule: If the duration of treatment is extended (see 
section 6.3, Treatment Modifications for details), unscheduled 
visits should be added every 3 weeks (+/- 7 days).  
1.
End of treatment visit (final treatment visit) should 
be done within 7 days AFTER the last dose of IMP. 
2.
If participant completes 26 weeks of therapy at 
week 33 due to full regimen pauses, an EXAMPLE 
of visit scheduling would be weeks 26, 29 and 33 (3 
weeks from week 29 plus 7-day window). In this 
scenario, the week 33 visit would be the end of 
treatment visit and should be completed within 7 
days after last dose.
3.
If participant completes treatment at week 39 due to 
treatment extension, an example of visit scheduling 
would be visits at weeks 26, 29, 32, 35 and 39/End 
of treatment (3 weeks plus 7-day window). 
4.
Follow-up visits should be scheduled based on 
timing of end of last dose of IMP (e.g., 4-week 
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Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 11 of 37
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weeks plus 7-day window), visit at week 39 would be the end 
of treatment visit.
4.
Follow-up visits should be scheduled based on timing of end 
of treatment/early withdrawal from treatment (e.g., 4-week 
follow-up to be scheduled 4 weeks after last dose of IMP).
follow-up to be scheduled 4 weeks after last dose of 
IMP).
14
1.2 Synopsis
Flowchart
c.
Follow-up Visits Early Withdrawal Participants: Once a participant 
has been discontinued from treatment, they will be required to attend 
an Early Withdrawal visit. If participant:
1.
Received/took < 14 doses, no additional follow-up visits are 
required.  
2.
Received 15 or more doses, follow-up after end of treatment 
at week 12, week 26 (if not already performed) and week 78 
are required. The week 12 visit will only require the 
ophthalmologic exams. The week 26 and 78 follow-up visits 
will be to collect Serious Adverse Event (SAE) information 
(including verification of survival) and patient reported TB 
outcome information only and may be telephonic, a home or 
a site visit. This includes participants who are withdrawn from 
the trial due to meeting the treatment failure endpoint.
Participant may need to return for visits to collect sputum 
samples to determine outcome status as per section “r”.
c.
Follow-up Visits Early Withdrawal Participants: Once a
participant has been discontinued, they will be required to 
attend an Early Withdrawal visit. If participant:
1.
Received/took < 14 doses, no additional follow-up visits 
are required.  
2.
Received 15 or more doses and is withdrawn during 
treatment, follow-up after end of treatment/EW visit at 
week 12, week 26 (if not already performed) and week 
78 are required. The follow-up week 12 visit will only 
require the ophthalmologic exams. The week 26 and 78 
follow-up visits will be to collect Serious Adverse Event 
(SAE) information (including verification of survival) and 
patient reported TB outcome information only and may 
be telephonic, a home or a site visit. This includes 
participants who are withdrawn from the trial due to 
meeting the treatment failure endpoint. Participant may 
need to return for visits to collect sputum samples to 
determine outcome status.
3.
For participants who are withdrawn during post treatment 
follow-up, site should perform study procedures required 
for week 78 post treatment follow-up visit. If participant 
will not return for visit, site should obtain information on 
SAE and patient reported TB outcome as noted above in 
no 2.
11
15
1.2 Synopsis
Flowchart
e.
HIV testing: If HIV status is a confirmed known positive, repeated 
HIV test is not needed provided that a documented HIV test result 
(ELISA, Western Blot or Electro-Chemiluminescence) is available. If 
HIV status is unknown or suspected negative, HIV test will be 
requested. If an ELISA and/or Western Blot and/or Electro-
Chemiluminescence based HIV test was performed within 4 weeks 
prior to screening, it should not be repeated if documentation of 
testing method and negative HIV results can be provided. Repeated 
e.
HIV testing: If HIV status is a confirmed known positive, 
repeated HIV test is not needed provided that a documented 
HIV 
test 
result 
(ELISA, 
Western 
Blot 
or 
Electro-
Chemiluminescence) is available. If HIV status is unknown or 
suspected negative, HIV test will be requested. If an ELISA 
and/or Western Blot and/or Electro-Chemiluminescence based 
HIV test was performed within 4 weeks prior to screening, it 
should not be repeated if documentation of testing method and 
negative HIV results can be provided. Repeated HIV testing, 
13
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Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
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HIV testing, during the Screening period is permitted for 
indeterminate HIV results.
during the Screening period is permitted for indeterminate HIV 
results.
16
1.2 Synopsis
Flowchart
f.
CD4 count and viral load: For all HIV-positive participants, viral load 
and CD4 at screening, CD4 only tested at end of treatment or early 
withdrawal.
f.
CD4 count and viral load: Required for all HIV-positive 
participants. Viral load and CD4 required at screening, CD4 
will be tested at end of treatment or early withdrawal from 
treatment visit.
14
17
1.2 Synopsis
Flowchart
g. Chest X-Ray: A chest x-ray (digital image) within one month prior to 
screening, will be obtained and read locally by Investigator or 
designee. Digital images will be provided to Sponsor, this process will 
be described in a separate document, the Radiology Manual.
g.
Chest X-Ray: A chest x-ray (digital image) within 6 months 
one month prior to or at screening, will be obtained and read 
locally by Investigator or designee. Digital images will be 
provided to Sponsor, this process will be described in a 
separate document, the Radiology Manual
15
18
1.2 Synopsis
Flowchart
k. Single 12-Lead ECG: To every extent possible, should be performed 
at approximately the same time of day (+/- 1 hours) and in the same 
fed/fasted state throughout the trial (e.g. 4 hours after lunch). Central 
ECG analysis will be performed.
k.
Single 12-Lead ECG: When possible, should be performed 
at approximately the same time of day (+/- 1 hours) and in the 
same fed/fasted state throughout the trial (e.g. 4 hours after 
lunch). Central ECG analysis will be performed. Central 
reading of screening results will be used to determine 
eligibility.
16
19
1. 2 Synopsis
Flowchart
l. 
Physical Exam: Limited Physical exams should include weight and 
a gross neurological, pulmonary, cardiovascular and abdominal 
exam.
l.        Physical Exam: Limited Physical exams should include 
weight and a gross neurological, pulmonary, cardiovascular 
and abdominal exam. Height will only be collected as part of 
full exam at screening.
17
20
1.2 Synopsis
Flowchart
m. Safety Laboratory Assessments: The Safety Laboratory sampling 
methodology and requirements will be described in a separate 
document, the Laboratory Manual, which will be provided prior to the 
trial start. The following analyses will be performed:
1.
Full Blood Count (hemoglobin, hematocrit, red blood cell 
count, white blood cell count with differential, platelet 
count). 
2.
Clinical Chemistry (albumin, serum urea, creatinine, 
direct, indirect and total bilirubin, uric acid, total protein, 
alkaline phosphatase, aspartate aminotransferase (AST),
alanine aminotransferase (ALT), lipase, phosphate, 
sodium, potassium, calcium (corrected for albumin), 
chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK).
3.
Urinalysis (pH, specific gravity, protein, glucose, micro-
albumin, ketones, bilirubin, creatinine, nitrite, sodium, 
m.
Safety Laboratory Assessments/Urine Drug Screen: The 
Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, 
which will be provided prior to the trial start. The following 
analyses will be performed:
Full Blood Count (hemoglobin, hematocrit, red blood cell 
count, white blood cell count with differential, platelet 
count). 
Clinical Chemistry (albumin, serum urea, creatinine, 
direct, indirect and total bilirubin, uric acid, total protein, 
alkaline 
phosphatase, 
aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase 
(ALT), 
lipase, 
phosphate, sodium, potassium, calcium (corrected for 
albumin), 
chloride, 
magnesium, 
glucose, 
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Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
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urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per 
discretion of Investigator.
4.
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, opiates, benzodiazepines, barbiturates,
at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 5. Positive 
results will not automatically exclude participant from the 
trial.
bicarbonate/CO2, creatine phosphokinase (CPK).  GGT 
will be done at screening.
When managing participants with elevated liver enzymes 
at an unscheduled visit, the Investigator can request 
additional tests, in addition to the repeated LFT [e.g. 
Gamma Glutamyl Transferase, screening for hepatitis A, 
B, C; to assist in ruling out other causes of abnormal liver 
test (e.g. alcohol induced hepatic cell injury, hepatobiliary 
disease, hepatic viral infection).
Urinalysis (pH, specific gravity, protein, glucose, micro-
albumin, ketones, bilirubin, creatinine, nitrite, sodium, 
urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis.
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, opiates, benzodiazepines, barbiturates,
at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 2.  Positive 
results will not automatically exclude participant from the 
trial.
21
1.2 Synopsis
Flowchart
o. PK Sampling: Specific PK blood draws as follows:
1.
Day 1; pre-dose (within 2 hours prior to dosing)
2.
Week 2: pre-dose (within 2 hours prior to dosing), 2–3
hours post-dose and 6–8 hours post-dose
3.
Week 8: pre-dose (within 2 hours prior to dosing), 2–3
hours post-dose and 6–8 hours post-dose
4.
Week 12: pre-dose (within 2 hours prior to dosing) 
5.
Week 20 or at early withdrawal if prior to week 20: pre-
dose (within 2 hours prior to dosing) and 2–3 hours post-
dose.
When participant is discharged and seen as an outpatient, site should 
make every effort to collect 6-8 hour samples at weeks 8 and when 
operationally and logistically feasible.
If dosing of any component of the regimen has been paused, and no 
dose of some component is given on the scheduled day of sampling, 
then defer the sampling until the dosing of all components has been 
resumed, even if some component is at a different dose level, and bring 
the patient back for sampling on an unscheduled visit when all 
o. PK Sampling: The dates and times of the two doses of IMP taken 
prior to all pre-dose PK samples will be collected in the eCRF.   
Specific PK blood draws will be obtained as follows (pre-dose to 
be done after ECGs):
1.
Day 1; pre-dose (within 2 hours prior to dosing)
2.
Week 2: pre-dose (within 2 hours prior to dosing), 2–3
hours post-dose and 6–8 hours post-dose
3.
Week 8: pre-dose (within 2 hours prior to dosing), 2–3
hours post-dose and 6–8 hours post-dose
4.
Week 12: pre-dose (within 2 hours prior to dosing) 
5.
Week 20 or at early withdrawal if prior to week 20: pre-
dose (within 2 hours prior to dosing) and 2–3 hours post-
dose
When participant is discharged and seen as an 
outpatient, site should make every effort to collect 6-8
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Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
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TMP02-C V3.0 dated 06Dec2017
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components are administered. If the site has permanently discontinued 
linezolid due to toxicity, sampling should be done on a day when the 
bedaquiline and pretomanid are dosed.
hour sample at week 8 when operationally and 
logistically feasible. 
Hospitalization information (e.g. discharge date) will be 
collected in the eCRF.
If the full regimen or linezolid is paused, PK sampling 
should be delayed until full regimen or linezolid are 
resumed.
PK sampling should be completed even if the 
participant’s linezolid dose has been lowered or 
Linezolid has been permanently discontinued. 
Sites may bring participant back at a scheduled or 
unscheduled visit (can occur outside of visit windows) to 
collect PKs to ensure draw is done when IMP is 
administered. 
22
1.2 Synopsis
Flowchart
SPUTUM SAMPLES GENERAL: If EMS is not available, site should make 
every attempt to collect two spot samples at least 30 minutes apart. 
BASELINE: If available, site will request pre-screening culture that was 
used for the tests that qualified the participant for inclusion into the trial to 
5 and 20
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Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
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TMP02-C V3.0 dated 06Dec2017
Page 15 of 37
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be subcultured and shipped to the study lab from the applicable lab for 
relevant participants with no positive cultures from screening through week 
4 (with consent). Samples should be stored according to the applicable lab 
procedures until shipment to the designated study lab. Included with each 
shipment will be a copy of the applicable lab reports and all participant 
identifying information redacted and a completed shipment inventory form 
with appropriate participant trial identifiers. Details on how samples will be 
packed and shipped will be provided in the lab manual.
POSITIVE MTB AT/AFTER END OF TREATMENT: Only one isolate 
(preferably from EMS) should be shipped. Second isolate may be 
requested if first is contaminated.
MOLECULAR TESTING:
At Screening: GeneXpert, Hain MTBDRplus or equivalent to 
determine MTB complex and R resistance.
Positive MTB at/after end of treatment: Hain MTBDRplus and 
HainMTBRsl
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including but not 
limited to FQ and injectables.
STORAGE: MTB isolates from all positive cultures to be stored at the 
study laboratory until trial closure for the applicable study tests. The 
extracted MTB DNA from the applicable baseline and follow-up isolates 
will also be stored at the central lab for potential further work to validate 
new assay tools for 5 years after trial closure.
CENTRAL LAB: Results from testing at Central myco lab (MIC, DST and 
genotyping) will not routinely be provided to sites.  In the event of 
participant relapse/failure, Sponsor will provide available results to the site 
in order to inform appropriate participant treatment.
UNSCHEDULED VISITS: If cultures of both spot sputum samples are 
contaminated at the following visits, or if necessary in order to help define 
a participant’s outcome status/assess culture status during follow-up, the 
participant should return for an unscheduled visit(s) to give additional 
samples or to document the participant is not able to produce sputum:
SPUTUM SAMPLES GENERAL: If EMS (early morning sputum) is 
not available, site should make every attempt to collect two spot 
samples at least 30 minutes apart. 
PRE-SCREENING SAMPLES: If consent granted by participant, and 
when applicable, site can request pre-screening culture/isolate/DNA 
from current TB diagnosis/disease course to be sub-cultured and 
shipped and/or tested:
at the study lab if/when those samples could support 
inclusion in trial. 
at the study/central lab for relevant participants with no 
baseline (no positive cultures from screening through week 
4).
MOLECULAR TESTING:
At Screening: GeneXpert, Hain MTBDRplus or equivalent to 
determine MTB complex and Rifampicin resistance.
Positive MTB at/after week 16: Hain MTBDRplus and 
HainMTBRsl
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including 
but not limited to fluoroquinolones and injectables.
STORAGE: MTB isolates from all positive cultures to be stored at the 
study laboratory until trial closure for the applicable study tests. The 
cultures as well as the extracted MTB DNA from the applicable 
baseline and follow-up isolates will also be stored at the central lab 
for potential further work to validate new assay tools for 5 years after 
trial closure.
CENTRAL LAB: Results from testing at central lab (MIC, DST and 
genotyping) will not routinely be provided to sites.  In the event that 
results are necessary to determine appropriate participant treatment, 
Sponsor will provide available drug susceptibility results to the site. 
Genotyping will be performed on paired DNA extracts to determine if 
the participant was a relapse or reinfection (See SAP for details).
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End of treatment visit;
Week 26 post treatment follow-up visit;
Post treatment follow-up visits from week 8 through week 65 
(in addition to week 26 follow-up);
End of Follow-up Period (week 78 post treatment completion 
visit);
Early Withdrawal (if applicable).
At the end of 26 weeks and 78 weeks post treatment completion, to define 
outcome status, need to confirm whether the participant has:
At least two sequential negative sputum culture results; or 
At least two sequential positive sputum culture results; or 
Has been unable to produce sputum after documentation of 
at least two negative sputum cultures with no intervening 
positive and are clinically asymptomatic.
If they do not fall into one of these categories, site should continue to 
collect sputum samples x 2 (one Early Morning and one Spot at the 
research site or 2 spots samples at least 30 minutes apart, under the 
coaching and observation of the trial staff) at a minimum of 7 days or 
more apart until they fall into one of the above categories.
If in any of the above scenarios the Investigator is unsure of the 
outcome, the Investigator must contact the Sponsor Medical Monitor to 
discuss and agree on how the patient is to be handled.
EXTENDED DST TESTING: Paired isolates from baseline and 
at/after week 16 should be shipped to a relevant lab (as 
applicable/available per Country) for DST extending beyond the 
panel of drugs tested at the central lab.  Extended results will be 
provided to the site to inform appropriate participant treatment.  
23
4.1 Summary of 
Trial Design
Enrolment will stop when 120 XDR-TB participants are randomized. 
Participants will be randomized to one of the four regimens in a 1:1:1:1 
ratio, using an interactive web response system (IXRS) which will utilize a 
dynamic randomization system using minimization with a random element 
to allocate participants evenly across the arms by HIV status and type of 
TB after they have given written, informed consent and met all eligibility 
criteria. 
Participants will be randomized to one of the four regimens in a 
1:1:1:1 ratio, using an interactive voice and web response system 
(IXRS) which will utilize a randomization system using stratification 
with a random element to allocate participants evenly across the arms 
by HIV status and type of TB after they have given written, informed 
consent and met all eligibility criteria. 
2
24
4.1 Summary of 
Trial Design
Each participant will receive 26 weeks of treatment.  If participant’s week 
16 sample remains culture positive, Investigator may consider option to 
extend current treatment to 39 weeks, in consultation with the Sponsor 
Each participant will receive 26 weeks of treatment. If participant’s 
sputum sample is culture positive between the week 16 and week 26 
treatment visits and their clinical condition suggests they may have 
4 and 5
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Medical Monitor. Participants will be followed for 78 weeks after end of 
treatment.
an ongoing TB infection, Investigator may consider extending current 
treatment to 39 weeks.   If the culture results between week 16 and 
week 26 are contaminated, missing or considered an isolated positive 
without clinical significance, available culture results should be used 
to make this decision. All decisions regarding treatment extension 
should be discussed with and approved by the Sponsor Medical 
Monitor before implementation. Participants will be followed for 78 
weeks after end of treatment.
25
5.1 Inclusion 
Criteria
3.
HIV testing (if an HIV test was performed within 1 month prior to 
screening, it should not be repeated as long as documentation can 
be provided [ELISA and/or Western Blot].  If HIV status is a 
confirmed known positive, repeated HIV test is not needed provided 
documentation is available
3.
HIV testing (if an HIV test was performed within 1 month prior to 
screening, it should not be repeated as long as a documented 
result can be provided [ELISA and/or Western Blot and/or 
Electro-Chemiluminescence].  If HIV status is a confirmed known 
positive, repeated HIV test is not needed if ELISA and/or Western 
Blot and/or Electro-Chemiluminescence documentation of 
positive is available.
13
26
5.1 Inclusion 
Criteria
5. Participants with one of the following pulmonary TB conditions:
a.
XDR-TB with 
i.
A documented culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 
months prior to screening or MTB confirmed in sputum 
based on molecular test within 3 months prior to or at 
screening and:
ii.
historical documented resistance to isoniazid, rifamycins, a 
fluoroquinolone AND an injectable during the current TB 
diagnosis/disease course; 
b.
Pre-XDR-TB with
i.
A documented culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 
months prior to screening or MTB confirmed in sputum 
based molecular test within 3 months prior to or at 
screening and;
ii.
historical documented resistance to isoniazid, rifamycins, 
and to a fluoroquinolone OR an injectable during the 
current TB diagnosis/disease course.
c.
MDR-TB with
i.
documented by culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected results within 
5. Participants with one of the following pulmonary TB conditions:
a.
XDR-TB with 
i. A documented culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 months 
prior to screening or MTB confirmed in sputum based on 
molecular test within 3 months prior to or at screening and:
ii. documented resistance to rifamycins, a fluoroquinolone 
AND an injectable during the current TB diagnosis/disease 
course any time prior to or during screening period (may be 
sensitive or resistant to isoniazid); 
b.
Pre-XDR-TB with
i. A documented culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 months 
prior to screening or MTB confirmed in sputum based 
molecular test within 3 months prior to or at screening and;
ii. documented 
resistance 
to 
rifamycins, 
and 
to 
a 
fluoroquinolone OR an injectable during the current TB 
diagnosis/disease course any time prior to or during 
screening period (may be sensitive or resistant to isoniazid);
c.
MDR-TB with
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3 months prior to screening or MTB confirmed in sputum 
based on molecular test within 3 months prior to or at 
screening and;
ii.
historical
documented resistance to 
isoniazid
and 
rifamycins during the current TB diagnosis/disease course;
iii.
with documented non-response to treatment with the best 
available regimen for 6 months or more prior to enrolment 
who in the opinion of the Investigator have been adherent 
to treatment and will be adherent to study regimen.  
d.
MDR-TB with 
i.
documented by culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 
months prior to screening or MTB confirmed in sputum 
based on molecular test within 3 months prior to or at 
screening and:
ii.
historical
documented resistance to 
isoniazid
and 
rifamycins during the current TB diagnosis/disease course
and;
iii.
who are unable to continue second line drug regimen due 
to a documented intolerance to:
a.
PAS, ethionamide, aminoglycosides or 
fluoroquinolones or ;
b.
Current treatment not listed above
that renders 
participant eligible for the study in the Investigator’s 
opinion.
i. documented by culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected results within 3 
months prior to screening or MTB confirmed in sputum 
based on molecular test within 3 months prior to or at 
screening and;
ii. documented resistance to rifamycins during the current TB 
diagnosis/disease course any time prior to or during 
screening period (may be sensitive or resistant to isoniazid) 
and;
iii. with documented non-response to treatment with the best 
available regimen for 6 months or more prior to enrolment 
who in the opinion of the Investigator have been adherent to 
treatment and will be adherent to study regimen.  
d.
MDR-TB with 
i. documented by culture positive or a molecular test positive 
(for MTB) from a sputum specimen collected within 3 months 
prior to screening or MTB confirmed in sputum based on 
molecular test within 3 months prior to or at screening and:
ii. documented resistance rifamycins during the current TB 
diagnosis/disease course
any time prior to or during 
screening period (may be sensitive or resistant to isoniazid) 
and;
iii. who are unable to continue second line drug regimen due to 
a documented intolerance to:
a. PAS, ethionamide, aminoglycosides or fluoroquinolones 
or ;
b. Current treatment not listed above that renders 
participant eligible for the study in the Investigator’s 
opinion. 
27
5.1 Inclusion 
Criteria
Chest X-Ray within 1 months prior at screening, obtained and read locally 
by investigator or designee with results consistent with pulmonary TB in 
the opinion of the Investigator.
Chest X-Ray within 6 months prior to or at screening, obtained and 
read locally by investigator or designee with results consistent with 
pulmonary TB in the opinion of the Investigator.
15
28
5.1 Inclusion 
Criteria
Contraception:
7.
Be of non-childbearing potential or using effective methods of birth 
control, as defined below:
Contraception:
7.
Be of non-childbearing potential or using effective methods 
of birth control, as defined below:
22
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Non-childbearing potential:
a.
Participant - not heterosexually active or practices sexual 
abstinence; or 
b.
Female 
participant/sexual 
partner 
-
bilateral 
oophorectomy, 
bilateral 
tubal 
ligation 
and/or 
hysterectomy or has been postmenopausal with a history 
of no menses for at least 12 consecutive months; or 
c.
Male participant/sexual partner - vasectomised or has 
had a bilateral orchidectomy at least three months prior 
to Screening.
Effective birth control methods:                                             
A double contraceptive method should be used as follows:
a.
Double barrier method which can include any 2 of the 
following: a male condom, diaphragm, cervical cap, or 
female condom (male and female condoms should not be 
used together); or 
b.
Barrier method (one of the above) combined with 
hormone-based contraceptives or an intra-uterine device 
for the female participant/partner;
And are willing to continue practicing birth control methods throughout 
treatment and for 6 months (both male and female participants) after the 
last dose of study medication.
Note: Hormone based contraception alone may not be reliable when 
taking IMP; therefore, hormone based contraceptives alone cannot be 
used by female participants or female partners of male participants to 
prevent pregnancy.
Non-childbearing potential:
a.
Participant - not heterosexually active or practices 
sexual abstinence; or 
b.
Female participant or male participant’s female 
sexual partner - bilateral oophorectomy, bilateral 
tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at 
least 12 consecutive months; or 
c.
Male participant or female participant’s male sexual 
partner - vasectomised or has had a bilateral 
orchidectomy at least three months prior to 
screening.
Effective birth control methods:                                      
a.
Double barrier method which can include a male 
condom, diaphragm, cervical cap, or female condom; 
or 
b.
Female participant: Barrier method combined with 
hormone-based contraceptives or an intra-uterine 
device for the female participant;
c.
Male participant’s female sexual partner: Double 
barrier method or hormone based contraceptives or
an intra-uterine device for the female partner.
And are willing to continue practicing birth control methods 
throughout treatment and for 6 months female participants and 12 
weeks (male participants) after the last dose of study medication.
Note: Hormone based contraception alone may not be reliable 
when taking IMP; therefore, hormone-based contraceptives alone 
cannot be used by female participants to prevent pregnancy.
29
5.2 Exclusion 
Criteria
7. TB infection with known resistance to pretomanid, delamanid, 
linezolid or bedaquiline.
7.
TB infection with historic DST or MIC results with values 
suggesting likely known resistance to pretomanid, 
delamanid, linezolid or bedaquiline; the Sponsor Medical 
Monitor should be consulted to help interpret any available 
historic results.
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30
5.2 Exclusion 
Criteria
10. Participants with any of the following at Screening:
•
QTcF interval on ECG >500 msec. Participants with QTcF > 
450 must be discussed with the Sponsor Medical Monitor 
before enrolment.
•
Heart failure
•
A personal or family history of congenital QT prolongation
•
A history of or known, untreated, ongoing hypothyroidism
•
A history of or ongoing bradyarrhythmia
•     A history of Torsade de Pointe
10. Participants with any of the following at Screening:
•
QTcF interval on ECG >500 msec. Participants with 
QTcF > 450 must be discussed with and approved by 
the Sponsor Medical Monitor before enrolment. (Per 
measurements and reading done from screening central 
ECG.)
•
Heart failure
•
A personal or family history of congenital QT 
prolongation
•
A history of or known, untreated, ongoing 
hypothyroidism
•
A history of or ongoing bradyarrhythmia
•
A history of Torsade de Pointe
5 and 16
31
5.2 Exclusion 
Criteria
Previous and Concomitant Therapy
15. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or 
prior use within 2 weeks of randomization. 
16. Concomitant use of serotonergic antidepressants or prior use 
within 3 days of randomization if Investigator foresees potential 
risks for serotonin syndrome when combined with linezolid.
17. Concomitant use of any drug known to prolong QTc interval 
(including, but not limited to, amiodarone, bepridil, chloroquine, 
chlorpromazine, 
cisapride, 
cyclobenzaprine, 
clarithromycin, 
disopyramide, dofetilide, domperidone, droperidol, erythromycin, 
fluoroquinolones, halofantrine, haloperidol, ibutilide, levomethadyl, 
mesoridazine, methadone, pentamidine, pimozide, procainamide, 
quinidine, sotalol, sparfloxacin, thioridazine). 
18. Concomitant use of any drug known to induce myelosuppression. 
19. Concomitant use of any drugs or substances known to be strong 
inhibitors or inducers of cytochrome P450 enzymes (including but 
not limited to efavirenz, quinidine, tyramine, ketoconazole, 
fluconazole, testosterone, quinine, gestodene, metyrapone, 
phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, 
erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). 
Exceptions may include use of lopinavir/ritonavir regimen as 
noted in section 5.3.3.
Previous and Concomitant Therapy
15.
Known (during screening) requirement for future 
Concomitant (during treatment) use of any prohibited and/or 
avoided medications noted in section 5.3.
16.
Prior use of Monoamine Oxidase Inhibitors (MAOIs) within 2 
weeks of randomization. 
17.
Prior use of serotonergic antidepressants within 3 days of 
randomization if Investigator foresees potential risks for 
serotonin syndrome when combined with linezolid. 
18.
Participants who have received more than 2 weeks of 
bedaquiline, linezolid or delamanid prior to first dose of IMP.
19.
Participants with newly diagnosed tuberculosis and HIV that 
require initiation of appropriate HIV therapy before 
participant has received at least 2 weeks of an anti-
tuberculosis regimen. 
20.
HIV infected participants with planned continued use of 
zidovudine, stavudine or didanosine. The antiretroviral 
therapy (ART) booster cobicistat should not be used. 
Please reference restrictions Section 5.3.3 Antiretroviral 
Therapy, for guidance on ART treatment during the 
treatment period.
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20. Concomitant use of adrenomimetics (including, but not limited to 
pseudoephedrine, 
phenylpropanolamine, 
epinephrine, 
norepinephrine, dobutamine), dopaminomimetics (e.g. dopamine).
21. Concomitant use of 5-HT1 agonists (triptans), meperidine or 
buspirone.
22. Participants who have received more than 2 weeks of bedaquiline, 
linezolid or delamanid prior to first dose of IMP.
23. Participants with an existing TB diagnosis (a diagnosis made > 4 
weeks prior to screening) and HIV co-infection, must have been on 
an ART for at least 4 weeks prior to screening. 
24. Participants with newly diagnosed tuberculosis and HIV may be 
enrolled provided that appropriate HIV therapy will not be initiated 
until participant has received at least 2 weeks of study 
medication. 
25. HIV infected participants: the following antiretroviral therapies 
should not be used: zidovudine, stavudine, didanosine. The 
antiretroviral therapy (ART) booster cobicistat should not be used. 
Please reference restrictions Section 5.3.3 Antiretroviral Therapy, 
for guidance on ART treatment during the treatment period. 
32
5.2 Exclusion 
Criteria
Diagnostic and Laboratory Abnormalities
26.
Participants with any of the following toxicities at Screening (labs 
may be repeated during screening period) as defined by the 
enhanced Division of Microbiology and Infectious Disease (DMID) 
adult toxicity table (November 2007):
a.
Viral load >1000 IU/ml (Unless newly diagnosed HIV and not yet 
on ART who otherwise qualify for participation);
b.
CD4+ count < 100 cells/µL (HIV positive participants);
c.
Serum potassium less than the lower limit of normal for the 
laboratory;
d.
Hemoglobin < 9.0 g/dL;
e.
Platelets <100,000/mm3;
f.
Absolute neutrophil count (ANC) < 1500/ mm3;
g.
Aspartate aminotransferase (AST) 
Diagnostic and Laboratory Abnormalities
21.
Participants with any of the following toxicities at Screening 
(labs may be repeated during screening period) as defined by 
the enhanced Division of Microbiology and Infectious Disease 
(DMID) adult toxicity table (November 2007):
a.
Viral load >1000 copies/mL (Unless newly diagnosed HIV 
and not yet on ART who otherwise qualify for participation);
b.
CD4+ count < 100 cells/µL (HIV positive participants);
c.
Serum potassium less than the lower limit of normal for the 
laboratory;
d.
Hemoglobin < 9.0 g/dL or < 90 g/L;
e.
Platelets <100,000/mm3 or < 100 x 10^9/L;
f.
Absolute neutrophil count (ANC) < 1500/ mm3 or < 1.5 x 
10^9/L;
25
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•
Grade 3 or greater (> 3.0 x ULN) to be excluded;
•
Results between 1.5 x ULN and 3 x ULN must be discussed with 
and approved by the Sponsor Medical Monitor
h.
Alanine aminotransferase 
•
Grade 3 or greater (> 3.0 x ULN) to be excluded;
•
Results between 1.5 x ULN and 3 x ULN must be discussed with 
and approved by the Sponsor medical monitor;
i.
Total bilirubin
•
greater than 1.5 x ULN to be excluded;
•
1-1.5 x ULN must be discussed with and approved by the 
Sponsor Medical Monitor 
j.
Direct bilirubin
•
Greater than ULN to be excluded
k.
Serum creatinine level greater than 1.5 times upper limit of 
normal
l.
Albumin <3.0 mg/dl
g.
Aspartate aminotransferase (AST) 
•
Grade 3 or greater (> 3.0 x ULN) to be excluded;
•
Results between 1.5 x ULN and 3 x ULN must be discussed 
with and approved by the Sponsor Medical Monitor
h.
Alanine aminotransferase 
•
Grade 3 or greater (> 3.0 x ULN) to be excluded;
•
Results between 1.5 x ULN and 3 x ULN must be discussed 
with and approved by the Sponsor medical monitor;
i.
Total bilirubin
•
greater than 1.5 x ULN to be excluded;
•
1-1.5 x ULN must be discussed with and approved by the 
Sponsor Medical Monitor 
j.
Direct bilirubin
•
Greater than ULN to be excluded
k.
Serum creatinine level greater than 1.5 times upper limit of 
normal
l.
Albumin <3.0 g/dl or < 30 g/L
33
5.2 Exclusion 
Criteria
26
34
5.3.1 Prior and 
Concomitant 
Medications and 
Other 
Treatments
The following concomitant medications are prohibited during the treatment 
period to avoid possible drug interactions with the IMP:
Medicinal products used to treat pulmonary TB:  including but not 
limited to gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, 
para-aminosalicylic 
acid, 
rifapentine, 
thioacetazone, 
capreomycin, quinolones, thioamides, and metronidazole.
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). (e.g., 
phenelzine, isocarboxazid)
Concomitant use of any drug known to prolong QTc interval 
(including but not limited to amiodarone, bepridil, chloroquine, 
chlorpromazine, 
cisapride, 
cyclobenzaprine, 
clarithromycin, 
disopyramide dofetilide, domperidone, droperidol, erythromycin, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozide, procainamide, quinidine, 
sotalol, sparfloxacin, thioridazine). 
The following concomitant medications are prohibited during the 
treatment period and during the 14 days after treatment completion:
Medicinal products used to treat pulmonary TB:  including but 
not limited to gatifloxacin, amikacin, cycloserine, rifabutin, 
kanamycin, 
para-aminosalicylic
acid, 
rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and 
metronidazole.
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). 
(e.g., phenelzine, isocarboxazid)
Concomitant use of adrenomimetics (including, but not 
limited 
to 
pseudoephedrine, 
phenylpropanolamine, 
epinephrine, 
norepinephrine, 
dobutamine), 
dopaminomimetics (e.g. dopamine).
Concomitant use of 5-HT1 agonists (triptans), meperidine or 
buspirone.
5 and 27
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Treatment with fluoroquinolones (as they are known prolong QTc), 
are strongly discouraged in the trial. They should only be used to 
treat intercurrent non-TB infections and if the benefit of treatment 
outweighs the risk of prolonged QTc.  
Concomitant use of any drug known to induce myelosuppression. 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: 
ketoconazole, voriconazole, itraconazole, fluconazole; ketolids 
such as telithromycin; and macrolide antibiotics other than 
azithromycin) for more than 3 consecutive days;
The systemic use of CYP3A4 inducers (e.g., phenytoin, 
carbamazepine, phenobarbital, St. John’s wort, rifamycins and 
systemic dexamethasone.
Concomitant use of serotonergic antidepressants should be avoided if 
possible as participants on these agents and linezolid are at risk for 
serotonin syndrome. 
Caution should be used in treating diabetic patients receiving insulin or 
oral hypoglycemic agents as cases have been reported of hypoglycemic 
reactions when patients on these agents have been treated with linezolid.
Any drug known to be hepatotoxic should be avoided as much as 
possible during screening and throughout the treatment period (including 
but not limited to acetaminophen/paracetamol,  acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, 
atorvastatin, augmentin/co-amoxiclav, azathioprine, baclofen, 
bumetanide, captopril, carbamazepine, celecoxib, chlorpromazine, 
chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-
trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, 
fluconazole, fluoxetine, fosamprenavir, furosemide, gliclazide, 
glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, 
loperamide, losartan, methotrexate, metolazone, mirtazepine, 
nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory drugs, 
paroxetine, phenobarbital, phenothiazines, phenytoin, pravastatin, 
probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, 
simeprevir, simvastatin, sodium valproate, sotalol, sulfasalazine, 
sumatriptan, tamsulosin, terbinafine, tetracycline, theophyllin/uniphyllin, 
The following concomitant medications should be avoided during the 
treatment period and during the 14 days after treatment completion 
to avoid possible drug interactions with the IMP. Use of any of the 
following must be discussed and approved by the Sponsor Medical 
Monitor prior to use:
Concomitant use of any drug known to prolong QTc interval 
(including 
but 
not 
limited 
to 
amiodarone, 
bepridil, 
chloroquine, chlorpromazine, cisapride, cyclobenzaprine, 
clarithromycin, 
disopyramide 
dofetilide, 
domperidone, 
droperidol, erythromycin, halofantrine, haloperidol, ibutilide, 
levomethadyl, 
mesoridazine, 
methadone, 
pentamidine, 
pimozide, procainamide, quinidine, sotalol, sparfloxacin, 
thioridazine). 
Treatment with fluoroquinolones (as they are known prolong 
QTc), are strongly discouraged in the trial. They should only 
be used to treat intercurrent non-TB infections and if the 
benefit of treatment outweighs the risk of prolonged QTc.  
Concomitant use of any drug known to induce significant 
myelosuppression
The systemic use of CYP3A4 inhibitors (e.g., azole 
antifungals: 
ketoconazole, 
voriconazole, 
itraconazole, 
fluconazole; ketolids such as telithromycin; and macrolide 
antibiotics other than azithromycin) for more than 3 
consecutive days;
The systemic use of CYP3A4 inducers (e.g., phenytoin, 
carbamazepine, phenobarbital, St. John’s wort, rifamycins 
and systemic dexamethasone. 
Concomitant use of serotonergic antidepressants should be 
avoided if possible as participants on these agents and 
linezolid are at risk for serotonin syndrome. 
Caution should be used in treating diabetic patients receiving 
insulin or oral hypoglycemic agents as cases have been 
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tipranavir, tolazamide, tolbutamide, topiramate, trazodone, tricyclic 
antidepressants, trimethoprim, verapamil).
reported of hypoglycemic reactions when patients on these 
agents have been treated with linezolid.
The following concomitant medications which are known to be 
hepatotoxic should be avoided as much as possible during screening 
and throughout the treatment period.  If there are concerns about the 
co-administration of  hepatoxic drugs, discussion with the Sponsor 
Medical Monitor is encouraged (including but not limited to 
acetaminophen/paracetamol, 
 
acetazolamide, 
allopurinol, 
amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, 
augmentin/co-amoxiclav, 
azathioprine, 
baclofen, 
bumetanide, 
captopril, 
carbamazepine, 
celecoxib, 
chlorpromazine, 
chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-
trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, 
fluconazole, fluoxetine, fosamprenavir, furosemide, gliclazide, 
glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, 
loperamide, losartan, methotrexate, metolazone, mirtazepine, 
nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory 
drugs, 
paroxetine, 
phenobarbital, 
phenothiazines, 
phenytoin, 
pravastatin, probenecid, prochlorperazine, risperidone, rosuvastatin, 
sertraline, simeprevir, simvastatin, sodium valproate, sotalol, 
sulfasalazine, sumatriptan, tamsulosin, terbinafine, tetracycline, 
theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, topiramate, 
trazodone, tricyclic antidepressants, trimethoprim, verapamil).
35
5.4 Trial 
Discontinuation 
and Visits
5.4 Discontinuation from Treatment/Trial 
The following may result in the discontinuation of trial treatment; 
Pregnancy;
Investigator considers it for safety reasons in the best interest of 
the participant that he/she be discontinued. This could include, but 
is not limited to:
o
Adverse event(s);
o
Myco testing results from baseline (Screening through 
Week 4) indicate sensitivity to isoniazid and/or rifamycins;
5.4 Trial Discontinuation and Visits
5.4.1
Treatment Discontinuation and Early Withdrawal
A participant must be withdrawn from the trial due to the following; 
Pregnancy;(unless female post visit for end of treatment/early 
withdrawal from treatment);
21 and 
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o
Myco testing results from baseline (Screening through 
Week 4) indicate resistance to bedaquiline, pretomanid or 
linezolid;
o
In the opinion of the investigator, fails to comply with the 
protocol, including non-compliance to IMP.
All participants who discontinue trial treatment (but have not withdrawn 
consent) and received at least one dose of IMP will be requested to 
return for an early withdrawal visit and applicable safety Follow Up visits, 
as per flow chart (Section 1.2).
In the event of the following, participants will be and/or are considered 
discontinued from the trial and no additional follow-up visits are required:
•
Withdrawal of informed consent;
•
Lost to follow-up;
•
Termination of the trial by the sponsor.
A participant may discontinue from the trial at any time at his/her request 
(withdrawal of consent).
Investigator considers it for safety reasons in the best interest 
of the participant that he/she be discontinued, including a 
concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB 
treatment. 
At the specific request of the sponsor or termination of the 
trial by Sponsor;
Lost to follow-up
In the opinion of the investigator, fails to comply with the 
protocol, including non-compliance to IMP.
Participants may be withdrawn from the trial based on the following. 
The specific situation should be discussed with the Medical Monitor 
before withdrawing the patient.
o
Myco testing results from baseline (Screening 
through Week 4) indicate sensitivity to rifamycins;
o
Myco testing results from baseline (Screening 
through Week 4) with MICs that indicate likely 
resistance to bedaquiline, pretomanid or linezolid;
All participants who discontinue trial treatment (but have not 
withdrawn consent) and received at least one dose of IMP will be 
requested to return for an early withdrawal visit and applicable safety 
Follow Up visits, as per flow chart (Section 1.2).
A participant may discontinue from the trial at any time at his/her 
request (withdrawal of consent) or may be withdrawn at any time at 
the discretion of the investigator for safety, behavioral compliance or 
administrative issues. When a participant withdraws consent from 
the trial, no additional follow-up visits will be performed. 
36
5.4.2 Early 
Withdrawal 
Follow-up
5.4.2
Early Withdrawal Follow-up
10 and 
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In case of early withdrawal during the treatment or follow-up period, 
all efforts shall be made to complete the Early Withdrawal 
assessments.  
Once a participant has been withdrawn early from the trial, they will 
be requested to attend follow-up visits as described in Table 9:
The 26 and 78 week post treatment follow-up visits will be performed 
to collect SAE information (including verification of survival) and 
participant reported TB outcome information.  This visit may be 
telephonic, a home or a site visit. 
37
5.4.3
Unscheduled 
Visits
5.4.3 Unscheduled Visits
Any visit which is conducted in addition to those required by the 
Synopsis Flow Chart and Procedures, should be considered 
unscheduled regardless of the reason for the visit. The assessments 
which are undertaken as part of an Unscheduled visit should be as
clinically indicated. 
The following situation/s require an unscheduled visit/s:
• If cultures of both spot sputum samples are contaminated at the 
following visits, or if necessary in order to help define a 
participant’s outcome status/assess culture status during follow-
up, the participant should return for an unscheduled visit(s) to give 
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additional samples or to document the participant is not able to 
produce sputum:
•
End of treatment visit;
•
Week 26 post treatment follow-up visit;
•
Post treatment follow-up visits from week 8 through week 
65 (in addition to week 26 follow-up);
•
End of Follow-up Period (week 78 post treatment 
completion visit);
•
Early Withdrawal (if applicable).
• At the end of 26 weeks and 78 weeks post treatment completion, 
to define outcome status, and to determine whether the 
participant has:
•
At least two sequential negative sputum culture results; or 
•
At least two sequential positive sputum culture results; or 
•
Has been unable to produce sputum after documentation of 
at least two negative sputum cultures with no intervening 
positive and are clinically asymptomatic.
If they do not fall into one of the above categories, site should 
continue to collect sputum samples x 2 (one early morning and one 
spot at the research site or 2 spots samples at least 30 minutes 
apart, under the coaching and observation of the trial staff) at a 
minimum of 7 days or more apart until they fall into one of the above 
categories.
5.4.4 Lost to Follow-up
Every reasonable attempt must be made to minimise Lost-to-Follow-
up (LTFU) participants.  A minimum of three contact attempts 
(telephonic/home visit) will be made for participants who do not 
arrive for their scheduled trial visits. If these attempts are 
unsuccessful the participant will be considered LTFU.  All attempts 
to contact the participant must be clearly documented in the 
participant’s source documents
38
5.4.4 Early 
Withdrawal due 
to TB
Discontinuation from treatment due to TB
5.4.5 Early Withdrawal due to TB
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39
6.1 IMP 
Administration
Table 9: Investigational Medicinal Product Details
Table 10:
Investigational Medicinal Product Details
6
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Treatment 
Group
Active and Placebo
Linezolid 
1200 mg 
daily for 26 
weeks
2 bedaquiline 100 mg active tablets once daily for 8 
weeks then 1 bedaquiline 100 mg active tablet 
once daily for 18 weeks plus; 
1 pretomanid 200 mg active tablet once daily for 26 
weeks.
2 linezolid 600 mg active tablets once daily for 26 
weeks
1 placebo linezolid 600 mg tablet once daily for 26 
weeks 
Linezolid 
1200 mg 
daily for 9 
weeks
2 bedaquiline 100 mg active tablets once daily for 8 
weeks then 1 bedaquiline 100 mg active tablet 
once daily for 18 weeks plus; 
1 pretomanid 200 mg active tablet once daily for 26 
weeks.
Weeks 1-9
2 linezolid 600 mg active tablets once daily for 9 
weeks
1 placebo linezolid 300 mg half tablet once daily for 
9 weeks
Weeks 10-26
2 placebo linezolid 600 mg tablets once daily for 17 
weeks
1 placebo linezolid 300 mg half tablet once daily for 
17 weeks
Linezolid 600 
mg daily for 
26 weeks
2 bedaquiline 100 mg active tablets once daily for 8 
weeks then 1 bedaquiline 100 mg active tablet 
once daily for 18 weeks plus; 
1 pretomanid 200 mg active tablet once daily for 26 
weeks.
1 linezolid 600 mg active tablet once daily for 26 
weeks
1 placebo linezolid 600 mg tablet once daily for 26 
weeks 
Treatment 
Group
Active and Placebo
Linezolid 
1200 mg 
daily for 26 
weeks
2 bedaquiline 100 mg active tablets once daily 
for 8 weeks then 1 bedaquiline 100 mg active 
tablet once daily for 18 weeks plus; 
1 pretomanid 200 mg active tablet once daily 
for 26 weeks.
2 linezolid 600 mg active tablets once daily for 
26 weeks
½ (one half) placebo linezolid tablet once daily 
for 26 weeks 
Linezolid 
1200 mg 
daily for 9 
weeks
2 bedaquiline 100 mg active tablets once daily 
for 8 weeks then 1 bedaquiline 100 mg active 
tablet once daily for 18 weeks plus; 
1 pretomanid 200 mg active tablet once daily 
for 26 weeks.
Weeks 1-9
2 linezolid 600 mg active tablets once daily for 
9 weeks 
½ (one half) placebo linezolid tablet once daily 
for 9 weeks
Weeks 10-26
2 placebo linezolid tablets once daily for 17 
weeks
½ (one half) placebo linezolid tablet once daily 
for 17 weeks
Linezolid 
600 mg 
daily for 26 
weeks
2 bedaquiline 100 mg active tablets once daily 
for 8 weeks then 1 bedaquiline 100 mg active 
tablet once daily for 18 weeks plus; 
1 pretomanid 200 mg active tablet once daily 
for 26 weeks.
1 linezolid 600 mg active tablet once daily for 
26 weeks
1 placebo linezolid tablet once daily for 26 
weeks 
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Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 30 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
1 placebo linezolid 300 mg half tablet once daily for 
26 weeks
Linezolid 600 
mg daily for 
9 weeks
2 bedaquiline 100 mg active tablets once daily for 8 
weeks then 1 bedaquiline 100 mg active tablet 
once daily for 18 weeks plus; 
1 pretomanid 200 mg active tablet once daily for 26 
weeks.
Weeks 1-9
1 linezolid 600 mg active tablet once daily for 9 
weeks
1 placebo linezolid 600 mg tablet for 9 weeks
1 placebo linezolid 300 mg half tablet once daily for 
9 weeks
Weeks 10-26
2 placebo linezolid 600 mg tablets once daily for 17 
weeks
1 placebo linezolid 300 mg half tablet once daily for 
17 weeks
½ (one half) placebo linezolid tablet once daily 
for 26 weeks
Linezolid 
600 mg 
daily for 9 
weeks
2 bedaquiline 100 mg active tablets once daily 
for 8 weeks then 1 bedaquiline 100 mg active 
tablet once daily for 18 weeks plus; 
1 pretomanid 200 mg active tablet once daily 
for 26 weeks.
Weeks 1-9
1 linezolid 600 mg active tablet once daily for 9 
weeks
1 placebo linezolid tablet for 9 weeks
½ (one half) placebo linezolid tablet once daily 
for 9 weeks
Weeks 10-26
2 placebo linezolid tablets once daily for 17 
weeks
½ (one half) placebo linezolid tablet once daily 
for 17 weeks
40
6.2 Participant 
Compliance
Additionally, participant cards will be checked for unused tablets in the 
blisters.
Additionally, participant cards/bottles will be checked for unused 
tablets at each visit during the treatment period. 
29
41
6.3 Treatment 
Modification(s)
All dose modifications should be discussed with the Sponsor Medical 
Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be 
informed within 24 hours of the change if not discussed prior to 
implementation.
All dose modifications should be discussed with the Sponsor Medical 
Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be 
informed within 24 hours of the change if not discussed prior to 
implementation.
In the event of linezolid specific toxicities, the following should be 
considered and implemented per guidance in the monitoring and safety for 
specific toxicities section of protocol:
All treatment modifications should be discussed with the Sponsor 
Medical Monitor prior to implementation, unless a pause or dose 
reduction is required urgently for a safety concern; the Medical 
Monitor should be informed within 24 hours of the change if not 
discussed prior to implementation.
In the event of linezolid specific toxicities, the following should be 
considered and implemented per guidance in the monitoring and 
safety for specific toxicities section of protocol (8.3):
Blinded one step reductions (maximum 2 steps) in the dose 
of linezolid managed by the IXRS as per instructions in 
pharmacy manual and/or IXRS user manual
4, 5, and
7
475 of 784


Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 31 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
Blinded one step reductions (maximum 3 steps) in the dose of 
linezolid (1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD 
or 300mg QD to placebo) managed by the IWRS as per 
instructions in pharmacy manual and/or IWRS user manual. 
Temporary pause of linezolid due to a linezolid-specific toxicity 
should be considered and implemented per guidance in the 
monitoring and safety for specific toxicities section of protocol.
Permanent discontinuation of linezolid.
Participants experiencing suspected drug related toxicities due to other 
drugs in the regimen (B-Pa), the full regimen may be halted for up to 35 
consecutive days. 
Pauses of the full regimen must not exceed 8 weeks (56 days) 
cumulatively. 
If participant’s week 16 sample remains culture positive, Investigator may 
consider option to extend current treatment to 39 weeks, in consultation 
with the Sponsor Medical Monitor. When treatment extended due to a 
positive culture at week 16, pauses of the full regimen must not exceed 13 
weeks (91 days) cumulatively.
When total of missed dosing days and/or pauses is greater than 7 days, 
additional make-up doses should be dispensed/treatment extended.
At no time should the participant be treated with a single agent.
o
1200 mg QD to 600 mg QD, 600 mg QD to 300 mg 
QD or; 
o
600 mg QD to 300 mg QD, 300mg QD to placebo). 
Temporary pause of linezolid 
Permanent discontinuation of linezolid.
Participants who have a linezolid reduction can go back to a 
higher dose (1 step or 2 steps) post discussion with and 
approval by the Sponsor Medical Monitor.
Participants experiencing suspected drug related toxicities due to 
other drugs in the regimen (B-Pa), the full regimen may be halted for 
up to 35 consecutive days. 
Interruptions/pauses of the full regimen must not exceed 8 weeks (56 
days) cumulatively.
If participant’s sample is culture positive between the week 16 and 
week 26 treatment visits and their clinical condition suggests they 
may have an ingoing TB infection, Investigator may consider the
option to extend treatment to which the participant is randomized to 
39 weeks. If the culture results between week 16 and week 26 are 
contaminated, missing or considered an isolated positive without 
clinical significance, available culture results should be used to make 
this decision. All decisions regarding treatment extension should be 
discussed with and approved by the Sponsor Medical Monitor before 
implementation.
When treatment extended to 39 weeks, pauses of the full regimen 
must not exceed 13 weeks (91 days) cumulatively.
When the total of missed dosing days of the prescribed regimen 
and/or pauses is greater than 7 days, the same number of missed 
doses should be dispensed/treatment extended to make up for the 
total missed doses.
At no time should the participant be treated with a single agent.
476 of 784


Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 32 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
Every effort should be made for participants to receive a total of at 
least 9 weeks of linezolid, even if pauses are required.
42
6.4 IMP 
Packaging and 
Labelling
The complete formulations of the IMP bedaquiline and pretomanid are 
found in the respective Investigator Brochures. The complete formulations 
of linezolid are found in the Package Inserts 
The IMP will be packaged as follows:
Bedaquiline: Bottles containing:
o
200 mg QD dose- 28 tablets- bedaquiline 100 mg
o
100mg QD dose- 14 tablets- bedaquiline 100 mg 
Pretomanid: Blister card containing 14 tablets- pretomanid 200 mg 
Linezolid: Blister Card containing 7 days of dosing as follows:
o
1200 mg QD Dose 
2 blister strips of 7 tablets each (14 tablets) 
containing active linezolid 600 mg  
1 blister strip of 7 half tablets containing placebo 
linezolid 300 mg 
o
600 mg QD Dose: 
1 blister strip of 7 tablets containing active 
linezolid 600 mg  
1 blister strip of 7 tablets containing placebo 
linezolid 600 mg
1 blister strip of 7 half tablets containing placebo 
linezolid 300 mg 
o
300 mg Dose (for reductions): 1 row of 7 active 600 mg 
tablets for 7 days of dosing
2 blister strips of 7 tablets each (14 tablets) 
containing placebo linezolid 600 mg  
1 blister strip of 7 half tablets containing active 
linezolid 300 mg 
o
Placebo Linezolid Dose: 2 rows of 7 placebo 600 mg 
tablets for 7 days of dosing
2 blister strips of 7 tablets each (14 tablets) 
containing placebo linezolid 600 mg  
The complete formulations of the IMP bedaquiline and pretomanid 
are found in the respective Investigator Brochures. The complete 
formulations of linezolid are found in the Package Inserts.
The IMP will be packaged as follows:
Bedaquiline: Bottles containing:
o
200 mg QD dose- 28 tablets- bedaquiline 100 mg
o
100mg QD dose- 14 tablets- bedaquiline 100 mg 
Pretomanid: Blister card containing 14 tablets- pretomanid 
200 mg 
Linezolid: Blister Card containing 7 days of dosing as follows:
o
1200 mg QD Dose 
2 blister strips of 7 tablets each (14 tablets) 
containing active linezolid 600 mg  
1 blister strip of 7 half tablets containing 
placebo linezolid 
o
600 mg QD Dose: 
1 blister strip of 7 tablets containing active 
linezolid 600 mg  
1 blister strip of 7 tablets containing placebo
linezolid 
1 blister strip of 7 half tablets containing 
placebo linezolid 
o
300 mg Dose (for reductions): 
2 blister strips of 7 tablets each (14 tablets) 
containing placebo linezolid
1 blister strip of 7 half tablets containing 
active linezolid 300 mg 
o
Placebo Linezolid Dose: 
2 blister strips of 7 tablets each (14 tablets) 
containing placebo linezolid 
6
477 of 784


Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 33 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
1 blister strip of 7 half tablets containing placebo 
linezolid 300 mg 
1 blister strip of 7 half tablets containing 
placebo linezolid 
43
6.4 IMP 
Packaging and 
Labelling
The packaging of each bottle/blister card will be labelled with, at a 
minimum, the following information:
•
Name, address and telephone number of Sponsor.
The packaging of each bottle/blister card will be labelled with, at a 
minimum, the following information:
•
Name of Sponsor.
30
44
6.5 Method of 
Treatment 
Assignment
Participants will be randomized to one of the four regimens in a 1:1:1:1 
ratio, using an interactive web response system (IWRS) which will utilize 
a dynamic randomization system using minimization with a random 
element to allocate participants evenly across the arms by HIV status and 
type of TB.  Information & directions will be provided to each site via the 
IWRS user manual.
Participants will be randomized to one of the four regimens in a 
1:1:1:1 ratio, using an interactive web/voice response system (IXRS) 
which will utilize a randomization system using stratification with a 
random element to allocate participants evenly across the arms by 
HIV status and type of TB.  Information & directions will be provided 
to each site via the IXRS user manual.
3
45
6.6 Blinding and 
Procedures for 
Breaking the 
Blind
The blind must not be broken except in the case of a medical emergency, 
where treatment of the participant is influenced by the knowledge of what 
dose and duration of linezolid the participant is receiving. It is requested 
that the Investigator make every effort to contact the Sponsors medical 
monitor (or designee) prior to breaking the blind. IWRS will be 
programmed with blind-breaking instructions, described in the user 
manual. The sponsor reserves the right to break the blind in order to fulfil 
any regulatory requirements regarding reporting of SAEs.
The blind must not be broken except in the case of a medical 
emergency, where treatment of the participant is influenced by the 
knowledge of what dose and duration of linezolid the participant is 
receiving. The investigator should discuss breaking the blind with the 
Sponsor Medical Monitor (or designee) prior to breaking the blind 
unless knowledge of treatment arm is required urgently for a safety 
concern. The Sponsor Medical Monitor should be informed of the 
blind break within 24 hours if not discussed prior. IXRS will be 
programmed with blind-breaking instructions, described in the user 
manual. The Sponsor reserves the right to break the blind to fulfil any 
regulatory requirements regarding reporting of SAEs. If a participant 
is unblinded, they are not required to be withdrawn from the study.
31
46
7.1 Demographic 
and Background 
Variables
Clinically significant medical and treatment history (including 
past and current TB diagnosis and smoking)
Clinically significant medical and treatment history 
(including past and current TB diagnosis, alcohol use 
and smoking)
32
47
7.1 Demographic 
and Background 
Variables
•
Serology: HIV and CD4 count. 
Serology: HIV, CD4 count and viral load. 
If an HIV test was performed within 1 month prior to 
trial start, it should not be repeated as long as 
33
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Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 34 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
If an HIV test was performed within 1 month prior to trial start, it 
should not be repeated as long as documentation of results can 
be provided (ELISA and/or Western Blot).
documentation of results can be provided (ELISA 
and/or 
Western 
Blot 
and/or 
Electro-
Chemiluminescence).
48
7.1 Demographic 
and Background 
Variables
N/A- bullet point did not exist in version 1.0
Concomitant medications
34
49
7.2 Efficacy 
Variables and 
procedures
TB Symptoms Profile: 
•
The TB Symptoms Profile (Appendix 7) will record participants’ 
ratings of the severity of common TB symptoms. 
Patient Reported Health Status Variables and Procedures: 
•
The Patient Reported Health Status variables will be collected at 
the time points described in the trial flow chart. Patient Reported 
Health Status will be collected using the EQ-5D-5L Health 
Questionnaire (Appendix 5). This descriptive system consists of five 
health-related quality of life dimensions, each of which will be 
recorded using five levels of severity. Methodology: The Patient 
Reported Health Status methodology and requirements will be 
described in a separate document/guideline which will be provided 
prior to the trial start.
TB Symptoms Profile: 
•
The TB Symptoms Profile (found in the Subject 
Questionnaires Guideline) will record participants’ ratings of 
the severity of common TB symptoms. 
Patient Reported Health Status Variables and Procedures: 
•
The Patient Reported Health Status variables will be 
collected at the time points described in the trial flow chart. 
Patient Reported Health Status will be collected using the 
EQ-5D-5L Health Questionnaire (found in the Subject 
Questionnaires Guideline). This descriptive system consists 
of five health-related quality of life dimensions, each of 
which will be recorded using five levels of severity. 
Methodology: The Patient Reported Health Status 
methodology and requirements will be described in a 
separate document/guideline which will be provided prior to 
the trial start.
35
50
7.3 Safety and 
Tolerability 
Assessments
Brief Peripheral Neuropathy Screen (Appendix 6) will record ratings.
Brief peripheral neuropathy screen (found in the Subject 
Questionnaires Guideline) will record ratings.
35
51
7.5 
Mycobacteriology 
Characterization 
Variable and 
Procedures
The following Mycobacterial Characterization variables will be collected:
Positive Culture (for MTB) from:
Day 1 or if Day 1 is not available, first positive between screening 
through Week 4;
Pre-screening culture that was used for the tests that qualified the 
participant for inclusion into the trial to be subcultured and shipped 
to the central from the applicable lab for relevant participants/with 
no positive cultures from screening through week 4 and appropriate 
consent
The following Mycobacterial Characterization variables will be 
collected:
Positive Culture (for MTB) from:
Day 1 or if Day 1 is not available, first positive between 
Screening through Week 4;
If consent granted, and when applicable, Pre-screening 
culture/isolate to be sub cultured and shipped and/or tested:
o
At the study lab if/when samples could support 
inclusion in the trial
35
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Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 35 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
When applicable, end of treatment or visits with positive cultures 
during post-treatment follow-up.
o
To the study/central lab for relevant participants/with 
no baseline (positive cultures from screening through 
Week 4) 
When applicable, 1st positive for MTB at/after week 16 for 
participant not responding to therapy and/or 1st positive 
during follow-up for potential new infection.
52
8.2.1 Follow up 
of Adverse 
Events
Certain long-term AEs cannot be followed until resolution within the setting 
of this protocol. In these cases follow-up will be the responsibility of the 
treating physician.  However, this will have to be agreed upon with the 
Sponsor Medical Monitor.
Certain long-term AEs cannot be followed until resolution within the 
setting of this protocol. In these cases, follow-up will be the 
responsibility of the treating physician.  If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor 
Medical Monitor.
5
53
8.3 Monitoring for 
Specific 
Toxicities
Monitoring for specific toxicities is based upon target organs as defined in 
preclinical toxicity studies Investigator’s Brochures and Package Inserts.
AEs still ongoing at the end of treatment in the trial will be followed until 
satisfactory clinical resolution or stabilization or until the end of the follow-
up period and until all queries on these AEs have been resolved.  Grade 
3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory 
resolution or stabilization.
Monitoring for specific toxicities is based upon target organs as 
defined in preclinical toxicity studies Investigator’s Brochures(5,6) 
and Package Inserts.(24,25,26,27) Please reference section 6.3. 
Treatment Modifications, which notes that all treatment modifications 
should be discussed with Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required urgently 
for a safety concern.  The Medical Monitor should be informed within 
24 hours of the change if not discussed prior to implementation.  
AEs still ongoing at the end of treatment in the trial will be followed 
until satisfactory clinical resolution or stabilization or until the end of 
the follow-up period and until all queries on these AEs have been 
resolved.  Grade 3 and grade 4 laboratory abnormalities and 
laboratory abnormalities considered clinically significant should be 
followed until satisfactory resolution or stabilization. Certain long-term 
AEs cannot be followed until resolution within the setting of this 
protocol. In these cases follow-up will be the responsibility of the 
treating physician. If there is uncertainty, Investigator can discuss 
appropriate follow-up with the Sponsor Medical Monitor.
5
54
8.3.2 ALT, AST 
and Alkaline 
Phosphatase 
elevations
The Investigator should refer to Appendix 8 – Liver Toxicity Management 
to appropriately manage the participant for clinically significant elevations 
of AST, ALT or Alkaline Phosphatase.
The Investigator should refer to Appendix 6 – Liver Toxicity 
Management and to the ZeNix Hepatotoxicity Management Guideline 
36
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Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 36 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
to appropriately manage the participant for clinically significant 
elevations of AST, ALT or Alkaline Phosphatase.
55
11.3 Protocol 
Deviations
It is the responsibility of the site to use continuous vigilance to identify and 
report deviations. All deviations must be addressed in study source 
documents and reported to Sponsor/designee. Protocol deviations must 
be sent to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements.
It is the responsibility of the site to use continuous vigilance to 
identify and report deviations. All deviations must be addressed in 
study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB and Health 
Authority per their guidelines. The site PI/all study staff is 
responsible for knowing and adhering to their IRB and Health 
Authority (as required) requirements
37
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Global Alliance for TB Drug Development
Protocol Number: NC-007-(B-Pa-L)
Protocol Version:  V2.0 RUS, dated 13 June 2018 
Protocol Name:     ZeNix
Protocol Amendment Template
TMP02-C V3.0 dated 06Dec2017
Page 37 of 37
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
Sponsor
I agree to the terms of this protocol amendment
Signature of Senior Medical Officer
Printed name
Date
Principal Investigator
I hereby confirm I have read the above Protocol Amendment and agree to conduct this clinical trial as outlined in the above 
Protocol Amendment. I will provide copies of the Protocol Amendment and access to all of the information required to conduct the 
clinical trial according to the above Protocol Amendment to the site personnel under my supervision. I will discuss this material with 
them and ensure they are fully informed on all trial requirements. 
Signature of Principal Investigator
Printed name
Date
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Certificate Of Completion
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Erica Egizi
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Record Tracking
Status: Original
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             erica.egizi@tballiance.org
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VP & Senior Medical Officer
Global Alliance for TB Drug Development (Part 11 
Compliant)
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version: MDA Protocol Version 1.0, dated 13 June 2018 
(incorporating Country Specific Amendment 1.0) 
Protocol Name: 
ZeNix 
Protocol Amendment Template 
TMP02-C V3.0 dated 06Dec2017
Page 1 of 2 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
 
 
 
Protocol Name / Number:   ZeNix/ NC-007-(B-Pa-L) 
 
Protocol Title: 
A Phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various doses and 
treatment durations of linezolid plus bedaquiline and pretomanid in participants with pulmonary infection 
of either extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non- 
  responsive multi-drug resistant tuberculosis (MDR-TB). 
 
 
 
Reasons for Protocol Amendment: 
 
 
 
# 
 
Section 
Previous Text 
Version 1.0, dated 23-Feb-17 
Amended Text 
MDA Protocol Version 1.0, dated 13-Jun-18 
(incorporating Country Specific Amendment 1.0) 
Additional text - bold font. Deleted text – strike-through. 
Reason 
for 
Change 
Insert reason # 
from table above 
1 
1.1 Synopsis 
Summary 
A total of up to 180 participants, male and female, aged 14 and over 
Sponsor may consider replacement of late screen failure and un- 
assessable (as detailed in the statistical analysis plan) participants. 
A total of up to 180 participants, male and female, aged 18 and over 
Sponsor may consider replacement of late screen failure and un- 
assessable (as detailed in the statistical analysis plan) participants. 
1 
2 
4.1 Summary of 
Trial Design 
The trial will be performed at multiple centers located in South Africa, 
Eastern Europe and Russia. A total of 180 XDR-TB and Pre-XDR/MDR 
intolerant or non-responsive participants who meet all of the inclusion 
criteria and none of the exclusion criteria, aged 14 and over, will be 
randomized to receive one of the 4 active treatment arms. 
The trial will be performed at multiple centers located in South 
Africa, Eastern Europe and Russia. A total of 180 XDR-TB and Pre- 
XDR/MDR intolerant or non-responsive participants who meet all of 
the inclusion criteria and none of the exclusion criteria, aged 18 and 
over, will be randomized to receive one of the 4 active treatment 
arms. 
1 
3 
5.1 Inclusion 
Criteria 
4. 
Male or female, aged 14 years or older. 
4. 
Male or female, aged 18 years or older. 
1 
Updated patient population from 14 and over to 18 and over as Moldova will not enroll patients under 18 (In section 1.1 Synopsis 
Summary, 4.1 Summary of Trial Design, and 5.1 Inclusion Criteria) 
1 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version: MDA Protocol Version 1.0, dated 13 June 2018 
(incorporating Country Specific Amendment 1.0) 
Protocol Name: 
ZeNix 
Protocol Amendment Template 
TMP02-C V3.0 dated 06Dec2017
Page 2 of 2 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
 
 
 
Sponsor 
 
I agree to the terms of this protocol amendment 
 
 
 
 
 
Dan Everitt 
June 27, 2018 | 7:49 AM EDT 
 
Signature of Senior Medical Officer 
Printed name 
Date 
 
 
Principal Investigator 
 
I hereby confirm I have read the above Protocol Amendment and agree to conduct this clinical trial as outlined in the above Protocol Amendment. 
I will provide copies of the Protocol Amendment and access to all of the information required to conduct the clinical trial according to the above 
Protocol Amendment to the site personnel under my supervision. I will discuss this material with them and ensure they are fully informed on all 
trial requirements. 
 
 
 
 
 
 
 
Signature of Principal Investigator 
Printed name 
Date 
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Certificate Of Completion 
 
Envelope Id: A3A6DEC62176449E8BDBE14701F75BA6 
Status: Completed 
Subject: Please DocuSign: NC-007 MDA_Prot_Amend v 1 13JUN2018.pdf 
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Erica Egizi 
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40 Wall St FL 24 
New York, NY 10005 
erica.egizi@tballiance.org 
IP Address: 38.105.215.226 
Record Tracking 
 
Status: Original 
6/26/2018 5:37:11 PM 
Holder: Erica Egizi 
erica.egizi@tballiance.org 
Location: DocuSign 
 
 
Dan Everitt 
dan.everitt@tballiance.org 
VP & Senior Medical Officer 
Global Alliance for TB Drug Development (Part 11 
Compliant) 
Security Level: Email, Account Authentication 
 
 
 
 
Signature ID: 
32534894-D929-4A59-B14B-10FC37E90452 
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TB Alliance 
Protocol Number: NC-007 
Protocol Amendment No.: 2.0 / 10 MAR-2020 
Protocol Name: 
ZeNix 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
 
Trial Number 
Trial Name 
NC-007 
ZeNix 
 
X Protocol Amendment Number 2.0, Dated 10/MAR/2020 
☐ Protocol Administrative Change Number _ _, Dated _ _/_ _ _/_ _ _ _ 
 
 
Summary - Protocol section changed 
Does amendment / 
administrative change 
affect any of the 
elements listed? 
YES 
NO 
A 
Purpose of trial 
☐ 
X 
B 
Design of trial 
☐ 
X 
C 
Informed consent 
☐ 
X 
D 
Recruitment procedure 
☐ 
X 
E 
Measures of efficacy 
☐ 
X 
F 
Schedule of samples 
☐ 
X 
G 
Addition or deletion of tests or measures 
☐ 
X 
H 
Number of participants 
☐ 
X 
I 
Age range of participants 
☐ 
X 
J 
Inclusion criteria 
☐ 
X 
K 
Exclusion criteria 
☐ 
X 
L 
Safety monitoring 
☐ 
X 
M 
Duration of exposure to the investigational medicinal product(s) 
☐ 
X 
N 
Change of posology of the investigational medicinal product(s) 
☐ 
X 
O 
Change of comparator 
☐ 
X 
P 
Statistical analysis 
X 
☐ 
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TB Alliance 
Protocol Number: NC-007 
Protocol Amendment No.: 2.0 / 10 MAR-2020 
Protocol Name: 
ZeNix 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
 
 
Reasons for Protocol Amendment or Administrative Change: 
1 Addition of planned unblinded (in aggregate) Analysis Post 26 weeks of treatment completion 
2 Updated timing of trial in synopsis 
3 Updated TB Alliance logo on first page 
4  
5  
 
 
 
 
# 
 
 
Section 
 
Previous Text 
Version 2.0, dated 13-Jun-18 
 
Amended Text 
Version 3.0, dated 10-Mar-20 
Additional text - bold font. Deleted text – strike- 
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
1 
Title Page 
 
 
3 
 
2 
Synopsis 
~3.5 Years (An enrolment period of at least 18 months 
plus 14 days pre-treatment plus 6 months treatment 
period plus 18 months post treatment follow-up). 
~3.5 4 Years (An enrolment period of at least 18 
approximately 24 months plus 14 days pre-treatment 
plus 6 months treatment period plus 18 months post 
treatment follow-up). 
2 
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TB Alliance 
Protocol Number: NC-007 
Protocol Amendment No.: 2.0 / 10 MAR-2020 
Protocol Name: 
ZeNix 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
6.6 
The blind must not be broken except in the case 
of a medical emergency, where treatment of the 
participant is influenced by the knowledge of 
what dose and duration of linezolid the 
participant is receiving. The investigator should 
discuss breaking the blind with the Sponsor 
Medical Monitor (or designee) prior to breaking 
the blind unless knowledge of treatment arm is 
required urgently for a safety concern. The 
Sponsor Medical Monitor should be informed of 
the blind break within 24 hours if not discussed 
prior. IXRS will be programmed with blind- 
breaking instructions, described in the user 
manual. The Sponsor reserves the right to break 
the blind to fulfil any regulatory requirements 
regarding reporting of SAEs. If a participant is 
unblinded, they are not required to be withdrawn 
from the study. 
The blind for a participant must not be broken 
by the site or sponsor except in the case of a 
medical emergency, where treatment of the a 
participant is influenced by the knowledge of 
what dose and duration of linezolid the 
participant is receiving. The investigator should 
discuss breaking the blind with the Sponsor 
Medical Monitor (or designee) prior to breaking 
the blind unless knowledge of treatment arm is 
required urgently for a safety concern. The 
Sponsor Medical Monitor should be informed of 
the blind break within 24 hours if not discussed 
prior. IXRS will be programmed with blind- 
breaking instructions, described in the user 
manual. The Sponsor reserves the right to break 
the blind to fulfil any regulatory requirements 
regarding reporting of SAEs. If a participant is 
unblinded, they are not required to be withdrawn 
from the study. 
1 
 
 
In the absence of any medical emergencies 
requiring a blind break, the blind for all 
participants will be broken once all clinical data 
and outcome parameters have been captured, 
no more data queries are pending and the 
statistical analysis plan has been finalized. 
 
In the absence of any medical emergencies 
requiring a blind break, the blind for all 
participants will be broken once all clinical data 
and outcome parameters have been captured, 
no more data queries are pending and the 
statistical analysis plan has been finalized. 
 
 
 
 
There will be three unblinded analyses which 
will contain results by linezolid treatment 
group in aggregate (see section 9.3). The first 
 
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TB Alliance 
Protocol Number: NC-007 
Protocol Amendment No.: 2.0 / 10 MAR-2020 
Protocol Name: 
ZeNix 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
 
 
 
# 
 
 
Section 
 
Previous Text 
Version 2.0, dated 13-Jun-18 
 
Amended Text 
Version 3.0, dated 10-Mar-20 
Additional text - bold font. Deleted text – strike- 
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
 
 
 
analysis will be after all participants have 
completed 26 weeks of treatment and here 
sites, participants, and Sponsor staff will not 
be unblinded to individual linezolid treatment 
information. A limited number of statisticians 
will have access to individual linezolid 
treatment assignments. 
The blind for all individual participants will be 
broken for the primary endpoint analysis (the 
second unblinded analysis) once all clinical 
data and outcome parameters have been 
captured, no more data queries are pending, 
and the statistical analysis plan has been 
finalized. The third analysis will occur when 
all participants have completed 78 weeks of 
follow-up after end of treatment. 
 
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TB Alliance 
Protocol Number: NC-007 
Protocol Amendment No.: 2.0 / 10 MAR-2020 
Protocol Name: 
ZeNix 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
9.3 
No formal interim analyses are planned. Primary 
analysis will be performed on the 26 week 
follow-up data (after end of treatment when the 
last randomized participant has completed 26 
weeks of follow-up after end of treatment). 
 
There will be two database locks, data analyses 
and trial reports generated for this trial: 
1. 
When all participants have completed 26 
weeks of follow-up after end of treatment. 
2. 
When all participants have completed 78 
weeks of follow-up from after end of treatment. 
No formal interim analyses are planned. 
However, there will be three planned 
unblinded analyses which will contain 
results by linezolid treatment group in 
aggregate as described below. The first 
analysis will be done after all participants 
have completed 26 weeks of treatment. The 
analysis will be on treatment safety events 
(mainly the specific toxicities described in 
section 8.3) and time to culture conversion 
(on treatment). The sites, participants, and 
Sponsor staff will not be unblinded to 
individual linezolid treatment information. A 
limited number of statisticians will have 
access to individual linezolid treatment 
assignments. 
The blind for all individual participants will 
be broken for the primary endpoint analysis 
(the second unblinded analysis) once all 
clinical data and outcome parameters for the 
primary endpoint have been captured, no 
more data queries are pending, and the 
statistical analysis plan has been updated 
accordingly. 
Primary analysis will be performed on the 26 
week follow-up data (after end of treatment 
when the last randomized participant has 
completed 26 weeks of follow-up after end of 
treatment). 
1 
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TB Alliance 
Protocol Number: NC-007 
Protocol Amendment No.: 2.0 / 10 MAR-2020 
Protocol Name: 
ZeNix 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
 
 
 
# 
 
 
Section 
 
Previous Text 
Version 2.0, dated 13-Jun-18 
 
Amended Text 
Version 3.0, dated 10-Mar-20 
Additional text - bold font. Deleted text – strike- 
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
 
 
 
There will be two three database locks for the 
three planned unblinded data analyses and 
trial reports generated for this trial: 
1. 
When all participants have completed 
26 weeks of treatment 
1. 2. When all participants have completed 26 
weeks of follow-up after end of treatment. 
2. 3. When all participants have completed 78 
weeks of follow-up from after end of treatment. 
 
492 of 784


TB Alliance 
Protocol Number: NC-007 
Protocol Amendment No.: 2.0 / 10 MAR-2020 
Protocol Name: 
ZeNix 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
 
Sponsor 
 
I agree to the terms of this Protocol Amendment or Administrative Change. 
 
 
 
 
Dan Everitt 
March 11, 2020 | 3:24 PM EDT 
 
Signature of Senior Medical Officer 
Printed name 
Date 
 
 
Principal Investigator 
 
I hereby confirm I have read the above Protocol Amendment or Protocol Administrative Change and agree to conduct this clinical trial as 
outlined in the above. I will provide copies of the Protocol Amendment or Protocol Administrative Change and access to all of the information 
required to conduct the clinical trial according to the above Protocol Amendment or Protocol Administrative Change to the site personnel under 
my supervision. I will discuss this material with them and ensure they are fully informed on all trial requirements. 
 
 
 
 
 
 
Signature of Principal Investigator 
Printed name 
Date 
493 of 784


 
Certificate Of Completion 
 
Envelope Id: 3697EC1C40FC499A8CEB9D3530C64CE3 
Status: Completed 
Subject: Please DocuSign: ZeNix Amend 2 10.03.20 FINAL.docx 
Source Envelope: 
Document Pages: 7 
Signatures: 1 
Envelope Originator: 
Certificate Pages: 1 
Initials: 0 
Erica Egizi 
AutoNav: Enabled 
EnvelopeId Stamping: Disabled 
Time Zone: (UTC-05:00) Eastern Time (US & Canada) 
40 Wall St FL 24 
New York, NY 10005 
erica.egizi@tballiance.org 
IP Address: 70.23.50.166 
Record Tracking 
 
Status: Original 
3/11/2020 12:59:40 PM 
Holder: Erica Egizi 
erica.egizi@tballiance.org 
Location: DocuSign 
 
 
Dan Everitt 
dan.everitt@tballiance.org 
VP & Senior Medical Officer 
Global Alliance for TB Drug Development (Part 11 
Compliant) 
Security Level: Email, Account Authentication 
 
 
 
 
Signature Adoption: Uploaded Signature Image 
Signature ID: 
Sent: 3/11/2020 1:00:53 PM 
Viewed: 3/11/2020 3:22:54 PM 
Signed: 3/11/2020 3:24:17 PM 
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I approve this document 
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Page 1 of 96 
CONFIDENTIAL  
 
Protocol Number 
NC-007-(B-Pa-L) 
Title: 
A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid 
plus bedaquiline and pretomanid in participants with pulmonary 
infection of either extensively drug-resistant tuberculosis (XDR-
TB), pre-XDR-TB or treatment intolerant or non-responsive multi-
drug resistant tuberculosis (MDR-TB). 
Drug(s)/Combination(s): Bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Amendment 
Version/Date:  
 
 
 
V3.0 dated 10 March 2020, (incorporating Protocol Version 1.0 
dated 23 Feb 2017, Protocol Amendment 1.0 dated 13 June 2018 
and Protocol Amendment 2.0 dated 10 March 2020) 
 
 
Protocol Name: 
ZeNix 
 
 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 MARCH 2020  
Protocol Name: ZeNix 
 
 
 
CONFIDENTIAL 
Page 2 of 96 
PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Date:  V3.0 dated 10 March 2020, (incorporating Protocol Version 1.0 dated 
23 Feb 2017, Protocol Amendment 1.0 dated 13 June 2018 and 
Protocol Amendment 2.0 dated 10 March 2020) 
Protocol Name: ZeNix 
SPONSOR  
I agree to the terms of this trial protocol. 
 
 
 
 
 
 
Signature of Senior Medical Officer 
 
Printed Name 
 
 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone 646-616-8671 
email: daniel.everitt@tballiance.org 
Date 
 
LEAD INVESTIGATOR 
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and local 
regulations. 
 
 
 
 
Signature  
 
Printed Name 
 
 
 
Date 
 
496 of 784


 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 MARCH 2020  
Protocol Name: ZeNix 
 
 
 
CONFIDENTIAL 
Page 3 of 96 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-resistant 
tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug 
resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Date:     V3.0 dated 10 March 2020, (incorporating Protocol Version 1.0 dated 23 
Feb 2017, Protocol Amendment 1.0 dated 13 June 2018 and Protocol 
Amendment 2.0 dated 10 March 2020) 
 
Protocol Name: ZeNix 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
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CONFIDENTIAL 
Page 4 of 96 
Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
1.1 
Synopsis Summary ...................................................................................................10 
1.2 
Synopsis Flowchart...................................................................................................15 
2 
Introduction and Rationale .............................................................................................. 20 
2.1 
Trial Rationale ..........................................................................................................21 
2.1.1 
Trial Design Rationale........................................................................................21 
2.1.2 
Trial Drug Rationale ...........................................................................................21 
2.1.3 
Pretomanid ........................................................................................................23 
2.1.4 
Linezolid ............................................................................................................23 
2.2 
Agents to be Studied ................................................................................................24 
2.2.1 
Bedaquiline .......................................................................................................24 
2.2.2 
Pretomanid ........................................................................................................27 
2.2.3 
Linezolid ............................................................................................................33 
2.3 
Regimens to be Studied............................................................................................38 
2.3.1 
Non-Clinical Studies ..........................................................................................38 
2.3.2 
Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or Linezolid ...40 
2.4 
Overall Benefit/Risk Assessment...............................................................................43 
3 
Trial Objectives .............................................................................................................. 44 
3.1 
Primary Objectives....................................................................................................44 
4 
Trial Design .................................................................................................................... 44 
4.1 
Summary of Trial Design...........................................................................................44 
4.2 
Treatment Plan: Schedule of Assessments ...............................................................44 
5 
Trial Population .............................................................................................................. 45 
5.1 
Inclusion Criteria .......................................................................................................46 
5.2 
Exclusion Criteria......................................................................................................47 
5.3 
Restrictions ..............................................................................................................50 
5.3.1 
Prior and Concomitant Medications and Other Treatments .................................50 
5.3.2 
Recommendations for Concomitant use of Anti-Malarials ...................................51 
5.3.3 
Antiretroviral Therapy.........................................................................................51 
5.3.4 
Other Restrictions ..............................................................................................52 
5.4 
Trial Discontinuation and Visits .................................................................................52 
5.4.1 
Treatment Discontinuation and Early Withdrawal ................................................52 
1 
Synopsis .............................................................................................. .............................10 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 5 of 96 
5.4.2 
Early Withdrawal Follow-up................................................................................53 
5.4.3 
Unscheduled Visits ............................................................................................53 
5.4.4 
Lost to Follow-up ...............................................................................................54 
5.4.5 
Early Withdrawal due to TB................................................................................54 
5.5 
Participant Progress Definitions ................................................................................55 
5.6 
Trial Stopping Rules .................................................................................................55 
6 
Treatment 55 
6.1 
IMP Administration....................................................................................................55 
6.2 
Participant Compliance .............................................................................................56 
6.3 
Treatment Modification(s) .........................................................................................57 
6.4 
IMP Packaging and Labelling ....................................................................................57 
6.5 
Method of Treatment Assignment..............................................................................58 
6.6 
Blinding and Procedures for Breaking the Blind .........................................................59 
6.7 
Handling, Storage and Accountability ........................................................................59 
7 
Trial Variables and Procedures ....................................................................................... 60 
7.1 
Demographic and Background Variables and Procedures .........................................60 
7.2 
Efficacy Variables and Procedures ............................................................................61 
7.3 
Safety and Tolerability Assessments .........................................................................61 
7.4 
PK Variables and Procedures ...................................................................................63 
7.5 
Mycobacteriology Characterization Variable and Procedures .....................................63 
8 
Adverse Events .............................................................................................................. 64 
8.1 
Definitions ................................................................................................................64 
8.1.1 
Adverse Event (AE) ...........................................................................................64 
8.1.2 
Serious Adverse Event (SAE) ............................................................................64 
8.1.3 
Attribution/Causality ...........................................................................................64 
8.1.4 
Severity .............................................................................................................65 
8.2 
Reporting .................................................................................................................66 
8.2.1 
Follow up of Adverse Events ..............................................................................66 
8.2.2 
Clinical Laboratory Adverse Events ....................................................................67 
8.2.3 
Disease under Study .........................................................................................67 
8.2.4 
Overdose ..........................................................................................................68 
8.2.5 
Drug Interaction .................................................................................................68 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 6 of 96 
8.2.6 
Pregnancy .........................................................................................................68 
8.3 
Monitoring for Specific Toxicities ...............................................................................68 
8.3.1 
Neurological ......................................................................................................69 
8.3.2 
ALT, AST and Alkaline Phosphatase elevations: ................................................69 
8.3.3 
Lipase ...............................................................................................................69 
8.3.4 
Musculoskeletal System and Cardiac Muscle .....................................................69 
8.3.5 
Cardiac Rhythm Disturbances............................................................................69 
8.3.6 
Monitoring Linezolid Toxicities............................................................................70 
8.4 
Safety Monitoring by Data Monitoring Committee ......................................................71 
9 
Statistical Analysis.......................................................................................................... 72 
9.1 
Analysis Population ..................................................................................................72 
9.2 
Sample Size .............................................................................................................72 
9.3 
Interim Analyses .......................................................................................................73 
9.4 
Primary and Secondary Endpoint Analysis ................................................................73 
9.5 
Safety and Tolerability Analysis.................................................................................73 
9.6 
Pharmacokinetics .....................................................................................................75 
9.7 
Pharmacokinetics/Pharmacodynamics ......................................................................75 
10 Records Management .................................................................................................... 75 
10.1 Data Collection .........................................................................................................75 
10.2 Source Documents ...................................................................................................76 
10.3 File Management at the Trial Centre .........................................................................76 
10.4 Records Retention at the Trial Centre .......................................................................76 
11 Quality Control and Assurance........................................................................................ 76 
11.1 Site Procedures ........................................................................................................76 
11.2 Monitoring ................................................................................................................77 
11.3 Protocol Deviations ...................................................................................................77 
11.4 Auditing ....................................................................................................................77 
12 Ethics and Regulatory .................................................................................................... 78 
12.1 Basic Principles ........................................................................................................78 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review .............78 
12.3 Regulatory Authorities...............................................................................................78 
12.4 Informed Consent .....................................................................................................78 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
CONFIDENTIAL 
Page 7 of 96 
12.5 Confidentiality ...........................................................................................................79 
13 Publication Policy ........................................................................................................... 79 
14 Protocol Amendment Policy ............................................................................................ 80 
15 Sponsor, Financial Aspects, Insurance and Indemnity ..................................................... 80 
16 References..................................................................................................................... 81 
Appendix 1: 
The IUATLD Scale ........................................................................................ 84 
Appendix 2: 
Division of Microbiology and Infectious Disease (DMID) Toxicity Table ........... 85 
Appendix 3: 
 Cardiovascular Safety................................................................................... 93 
Appendix 4: 
 Karnofsky Performance Status Scale Definitions Rating (%) Criteria .............. 94 
Appendix 5: 
Liver Toxicity Management ............................................................................ 95 
TABLES 
Table 1: 
ADRs C208 Stage 1 and Stage 2 ........................................................................26 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies .......................................28 
Table 3: 
Murine Lung CFU counts during Treatment with Linezolid .......................................34 
Table 4: 
Murine Relapse Data .........................................................................................39 
Table 5: 
Summary Statistics for EBA................................................................................40 
Table 6: 
NC-003 Efficacy Results: Daily BAlog ..................................................................41 
Table 7: 
NC-003 Safety Data ..........................................................................................41 
Table 8: 
Treatment Groups .............................................................................................44 
Table 9: 
Follow-up Visits Required for Early Withdrawal Participants.....................................53 
Table 10:  
Investigational Medicinal Product Details ..............................................................56 
Table 11:  
Adverse Events Attribution/Causality Ratings ........................................................65 
Table 12: 
Definitions for Adverse Event Severity Gradings ....................................................65 
FIGURES 
Figure 1: 
Log10 CFU Counts in Lungs .....................................................................................28 
Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010......................................31 
Figure 3: 
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin CL-001............35 
Figure 4: 
Trial Schematic .......................................................................................................45 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 8 of 96 
 
Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
Abacavir 
ADR 
Adverse drug reactions 
AE  
Adverse event  
AIDS 
Acquired immune deficiency syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AREDS2 Age related eye disease scale 2 
ART 
Anti-retroviral therapy 
AST 
Aspartate amino transferase 
AT 
Amino transferase 
AUCτ 
Area under curve over a dosing interval 
B 
Bedaquiline 
BMI 
Body mass index 
bpm 
Beats per minute 
BPNS 
Brief peripheral neuropathy scale 
C 
Clofazimine 
CFU 
Colony forming units 
CK(-MB) 
Creatine kinase (-MB isoenzyme) 
C(max), 
(min) 
Plasma concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine phosphokinase 
CS 
Clinically significant 
Ctrough 
Plasma concentration trough 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of microbiology and infection disease 
DNA 
Deoxyribonucleic acid 
DOH 
Department of health 
DILI 
Drug induced liver injury 
DSMC 
Data safety monitoring committee 
DST 
Drug susceptibility testing 
E 
Ethambutol 
EBA 
Early bactericidal activity 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
Electronic case report form 
FQ  
Fluoroquinolone 
FTC 
Emtricitabine 
g/L 
Grams per liter 
GI 
Gastrointestinal 
GCP  
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMR 
Geometric mean ratio 
H 
Isoniazid 
hERG 
Human ether-à-go-go related gene 
HIV  
Human immunodeficiency virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 9 of 96 
IRB 
Institutional review board 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IXRS 
Interactive Voice and Web Response System 
kg 
Kilogram 
/L 
Liter 
L 
Linezolid 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
M 
Moxifloxacin 
MAO(I) 
Monoamine oxidase (Inhibitor) 
MBD 
Minimum bactericidal dose 
MIC 
Minimum inhibitory concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi drug resistant tuberculosis 
MGIT 
Mycobacterial growth inhibiting tube 
mITT 
Modified intent to treat 
mL 
Milliliter 
ms 
Millisecond 
NCS 
Not clinically significant 
NEJM 
New England Journal of Medicine 
NVP 
Nevirapine 
NO 
Nitric oxide 
NOAEL 
No observed adverse effect level 
NRTI 
(Triple) nuleosidase reverse transcriptase inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
QD 
Once daily 
R 
Rifampicin 
S 
Streptomycin 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SIRE 
Streptomycin isoniazid rifampicin ethambutol 
SOC 
System organ class 
TB 
Tuberculosis 
TBL 
Serum total bilirubin 
TDF 
Tenofovir 
TEAE 
Treatment emergent adverse events 
T>MIC 
Time above minimum inhibitory concentration 
t.i.w. 
Three times a week 
(BA) TTP (Bacteriocidal activity) time to positivity  
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
XDR-TB 
Extensively drug resistant tuberculosis 
μg 
Microgram 
Z 
Pyrazinamide 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 10 of 96 
1 
Synopsis 
1.1 Synopsis Summary 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Number/Title: 
NC-007: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB) 
Treatment Indication: 
Pulmonary XDR-TB, pre-XDR-TB, and treatment intolerant or non-responsive 
MDR-TB 
Trial Objective: 
To evaluate the efficacy, safety and tolerability of various doses and durations 
of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in 
participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment 
intolerant or non-responsive MDR-TB. 
Trial Design: 
A phase 3, multi-center, partially-blinded, randomized clinical trial in four parallel 
treatment groups. Bedaquiline and pretomanid treatment will not be blinded.  
Linezolid treatment dose and duration will be double-blinded. 
 
Participants will have a screening period of up to 14 days and will be 
randomized to receive one of the 4 active treatment arms. Participants will be 
randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
voice and web response system (IXRS) which will utilize a randomization 
system using stratification with a random element to allocate participants evenly 
across the arms by HIV status and type of TB.   
 
Each participant will receive 26 weeks of treatment.  If participant’s  sputum 
sample is culture positive between the week 16 and week 26 treatment visits 
and their clinical condition suggests they may have an ongoing TB infection, 
Investigator may consider extending current treatment to 39 weeks.   If the 
culture results between week 16 and week 26 are contaminated, missing or 
considered an isolated positive without clinical significance, available culture 
results should be used to make this decision. All decisions regarding treatment 
extension should be discussed with and approved by  the Sponsor Medical 
Monitor before implementation. 
 
Participants will be followed for 78 weeks after end of treatment. 
Patient Population: 
A total of up to 180 participants, male and female, aged 14 and over Sponsor 
may consider replacement of late screen failure and un-assessable (as 
detailed in the statistical analysis plan) participants. 
Test product, Dose and 
Mode of Administration: 
The regimen will be supplied as the following: 
 
Product 
Tablet Strength 
Abbreviation  
Bedaquiline 
100 mg  
(B) 
Pretomanid 
200 mg  
(Pa) 
Linezolid (scored) 
 
 
600 mg 
(L) 
Placebo Linezolid 
(scored) 
placebo 
(L) 
Linezolid 600 mg half 
tablet (pre-cut) 
300 mg 
(L) 
 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 11 of 96 
Placebo linezolid half 
tablet (pre-cut) 
placebo 
(L) 
 
Linezolid treatment will be supplied as 2 rows of full tablets (active or 
placebo) and one row of half-tablets (active or placebo) to allow for all 
possible dosing options while maintaining the blind.  
 
Instructions for Dosing: 
Treatment will be administered orally, once daily, with a full glass of water and 
a meal in the following dosing schemes (treatment arms): 
 
Participants will receive the following: 
• 
Bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 
18 weeks plus;  
• 
Pretomanid 200 mg once daily for 26 weeks plus; 
• 
Linezolid- participants will be randomly assigned to receive one of the 
following four blinded linezolid treatment doses and durations:  
Linezolid 1200 mg daily for 26 weeks 
• 
2 linezolid 600 mg active tablets once daily for 26 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
 
Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
• 
2 linezolid 600 mg active tablets once daily for 9 weeks  
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
Linezolid 600 mg daily for 26 weeks 
• 
1 linezolid 600 mg active tablet once daily for 26 weeks 
• 
1 placebo linezolid tablet once daily for 26 weeks  
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
 
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid tablet for 9 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
  
Treatment Modifications: 
The above treatment schemes may require modification due to toxicities as 
noted below. All dose modifications should be discussed with the Sponsor 
Medical Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be informed 
within 24 hours of the change if not discussed prior to implementation 
 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 12 of 96 
In the event of linezolid specific toxicities, the following should be considered 
and implemented per guidance in the monitoring and safety for specific 
toxicities section (8.3) of protocol:   
 
• 
Blinded one step reductions (maximum 2 steps) in the dose of linezolid 
managed by the IXRS as per instructions in pharmacy manual and/or 
IXRS user manual.  
o 1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or   
o 600 mg QD to 300 mg QD, 300mg QD to placebo  
• 
Temporary pause of linezolid. 
• 
Permanent discontinuation of linezolid. 
• 
Participants who have a linezolid reduction can go back to a higher dose 
(1 step or 2 steps) post discussion with and approval by the Sponsor 
Medical Monitor. 
 
For participants experiencing suspected drug related toxicities due to other 
drugs in the regimen (B-Pa), the full regimen may be halted for up to 35 
consecutive days.  
 
Interruptions/pauses of all Investigational Medicinal Product (IMP) must not 
exceed 8 weeks (56 days) cumulatively.  
 
When treatment is extended to 39 weeks, interruptions/pauses of all IMP must 
not exceed 13 weeks (91 days) cumulatively. 
 
When the total of missed dosing days of the prescribed regimen and/or 
pauses is greater than 7 days, the same number of missed doses should be 
dispensed/treatment extended to make up for the total missed doses. 
 
At no time should the participant be treated with a single agent. 
 
Every effort should be made for participants to receive a total of 9 weeks of 
linezolid, even if pauses are required 
Criteria for Evaluation: 
Primary Endpoint: 
Incidence of bacteriologic failure or relapse, or clinical failure at 26 weeks after the end of treatment. 
 
Abbreviated Definitions, full definitions will be described in the Statistical Analysis Plan (SAP): 
• 
Bacteriologic failure: During the treatment period, failure to attain or maintain culture conversion to 
negative. 
• 
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative 
status, with culture conversion to positive status with a strain of Mycobacterium tuberculosis (MTB) 
genetically identical to the infecting strain at baseline.  
• 
Clinical failure: A change from protocol-specified TB treatment to a new regimen before end of 
protocol specified treatment due to treatment failure, retreatment for TB during follow up, or TB-
related death. 
Note: 
• 
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days 
apart. 
• 
Participants who are documented at a visit as unable to produce sputum and who are clinically 
considered to be responding well to treatment will be considered to be culture negative at that visit. 
 
Further details of definitions to be provided in the SAP. 
 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 13 of 96 
Secondary Endpoints: 
• 
Incidence of bacteriologic failure or relapse, or clinical failure through follow up until 78 weeks after 
the end of treatment. 
• 
Time to sputum culture conversion to negative status through the treatment period. 
• 
Proportion of participants with sputum culture conversion to negative status at weeks 4, 6, 8, 12, 16 
and end of treatment. 
• 
Change from baseline TB symptoms. 
• 
Change from baseline in Patient Reported Health Status. 
• 
Change from baseline weight. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations of bedaquiline and its M2, pretomanid and linezolid from sparse sampling (see Table 
1.2) will be measured and used to update population PK models for bedaquiline and its M2 metabolite, 
pretomanid, and linezolid to further evaluate the effects of covariates on model parameters in this study 
population. PK data from the current trial may be combined with prior data (e.g., from the NiX-TB trial) to 
enhance this population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between drug 
exposure and efficacy and safety endpoints.   
 
Safety and Tolerability: 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
• 
All-cause mortality. 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by, drug relatedness 
and seriousness, leading to early withdrawal from treatment, leading to pauses of linezolid, leading 
to linezolid reductions and leading to death.   
• 
Quantitative and qualitative clinical laboratory result measurements, including observed and change 
from baseline.  
• 
Quantitative and qualitative electrocardiogram (ECG) results read by a central cardiology service, 
including observed and change from baseline. 
• 
Descriptive statistics of ophthalmology slit lamp examination data (age related eye disease study 2 
[AREDS2]) lens opacity classification and grading). Categorical data for lens opacity will be 
summarized in a frequency table for the right and left eye, respectively, including observed and 
change from baseline. 
• 
Changes in ophthalmic exam for visual acuity and color vision, including observed and change from 
baseline. 
• 
Changes noted in peripheral neuropathy signs and symptoms, including observed and change from 
baseline. 
 
Mycobacteriology Assessments: 
Sputum samples will be obtained at all scheduled visits.  The following tests will be performed.   
• 
Smear microscopy for acid-fast bacilli (AFB); 
• 
Liquid Culture (MGIT), followed by a speciation test to detect presence or absence of MTB and 
obtain time to positivity (TTP); 
• 
GeneXpert, Hain Genotype MTBDRplus or an alternative molecular to confirm MTB and rifamycin 
resistance. 
• 
Minimum Inhibitory concentration (MIC) of bedaquiline, pretomanid and linezolid; 
• 
Drug Susceptibility Testing (DST) in liquid culture for rifampicin, isoniazid, streptomycin, ethambutol, 
pyrazinamide and second line TB drugs including fluoroquinolones and injectable; 
• 
Genotyping. 
 
Details on the testing and the collection and timing of samples are in sections 1.2 and 7.2 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 14 of 96 
Statistical Methods: 
A general description of the statistical methods planned for the primary efficacy outcome is outlined below. 
Specific details will be provided in the SAP. 
 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT).  We will 
evaluate the hypothesis, separately for each of the experimental B-Pa-L treatment arms, that the incidence 
of bacteriologic and clinical cure at 26 weeks after the end of therapy is greater than 50%.   
 
The incidence will be estimated from the binomial proportion for participants with success criteria based on 
the lower bound of the confidence interval for this proportion being greater than 50%. 
 
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as the target, 
because it is above the entire range of the historical control for cure of XDR-TB and because a cure rate of 
50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a shortened, simplified, all oral, 
inexpensive and safer regimen would clearly represent an important therapeutic advancement.  
 
The primary analysis population will include both XDR and non-XDR participants (up to 45 per arm).  A 
secondary analysis will be restricted to the XDR participants only (30 per arm).   A sample size of 30-45 per 
arm will provide more than 90% power to demonstrate that the lower bound of the 95% confidence interval 
of this estimate is greater than 50%, using a 2-sided 5% significance level. This assumes that the true cure 
rate is 80 percent.   
 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 6 months) with the 
L1200 2 months and L600 26 weeks only being tested if L1200 26 weeks is a success.  Similarly, L600 9 
weeks will only be tested if L600 26 weeks is a success.  A Bonferroni adjustment will be made for 
comparing the L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025.  For these 
comparisons the lower bound of the 97.5% confidence interval will need to exceed 50% for success.   
 
Both a Modified Intent to Treat (mITT) and a Per Protocol (PP) analysis for each arm will be conducted.  No 
formal statistical pairwise comparisons between the arms will be performed.   
Trial Duration: 
~4 Years (An enrolment period of  approximately 24 months plus 14 days pre-treatment plus 6 months 
treatment period plus 18 months post treatment follow-up). 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 15 of 96 
1.2 Synopsis Flowchart 
Period Screeninga 
Treatment 
 Visits every 3 
weeks if 
treatment 
extendedb 
End of OR Early 
Withdrawal from 
Treatmentc 
Post Treatment Follow-up 
Time of Visit 
Up to 14 days 
prior to first 
dose 
Day 1 
Week  1 
Week  2 
Week 3 
Week  4 
Week 5 
Week  6 
Week 7  
Week  8 
Week 10 
Week 12 
Week 14 
Week  16 
Week 18 
Week 20 
Week 23 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks/EWc 
Visit Window q 
N/A 
+/- 3 days 
+/- 5 days 
+/- 7 days 
Post last 
dose IMP 
+7 days 
+/-  14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Trtmnt/Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusiond 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Statuse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 Count and Viral Loadf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest X-Rayg  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Testh 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Patient Reported Health Status 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Slit Lamp Exam i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
X 
 
 
 
 
 
Ophthalmic Exam j 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X X X 
Single 12-LeadECGk 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X   
 
 
 
 
X 
 
 
 
 
 
 
 
 
Limited Physical Exam l 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X X 
X X 
Full Physical Exam l 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Laboratory Safety Tests 
(includes Full Blood Count)m 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Full Blood Count 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Study Medication/Compliancen 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PK Samplingo 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Xo 
 
 
 
 
 
 
 
 
Early Morning & Spot Sputum r 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Peripheral Neuropathy 
Assessment 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
Investigator Assessmentp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 16 of 96 
 
GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
 
a. 
Screening: Screening assessments can occur on different days within 14 days prior to Day 
1 dosing (randomization). If a participant fails screening, a full re-screen may occur at a later 
date.  All screening procedures must be repeated at re-screen visit, with the exception of the 
slit lamp examination, which can be used from a previous screening if within 8 weeks of 
anticipated randomization. 
b. 
Visit Schedule: If the duration of treatment is extended (see section 6.3, Treatment 
Modifications for details), unscheduled visits should be added every 3 weeks (+/- 7 days).   
1. End of treatment visit (final treatment visit) should be done within 7 days AFTER the 
last dose of IMP.  
2. If participant completes 26 weeks of therapy at week 33 due to full regimen pauses, 
an EXAMPLE of visit scheduling would be weeks 26, 29 and 33 (3 weeks from week 
29 plus 7-day window). In this scenario, the week 33 visit would be the end of treatment 
visit and should be completed within 7 days after last dose. 
3. If participant completes treatment at week 39 due to treatment extension, an example 
of visit scheduling would be visits at weeks 26, 29, 32, 35 and 39/End of treatment (3 
weeks plus 7-day window).  
4. Follow-up visits should be scheduled based on timing of last dose of IMP (e.g., 4-week 
follow-up to be scheduled 4 weeks after last dose of IMP). 
c. 
Follow-up Visits Early Withdrawal Participants: Once a participant has been discontinued, 
they will be required to attend an Early Withdrawal visit. If participant: 
1. Received/took < 14 doses, no additional follow-up visits are required.   
2. Received 15 or more doses and is withdrawn during treatment, follow-up after end of 
treatment/EW visit at week 12, week 26 (if not already performed) and week 78 are 
required. The week 12 visit will only require the ophthalmologic exams. The week 26 
and 78 follow-up visits will be to collect Serious Adverse Event (SAE) information 
(including verification of survival) and patient reported TB outcome information only 
and may be telephonic, a home or a site visit. This includes participants who are 
withdrawn from the trial due to meeting the treatment failure endpoint. Participant may 
need to return for visits to collect sputum samples to determine outcome status. 
3. For participants who are withdrawn during post treatment follow-up, site should 
perform study procedures required for week 78 post treatment follow-up visit. If 
participant will not return for visit, site should obtain information on SAE and patient 
reported TB outcome as noted above in no 2. 
d. 
Inclusion/Exclusion: to be confirmed at screening and prior to randomization.  
e. 
HIV testing: If HIV status is a confirmed known positive, repeated HIV test is not needed 
provided that a documented HIV test result (ELISA, Western Blot or Electro-
Chemiluminescence) is available. If HIV status is unknown or suspected negative, HIV test 
will be requested. If an ELISA and/or Western Blot and/or Electro-Chemiluminescence based 
HIV test was performed within 4 weeks prior to screening, it should not be repeated if 
documentation of testing method and negative HIV results can be provided. Repeated HIV 
testing, during the Screening period is permitted for indeterminate HIV results. 
f. 
CD4 count and viral load:  Required for all HIV-positive participants, viral load and CD4 
required at screening, CD4 will be tested at end of treatment or early withdrawal from 
treatment visit. 
g. 
Chest X-Ray: A chest x-ray (digital image) within 6 months prior to or at screening, will be 
obtained and read locally by Investigator or designee. Digital images will be provided to 
Sponsor, this process will be described in a separate document, the Radiology Manual. 
h. 
Urine Pregnancy: Women of child-bearing potential only, whether they are sexually active or 
not.   
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 17 of 96 
i. 
Slit-Lamp Exam: Slit Lamp examination will be performed by an Ophthalmologist with 
AREDS2 training: 
1. For participants who receive < 14 doses of IMP, exam at: Screening only. 
2. For participants who receive 15 days to < 12 weeks of treatment, exams at: Screening 
and the 12-week post treatment follow-up visit. 
3. Participants who complete > 12 weeks of treatment exams at: Screening, End of 
Treatment or Early Withdrawal and the 12-week post treatment follow-up. 
j. 
Ophthalmic Exam: to include Ophthalmologic Medical history at Screening; All exams to 
include Visual Acuity (distance testing) and Colour Vision assessment.   Can be done by any 
trained study staff throughout study.  Screening exam must be done by Ophthalmologist in 
addition to trained study staff that will perform exams throughout the study. 
k. 
Single 12-Lead ECG: When possible, should be performed at approximately the same time 
of day (+/- 1 hours) and in the same fed/fasted state throughout the trial (e.g. 4 hours after 
lunch). Central ECG analysis will be performed. Central reading of screening results will be 
used to determine eligibility. 
l. 
Physical Exam:  Limited Physical exams should include weight and a gross neurological, 
pulmonary, cardiovascular and abdominal exam. Height will only be collected as part of full 
exam at screening. 
m. Safety Laboratory Assessments/Urine Drug Screen: The Safety Laboratory sampling 
methodology and requirements will be described in a separate document, the Laboratory 
Manual, which will be provided prior to the trial start. The following analyses will be performed: 
• 
Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential, platelet count).  
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK).  GGT will be done at screening. 
• 
When managing participants with elevated liver enzymes at an unscheduled visit, the 
Investigator can request additional tests, in addition to the repeated LFT [e.g. 
Gamma Glutamyl Transferase, screening for hepatitis A, B, C; to assist in ruling out 
other causes of abnormal liver test (e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection). 
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis. 
• 
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates, 
benzodiazepines, barbiturates, at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 2.  Positive results will not automatically 
exclude participant from the trial. 
n. 
Study Medication/Compliance: Study medication administration will be supervised per local 
site practice to assure compliance to regimen. 
o. 
PK Sampling:   The dates and times of the two doses of IMP taken prior to all pre-dose PK 
samples will be collected in the eCRF.    
Specific PK blood draws will be obtained as follows (pre-dose to be done after ECGs): 
1. Day 1; pre-dose (within 2 hours prior to dosing) 
2. Week 2: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
3. Week 8: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
4. Week 12: pre-dose (within 2 hours prior to dosing)  
5. Week 20 or at early withdrawal if prior to week 20: pre-dose (within 2 hours prior to 
dosing) and 2–3 hours post-dose 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 10 March 2020   
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 18 of 96 
• When participant is discharged and seen as an outpatient, site should make every effort to 
collect 6-8 hour sample at week 8 when operationally and logistically feasible.  
• Hospitalization information (e.g. discharge date) will be collected in the eCRF. 
• If the full regimen or linezolid is paused, PK sampling should be delayed until full regimen 
or linezolid are resumed. 
• PK sampling should be completed even if the participant’s linezolid dose has been 
lowered or linezolid has been permanently discontinued.  
• Sites may bring participant back at a scheduled or unscheduled visit (can occur outside of 
visit windows) to collect PKs to ensure draw is done when IMP is administered.  
p. 
Investigator Assessment: Principal Investigator to review participant status and assess 
whether TB treatment at current visit is considered a “success” or “failure”.  If considered a 
failure, should specify if based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. To be completed at 26 and 78 week post treatment follow-up visits and at any 
time Investigator determines that participant fulfills criteria for outcome of treatment failure. 
q. 
Visit Windows: the windows noted on the flowchart for timing of visit also apply to timing 
within a visit.  For example, procedures that are difficult to schedule such as ophthalmology 
exams, should be scheduled within +/- 3 days of scheduled visit from Day 1 to Week 8 or +/- 
14 days within scheduled visit at the week 12 post treatment follow-up visit.  Sites should 
make every effort to ensure all other procedures are done on the same day when possible. 
r. 
Sputum Sampling: 
Visit 
 
Sample 
Tests 
EMS 
SPOT 
ISOLATE* 
 AFB Smear  
microscopy  
MGIT culture, 
speciation 
Molecular 
testing 
MIC:  
B, Pa, L 
MGIT DST  
 
Genotyping 
Extended 
DST (paired 
with baseline 
isolate) 
Screening  
(Day -14 to -1) 
 
 
 
 
S 
S 
S 
  
  
  
 
Baseline (Day 1) 
or 1st positive 
between screening 
and wk4 if Day 1 
negative or 
contaminated  
 
 
 
  
  
  
C 
C 
C 
L (when 
applicable, with 
isolate below) 
All Visits Post 
Screening 
 
 
 
  
S 
  
  
  
  
 
1st positive for MTB 
at/after week 16 for 
participant not 
responding to 
therapy and/or 1st 
positive during 
follow-up for 
potential new 
infection 
 
 
 
 
 
S 
C 
C 
C 
L 
C –   Central Mycobacteriology Laboratory (specialized facility) 
S –   Study Mycobacteriology Laboratory (facility that receives sputum samples directly from site) 
L –   Lab (as applicable per Country) that performs extended DST beyond panel at Central lab 
*Preferably from EMS Sample w hen available.  Alternate isolate can be requested if initial one is 
contaminated, or the test needs to be repeated. 
 
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SPUTUM SAMPLES GENERAL: If EMS (early morning sputum) is not available, site should 
make every attempt to collect two spot samples at least 30 minutes apart.  
 
PRE-SCREENING SAMPLES: If consent granted by participant, and when applicable, site can 
request pre-screening culture/isolate/DNA from current TB diagnosis/disease course to be sub-
cultured and shipped and/or tested: 
• 
at the study lab if/when those samples could support inclusion in trial.  
• 
at the study/central lab for relevant participants with no baseline (no positive cultures from 
screening through week 4). 
 
MOLECULAR TESTING:  
• 
At Screening: GeneXpert, Hain MTBDRplus or equivalent to determine MTB complex and 
Rifampicin resistance. 
• 
Positive MTB at/after week 16: Hain MTBDRplus and HainMTBRsl 
 
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including but not limited to 
fluoroquinolones and injectables. 
 
STORAGE: MTB isolates from all positive cultures to be stored at the study laboratory until trial 
closure for the applicable study tests. The cultures as well as the extracted MTB DNA from the 
applicable baseline and follow-up isolates will also be stored at the central lab for potential further 
work to validate new assay tools for 5 years after trial closure. 
 
CENTRAL LAB: Results from testing at central lab (MIC, DST and genotyping) will not routinely 
be provided to sites.  In the event that results are necessary to determine appropriate participant 
treatment, Sponsor will provide available drug susceptibility results to the site. Genotyping will be 
performed on paired DNA extracts to determine if the participant was a relapse or reinfection (See 
SAP for details). 
 
EXTENDED DST TESTING: Paired isolates from baseline and at/after week 16 should be 
shipped to a relevant lab (as applicable/available per Country) for DST extending beyond the 
panel of drugs tested at the central lab.  Extended results will be provided to the site to inform 
appropriate participant treatment.   
 
 
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2 
Introduction and Rationale 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is now the world’s leading infectious 
disease killer and is responsible for more deaths than HIV.(43) It is the leading cause of death 
among HIV-infected individuals, and there is more TB in the world today than at any other time in 
history. As a result of poor treatment adherence, in addition to primary transmission, drug 
resistance is becoming more common and fears of an epidemic with strains of extensively drug-
resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs and regimens for TB 
are needed for the growing number of patients with XDR TB.  
Outcomes of treatment for XDR-TB using the best available treatments have traditionally been 
very poor.  The best treatment historically has been to use available second line drugs individually 
tailored based on drug susceptibility testing in an inpatient setting to assure adherence with 
treatment lasting from 24 months to much longer for patients without culture conversion.  The 
most detailed report using this approach with long term follow-up prior to the use of linezolid, 
bedaquiline or delamanid in regimens has come from South Africa, where the HIV co-infection 
rate among patients with XDR-TB ranges from 40 to 70%.  A cohort study of 107 patients with 
XDR-TB found cure or completion of therapy at 24 months to be 16%, with 46% having died.(28)  
In another report from South Africa of 114 patients with XDR-TB, 22% completed treatment 
successfully.(21)  The largest evaluation of treatment outcomes was noted in the WHO 2014 annual 
tuberculosis report of 1269 patients in 40 countries, where 22% of patients with XDR-TB 
completed treatment successfully and 35% died.(42) A meta-analysis of 397 patients with XDR-TB 
from 31 centers, with HIV coinfection <10%, reported 32% treatment success.(17)  Reports of the 
outcome of XDR-TB treatment from Peru (43 patients, 42% treatment success)(2) and Ukraine 
(114 patients, 22% treatment success)(11) have been similar.  Based on these reports, the success 
of traditionally available drug therapies for treating XDR-TB infection is substantially less than 
50% and in the most detailed and largest reports is less than 25%. 
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with XDR-TB might be improved when added to background regimens. Experience 
recently published from the C209 uncontrolled study of bedaquiline given on a background of 
multiple drugs notes that the subset of 38 patients with XDR-TB had rates of sputum culture 
conversion to negative of 62.2%.(29) However, in this study only one patient with XDR-TB was co-
infected with HIV. All participants were required to have Mycobacterium tuberculosis (MTB) 
isolates susceptible to at least 3 drugs at enrolment, and patients had a median of only 5.4 months 
of treatment-free follow-up. This study added bedaquiline for 6 months to a background regimen 
of many drugs given for 18 months or longer. 
While treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR-
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.(43)  This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% 
died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information.   
With such poor historical outcomes for patients with XDR-TB and with the complexity, expense 
and toxicity of treatments for all forms of drug resistant TB, novel drug combinations are 
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desperately needed to improve treatment outcomes. Linezolid was identified in a small study as 
a potentially efficacious drug in patients with XDR-TB when added to a failing regimen(9) and this 
drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of three drugs for which there is little, if any, pre-existing resistance 
among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]), there is the opportunity 
to evaluate a new regimen that may be administered orally once daily to treat patients with XDR-
TB. Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, it is 
hypothesized in the design of the ongoing Nix-TB clinical study that patients with pulmonary XDR-
TB may have relapse-free cure after as little as 6 months’ treatment with the B-Pa-L regimen. 
Therefore, since 2015, the TB Alliance has sponsored a study with a 6 month treatment duration 
with the B-Pa-L regimen in participants with XDR-TB or MDR TB not responsive to or intolerant 
to therapy (the Nix-TB study).(1) 
A key advantage of this regimen over standard of care for MDR-TB as well as XDR-TB is that this 
is an all-oral daily regimen for 6 months of treatment in comparison to standard regimens of 6-8 
drugs over 9-30 months of treatment that includes daily injections for a minimum of 6 months. 
The NC-007 trial takes this regimen into a randomized Phase 3 trial to optimize the dosing scheme 
for linezolid and the benefit relative to risk, and to expand the patient population to include 
individuals with pre-XDR TB. 
The information presented below first details the trial rationale, then key preclinical information 
and human efficacy and safety information for each of the drugs in the regimen and then presents 
preclinical and clinical data to support the combination of these drugs in a regimen to treat patients 
with XDR, pre-XDR and MDR treatment intolerant/failure-TB. 
2.1 Trial Rationale 
2.1.1 Trial Design Rationale 
This trial will provide a regimen containing 3 drugs against which there is no expected MTB 
resistance in the community for patients with limited treatment options while simultaneously 
gathering important efficacy and safety data on a regimen that could potentially treat all strains of 
MTB. Data from previous trials shows that the combination of B-Pa is well tolerated and has the 
potential to shorten treatment in patients who are susceptible to the drugs. The ongoing Nix-TB 
trial has shown that the B-Pa-L regimen has manageable toxicity and encouraging efficacy as an 
all oral 6 month regimen administered to patients with XDR-TB. This current trial will provide 
important information on the toxicity and efficacy of the regimen under alternate doses and 
durations of linezolid to optimize the dosing scheme for the best benefit to risk balance. 
2.1.2 Trial Drug Rationale 
2.1.2.1 Bedaquiline  
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this study bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 18 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
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combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 study that administered bedaquiline 200 mg daily over 8 weeks, and 
by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
The NC-005 study allows the efficacy and safety to be compared for treatment arms that dosed 
bedaquiline at the currently registered dose and at 200 mg daily for the 8 weeks of the trial.  Briefly, 
Study NC-005 evaluated a regimen in patients with drug susceptible pulmonary TB given 
bedaquiline with pretomanid and pyrazinamide over an 8 week period.  One arm was to enroll 60 
patients who were to be given this regimen with bedaquiline dosed as approved for marketing 
(referred to as the B (loading dose/t.i.w.) PaZ arm), and another 60 patients were to be enrolled 
who would be given the regimen with bedaquiline dosed at 200 mg daily (referred to as the B 
(200mg) PaZ arm).  Another group of patients with DS TB were randomized to treatment with 
standard HRZE therapy.  Patients with MDR-TB were given the regimen with bedaquiline dosed 
at 200 mg daily in addition to moxifloxacin (referred to as the B (200 mg) MPaZ MDR-TB arm).  
The primary endpoint was The Bactericidal Activity (BATTP (0‐56)) as determined by the rate of 
change in time to sputum culture positivity (TTP) over 8 weeks of treatment in the Mycobacterial 
Growth Indicator Tube system, represented by the model‐fitted log (TTP) results as calculated by 
the regression of the observed log (TTP) results over time.  The assessments of safety and 
tolerability included the incidence of Treatment Emergent Adverse Events (TEAEs) presented by 
severity (DMID Grade), by drug relatedness and seriousness, and for those leading to early 
withdrawal and leading to death, by group.  In addition, quantitative and qualitative clinical 
laboratory result measurements were evaluated, including group summaries of observed values 
and changes from baseline.  Pharmacokinetics for all participants included pre-dose samples on 
9 days during and one day following dosing with the regimen.  Fifteen PK Sub‐study participants 
in each treatment arm had in addition intense PK sampling on Days 14 and 56. 
Efficacy of bedaquiline 200 mg daily dose vs the marketed dosing scheme over 8 weeks 
In the efficacy analysis of the NC-005 trial, based on liquid media collected from overnight sputum 
samples, the B(200 mg)MPaZ MDR-TB treatment group showed the highest bactericidal activity 
over the 8-week treatment period, followed by that of B(200 mg)PaZ, B(loading dose/t.i.w.)PaZ 
and then HRZE. It appears clear that the daily dosing regimen for bedaquiline provided at least 
as good a result in the primary efficacy analysis as the registered dosing scheme for bedaquiline.   
Safety of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
Adverse events, including serious adverse events and Grade III/IV adverse events were similar 
among groups.  In particular, the mean change from baseline in the corrected QTc intervals was 
numerically less in the participants given bedaquiline daily than in the participants given 
bedaquiline with the labelled dosing scheme.  Measures of potential hepatic toxicity, including 
participants with greater than 3 fold or 10 fold elevations in aminotransferase levels, were 
numerically greater in participants given the labelled dosing scheme than subjects given daily 
doses of bedaquiline.   
Pharmacokinetics of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
A population PK model published by McLeay in 2014 was used with PK data from Study NC-005 
to simulate the expected bedaquiline exposures when dosed at 200 mg daily followed by 100 mg 
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daily for the remainder of the study in comparison to the labelled dosing scheme with bedaquiline 
administered for 6 months.(14)  The key findings from the simulations of the proposed dosing 
scheme for NC-007 of bedaquiline administered 200 mg daily over 8 weeks followed by 100 mg 
daily for an additional 16 weeks are: 
• 
The exposures of the proposed dosing scheme (Cmax, mean or trough) are not expected to exceed 
the exposures associated with the labelled scheme on Day 14 at the end of the 400 mg daily 
dose.  With the labelled dosing scheme, the highest exposures are on Day 14 at the end of 
the 400 mg daily loading dose. 
• 
The average daily exposures with the proposed dosing scheme over 6 months are within (or 
not substantially different from) the range of exposures over 6 months of the labelled dosing 
scheme. 
• 
The cumulative exposure, in terms of AUC over time, is similar between the proposed dosing 
scheme and the labelled scheme 
2.1.3 Pretomanid 
Pretomanid has demonstrated good microbicidal activity at the 200mg daily dose as monotherapy 
in studies PA-824-CL-007 and PA-824-CL-010, in combination with either bedaquiline or 
pyrazinamide over 14 days in the early bacteriocidal activity (EBA) Study NC-001-(B-M-Pa-Z), in 
combination with either bedaquiline and/or pyrazinamide and/or clofazimine over 14 days in the 
EBA Study NC-003-(B-C-Pa-Z), and in combination with bedaquiline and linezolid over 6 months 
in the Nix-TB study.  In the EBA Study PA-824-CL-010 the 100mg dose demonstrated similar 
microbicidal activity to the 150 and the 200mg daily dose over 14 days. The Phase 2 trial NC-
002-(M-Pa-Z) evaluated this regimen at doses of pretomanid of both 100 mg and 200 mg relative 
to the HRZE control.   In this trial the efficacy results were similar between participants treated 
with 100 mg/day and 200 mg/day of pretomanid in the regimen, although for the primary endpoint, 
reduction in colony forming units of MTB from sputum, only the 200 mg/day dose group was 
statistically significantly better than the group randomized to standard HRZE therapy.  Safety was 
also similar between the groups, although the 200 mg/day group had more grade 2 adverse 
events than either the 100 mg/day group or the HRZE control group.  Because sterilizing relapse-
free cure of TB in patients with XDR-TB may ultimately require a regimen with higher drug 
exposures, the 200mg dose was chosen for evaluation in the Nix-TB study of the B-Pa-L regimen.  
The manageable toxicity of the regimen and very encouraging efficacy in the Nix-TB trial support 
taking the 200 mg dose of pretomanid forward in the NC-007 trial. 
2.1.4 Linezolid 
The standard dose of linezolid for a multitude of indications is 400mg or 600mg BID.  Doses of 
linezolid used to treat pulmonary TB in reported observational trials and case series range from 
300 mg to 1200 mg per day over periods of up to 20 months of treatment.  While the development 
of adverse events is generally higher with higher doses, the adverse events often ameliorate with 
a reduction of the dose or discontinuation of drug for several weeks and then reintroduction at a 
lower dose.  No controlled trials have clearly identified differences in anti-TB effect across a range 
of doses over long term treatment of TB. 
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In this trial, each arm will vary the linezolid dosing to identify the optimal ratio of efficacy to adverse 
events as noted below. The 4 arms, to which participants will be randomly assigned in a blinded 
manner, are: 
• 
Linezolid 1200 mg orally once daily for 26 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
• 
Linezolid 1200 mg orally once daily for the first 9 weeks, with the ability to interrupt or 
reduce the dose if needed based on toxicity.  
• 
Linezolid 600 mg orally once daily for 26 weeks, with the ability to interrupt or reduce the 
dose if needed based on toxicity. 
• 
Linezolid 600 mg orally once daily for the first 9 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
These dosing schemes for linezolid are chosen based on clinical experience in the Nix-TB trial, 
the company’s linezolid early bactericidal activity (EBA) study findings in the Lin CL-001 study, 
and preclinical data in the mouse model of infection. While the EBA study showed that a modestly 
greater bactericidal effect over 14 days at the highest 1200 mg daily dose (see further details 
below in Section 2.2.3), this dose appears to be associated in the Nix-TB trial and in published 
literature with a greater incidence of unwanted neuropathic and myelosuppressive effects than 
the 600 mg daily dose. While a full 6 months of linezolid therapy in the regimen may give greater 
culture conversion and avoid relapse, the mouse model found that linezolid dosing of only 1 or 2 
months, when B and Pa were given continuously for a total of 3 months, maximized relapse-free 
cure; in other words, similar to pyrazinamide in the present first line HRZE therapy, more than 2 
months of linezolid when combined with B and Pa does not increase relapse-free cure in the 
mouse model. Thus, the 4 treatment arms in this study will give randomized comparative 
information about the optimal duration and dose of linezolid in the regimen relative to efficacy and 
toxicity.  
The decision to give linezolid as a single daily dose is based on the results of the linezolid EBA 
study that showed over 14 days that similar bactericidal activity was noted whether the drug was 
given as a single daily dose or divided in to 2 doses. A single daily dose will ultimately enhance 
patient adherence and will reduce the total time the drug concentration is greater than the 
calculated concentration associated with mitochondrial toxicity (which we hypothesize to be the 
likely mechanism for the toxicities of peripheral neuropathy and myelosuppression). 
2.2 Agents to be Studied 
2.2.1 Bedaquiline 
Bedaquiline is being developed as part of combination therapies for pulmonary TB due to MDR-
TB and approved in 2012 in the USA under the provisions of accelerated approval regulations. 
Bedaquiline received conditional Marketing Authorization in the EU in 2014 and is approved in 
over 40 countries (EU countries counted individually). The approved indication may vary per 
country. Bedaquiline is marketed under the trade name SIRTUROTM.  Bedaquiline has a novel 
mechanism of action as it specifically inhibits mycobacterial ATP synthase, an enzyme that is 
essential for the generation of energy in MTB The inhibition of ATP synthase leads to bactericidal 
effects for both replicating and non-replicating tubercle bacilli. 
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In the placebo-controlled Phase 2b study C208 conducted in newly-diagnosed patients with 
sputum smear-positive pulmonary MDR-TB (including pre-XDR-TB), the addition of bedaquiline 
to a preferred background regimen of MDR-TB treatment resulted in a decreased time to culture 
conversion and improved culture conversion rates compared to placebo. Median time to culture 
conversion according to the primary analysis method was 83 days for the bedaquiline group 
compared to 125 days for the placebo group (p<0.0001; hazard ratio, 95% CI: 2.44 [1.57; 3.80]). 
The proportion of patients in the mITT population with sputum culture conversion after 24 weeks 
of treatment with bedaquiline or placebo in combination with background regimen (with patients 
who discontinued considered as non-responders), was 52/66 (78.8%) in the bedaquiline group 
and 38/66 (57.6%) in the placebo group. Durability of response seen in the bedaquiline treatment 
group was supported by the results at Week 120. The proportion of responders (with patients who 
discontinued considered as non-responders) at Week 120 was 41/66 (62.1%) in the bedaquiline 
group and 29/66 (43.9%) in the placebo group. 
In the Phase 2b, open-label study C209, conducted in 233 patients with sputum smear positive 
pulmonary MDR-TB, the median time to sputum culture conversion excluding patients with DS-TB 
and those that did not have a positive sputum culture at screening and/or baseline (mITT; 205 
patients), was 57 days. At Week 24, 163 of 205 (79.5%) patients responded to bedaquiline 
treatment as determined by sputum culture conversion rates. Conversion rates at Week 24 were 
highest (87.1%; 81/93) in patients with MDR-TB resistant to only RMP and INH, 77.3% (34/44) in 
pre-XDR-TB patients and lowest (54.1%; 20/37) in XDR-TB patients. 
The average terminal half-life of bedaquiline, is about 5.5 months. After reaching Cmax, however, 
there is initially a fairly rapid reduction in plasma bedaquiline concentrations over the dosing 
interval (with an estimated half-life of about 13 hours). Four weeks after ceasing bedaquiline 
intake, the mean bedaquiline concentrations were reduced by approximately 40% compared to 
the end of the bedaquiline treatment period in the C208 study. Administration of bedaquiline with 
food increased the relative bioavailability by about 2-fold compared to administration under fasted 
conditions. It is therefore recommended to take bedaquiline with food to enhance its oral 
bioavailability. 
CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline. Drug-
drug interaction (DDI) studies have showed reduced exposure to bedaquiline during combination 
with a strong or moderate inducer of CYP3A4 metabolism (i.e., rifampicin) and increased 
exposure during combination with a strong or moderate inhibitor of CYP3A4 metabolism (i.e., 
ketoconazole). Potential drug interactions with anti-retroviral drugs have been evaluated in three 
studies.  In an interaction study of single-dose bedaquiline and multiple-dose Lopinavir/ritonavir, 
exposure (AUC) to bedaquiline was increased by 22% (90% CI: 11-34). Co-administration of 
single-dose bedaquiline and multiple-dose nevaripine did not result in clinically relevant changes 
in the exposure to bedaquiline. Co-administration of a single dose of bedaquiline and multiple-
dose efavirenz (EFV) resulted in approximately a 20% decrease in the AUCinf  of bedaquiline with 
no alteration in the Cmax.  Modeling based on the data from this DDI study predicts average steady-
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state concentrations of bedaquiline and M2 to be reduced by 52% with chronic co-administration 
of bedaquiline and EFV.(5)  
Safety of Bedaquiline 
The Investigator’s Brochure for bedaquiline provides detailed safety information.5 
Data were used from 14 completed clinical studies to identify Adverse Drug Reactions (ADRs) 
according to the ICH guideline entitled, E6: Good Clinical Practice, Consolidated Guideline (ICH, 
1996): “…all noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. The phrase “responses to a medicinal product” means that 
a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out." 
The ADRs were identified from the pooled safety database of reported AEs in the Phase 2b clinical 
studies with bedaquiline, based upon a systematic well-documented approach and are presented 
for study C208 below in Table 1.  None of the ADRs reported in the controlled studies during the 
Investigational Treatment phase were considered serious. 
Table 1: 
ADRs C208 Stage 1 and Stage 2 
Adverse Drug Reactions (ADRs) in the Controlled Studies (C208 Stage 1 and Stage 2)  
During the Investigational Treatment Phase 
ADR (Grouped term), n (%) 
Frequency 
Any BDQ 
N=102 
Any Placebo 
N=105 
Nervous system disorders 
Headache 
Very Common 
24 (23.5) 
12 (11.4) 
Dizziness 
Very Common 
13 (12.7) 
12 (11.4) 
Cardiac disorders 
ECG QT prolonged 
Common 
3 (2.9) 
4 (3.8) 
Gastrointestinal disorders 
Nausea 
Very Common 
36 (35.3) 
27 (25.7) 
Vomiting 
Very Common 
21 (20.6) 
24 (22.9) 
Diarrhea 
Common 
6 (5.9) 
12 (11.4) 
Hepatobiliary disorders 
Transaminases increaseda 
Common 
7 (6.9) 
1 (1.0) 
Musculoskeletal and connective tissue disorders 
Arthralgia 
Very Common 
30 (29.4) 
21 (20.0) 
Myalgia 
Common 
6 (5.9) 
7 (6.7) 
 
a. 
Different AE preferred terms (i.e., transaminases increased, aspartate aminotransferase [AST] increased, 
alanine aminotransferase [ALT] increased, hepatic enzyme increased, and hepatic function abnormal) contribute 
to this ADR, w hile for the other ADRs the ADR is the preferred term. 
 
Of note, 13 deaths occurred in the C208 Stage 2 study: 10 subjects (12.7%) in the bedaquiline 
group and 3 subjects (3.7%) in the placebo group experienced an SAE leading to death. One 
death (alcohol poisoning) occurred during administration of bedaquiline. The median time to death 
for the remaining 9 subjects was 344 days after last intake of bedaquiline. One of the 10 deaths 
in the bedaquiline treatment group and 1 of the 3 deaths in the placebo group occurred after the 
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Week 120 window. In the bedaquiline group, the most common cause of death as reported by the 
investigator was TB or TB-related illness (5 subjects). For all deaths due to TB, the subject’s last 
microbiological outcome was either failure to convert or relapse. The causes of death in the 
remaining bedaquiline subjects varied. The investigator considered all the SAEs leading to death 
not or doubtfully related to bedaquiline/placebo. The imbalance in deaths is unexplained. In 
addition, no discernible pattern between death and sputum culture conversion, relapse, sensitivity 
to other drugs used to treat TB, HIV status, or severity of disease was observed.  
During clinical studies with bedaquiline a prolongation of QTc interval on the ECG was observed.  
Consequently, bedaquiline treatment initiation is not recommended in patients with, personal or 
family history of prolonged QT intervals, or additional risk factors for Torsades de Pointes. 
Detailed criteria are noted in Section 5.2 Exclusion Criteria. 
Increases in transaminases were seen in clinical studies during administration of bedaquiline in 
combination with a background regimen. Based on a review confirmed by an external 
hepatologist, it was concluded that bedaquiline has a signal for liver injury manifested by 
increases in AST and to a lesser extent ALT. Transaminase elevations are not unexpected given 
the number of other hepatotoxic drugs in the background regimens in clinical trials based on the 
publication by Keshavjee, which describes a 16.5% incidence of hepatotoxicity during MDR-TB 
treatment. (7) 
2.2.2 Pretomanid 
As detailed in the Investigator’s Brochure(6), pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti-
tuberculosis activity and a unique mechanism of action(35). Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB(10), and in vivo activity in a mouse model of tuberculosis(10, 
35).  
2.2.2.1 Pharmacology 
2.2.2.1.1 Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro studies demonstrated that pretomanid was active against actively growing 
drug-sensitive and drug-resistant MTB strains as well as against non-replicating MTB The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be similar to the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 
0.25 µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against 
drug-resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity. (6) 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO), (33) although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling studies also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.(12,13) 
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2.2.2.1.2 Key Non-Clinical Studies of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse studies.(18,19,20,36,40) In a mouse model of established TB, 
the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 
22 days after inhalation infection with H37Rv MTB is shown in Figure 1. In this model, the 
minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the 
development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum 
bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony forming units 
(CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 
100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
Figure 1: 
Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
2.2.2.2 Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology studies, 
in repeat-dose toxicity studies in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity studies, and in fertility and teratology studies in rats and rabbits.  
In the repeat-dose toxicity studies, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week study in rats, 50 mg/kg/day in a 13-week study in monkeys and 
<25 mg/kg/day (based on findings of thickening of the GI tract at all doses) in a 9-month study in 
monkeys. The major findings in safety and toxicity studies are listed below in Table 2 and are 
detailed in the Investigator’s Brochure .(6) 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
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repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development studies indicate no effects of PA-824 on fetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology studies and a Segment I fertility study. In this fertility study, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed study in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week study in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
study in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the electrocardiogram (ECG) as a prolonged QT interval corrected for heart 
rate (QTc). Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. 
Following a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation 
ranged from 21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-
administration of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog 
did not result in any greater effect on the QT interval than with either agent alone. After 
repeated daily doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
2.2.2.3 Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 studies with healthy adult 
male and female subjects, with 163 subjects receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 studies sponsored by the NIH included a Thorough QT study and a study 
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of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the 
studies are in the Investigator’s Brochure. 
2.2.2.3.1 Pharmacokinetics 
Several Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200 mg dose that increases total 
exposure by 88%. Interaction studies with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Study CL-006 was an open-label, fixed-sequence drug-drug 
interaction study to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs metabolised 
by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had 
minimal effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by 
measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax), area under the 
curve to the last available time point (AUC0-t), and area under the curve extrapolated to infinity 
(AUC0-inf ). The Cmax and AUC values for midazolam after co-administration with pretomanid 
were approximately 85% of those observed after treatment with midazolam alone. Furthermore, 
midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and half-life (t1/2) 
values were not different in the presence or absence of pretomanid. Therefore, 14 days’ dosing 
with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH sponsored this 
drug interaction study with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy subjects. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for the maximum concentration (Cmax) was 0.71, the GMR for the 24-hour area 
under the time-concentration curve (AUC0-24h) was 0.65, and the GMR for the trough 
concentration (Cmin) was 0.54. Concentrations of EFV when given with pretomanid versus given 
alone were similar. Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg 
once daily for 7 days, then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 
days, then LPV/r + pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + 
pretomanid, washout, then pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid 
alone from 16 PK-evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and 
for Cmin was 0.78. In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg 
for 7 days, then pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin 
versus pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and 
Cmin were 0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for maximum concentration (Cmax), area under the concentration-time curve (AUC0-
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24h), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz; 13%, 17%, 
and 21% with LPV/r; and 53%, 66%, and 85% with rifampin, respectively. 
2.2.2.3.2 Pretomanid Clinical Efficacy 
The first two Phase 2 studies to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first study (CL-007) demonstrated 
good EBA, but all doses in this study (200 to 1200 mg/day) had the same activity. The second 
study (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA 
was seen at a dose of 100 mg/day over 14 days (4) (Figure 2). 
Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010 
 
CFU = colony-forming unit; PA-824 = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Studies of Pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below in Section 2.3.2.  
2.2.2.3.3 Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure(6) provides detailed safety information. 
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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Across the 16 clinical studies with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy subjects across the 10 Phase 1 studies and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
studies.  Among the 289 healthy Subjects, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 1200 
mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical studies completed to date indicates pretomanid 
is well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these studies, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical studies completed to date as likely caused by 
pretomanid is blood creatinine increased.  A study of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close surveillance 
and careful management of participants who have elevations in aminotransferases and/or 
bilirubin. Serious liver injury, including death in 3 participants taking a combination of 
pretomanid, pyrazinamide and moxifloxacin, has occurred during clinical studies and the risk 
of liver injury may be higher for participants taking a combination of PA-824 and pyrazinamide 
than it is for the standard HRZE treatment. Therefore, close monitoring of liver function is 
required for participants who are administered PA-824, especially when combined with 
pyrazinamide.  Administration of the regimen of PaMZ has been associated with death in 3 
participants associated with hepatic injury. Furthermore, the HRZE control regimen, and both 
pyrazinamide and moxifloxacin, has been associated with drug induced liver injury and in rare 
cases hepatic necrosis.  Consequently, hepatic safety will be under close surveillance in all 
clinical studies. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human studies that involve exposure to pretomanid longer than 
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14 days.  These examinations will be conducted at baseline, near the end of the dosing period 
and 3 months after the end of study drug exposure.  These examinations are to follow up on 
the finding of cataracts in rats exposed to pretomanid in clinical studies. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple time 
points during the study.  Although the Thorough QT Study in healthy subjects found that 
pretomanid did not increase corrected QT intervals in a clinically meaningful way and did not 
add to the known effect of moxifloxacin, the ECGs will be carefully monitored during Phase 3.  
All ECGs will be interpreted and conduction intervals will be confirmed by a central cardiology 
service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Study NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology studies have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 study for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology studies found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 studies have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 studies) or FSH values (3 studies) at baseline and after daily 
dosing of regimens containing pretomanid in various combinations with moxifloxacin, 
pyrazinamide and bedaquiline.  A review of data from the 3 studies by an independent 
reproductive endocrine expert concluded that, based on the hormone evaluations to date, there 
is no evidence that PA-824 is a testicular toxicant in men at the doses and exposure times 
evaluated. 
2.2.3 Linezolid 
Linezolid is a synthetic antibacterial agent of the oxazolidanone class approved in many countries 
around the world for drug-resistant, gram-positive bacterial infections, including gram positive 
organisms such as Staphylococcus aureus, coagulase negative Staphlococcus and Enterococcal 
infections.  The recommended dose for these infections is 600 mg twice daily for up to 28 days of 
therapy.(23,24,26) Antimicrobial effects likely come from inhibition of protein synthesis in the 
ribosomes of the infecting organism.(8)  Resistance of MTB to linezolid is rare, as this drug has 
not been widely used to treat tuberculosis.  In a recent study using linezolid to treat patients with 
XDR-TB in Korea, none of 41 patients had resistance to linezolid at baseline.(9) 
Preclinical in vitro data shows linezolid is active against MTB, including MDR strains with minimum 
inhibitory concentrations (MICs) that range from 0.125-1 μg/mL.(38)  Recent studies of the 
bactericidal and sterilizing activity of linezolid in a mouse model of MTB infection have 
demonstrated linezolid alone causes marked reductions in lung colony forming units (CFUs) from 
mice following 1-3 months of therapy.(36) (Table 3, below) 
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Table 3: 
Murine Lung CFU counts during Treatment with Linezolid 
Monotherapy versus Standard Therapy 
 
Mean lung log10 CFU count (± S.D.) at: 
Regimen 
D0 
Month 1 
Month 2 
Month 3 
Untreated 
6.17 + 
0.27 
6.47 + 0.06 
 
 
2RHZ/4R
H 
 
3.47 + 0.37 
1.59 + 0.25 
0.50 + 0.51 
L 
 
4.97 + 0.26 
 
 
 
In recent years linezolid has been used to treat patients with MDR(28) and XDR-TB, although there 
have been no fully controlled trials of linezolid in a regimen for this indication.  The World Health 
Organization management guidelines place linezolid in Group 5 (“Agents with unclear role in 
treatment of drug resistant-TB”) in their groups of drugs to treat MDR-TB.(41) Over the past 10 
years small retrospective observational studies have reported good results when linezolid has 
been added to failing regimens for patients with MDR-TB.(9, 27, 34) The most compelling recent 
evidence linezolid may be of benefit to patients with XDR-TB was reported by Lee and colleagues 
from a study in S. Korea.(9)  Forty-one patients who had sputum culture–positive XDR-TB and who 
had not had a response to any available chemotherapeutic option during the previous 6 months 
were randomized to start linezolid at 600 mg daily or to delay therapy with linezolid at 600 mg 
daily for 2 months without changing their failing background regimen.  After confirmed sputum-
smear conversion, or at 4 months, patients underwent a second randomization to continued 
linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 
months.  Thirty four of 39 (87%) of the patients had a negative sputum culture within 6 months 
after linezolid had been added to their drug regimen.  As of the cutoff date prior to publication, of 
the 38 patients who received linezolid, 17 were still receiving the treatment per protocol, and 13 
had completed treatment, including 6 with no relapse during the treatment period, 4 with no 
relapse at the 6-month follow-up, and 3 with no relapse at the 12-month follow-up (end of study).  
While the standard dose of linezolid for short term use for severe bacterial infections is 600 mg 
bid, some clinicians and clinical trials using linezolid as Group 5 therapy to treat TB use only 300 
mg or 600 mg daily due to concerns about toxicity developing when used over a period of months 
(see below for a review of linezolid toxicity). (9)  However, there are no data to indicate what dose 
of linezolid is required or optimal to effectively treat TB infection.  Consequently, TB Alliance has 
recently conducted and completed an Early Bactericidal Activity trial to evaluate the use of 
linezolid over 14 days in patients with newly diagnosed DS Pulmonary TB in dosing schedules 
including 300 mg daily, 300 mg bid, 600 mg daily, 600 mg bid, 1200 mg daily, and HRZE at 
standard doses daily.  Preliminary unpublished in-house results using Bayesian mixed effects 
modelling have noted that there is a bactericidal effect of linezolid over 14 days that is substantial, 
but less than for the full HRZE regimen.  There is little difference between daily or twice daily 
dosing of the same total daily dose of drug, and there is a dose-response relationship between 
total daily dose and daily reductions in either total CFU counts on solid culture or increases in 
Time to Positivity in liquid culture (a decreased load of MTB is associated with an increase in Time 
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to Positivity).  Point estimates of the log of the daily increase in Time to Positivity over 14 days 
ranged from 2.278 for Linezolid 300 mg QD to 4.446 for linezolid 1200 mg QD, with the estimate 
of 6.860 for HRZE for reference. 
Figure 3:  
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin 
CL-001 
Bayesian Nonlinear Mixed Effects Regression Model: Posterior Estimates and 95% 
Bayesian Confidence Intervals 
 
HRZE = isoniazid, rifampin, pyrazinamide, and ethambutol 
2.2.3.1 Linezolid Clinical Safety 
Linezolid is currently marketed globally for a variety of acute infectious diseases and has been 
studied for the treatment of XDR-TB in several recent trials.(3,9) The following list of known and 
potential risks is based on the warnings and precautions and adverse reactions sections of the 
current package label.(23,24,26)  Of note, the approved indication for linezolid is for administration 
up to 28 days. 
 Warnings and Precautions 
• 
Linezolid should not be used in patients taking any medicinal product which inhibits 
monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking 
any such product. 
• 
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) 
has been reported in patients receiving linezolid. In cases where the outcome is known, 
when linezolid was discontinued, the affected hematologic parameters have risen toward 
pretreatment levels. Complete blood counts should be monitored weekly in patients who 
receive linezolid, particularly in those who receive linezolid for longer than two weeks, 
those with pre-existing myelosuppression, those receiving concomitant drugs that produce 
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bone marrow suppression or those with a chronic infection who have received previous or 
concomitant antibiotic therapy.  
•
Lactic acidosis has been reported with the use of linezolid. In reported cases, patients 
experienced repeated episodes of nausea and vomiting. Patients who develop recurrent 
nausea or vomiting, unexplained acidosis, or low bicarbonate level while 
receiving linezolid should receive immediate medical evaluation.
•
Spontaneous reports of serotonin syndrome associated with the co-administration of 
linezolid and serotonergic agents, including antidepressants such as selective 
serotonin reuptake inhibitors (SSRIs), have been reported.  Where administration of 
linezolid and concomitant serotonergic agents is clinically appropriate, patients 
should be closely observed for signs and symptoms of serotonin syndrome such as 
cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or 
symptoms occur physicians should consider discontinuation of either one or both 
agents. If the concomitant serotonergic agent is withdrawn, discontinuation 
symptoms can be observed (see package insert of the specified agent(s) for a 
description of the associated discontinuation symptoms).
•
Peripheral and optic neuropathy has been reported in patients treated with linezolid, 
primarily those patients treated for longer than the maximum recommended duration of 28 
days. In cases of optic neuropathy that progressed to loss of vision, patients were treated 
for extended periods beyond the maximum recommended duration. Visual blurring has 
been reported in some patients treated with linezolid for less than 28 days. If 
patients experience symptoms of visual impairment, such as changes in visual acuity, 
changes in color vision, blurred vision, or visual field defect, prompt ophthalmic 
evaluation is recommended. Visual function should be monitored in all patients 
taking linezolid for extended periods and in all patients reporting new visual symptoms 
regardless of length of therapy with linezolid. If peripheral or optic neuropathy occurs, 
the continued use of linezolid in these patients should be weighed against the 
potential risks.  Additional information on the neuropathies reported in recent studies 
of linezolid administered over prolonged periods to patients with TB infection is 
presented above in Section 2.2.3.
•
Convulsions have been reported in patients when treated with linezolid. In some of 
these cases, a history of seizures or risk factors for seizures was reported.
•
Postmarketing cases of symptomatic hypoglycemia have been reported in patients 
with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with 
linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been 
associated with hypoglycemic episodes in diabetic patients receiving insulin or 
hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia 
has not been established, diabetic patients should be cautioned of potential 
hypoglycemic reactions when treated with linezolid. 
In addition, the linezolid product label notes that there was an excess of abnormal liver function 
tests in comparator-controlled trials.  These abnormalities were noted in 0.4% of linezolid treated 
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patients in trials of skin and skin structure infections vs in 0.2% of clarithromycin treated patients, 
and in 1.6% of patients treated with linezolid versus 0.8% of patients with other treatments in trials 
of all other infections. 
Adverse events of linezolid long term therapy for Tuberculosis have been described in several 
literature reports. The most complete review is a meta-analysis by Cox which noted the proportion 
of adverse events necessitating treatment discontinuation was significantly different by dose: 
29.49% (95%CI 3.24–55.74) for ⩽600 mg daily vs. 60.75% (95%CI 42.69–78.81) for >600 mg 
daily (P = 0.05). (3) 
In a trial reported by Lee et al in S Korea(9), seven of 41 participants had myelosuppression, 
including anemia and neutropenia, primarily within the first 5 months, and only one participant 
withdrew due to anemia.  Six had clinically significant myelosuppression:  5 in 0-4 months and 1 
in 4-8 months, with 0 in 8-12 months. 
Peripheral and Optic Neuropathy:  
The linezolid product label notes these adverse events have been “ reported in patients, primarily 
those patients treated for longer than the maximum recommended duration of 28 days.  In cases 
of optic neuropathy that progressed to loss of vision, patients were treated for extended periods 
beyond the maximum recommended duration.  Visual function should be monitored in all patients 
taking ZVYOX for extended periods (>3 months) and in all patients reporting new visual 
symptoms, regardless of length of therapy.(26) 
In Lee, NEJM, 2012(9), the publication’s Supplemental Table 3 notes that 21 patients had clinically 
significant peripheral neuropathy spread over 12 months:  5 in months 0-4, 10 in months 4-8 and 
5 in months 8-12 (time of onset not noted for one).  Participants who developed any peripheral 
neuropathy had their dosing of linezolid interrupted, generally for several weeks, and then 
resumed at the lower dose of 300 mg/day (C. Barry, personal communication).  None of the 
participants withdrew from the study based on peripheral neuropathies.  At baseline, patients 
received visual acuity testing, contrast sensitivity and color vision tests. Seven cases were 
observed as having potential effects on vision; only two of 38 patients withdrew from study due to 
optic neuropathy.  For clinically significant optic neuropathy, one had this at 0-4 months, 2 at 4-8 
months and 3 at months 8-12.  Except for the 2 participants who withdrew from the study, the 
others resumed linezolid at the 300 mg dose after a hiatus of several weeks of treatment and 
completed the study with resolution of their visual acuity changes (C. Barry, personal 
communication). 
In the Schecter California Department of Health (DOH) review(32), peripheral neuropathy 
developed in 5 of 30 patients (no standardized monitoring), but only one withdrew from linezolid 
therapy.  One patient developed visual loss secondary to optic neuropathy after 10 months of 
linezolid therapy, but vision returned to normal 3-4 weeks after discontinuation. 
In Park, 2006(27), two patients of eight in the case series developed optic neuropathy after 8-9 
month and had linezolid discontinued; these patients also had peripheral neuropathy. After 
linezolid treatment was stopped, the optic neuropathy fully resolved after 2-3 months.  A total of 
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4 patients developed peripheral neuropathy at 4, 5, 8, 11 months; in the patients with optic 
neuropathy who stopped treatment, the peripheral neuropathic symptoms continued or improved 
only marginally. 
In Singla, 2012(34), two of 29 patients treated with linezolid, 600 mg daily over 12 months, stopped 
the drug because of peripheral neuritis (one patient) and optic neuritis (one patient).  The time 
course of these adverse events was not noted. 
2.3 Regimens to be Studied 
The regimen included in this study (B-Pa-L) has been selected based on the performance of the 
regimen in non-clinical pharmacology studies and on the combination of bedaquiline and 
pretomanid with other drugs in clinical studies NC-001 and NC-003.  In addition, improved 
treatment outcomes in XDR patients with the addition of linezolid to existing therapy provide 
support for combining linezolid with other drugs that have no pre-existing resistance.  Preliminary 
results from the ongoing Nix-TB clinical study demonstrate the encouraging potential of this 
regimen. 
This regimen has the potential to treat drug resistant strains of tuberculosis. This is an oral 
regimen, removing the need for injectables as part of drug resistant treatment, and is also 
projected to be markedly less expensive than current XDR-TB therapy. Treatment duration is 
anticipated to be shorter than current regimens for drug resistant TB, based on findings in mouse 
models of infection and the fact that all participants will be treated with three active drugs against 
TB for which there is no expected resistance.  
The key data supporting the use of the B-L-Pa regimen are described below. 
2.3.1 Non-Clinical Studies 
In the murine model of TB, addition of bedaquiline to HRZ results in accelerated clearance of MTB 
(5,36) when compared to HRZ alone. While the combination of bedaquiline and pretomanid in the 
murine model of TB in initial studies appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ(15) and in a subsequent study it was more 
active in the mouse model than HRZ.(16) Thus a novel regimen with bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance.   
Recent studies of the bactericidal and sterilising activity of linezolid in an animal model where 
mice were given high dose aerosol MTB infection have demonstrated that linezolid alone and in 
combination with bedaquiline and pretomanid causes marked reductions in lung CFUs from mice 
following 1 to 3 months of therapy (Table 4 below). Additionally, all mice treated daily with 
bedaquiline, pretomanid and linezolid (B-L-Pa) were cured of the infection after 3 months of 
therapy as evidenced by no MTB cultured from lungs when mice were sacrificed 3 months after 
the completion of therapy that lasted 3 months or more (Table 4, below). This is in contrast to the 
5-6 months required in previous studies to cure all mice when treated with the standard of care 
isoniazid, rifampicin and pyrazinamide (HRZ; note that typically ethambutol is not used in the 
mouse model of infection). Additional mouse studies were performed to determine whether 
shorter durations of linezolid, with continuation of the other drugs, would result in relapse-free 
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cure in the mouse (Table 4 below). Treatment with linezolid for only the first 4 to 8 weeks of a 
3-month treatment also resulted in relapse-free cure when lungs from the mice were cultured 
3 months after the completion of therapy.(37) 
Table 4: 
Murine Relapse Data 
Impact of Linezolid Treatment Duration on Lung Colony Forming Unit Counts 
Assessed during Treatment and Proportion of Mice Relapsing after Treatment 
Completion 
Proportion of mice relapsing after treatment for: 
Regimen 
2 months 
3 months 
2RHZ/RH* 
8/14 
(57%) 
BPa 
3/14 
(21%) 
3BPaL ** 
6/15 
(40%) 
0/15#† 
(0%) 
2BPaL/1BPa*** 
0/15#† 
(0%) 
1BPaL/2BPa 
9/15 
(60%) 
0/15#† 
(0%) 
#p = 0.11 vs. BPa; †p≤ 0.001 vs. RHZ 
*2RHZ/RH means 2 months on the full regimen and a third month on only RH 
**3BPaL means 3 months on the full regimen 
***2BPaL/1BPa means 2 months on the full regimen and a third month on only BPa 
****1BPaL/2Bpa means 1 month on the full regimen and a third month on only BPa 
B – bedaquiline, H-isoniazid, L-linezolid, Pa-pretomanid, R-rifampicin, Z-pyrazinamide 
 
In conclusion, linezolid increases the sterilising activity of the bedaquiline-pretomanid 
combination; no MTB could be cultured from the lungs of mice 3 months after cessation of 3 
months of treatment with the combination, in contrast to MTB cultured from 13 of 15 mice treated 
with the standard 2RHZ/4RH regimen over 3 months. In addition, limiting the duration of linezolid 
to the first month of treatment does not affect linezolid’s contribution to the sterilising activity of 
the regimen in the preclinical mouse study.   
Prior to the use of pretomanid in combination with bedaquiline in clinical study NC-001, a 
preclinical cardiovascular safety pharmacology study was conducted in unrestrained beagle dogs 
with both drugs to explore the potential for additive effects on QT prolongation induced by the 
combination.  Results indicate that administration of 100 mg/kg bedaquiline daily for 7 days 
causes a small increase in QTc interval by Day 6 in some animals that is not influenced by the 
addition of 100 mg/kg pretomanid on Day 7. The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the subcutaneous route of administration and not 
related to the plasma exposure.   
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2.3.2 Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or 
Linezolid 
2.3.2.1 Clinical Study NC-001 
Study NC-001 was a partially double-blind, randomized, parallel group study in adult male and 
female participants with newly diagnosed, uncomplicated, smear-positive, pulmonary TB. A total 
of 85 participants met study eligibility criteria and were randomly assigned to one of the six 
treatment groups. All study treatments were given once daily for 14 days. Substantial EBA activity 
was demonstrated across participants in all arms of the study and the daily reductions in cultured 
colony counts per mL of sputum are presented in Table 5 below. 
Table 5: 
Summary Statistics for EBACFU(0-14) 
Derived Using Bi-Linear Regression, Study NC-001 
Treatment Group 
N 
Daily Mean (SD)  
EBACFU(0-14) 
Pretomanid + pyrazinamide + moxifloxacin 
13 
0.23 (0.128) 
Pretomanid + pyrazinamide 
14 
0.15 (0.040) 
Pretomanid + bedaquiline  
15a 
0.11 (0.050) 
Bedaquiline alone 
14 
0.07 (0.068) 
Bedaquiline + pyrazinamide 
15 
0.13 (0.102) 
Rifafour e-275 
10 
0.14 (0.094) 
 
There were no Serious Adverse Events from the study among participants treated with 
pretomanid and bedaquiline.  Three participants in a bedaquiline-containing treatment arm were 
withdrawn: one participant on the bedaquiline only arm for a Grade 3 ALT and Gamma-Glutamyl 
Transferase (GGT) elevation (although the elevation occurred prior to the first dose of study 
medication), one on a bedaquiline plus pyrazinamide (weight banded) arm for a Grade 3 ALT 
and AST elevation, and one on a pretomanid and bedaquiline arm for to a Grade 3 ALT 
elevation. 
2.3.2.2 Clinical Study NC-003  
Efficacy 
In the 14 day EBA study NC-003 two monotherapy and four different combinations of bedaquiline, 
pretomanid, pyrazinamide and clofazimine were evaluated in DS-TB participants. Fifteen 
participants were randomized into 7 treatment arms: C, Z, B-Pa-Z-C, B-Pa-Z, B-Pa-C, B-Z-C, and 
HRZE control. This study demonstrated no EBA for the clofazimine monotherapy arm and modest 
EBA for the pyrazinamide monotherapy arm. However, all of the experimental regimens 
demonstrated EBA. In general, adding clofazimine to the various agents resulted in either no 
increase in EBA, or a decrease when compared to a similar regimen that did not include 
clofazimine. In this study, the experimental regimen with the best EBA was B-Pa-Z which 
demonstrated a rate of decrease in both logCFU and logTTP that was at least as good as the HRZE 
control. The daily logCFU results are presented in Table 6. Similar results were found when TTP 
was used to calculate the bactericidal activity over 14 days (BA(0-14)). 
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Table 6: 
NC-003 Efficacy Results: Daily BAlog CFU(0-14) 
Arm 
logCFU 
BPaZC 
.124 
BPaZ 
.180 
BPaC 
.086 
BZC 
.098 
Z 
.036 
C 
-.025 
Rifafour 
.152 
Safety 
Generally, the regimens in this study were well tolerated. Table 7 provides a list of the overall 
safety findings. The only SAE experienced in the study was in a participant in the clofazimine 
monotherapy arm. Otherwise, the rates of treatment emergent AEs (TEAEs) were similar across 
the treatment arms. One participant in the B-Pa-Z arm was withdrawn from the study due an 
adverse event of increased liver function tests (alanine aminotransferase (ALT), AST and GGT).  
Table 7: 
NC-003 Safety Data 
 
BPaZ
C 
BPaZ 
BPa
C 
BZC 
Z 
C 
HRZ
E 
Total 
N 
15 
15 
15 
15 
15 
15 
15 
105 
Participants with: 
TEAEs 
11 
9 
8 
10 
10 
9 
8 
65 
TEAEs leading to death: 
Serious TEAEs 
 
 
 
 
 
1 
 
1 
TEAES leading to early withdrawal 
 
1 
 
 
 
 
 
1 
TEAEs leading to discontinuation 
of study drug 
 
1 
 
 
 
 
 
1 
Drug-related TEAES 
8 
5 
7 
3 
5 
6 
5 
39 
Serious, drug-related TEAEs 
 
 
 
 
 
 
 
 
Grade III AEs 
 
2 
1 
2 
 
1 
 
6 
Grade IV AEs 
 
1 
1 
 
 
 
 
2 
Grade II/IV AEs 
 
2 
1 
2 
 
1 
 
6 
 
QT Prolongation 
Because bedaquiline and clofazimine are both known to prolong the QT interval, intensive ECG 
monitoring was included in the study endpoints. The mean change from baseline in QTcB and 
QTcF tended to be larger at 5 hours than at 10 hours post-dose in the (B-Pa-Z-C) arm and in the 
(B-Pa-C) arm.  No QTcB or QTcF ≥500 ms were reported.  An increase from baseline to Visit 5 
and subsequent visits of ≥60 ms in QTcB was reported for 2 participants in the (B-Pa-C) arm and 
for 1 participant in the clofazimine alone arm.  An increase from baseline to Visit 5 and subsequent 
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visits of ≥60 msec in QTcF was reported for 4 participants in the (B-Pa-C) arm and for 1 participant 
in the clofazimine alone arm.  For both QTcB and QTcF, the (B-Pa-Z-C) arm and the (B-Pa-C) 
arm showed the largest increase from baseline. Clofazimine will not be used in any treatment 
arms in the NC-007 study. 
2.3.2.3 The Nix-TB Study  
The NiX-TB Study is an ongoing open-label study assessing the safety and efficacy of bedaquiline 
plus linezolid plus pretomanid in participants with pulmonary infection of either XDR-TB or 
treatment intolerant/non-responsive MDR-TB. The study regimen includes: bedaquiline 400 mg 
once daily for 2 weeks then 200 mg 3 times per week plus pretomanid 200 mg once daily plus 
linezolid 600 mg twice daily amended (22 Jan 2016 protocol) to 1200 mg once daily. Treatment 
duration is 6 months, although if participants are still culture positive at month 4, there is the option 
to extend treatment to 9 months or withdraw. The primary endpoint is the incidence of 
bacteriologic failure or relapse or clinical failure through follow-up until 6 months after the end of 
treatment. Secondary Endpoints include: incidence of bacteriologic failure or relapse or clinical 
failure through follow-up until 24 months after the end of treatment as a confirmatory analysis, 
time to sputum culture conversion to negative status through the treatment period, and the 
proportion of participants with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 
end of treatment. In addition, linezolid dosing (actual) and efficacy will be explored and changes 
from baseline will be evaluated for TB symptoms, Patient Reported Health Status, body weight, 
and measures of safety. 
Efficacy Experience to Date:   
Sixty-nine participants have been enrolled as of February 1, 2017, at 2 sites in South Africa. Forty-
nine percent of the participants are HIV positive, 79% have XDR-TB and 21% have MDR 
intolerant or resistant to prior therapy.  Forty have completed the 6 months of therapy with the 
drug regimen and 31 have been followed to the primary endpoint at 6 months after treatment. All 
surviving patients were culture negative by 4 months, with 74% negative at 8 wks. As of February 
1, 2017, there has been 1 microbiological relapse during follow up after drug therapy and 1 
participant has had a new infection during follow-up with Drug Sensitive TB.  This study will 
continue to enrol participants until the NC-007 study is initiated. 
Safety of the B-Pa-L Regimen in the Nix-TB Study:  As of December 2016, four participants have 
died in the study. The causes of death have varied and include: 2 with multi-organ disseminated 
TB who died within the first 5 weeks of therapy, 1 who had a gastrointestinal bleed and 1 with 
multi-organ failure and disseminated TB on autopsy. No deaths or SAEs have been caused by 
hepatic injury. No participants have been withdrawn from the study except for the 4 who died.  
The expected linezolid toxicities of peripheral neuropathy and myelosuppression were common 
but manageable.  Seventy-one percent of participants had at least one linezolid dose pause (22% 
of all participants due to myelosuppression and 28% due to peripheral neuropathy), during the 6 
months of treatment. One had peak ALT and AST > 3 X ULN and total bili > 2X ULN, but these 
improved and treatment restarted without a recurrence.  There were 7 cases of grade 3 or 4 
transaminitis and all resolved and allowed the study regimen to be continued. There were no 
cases of optic neuritis. While participants have required close surveillance for signs and 
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symptoms of neuropathies and bone marrow suppression, these toxicities have been 
manageable.  
2.4 Overall Benefit/Risk Assessment 
The recent report of the long term outcome of patients with XDR-TB treated in S. Africa highlighted 
the very poor prognosis for patients with this disease.  After 60 months of follow up 73% of 107 
patients had died and only 11% had a favourable outcome(28).  These patients have infection with 
MTB resistant to many/most of the available drugs to treat tuberculosis.  Patients with XDR-TB 
have limited treatment options due to their resistance profile, and the drugs that are typically used 
in Standard of Care have many side effects, some are administered as injectables and have poor 
treatment outcomes in XDR-TB.  Similarly, patients with Pre-XDR-TB and patients with MDR-TB 
who are failing or are intolerant to treatment have traditionally poor outcomes and are a challenge 
to treat. While treatment success for MDR-TB is better than for XDR-TB, overall success in 
treating MDR-TB is still approximately 50% according to the World Health Organization 2015 
Global TB Report.(43) and it would be lower for patients failing or not able to take an optimal 
traditional regimen.  This trial provides an opportunity to treat these high-need patients with three 
active drugs, for which there is no or minimal pre-existing resistance, in a very closely controlled 
and monitored clinical trial setting with the opportunity to define the optimal dosing scheme for 
linezolid.  Participants will be monitored closely and regular reviews of safety and efficacy will be 
made by the Data Safety Monitoring Committee (DSMC).  Preliminary results of the ongoing Nix-
TB trial from patients with XDR-TB and who are failing or intolerant to treatment of MDR-TB 
demonstrate that this regimen has the potential to give relapse-free cure of XDR-TB with a simple 
regimen in a much shorter period of time than currently required by the available drugs used in 
the best standard of care.  Preclinical studies of this regimen in a murine model of infection 
demonstrated relapse free cure of MTB in half the time (3 vs 6 months) required by standard HRZ 
therapy.  Clinical studies of linezolid alone and pretomanid and bedaquiline alone and in 
combination have demonstrated activity against TB infection. 
These three drugs have not been used in combination in humans prior to the Nix-TB trial, and 
thus their combined toxicity profile is emerging.  The greatest risks of key concern for participants 
in this trial from linezolid are from the adverse events of myelosuppression and peripheral and 
optic neuropathy.  Participants will be closely monitored with full blood counts, vision 
examinations, and screening for peripheral neuropathy.  The investigator may interrupt dosing of 
either linezolid or linezolid with pretomanid and bedaquiline if adverse events of concern develop, 
and a resumption of the drugs, with linezolid at the same or at a lower dose, may be made 
cautiously.  Participants will be under close surveillance for hepatotoxicity, as that risk for 
pretomanid and bedaquiline is not yet well characterized.   
Overall the benefit-risk balance justifies evaluating the B-Pa-L regimen in this study, with the 
cautious surveillance in place, to treat patients with XDR-TB who have few options for a 
successful outcome. 
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3 
Trial Objectives  
3.1 Primary Objectives 
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus 
bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary 
XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
4 
Trial Design 
4.1 Summary of Trial Design 
This is a Phase 3, multi-center, partially-blinded, randomized clinical trial conducted in 4 treatment 
groups.  Participants, trial investigators and staff, including laboratory staff, will be blinded to dose 
and scheduled duration of linezolid.   Bedaquiline and pretomanid dosing will not be blinded. 
The trial will be performed at multiple centers located in South Africa, Eastern Europe and Russia.  
A total of 180 XDR-TB and Pre-XDR/MDR intolerant or non-responsive participants who meet all 
of the inclusion criteria and none of the exclusion criteria, aged 14 and over, will be randomized 
to receive one of the 4 active treatment arms. Participants will be randomized to one of the four 
regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will 
utilize a randomization system using stratification with a random element to allocate participants 
evenly across the arms by HIV status and type of TB after they have given written, informed 
consent and met all eligibility criteria.  
Each participant will receive 26 weeks of treatment. If participant’s sputum sample is culture 
positive between the week 16 and week 26 treatment visits and their clinical condition suggests 
they may have an ongoing TB infection, Investigator may consider extending current treatment 
to 39 weeks.   If the culture results between week 16 and week 26 are contaminated, missing or 
considered an isolated positive without clinical significance, available culture results should be 
used to make this decision. All decisions regarding treatment extension should be discussed with 
and approved by the Sponsor Medical Monitor before implementation. Participants will be 
followed for 78 weeks after end of treatment. 
 
4.2 Treatment Plan: Schedule of Assessments 
• 
Screening Period- Screening Visit up to 14 days prior to Treatment 
• 
Treatment Period- Day 1 to Week 26. Additional visits every 3 weeks until last dose when 
dosing extended due to pauses or positive culture at Week 16  
• 
Follow-up Period- 4 Week post end of treatment follow-up Visit to 78 Week post end of 
treatment follow-up Visit 
Refer to: 
• 
Trial Flow Chart (Section 1.2) for the timing of all procedures and laboratory 
samples to done at each visit.   
• 
Trial Procedures (Section 7) for details regarding specific procedures or 
laboratory tests. 
Participants will receive oral daily dosing. They will be randomized to one of the following arms: 
 
Table 8: 
Treatment Groups 
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Treatment Group 
No of Participants 
1 
Linezolid 1200 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
2 
Linezolid 1200 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
3 
Linezolid 600 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
4 
Linezolid 600 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
 
Figure 4: 
Trial Schematic 
 
26 Weeks of Treatment* 
 
Weeks 1-9 
Weeks 10-26 
1 
1200 mg Linezolid QD 
 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
Primary Endpoint 
follow-up for relapse-
free cure 26 weeks 
after end of treatment 
 
Full follow up 78 
weeks after end of 
treatment 
2 
1200 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100mg QD week 9 
Pretomanid 200 mg QD 
1200 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
3 
600 mg Linezolid QD 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
4 
600 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
600 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
Participants will be randomized to 1 of the 4 groups listed above.  
N = 45 Participants per group for a total of 180. 30 XDR-TB participants per group    
* Treatment will be extended to 39 weeks for participants who have a positive culture at week 16  
 
5 
Trial Population 
Participants must meet all inclusion and no exclusion criteria within the screening period.  Re-
testing for laboratory or ECG parameters is allowed within the 14-day screening period. Sponsor 
may consider replacement of late screen failure and un-assessable (as detailed in the statistical 
analysis plan) participants. 
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5.1 Inclusion Criteria 
Participants are required to meet all of the following inclusion criteria during the screening period 
in order to be randomized. 
1. Provide written, informed consent prior to all trial-related procedures (including any 
additional consent required for participants considered as minors per applicable regulatory 
authority or ethics committee). 
2. Willingness and ability to attend scheduled follow-up visits and undergo study 
assessments. 
3. HIV testing (if an HIV test was performed within 1 month prior to screening, it should not 
be repeated as long as a documented  result can be provided [ELISA and/or Western Blot 
and/or Electro-Chemiluminescence].  If HIV status is a confirmed known positive, repeated 
HIV test is not needed if ELISA and/or Western Blot and/or Electro-Chemiluminescence 
documentation of presence of HIV infection is available. 
4. Male or female, aged 14 years or older.  
 
Disease Characteristics: 
 
5. Participants with one of the following pulmonary TB conditions: 
a. 
 XDR-TB with  
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
documented resistance to rifamycins, a fluoroquinolone AND an injectable 
during the current TB diagnosis/disease course any time prior to or during 
screening period (may be sensitive or resistant to isoniazid);  
b. 
Pre-XDR-TB with 
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based molecular test within 3 months prior to or at 
screening and; 
ii. 
documented resistance to rifamycins, and to a fluoroquinolone OR an 
injectable during the current TB diagnosis/disease course any time prior to 
or during screening period (may be sensitive or resistant to isoniazid); 
c. 
MDR-TB with 
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected results within 3 months prior to screening or 
MTB confirmed in sputum based on molecular test within 3 months prior to 
or at screening and; 
ii. 
documented 
resistance to 
rifamycins 
during 
the 
current 
TB 
diagnosis/disease course any time prior to or during screening period (may 
be sensitive or resistant to isoniazid) and; 
iii. 
with documented non-response to treatment with the best available regimen 
for 6 months or more prior to enrolment who in the opinion of the Investigator 
have been adherent to treatment and will be adherent to study regimen.   
d. 
MDR-TB with  
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected within 3 months prior to screening or MTB 
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confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
documented 
resistance to 
rifamycins 
during 
the 
current 
TB 
diagnosis/disease course any time prior to or during screening period (may 
be sensitive or resistant to isoniazid) and; 
iii. 
who are unable to continue second line drug regimen due to a documented 
intolerance to: 
a. PAS, ethionamide, aminoglycosides or fluoroquinolones or ; 
b. Current treatment not listed above that renders participant eligible for 
the study in the Investigator’s opinion.  
6. Chest X-Ray within 6 months prior to or at screening, obtained and read locally by 
investigator or designee with results consistent with pulmonary TB in the opinion of the 
Investigator. 
 
Contraception: 
7. Be of non-childbearing potential or using effective methods of birth control, as defined 
below: 
 
Non-childbearing potential: 
a. Participant - not heterosexually active or practices sexual abstinence; or  
b. Female participant or male participant’s female sexual partner - bilateral 
oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months; 
or  
c. Male participant or female participant’s male sexual partner - vasectomised or 
has had a bilateral orchidectomy at least three months prior to screening. 
 
Effective birth control methods:                                                        
a. Double barrier method which can include a male condom, diaphragm, cervical cap, 
or female condom; or  
b. Female participant: Barrier method combined with hormone-based contraceptives 
or an intra-uterine device for the female participant; 
c. Male participant’s female sexual partner: Double barrier method or hormone based 
contraceptives or an intra-uterine device for the female partner. 
 
And are willing to continue practicing birth control methods throughout treatment and for 6 
months  (female participants) and 12 weeks (male participants) after the last dose of study 
medication. 
 
Note: Hormone based contraception alone may not be reliable when taking IMP; 
therefore, hormone-based contraceptives alone cannot be used by female participants 
to prevent pregnancy. 
 
5.2 Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria during 
the screening period: 
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Medical History and Concurrent Conditions 
1. Any condition in the Investigator’s opinion (i.e., an unstable disease such as 
uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended 
treatment, cancer that could affect survival through the protocol-specified follow up 
period), where participation in the trial would compromise the well-being of participant 
or prevent, limit or confound protocol specified assessments.  
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations.  
3. In the judgment of the Investigator, the participant is not expected to survive for more 
than 6 months. 
4. Karnofsky score < 60 at screening. 
5. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal 
Products or related substances. 
6. Body mass index (BMI) < 17 kg/m2 
7. TB infection with historic DST or MIC results with values suggesting likely resistance 
to pretomanid, delamanid, linezolid or bedaquiline; the Sponsor Medical Monitor must 
be consulted to help interpret any available historic results. 
8. Participants who, upon the evaluation of their pulmonary disease, are expected to 
require a surgical procedure. 
9. Having participated in other clinical studies with dosing of investigational agents within 
8 weeks prior to screening or currently enrolled in an investigational study that includes 
treatment with medicinal agents.  Participants who are participating in observational 
studies or who are in a follow up period of a trial that included drug therapy may be 
considered for inclusion. 
10. Participants with any of the following at Screening: 
• 
QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be 
discussed with and approved by the Sponsor Medical Monitor before enrolment. 
(Per measurements and reading done from screening central ECG.) 
• 
Heart failure 
• 
A personal or family history of congenital QT prolongation 
• 
A history of or known, untreated, ongoing hypothyroidism 
• 
A history of or ongoing bradyarrhythmia 
• 
A history of Torsade de Pointe 
11. Females who have a positive pregnancy test at Screening or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the study or within 6 
months of cessation of treatment.  Males planning to conceive a child during the study 
or within 6 months of cessation of treatment. 
12. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, 
participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the 
course of the study, in the opinion of the Investigator. 
 
Previous and Concomitant Therapy 
13. Known (during screening) requirement for future Concomitant (during treatment) use 
of any prohibited and/or avoided medications noted in section 5.3. 
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14. Prior use of Monoamine Oxidase Inhibitors (MAOIs) within 2 weeks of randomization.  
15. Prior use of serotonergic antidepressants within 3 days of randomization if Investigator 
foresees potential risks for serotonin syndrome when combined with linezolid.  
16. Participants who have received more than 2 weeks of bedaquiline, linezolid or 
delamanid prior to first dose of IMP. 
17. Participants with newly diagnosed tuberculosis and HIV that require initiation of 
appropriate HIV therapy before participant has received at least 2 weeks of an anti-
tuberculosis regimen.  
18. HIV infected participants with planned continued use of zidovudine, stavudine or 
didanosine. The antiretroviral therapy (ART) booster cobicistat should not be used. 
Please reference restrictions Section 5.3.3 Antiretroviral Therapy, for guidance on 
ART treatment during the treatment period.  
 
Diagnostic and Laboratory Abnormalities 
 
19. Participants with any of the following toxicities at Screening (labs may be repeated 
during screening period) as defined by the enhanced Division of Microbiology and 
Infectious Disease (DMID) adult toxicity table (November 2007): 
 
a. Viral load >1000 copies/mL (Unless newly diagnosed HIV and not yet on ART who 
otherwise qualify for participation); 
b. CD4+ count < 100 cells/µL (HIV positive participants); 
c. Serum potassium less than the lower limit of normal for the laboratory; 
d. Hemoglobin < 9.0 g/dL or < 90 g/L; 
e. Platelets <100,000/mm3 or < 100 x 10^9/L; 
f. Absolute neutrophil count (ANC) < 1500/ mm3 or < 1.5 x 10^9/L; 
g. Aspartate aminotransferase (AST)  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor Medical Monitor 
h. Alanine aminotransferase  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor medical monitor; 
i. Total bilirubin 
• 
greater than 1.5 x ULN to be excluded; 
• 
1-1.5 x ULN must be discussed with and approved by the Sponsor Medical 
Monitor  
j. Direct bilirubin 
• 
Greater than ULN to be excluded 
k. Serum creatinine level greater than 1.5 times upper limit of normal 
l. Albumin <3.0 g/dl or < 30 g/L  
 
All inclusion and no exclusion criteria must be met.  If no single variable/value is outside of the 
ranges of acceptability, but when multiple values are close to the limits and/or whenever the 
Investigator has reason to suspect that there might be a health problem (other than TB), enrolment 
should only be considered after discussing the case with the Sponsor Medical Monitor. 
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No protocol waivers will be granted by the TB Alliance. 
 
5.3 Restrictions 
5.3.1 Prior and Concomitant Medications and Other Treatments 
Concomitant medications should be kept to a minimum during the treatment period of the trial.  
However, if concomitant medications are necessary for the participant’s welfare and are unlikely 
to interfere with the IMP, they may be given at the discretion of the Investigator.  For any 
concomitant medications given as a treatment for a new condition or a worsening of an existing 
condition occurring after signing of the Informed Consent Form, the condition must be 
documented on the Adverse Event pages of the electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be consulted and reviewed 
carefully.  The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected to prevent any potentially serious and/or life-threatening drug 
interactions. 
The following concomitant medications are prohibited during the treatment period and during the 
14 days after treatment completion: 
• 
Medicinal products used to treat pulmonary TB:  including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and metronidazole. 
• 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). (e.g., phenelzine, 
isocarboxazid) 
The following concomitant medications should be avoided during the treatment period and during 
the 14 days after treatment completion to avoid possible drug interactions with the IMP. Use of 
any of the following must be discussed and approved by the Sponsor Medical Monitor prior to 
use: 
• 
Concomitant use of any drug known to prolong QTc interval (including but not limited to 
amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, 
clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, 
pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).  
• 
Treatment with fluoroquinolones (as they are known prolong QTc), are strongly 
discouraged in the trial. They should only be used to treat intercurrent non-TB infections 
and if the benefit of treatment outweighs the risk of prolonged QTc.   
• 
Concomitant use of any drug known to induce significant myelosuppression 
• 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: ketoconazole, 
voriconazole, itraconazole, fluconazole; ketolids such as telithromycin; and macrolide 
antibiotics other than azithromycin) for more than 3 consecutive days; 
• 
The systemic use of CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, 
St. John’s wort, rifamycins and systemic dexamethasone.  
• 
Concomitant use of serotonergic antidepressants should be avoided if possible as 
participants on these agents and linezolid are at risk for serotonin syndrome.  
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• 
Caution should be used in treating diabetic patients receiving insulin or oral hypoglycemic 
agents as cases have been reported of hypoglycemic reactions when patients on these 
agents have been treated with linezolid. 
The following concomitant medications which are known to be hepatotoxic should be avoided as 
much as possible during screening and throughout the treatment period.  If there are concerns 
about the co-administration of  hepatoxic drugs, discussion with the Sponsor Medical Monitor is 
encouraged (including but not limited to acetaminophen/paracetamol,  acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, augmentin/co-
amoxiclav, azathioprine, baclofen, bumetanide, captopril, carbamazepine, celecoxib, 
chlorpromazine, chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-trimoxazole, 
darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, fosamprenavir, 
furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, 
loperamide, losartan, methotrexate, metolazone, mirtazepine, nitrofurantoin, omeprazole, other 
non-steroidal anti-inflammatory drugs, paroxetine, phenobarbital, phenothiazines, phenytoin, 
pravastatin, probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, simeprevir, 
simvastatin, sodium valproate, sotalol, sulfasalazine, sumatriptan, tamsulosin, terbinafine, 
tetracycline, theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, topiramate, trazodone, 
tricyclic antidepressants, trimethoprim, verapamil). 
5.3.2 Recommendations for Concomitant use of Anti-Malarials 
The following treatments for malaria are recommended for concomitant use with the IMP, should 
it be necessary: 
• 
Proguanil/atovaquone or  
• 
Artesunate plus sulfadoxine-pyrimethamine  
 
These recommendations are based on the potential for QT prolongation by bedaquiline and many 
anti-malarials. Due to the extended half-life of bedaquiline commencing anti-malarial treatment 
containing drugs that could prolong the QT interval, shortly after discontinuing bedaquiline, is not 
recommended. 
5.3.3 Antiretroviral Therapy 
For HIV infected participants, to avoid potentiating known key toxicities of linezolid (neuropathy 
and myelosuppression), the following antiretroviral therapies should not be used during the 
treatment period: zidovudine, stavudine, didanosine.  
The ART booster cobicistat should not be used. 
Only the following types of antiretroviral therapy (ART) are permissible during administration of 
regimens: 
• 
Nevirapine based regimen consisting of NVP in combination with any two NRTIs TDF/ABC 
and FTC/3TC.  
• 
Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any 
two NRTIs TDF/ABC and FTC/3TC. 
• 
Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC. 
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• 
In patients who have viral load suppressed on efavirenz at the time of screening, their 
ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. If possible, 
the same nucleoside backbone should be used. 
 
The investigator must assess the risks and benefits of these antiretroviral regimens in the 
context of co-infection with TB acknowledging the following caveats: 
• 
Triple NRTI is generally not considered optimal chronic ART; 
• 
Nevirapine based regimens are associated with higher ART failure in participants having 
or known to have previously had a viral load more than or equal to 100,000/ mL. 
5.3.4 Other Restrictions 
Large quantities of foods or beverages with high tyramine content should be avoided while taking 
linezolid.  Quantities of tyramine consumed should be less than 100mg per meal. Foods high in 
tyramine content include those that may have undergone protein changes by aging, fermentation, 
pickling, or smoking to improve flavour, such as aged cheeses (0 to 15 mg tyramine per ounce); 
fermented or air-dried meats (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 
ounces); soy sauce (5mg tyramine per 1 teaspoon). The tyramine content of any protein-rich food 
may be increased if stored for long periods or improperly refrigerated. 
Alcohol should be avoided while on IMP, especially in participants with impaired hepatic function. 
5.4 Trial Discontinuation and Visits 
5.4.1 Treatment Discontinuation and Early Withdrawal 
A participant must be withdrawn from the trial due to the following;  
• 
Pregnancy (unless female post visit for end of treatment/early withdrawal from treatment); 
• 
Investigator considers it for safety reasons in the best interest of the participant that he/she 
be discontinued, including a concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB treatment.  
• 
At the specific request of the Sponsor or termination of the trial by Sponsor; 
• 
Lost to follow-up 
• 
In the opinion of the investigator, fails to comply with the protocol, including non-
compliance to IMP. 
Participants may be withdrawn from the trial based on the following. The specific situation should 
be discussed with the Medical Monitor before withdrawing the patient. 
o Myco testing results from baseline (Screening through Week 4) indicate sensitivity  
to rifamycins; 
o Myco testing results from baseline (Screening through Week 4) with MICs that 
indicate likely resistance to bedaquiline, pretomanid or linezolid; 
All participants who discontinue trial treatment (but have not withdrawn consent) and received at 
least one dose of IMP will be requested to return for an early withdrawal visit and applicable safety 
Follow Up visits, as per flow chart (Section 1.2). 
A participant may discontinue from the trial at any time at his/her request (withdrawal of 
consent) or may be withdrawn at any time at the discretion of the investigator for safety, 
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behavioral compliance or administrative issues. When a participant withdraws consent from the 
trial, no additional follow-up visits will be performed.  
5.4.2 Early Withdrawal Follow-up 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made to 
complete the Early Withdrawal assessments.   
Once a participant has been withdrawn early from the trial, they will be requested to attend follow-
up visits as described in Table 9: 
Table 9: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EW visit 
Ophthalmology 
Examination at 
EWa 
Ophthalmology 
Examination  
 
12 week Post 
treatment follow-
up visita 
26 Week  
Post 
Treatment  
Follow-up 
Visit 
78 Week Post 
Treatment 
Follow-up 
Visit 
≤ 14 days 
NA 
NA 
NA 
NA 
15 days to      
≤ 12 weeks 
NA 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if not 
already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 12 weeks after the 
EWD visit date. 
The 26 and 78 week post treatment follow-up visits will be performed to collect SAE information 
(including verification of survival) and participant reported TB outcome information.  This visit may 
be telephonic, a home or a site visit.  
5.4.3 Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures, should be considered unscheduled regardless of the reason for the visit. The 
assessments which are undertaken as part of an Unscheduled visit should be as clinically 
indicated.  
The following situation/s require an unscheduled visit/s: 
• 
If cultures of both spot sputum samples are contaminated at the following visits, or if 
necessary, in order to help define a participant’s outcome status/assess culture status 
during follow-up, the participant should return for an unscheduled visit(s) to give additional 
samples or to document the participant is not able to produce sputum: 
  
• 
End of treatment visit 
• 
Week 26 post treatment follow-up visit 
• 
Post treatment follow-up visits from week 8 through week 65 (in addition to week 26 
follow-up) 
• 
End of Follow-up Period (week 78 post treatment completion visit) 
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• 
Early Withdrawal (if applicable). 
 
• 
At the end of 26 weeks and 78 weeks post treatment completion, to define outcome status, 
and to determine whether the participant has: 
• 
At least two sequential negative sputum culture results; or  
• 
At least two sequential positive sputum culture results; or  
• 
Has been unable to produce sputum after documentation of at least two negative 
sputum cultures with no intervening positive and are clinically asymptomatic. 
 
If they do not fall into one of the above categories, site should continue to collect sputum samples 
x 2 (one early morning and one spot at the research site or 2 spots samples at least 30 minutes 
apart, under the coaching and observation of the trial staff) at a minimum of 7 days or more apart 
until they fall into one of the above categories. 
 
5.4.4 Lost to Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants.  A 
minimum of three contact attempts (telephonic/home visit) will be made for participants who do 
not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant will be 
considered LTFU.  All attempts to contact the participant must be clearly documented in the 
participant’s source documents. 
5.4.5 Early Withdrawal due to TB 
Ultimately it is the investigator’s decision whether a participant should discontinue treatment due 
to a concern that the participant has symptomatic worsening TB and/or bacteriological 
failure/relapse.  
Discontinuation is usually not indicated by a single positive culture.  Should a participant have a 
single positive culture result after being negative, the investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether it 
is in the participant’s best interest that he/she be discontinued. Prior to discontinuation of a 
participant due to TB, the investigator must discuss the participant with the Sponsor Medical 
Monitor, unless the investigator cannot contact the Sponsor Medical Monitor and considers that 
discontinuation must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the Investigator decides to discontinue trial treatment for a participant due to TB, additional 
sputum samples may need to be collected in order to ensure the participant’s outcome status may 
be determined, details noted in trial flowchart (Section 1.2). 
All Early Withdrawal participants who are confirmed sputum positive (at least two sequential 
sputum positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to specialists who treat XDR-TB, pre-XDR TB or MDR-TB as 
applicable.  
 
 
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5.5 Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who is not randomized 
Completed 
Treatment / 
Completed FU* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued FU 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
FU** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* Note that this includes treatment failures who complete all applicable follow-up visits 
** Early Withdrawal 
5.6 Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific Investigational Site at any time, although this should 
only occur after consultation between involved parties.  Should this occur, the local and central 
Ethics Committee/Institutional review Board (EC/IRB) and Regulatory Authorities will be informed.  
Should the Trial/Investigational Site be closed prematurely, all trial materials (except 
documentation that has to remain stored at the Investigational Site) will be returned to the Sponsor 
or vendor.   The Investigator will retain all other documents until notification given by the Sponsor 
for destruction.  Participants currently on treatment will receive an appropriate regimen and all 
participants will be referred to a unit specializing in the treatment of XDR-TB, Pre-XDR-TB or 
MDR-TB as applicable. 
6 
Treatment 
6.1 IMP Administration  
 Treatment will be administered orally, once daily, with a full glass of water and a meal in the 
dosing schemes (treatment arms) outlined in Table 9. The study drug regimen should be 
initiated as specified below regardless of whether participant has received any of the allowed 
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prior exposure of bedaquiline or linezolid (up to 14 days), including a loading dose of 
bedaquiline. The Pharmacy Manual should be referenced for further details. 
Table 10: 
 Investigational Medicinal Product Details  
Treatment Group 
Active and Placebo 
Linezolid 1200 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 2 linezolid 600 mg active tablets once daily for 26 weeks 
• 1/2 (one half) placebo linezolid tablet once daily for 26 weeks  
Linezolid 1200 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9  
• 2 linezolid 600 mg active tablets once daily for 9 weeks  
• ½ (one half) placebo linezolid  tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid tablets once daily for 17 weeks 
• ½ (one half) placebo linezolid tablet once daily for 17 weeks 
Linezolid 600 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 1 linezolid 600 mg active tablet once daily for 26 weeks 
• 1 placebo linezolid tablet once daily for 26 weeks  
• ½ (one half) placebo linezolid tablet once daily for 26 weeks 
Linezolid 600 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9 
• 1 linezolid 600 mg active tablet once daily for 9 weeks 
• 1 placebo linezolid tablet for 9 weeks 
• ½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolidtablets once daily for 17 weeks 
• ½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
6.2 Participant Compliance 
During site clinic visits or hospitalization, the IMP will be administered by the 
Investigator/designated site personnel. During the study, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully trained on how IMP is to be taken. When 
possible, participants will be checked for IMP compliance by the Investigators or trial 
personnel/National TB Treatment Program personnel via the hand-and-mouth procedure (both 
the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP).  Additionally, participant cards/bottles will be checked for unused tablets at 
each visit during the treatment period  
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6.3 Treatment Modification(s) 
All treatment modifications should be discussed with the Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required urgently for a safety concern; the 
Medical Monitor should be informed within 24 hours of the change if not discussed prior to 
implementation.  
In the event of linezolid specific toxicities, the following should be considered and implemented 
per guidance in the monitoring and safety for specific toxicities section of protocol (8.3): 
• 
Blinded one step reductions (maximum 2 steps) in the dose of linezolid managed by the 
IXRS as per instructions in pharmacy manual and/or IXRS user manual 
o 1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or;  
o 600 mg QD to 300 mg QD, 300mg QD to placebo).  
• 
Temporary pause of linezolid  
• 
Permanent discontinuation of linezolid. 
• 
Participants who have a linezolid reduction can go back to a higher dose (1 step or 2 
steps) post discussion with and approval by the Sponsor Medical Monitor. 
Participants experiencing suspected drug related toxicities due to other drugs in the regimen (B-
Pa), the full regimen may be halted for up to 35 consecutive days.  
Interruptions/pauses of the full regimen must not exceed 8 weeks (56 days) cumulatively.   
If participant’s sample is culture positive between the week 16 and week 26 treatment visits and 
their clinical condition suggests they may have an ongoing TB infection, Investigator may consider 
the option to extend  the treatment to which the participant is randomized to 39 weeks. If the 
culture results between week 16 and week 26 are contaminated, missing or considered an 
isolated positive without clinical significance, available culture results should be used to make this 
decision. All decisions regarding treatment extension should be discussed with and approved by 
the Sponsor Medical Monitor before implementation.  
When treatment extended to 39 weeks, pauses of the full regimen must not exceed 13 weeks (91 
days) cumulatively. 
When the total of missed dosing days of the prescribed regimen and/or pauses is greater than 7 
days, the same number of missed doses should be dispensed/treatment extended to make up for 
the total missed doses. 
At no time should the participant be treated with a single agent. 
Every effort should be made for participants to receive a total of at least 9 weeks of linezolid, even 
if pauses are required. 
6.4 IMP Packaging and Labelling 
The complete formulations of the IMP bedaquiline and pretomanid are found in the respective 
Investigator Brochures(5,6). The complete formulations of linezolid are found in the Package 
Inserts(23,24,26).  
The IMP will be packaged as follows: 
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• 
Bedaquiline: Bottles containing: 
o 200 mg QD dose- 28 tablets- bedaquiline 100 mg 
o 100mg QD dose- 14 tablets- bedaquiline 100 mg  
• 
Pretomanid: Blister card containing 14 tablets- pretomanid 200 mg  
• 
Linezolid: Blister Card containing 7 days of dosing as follows: 
o 1200 mg QD Dose  
 
2 blister strips of 7 tablets each (14 tablets) containing active linezolid 600 
mg   
 
1 blister strip of 7 half tablets containing placebo linezolid  
o 600 mg QD Dose:  
 
1 blister strip of 7 tablets containing active linezolid 600 mg   
 
1 blister strip of 7 tablets containing placebo linezolid  
 
1 blister strip of 7 half tablets containing placebo linezolid  
o 300 mg Dose (for reductions):  
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid  
 
1 blister strip of 7 half tablets containing active linezolid 300 mg  
o Placebo Linezolid Dose:  
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid  
 
1 blister strip of 7 half tablets containing placebo linezolid  
 
The packaging of each bottle/blister card will be labelled with, at a minimum, the following 
information: 
• 
Name of Sponsor. 
• 
Name of medication. 
• 
Dosage, quantity and method of administration for bedaquiline and 
pretomanid. 
• 
Potential dosage, quantity and method of administration for linezolid. 
• 
Reference/Lot Number. 
• 
The statement “For Clinical Trial Use Only”. 
• 
Space for completion of Name of Investigator and Site Number. 
• 
MedID: medication identification number  
• 
Storage conditions. 
• 
Period of Use. 
• 
The statement “Keep out of reach of children”. 
• 
Expiry Date. 
• 
Directions for use. 
• 
Space for completion of participant number and visit/date dispensed. 
6.5 Method of Treatment Assignment 
Participants will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
web/voice response system (IXRS) which will utilize a randomization system using stratification 
with a random element to allocate participants evenly across the arms by HIV status and type of 
TB.  Information & directions will be provided to each site via the IXRS user manual. 
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6.6 Blinding and Procedures for Breaking the Blind 
The blind for a participant must not be broken by the site or sponsor except in the case of a 
medical emergency, where treatment of a participant is influenced by the knowledge of what dose 
and duration of linezolid the participant is receiving. The investigator should discuss breaking the 
blind with the Sponsor Medical Monitor (or designee) prior to breaking the blind unless knowledge 
of treatment arm is required urgently for a safety concern. The Sponsor Medical Monitor should 
be informed of the blind break within 24 hours if not discussed prior. IXRS will be programmed 
with blind-breaking instructions, described in the user manual. The Sponsor reserves the right to 
break the blind to fulfil any regulatory requirements regarding reporting of SAEs. If a participant 
is unblinded, they are not required to be withdrawn from the study.  
There will be three unblinded analyses which will contain results by linezolid treatment group in 
aggregate (see section 9.3). The first analysis will be after all participants have completed 26 
weeks of treatment and here sites, participants, and Sponsor staff will not be unblinded to 
individual linezolid treatment information. A limited number of statisticians will have access to 
individual linezolid treatment assignments.  
The blind for all individual participants will be broken for the primary endpoint analysis (the second 
unblinded analysis) once all clinical data and outcome parameters have been captured, no more 
data queries are pending, and the statistical analysis plan has been finalized. The third analysis 
will occur when all participants have completed 78 weeks of follow-up after end of treatment.   
 
6.7 Handling, Storage and Accountability  
The investigator or designee must confirm appropriate temperature conditions as per details on 
IMP labelling, have been maintained during transit for all trial treatment received and any 
discrepancies are reported and resolved before use of the trial treatment. 
Only participants enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Upon completion or termination of the trial, all unused 
and/or partially used IMPs must either be returned to Sponsor (or designated vendor) who will 
arrange for destruction or destroyed at site as agreed by Sponsor after final accountability has 
been confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising with 
respect to the trial medication. The Sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
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7 
Trial Variables and Procedures 
The trial flowchart in Section (1.2) should be referenced for timing and sequence of 
assessments. 
7.1 Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written informed consent. 
• 
Visit dates 
• 
Participant disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and treatment history (including past and current TB 
diagnosis, alcohol use and smoking) 
• 
Screening coached spot sputum samples: 
o Smear microscopy for acid-fast bacilli. 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB 
complex and rifamycin resistance. 
• 
Urine pregnancy test: women of child-bearing potential only, whether they are 
sexually active or not. 
• 
Serology: HIV,CD4 count and viral load.  
o If an HIV test was performed within 1 month prior to trial start, it should not be 
repeated as long as documentation of results can be provided (ELISA and/or 
Western Blot and/or Electro-Chemiluminescence). 
o Where required by regulatory authorities or ethics committees: 
 
Separate approval for this to be performed will be obtained from 
participants in the written informed consent process.  
o prior to HIV testing and on receipt of the results, participants will be 
counselled on HIV by trained counsellors if they have indicated as such on 
the HIV consent form. If requested by the participant, HIV counselling 
provided to the participant by the study site should be clearly documented in 
the participant’s medical records/source.  Participants have the right to 
decline to know or receive their HIV test results. This decision should be 
clearly documented in the participant’s medical records/source.   
• 
Karnofsky score (Appendix 4). 
• 
Chest X-Ray: A Chest X-Ray digital image will be obtained and read locally by the 
Investigator or designee.  Digital images will be provided to the Sponsor; this process 
will be documented in the Radiology Manual.  The Investigator is responsible for 
review and analysis for participant inclusion. 
• 
Method of birth control: male and female participants and their partners. 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
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7.2 Efficacy Variables and Procedures 
Two spot sputum samples are collected, one early morning brought from home or collected in the 
hospital ward and one spot collected at the research site under the coaching and observation of 
the trial staff or, if no early morning sample was provided, 2 samples collected on site at least 30 
minutes apart. The Mycobacteriology sampling methodology and requirements will be described 
in a separate document, the Laboratory Manual, which will be provided prior to the trial start.  
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the time to 
positivity (TTP) followed by a speciation test when applicable, to confirm MTB. 
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse; 
• 
Time to Sputum Culture Conversion; 
• 
Number of participants with Sputum Culture Conversion. 
Every effort is to be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favorable) result.  A participant 
who never achieves culture negative status due to inability to produce sputum, but has completed 
26 week /78 week post treatment completion follow-up and is without clinical or biological 
evidence of relapse, will be considered to have a favorable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (found in the Subject Questionnaires Guideline) will record 
participants’ ratings of the severity of common TB symptoms.  
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the trial flow chart. Patient Reported Health Status will be collected using the EQ-5D-5L 
Health Questionnaire (found in the Subject Questionnaires Guideline). This descriptive 
system consists of five health-related quality of life dimensions, each of which will be 
recorded using five levels of severity. Methodology: The Patient Reported Health Status 
methodology and requirements will be described in a separate document/guideline which 
will be provided prior to the trial start. 
 
7.3 Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
trial flow chart and assessed for evaluation of the safety endpoints: 
• 
Laboratory parameters. The Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, which will be provided prior to 
the trial start. The following analyses will be performed: 
o Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential, platelet count),  
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o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, 
calcium (corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, 
creatine phosphokinase (CPK).                  
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis.  
• 
12-lead Electrocardiogram (ECG): 
o Investigator assessment: normal, abnormal. 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected 
QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all 
participants and will be described in a separate document which will be 
provided prior to the trial start; 
 
Participants should be lying down (recumbent) for at least 5 minutes prior 
to each 12-lead ECG evaluation; 
 
ECGs are to be recorded for 10 seconds; 
 
All ECGs are to be performed in single. 
 
ECGs should be done before any labs when both included in a visit) 
 
For each participant, the ECGs should, to every extent possible, be 
collected at approximately the same time of day (+/- 1 hours) and in the 
same fed/fast state throughout the trial (e.g. 4 hours after lunch). 
• 
Vital signs: 
o Vital Signs, including weight (should be done before any labs) 
o Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 minutes of 
rest) using an appropriately sized cuff, and using the same type of sphygmomanometer, 
if possible by the same observer, at each relevant visit. 
o Heart rate (bpm). 
o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C). 
• 
Physical examination:  
o Height is measured at screening only. 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and abdominal) 
examinations will be performed and any clinically significant findings will be recorded.   
o Weight (kg) (in light clothing and with no shoes).  
o Using the observed variables weight and height, calculated body mass index (BMI) will be 
derived. 
• 
Ophthalmology slit lamp examination. To be done by an Ophthalmologist trained on AREDS2 
assessment. The ophthalmology slit lamp methodology and requirements will be described in 
a separate document, the Ophthalmology Guideline. The following analyses will be 
performed: AREDS2 opacity typing and grading. 
• 
Ophthalmic examination. The ophthalmic examinations can be performed by any trained study 
staff. The screening exams must be done by the trained site study staff AND an 
Ophthalmologist.  Methodology and requirements will be detailed in the Ophthalmology 
Guideline. 
• 
Ophthalmology History (Screening only); 
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• 
Visual Acuity Test – Corrected. Distance Vision; 
• 
Color Vision Assessment. 
• 
Adverse events. 
• 
Brief peripheral neuropathy screen (found in the Subject Questionnaires Guideline) will record 
ratings. 
• 
Investigator assessment:  
Principal Investigator to review participant status at specified visits in flow chart including any 
time Investigator determines that participant fulfills criteria for primary outcome of treatment 
failure. Investigator to assess whether TB treatment is considered a “success” or “failure”.  If 
considered a failure, should specify if based on bacteriology and/or clinical deterioration 
and/or radiological deterioration. 
7.4 PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Synopsis Flowchart 1.2) will be used to update 
population PK models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this trial population.  PK data from the 
current trial may be combined with prior data (e.g., from the NiX-TB trial) to enhance this 
population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T >MIC) for subsequent analyses exploring relationships between 
drug exposure and efficacy and safety endpoints.   
 
7.5 Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between Screening through Week 4; 
• 
If consent granted, and when applicable, Pre-screening culture/isolate to be sub cultured 
and shipped and/or tested: 
o At the study lab if/when samples could support inclusion in the trial 
o To the study/central lab for relevant participants/with no baseline (positive cultures 
from screening through Week 4)  
• 
When applicable, 1st positive for MTB at/after week 16 for participant not responding to 
therapy and/or 1st positive during follow-up for potential new infection. 
 
The MTB isolates will be processed at the central lab(s) for: 
• 
MIC against bedaquiline, pretomanid and linezolid;   
• 
Drug Susceptibility Testing in liquid culture for rifampicin, isoniazid, streptomycin, 
ethambutol, pyrazinamide and second line TB drugs including but not limited to 
fluoroquinolones, and injectables; 
• 
Genotyping. 
 
The MTB isolates will be processed at the central lab(s) for: Positive MTB at/after end of 
treatment: Hain MTBDRplus and HainMTBRsl 
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8 
Adverse Events 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; In general, 
hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event. 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalization, 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.   A “suspected 
transmission of infectious agent by a medicinal product” is also considered a serious adverse 
event under the SAE criterion “Other medically important condition”.   
8.1.3 Attribution/Causality 
• 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. 
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• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration will 
be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor/designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
Table 11: 
Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive.  The relationship in time is reasonable; 
therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event, which might be due to the use of the drug.  The 
relationship in time is suggestive, e.g., confirmed by dechallenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).   
 
8.1.4 Severity 
Table 12: 
Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
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Grade 
Severity Rating 
Definition 
GRADE 4 
Potentially Life-
Threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected from the signing of the ICF until the 78-week post treatment follow-up 
visit at the time points specified in the Flowchart (Section 1.2) and recorded in the case report 
from (CRF). The exception is early withdrawal participants who will only have SAEs collected from 
the time of their early withdrawal through the 78-week post treatment visit. 
Medical occurrences that begin after obtaining informed consent will be recorded as adverse 
events. If an adverse event started before signing of the informed consent, but is ongoing at trial 
start, it should be recorded as medical history.  If the pre-existing medical occurrence worsens 
during the trial, and adverse event will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the investigator.  
The Sponsor/investigator/designee will inform Regulatory Authorities and/or IEC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the IEC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in participants who have 
completed the trial. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the trial, and he/she considers the event to be 
reasonably related to the trial treatment or trial participation, the investigator must promptly notify 
the Sponsor, IEC/IRB and regulatory authorities on an expedited basis in accordance with local 
requirements and ICH guidelines for GCP. 
8.2.1 Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
Until the end of the follow-up period; and  
• 
Until all queries on these AEs have been resolved.   
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Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the treating physician.  If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor Medical Monitor. 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  Investigator should contact Sponsor/designee to discuss 
appropriate medical follow-up if consultation required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide Sponsor/representative with a copy of any post-mortem findings including 
histopathology. 
New or updated information on an SAE will be recorded in the originally completed CRF and 
submitted to Sponsor within 24 hours of the information becoming known per SAE reporting 
guidelines. 
8.2.2 Clinical Laboratory Adverse Events 
Changes in the results of the Clinical Laboratory assessment results which the Investigator feels 
are clinically significant will be reported as adverse events.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an adverse event. 
8.2.3 Disease under Study 
Symptoms of the disease under trial (Pulmonary Tuberculosis) experienced by the participant 
while on the trial will be assessed by the Investigator.  If the symptom has: 
• 
worsened while the participant is in the trial; and 
• 
the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event.  
If there is: 
• 
no change; and  
 
• 
the Investigator assesses the symptom as due to the participant’s TB; and  
• 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation.  
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
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8.2.4 Overdose 
Overdose of IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an Adverse Event, including if the taking of 
the suspect medicine led to suicidal intention and subsequent overdose of the suspect medicine, 
or other medication. In this case it will be recorded as an adverse event. If it does not lead to an 
Adverse Event, it will not be recorded as an AE and this will be noted in the participant’s source 
documentation. 
8.2.5 Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
Investigator will report to the Sponsor follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed for 6 months.   
All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following time-
periods: 
• 
During the trial 
• 
Within 6 months after last dose of IMP 
If pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow up will be performed 
unless contraindicated by the pregnancy. 
Pregnancy reporting will follow the same time lines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in preclinical toxicity 
studies Investigator’s Brochures(5,6) and Package Inserts.(23,24,25,26) Please reference section 6.3 
Treatment Modifications, which notes that all treatment modifications should be discussed with 
Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required 
urgently for a safety concern.  The Medical Monitor should be informed within 24 hours of the 
change if not discussed prior to implementation.   
AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization or until the end of the follow-up period and until all queries on these AEs 
have been resolved.  Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization. 
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
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these cases follow-up will be the responsibility of the treating physician. If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor Medical Monitor.  
 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours where possible. The recommendations for managing participants 
below assumes the laboratory abnormalities of concern have been confirmed. 
8.3.1 Neurological 
Participants with co-administration of a serotonergic agent, including anti-depressants, should be 
monitored closely for signs of serotonin syndrome.  The Investigator should determine whether 
the full regimen or the concomitant agent should be discontinued for those who experience signs 
or symptoms of serotonin syndrome such as cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
Linezolid and/or the full regimen should be paused for participants experiencing a seizure. The 
Sponsor Medical Monitor should be contacted to review details and discuss whether linezolid or 
full regimen should be resumed.  
8.3.2 ALT, AST and Alkaline Phosphatase elevations: 
The Investigator should refer to Appendix 5 – Liver Toxicity Management and to the ZeNix 
Hepatotoxicity Management Guideline to appropriately manage the participant for clinically 
significant elevations of AST, ALT or Alkaline Phosphatase. 
8.3.3 Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
Contact Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 4 elevations 
of lipase, Investigator should consider pausing the full regimen, pending further evaluation. 
8.3.4 Musculoskeletal System and Cardiac Muscle 
Myalgia 
Grade 2 (muscle tenderness at site other than sites of injection and/or venipuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
Participants with Grade 2 signs and symptoms should be followed closely. Participants with Grade 
3 or 4 signs and symptoms should be discussed with the Sponsor Medical Monitor to consider 
pausing trial medication, pending further evaluation. 
CPK 
For participants having elevations in CPK of potential clinical concern, the Investigator should 
check the CK-MB subunit, if high, consider pausing regimen and discuss with Sponsor Medical 
Monitor.  
8.3.5 Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
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Participants should be monitored closely.  The Investigator should discuss with the Sponsor 
Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artifacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen. 
8.3.6 Monitoring Linezolid Toxicities 
The following are guidelines for decisions to pause, reduce and to resume linezolid in response 
to the onset and resolution of known linezolid-specific toxicities.  These are guidelines, and 
decisions must be made in the context of the entire clinical status of the participant.  While the 
investigator may need to urgently interrupt dosing for potentially life threatening symptoms or 
laboratory findings, the Medical Monitor should be contacted and informed of any changes in 
dose within 24 hours.  Questions should be raised to the Sponsor’s Medical Monitor if the 
decision is not clear. 
8.3.6.1 Myelosuppression 
The hematologic parameters of hemoglobin and counts of Neutrophils and platelets are variable 
from measurement to measurement.  While decreases in any of these may be caused by linezolid 
toxicity, decreases of concern should be evaluated in the context of the participant’s full clinical 
status and alternate explanations.  Guidelines below are for situations of concern when it is 
considered likely that linezolid has caused the decrease. 
Anemia 
• 
Consider pausing linezolid if hemoglobin falls below 8 gm/dL or 80g/L (Grade 3) and 
significantly below baseline, or if hemoglobin falls > 25% of baseline. If it is clear that the 
anemia was caused by linezolid, consider resuming linezolid at half the dose when 
hemoglobin improves and linezolid is resumed.  
Leukopenia 
• 
Consider pausing linezolid if the Absolute Neutrophil Count (ANC) falls below 750/mm3  
or 0.75 x 10^9/L (Grade 3) and significantly below baseline.  Ideally confirm with a repeat 
test before making further decisions as ANCs can have diurnal and other variability. If it is 
clear that the leukopenia was caused by linezolid, consider resuming linezolid at half the 
dose when ANC improves and linezolid is resumed.  
Thrombocytopenia 
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• 
Consider pausing linezolid if platelets fall below 50,000/mm3 or 50 x 10^9/L (Grade 3) and 
significantly below baseline. Ideally confirm with a repeat test before making further 
decisions.  If it is clear that the thrombocytopenia was caused by linezolid, consider 
resuming linezolid at half the dose when platelets improves and linezolid is resumed. 
8.3.6.2 Peripheral Neuropathy 
The decision to reduce the dose, or to pause linezolid until symptoms improve is a judgment 
based on changes in signs and symptoms identified by the investigator and informed by 
discussion with the trial participant.  As general guidance, consider pausing and/or reducing 
linezolid when the grade of a neuropathy sign or symptom increases by a grade to grade two or 
greater.  If it is clear that linezolid caused the neuropathy, consider resuming linezolid at half the 
dose, when the neuropathy improves. 
8.3.6.3 Optic Neuropathy 
A participant with visual symptoms of concern or change in visual acuity of 2 lines or more or 
change in color vision of more than one plate should be referred to the site ophthalmologist for 
evaluation with a retinal examination.  Any changes as assessed by the ophthalmologist that raise 
concern that an optic neuropathy may be developing should be discussed with the medical 
monitor and linezolid should be paused.  If a likely or definite optic neuropathy is confirmed, 
linezolid should be permanently discontinued. 
8.3.6.4 Lactic Acidosis 
Lactic acidosis as a toxicity of linezolid should be considered if participants have gastrointestinal 
symptoms that are not explained by other more common causes of their symptoms.  Such 
participants should have lactate measured and, as indicated, a full evaluation of pH and 
bicarbonate. Note that lactate should not be measured in participants who have no symptoms of 
concern, as elevated asymptomatic lactate may be common and it is difficult to interpret the 
clinical relevance of this. Also evaluate whether any concomitant medications, such as anti-
retroviral therapies, may be associated with lactic acidosis and consider pausing them until the 
acidosis resolves. Consider pausing linezolid if a patient has GI symptoms and acidosis likely to 
be secondary to linezolid toxicity that is not otherwise explained. 
8.4 Safety Monitoring by Data Monitoring Committee 
A DSMC will be appointed for the trial. The primary responsibility of the DSMC will be to act in an 
advisory capacity to the Sponsor to safeguard the interests of trial participants by monitoring 
participant safety, assess participant risk versus benefit, and assess data quality and general 
evaluation of the trial progress. Its activities will be delineated in a DSMC charter that will define 
the membership, responsibilities and the scope and frequency of data reviews. The DSMC will 
operate on a conflict-free basis independently of the Sponsor and the trial team. It will comprise 
at least 3 voting members that include at least 2 clinicians and one statistician.  The DSMC may 
have an organizational meeting prior to commencement of the trial. The DSMC will have meetings 
where it will review unblinded data during a closed session. These meetings will be planned at 
regular intervals. The Sponsor or the DSMC may convene ad hoc meetings based on rates of 
SAEs and/or to review results of the futility analysis or if safety concerns arise during the trial.  
After its assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
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9 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 Analysis Population 
The primary analysis population will include both XDR and non-XDR (pre-XDR and MDR 
intolerant and non-responsive TB) participants (up to 45 per arm).  A secondary analysis will be 
restricted to the XDR participants only (30 per arm).    
A modified intent-to-treat (mITT) and a per-protocol (PP) analysis for each arm and analysis 
population will be conducted.    The mITT will be considered the primary analysis and will include 
all those in the ITT analysis with additional specific exclusions detailed in the statistical analysis 
plan (SAP). 
Other analyses will be performed (for sensitivity) including a full intent-to-treat (ITT) analysis with 
no exclusions, and an analysis excluding only those who were later found to be ineligible at 
baseline (based on data collected prior to randomization).    
The Safety analysis population will include data from all randomized participants who received at 
least one dose of IMP.  
Full details of all the analysis populations will be defined in the SAP. 
9.2 Sample Size 
The objective of this trial is to evaluate the efficacy, safety and tolerability of various doses and 
durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants 
with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
In order to fulfil this objective, it is planned to randomize 30 XDR-TB participants per treatment 
group and up to 15 pre-XDR and/or MDR intolerant/non-responsive -TB participants per group. A 
sample size of 30-45 per arm will provide more than 90% power to demonstrate that the lower 
bound of the 95% confidence interval of this estimate is greater than 50%, using a 2-sided 5% 
significance level. This assumes that the true cure rate is 80 percent.   
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as 
the target, because it is above the entire range of the historical control for cure of XDR-TB and 
because a cure rate of 50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a 
shortened, simplified, all oral, inexpensive and safer regimen would clearly represent an important 
therapeutic advancement. A standard-of-care control group cannot reasonably be included in the 
trial for several reasons.  1) Given that the regimens being tested contain B and L, these drugs 
would need to be excluded from the control group.  However, they are beginning to be used 
increasingly in XDR-TB, despite lack of firm evidence, but with positive anecdotal reports.  Asking 
patients in the control group to avoid these medications could present an ethical issue.  2) The 
success rate of standard-of-care treatment for XDR-TB, particularly without B and L (see below), 
and the risk and difficulty of its administration contrast markedly with the early findings of B-L-Pa 
in the Nix-TB trial.  It is unlikely that patients would sign informed consent to receive standard-of-
care treatment if there is an alternative, but even if they do there remains an ethical issue of 
comparing such a disadvantaged treatment with such an advantaged treatment.  3) The scientific 
validity of comparing a 12-month endpoint (B-L-Pa) with a 30- or 36-month endpoint (standard of 
care) would represent a significant challenge.   
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9.3 Interim Analyses 
No formal interim analyses are planned. However, there will be three planned unblinded 
analyses which will contain results by linezolid treatment group in aggregate as described 
below. The first analysis will be done after all participants have completed 26 weeks of 
treatment. The analysis will be on treatment safety events (mainly the specific toxicities 
described in section 8.3) and time to culture conversion (on treatment). The sites, participants, 
and Sponsor staff will not be unblinded to individual linezolid treatment information. A limited 
number of statisticians will have access to individual linezolid treatment assignments.  
The blind for all individual participants will be broken for the primary endpoint analysis (the 
second unblinded analysis) once all clinical data and outcome parameters for the primary 
endpoint have been captured, no more data queries are pending, and the statistical analysis 
plan has been updated accordingly.   
There will be three database locks for the three planned unblinded data analyses generated for 
this trial:  
1.
When all participants have completed 26 weeks of treatment
2.
When all participants have completed 26 weeks of follow-up after end of treatment.
3.
When all participants have completed 78 weeks of follow-up from after end of treatment.
9.4 Primary and Secondary Endpoint Analysis 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT). 
A secondary analysis will be restricted to the XDR participants only (30 per arm). We will 
evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that 
the incidence of bacteriologic failure or relapse or clinical failure (including mortality) at 6 months 
(26 weeks) after the end of therapy is less than 50%.   
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and 
safety and to control the overall type I error rate the following analysis strategy will be adopted 
for both the primary and secondary analysis populations: 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 
weeks) with the L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a 
success.  Similarly, L600 9 weeks will only be tested if L600 26 weeks is a success.   A 
Bonferroni adjustment will be made for comparing the L1200 9 weeks and L600 26 weeks arms 
simultaneously, using p<0.025.  For these comparisons the lower bound of the 97.5% 
confidence interval will need to exceed 50% for success.   
No formal statistical pairwise comparisons between the arms will be performed. 
9.5 Safety and Tolerability Analysis 
•
The incidence of all-cause mortality will be summarized.
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• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake.  Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
• 
Cardiovascular Safety:  QT intervals will be adjusted using Fridericia’s correction and Bazett’s 
correction. QT/QTc values and changes from pre-dose (average of Screening and Day 1 
values) at each time point will be summarized using descriptive statistics by group and time 
of collection.  These will be presented as descriptive analyses, and no inferential tests will be 
carried out. 
o Post-baseline QT/QTc intervals will be classified into the following categories:   
 
QT/QTc < 450 msec 
 
450 msec < QT/QTc < 480 msec 
 
480 msec < QT/QTc < 500 msec 
 
QT/QTc > 500 msec   
o QTc changes from baseline will be classified into the following categories: 
 
increase < 30 msec,  
 
30 msec and < 60 msec, and  
 
increase > 60 msec.  
o Frequency counts will be used to summarize the number of participants at each 
time point according to the above categories. 
o ECG results will be classified as normal or abnormal (investigator assessment) 
and summarized using frequency counts by dose group and time of collection. 
• 
Ophthalmology: Descriptive statistics, including changes from baseline, will be summarized 
and listed by participant for ophthalmology slit lamp examination (age related eye disease 
study 2 [AREDS2] lens opacity classification and grading). Categorical data for lens opacity 
will be summarized in a frequency table for the right and left eye, respectively.  
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• 
Visual acuity and color vision:   Descriptive statistics, including changes from baseline, will be 
summarized and listed by participant for both Visual Acuity and Color Assessments. 
Categorical data for changes in visual acuity and color vision from baseline will be summarized 
in a frequency table for the right and left eye, respectively.  
• 
Descriptive statistics of neuropathy data derived from Brief Peripheral Neuropathy Screen. 
Categorical data for observed signs and symptoms of neuropathy will be summarized in 
frequency tables, including changes in signs and symptoms from baseline.  
• 
Other safety variables: Laboratory Parameters, Physical Examination, Vital signs (see 
Appendix 3), Concomitant medication, ophthalmic examination and peripheral neuropathy.  
Descriptive summary statistics will be presented. The incidence of liver related laboratory 
abnormalities will be explored. 
9.6 Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update population pharmacokinetic 
(PopPK) models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study trial population, and to derive 
individual exposure metrics for use in exposure-response analyses. PK data from the current trial 
may be combined with prior data (e.g., from the NiX-TB trial) to enhance this population PK 
analysis. Detailed plans for the PopPK analysis will be outlined in a separate modeling plan, and 
results will be reported in separate modeling report. 
9.7 Pharmacokinetics/Pharmacodynamics 
For each analyte, the PopPK model will be used to derive individual exposure metrics such as 
steady-state Ctrough, Cmax, AUCτ, and time-above-minimum-inhibitory-concentration (T>MIC), 
or alternative individual summaries of these metrics over the treatment period to account for dose 
adjustments and interruptions as appropriate. Relationships between such exposure metrics and 
efficacy and safety endpoints will be explored graphically and by model-based analyses as 
appropriate. Planning details and results will be included in the separate modeling plan and report. 
10 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants specific eCRF pages will be 
completed as described in the eCRF Completion Guidelines.  For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
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10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-Patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator has 
to 
permit 
trial 
related 
monitoring, audits, 
Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-Patient records while participants is on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial center files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection subsequent to trial completion.  The essential documents should be retained for 
not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify Sponsor/designees 
prior to destroying any records pertaining to the trial. 
11 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, ICH GCP, and the ethical principles that have their origin in the Declaration of 
Helsinki.  
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures, where available will be adhered to for all clinical and 
bioanalytical activities relevant to the quality of the trial.  Participant compliance will be monitored 
throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-investigators. Written 
IEC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements 
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11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, ICH GCP, the ethical principles that have their origin in the Declaration of 
Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for the purpose of monitoring various aspects of the trial, and to assure appropriate conduct of 
the trial in accordance with ICH GCP.  Visits will take place usually within a predetermined interval, 
but this may vary during the course of the trial.  The Investigator and site staff will allow the trial 
monitor and authorized representatives of the Sponsor to (1) inspect all CRFs, written informed 
consent documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs (where applicable), training records, facilities and 
other trial related systems/processes, and (2) access clinical supplies, dispensing and storage 
areas.  The Investigator and site staff should also (1) agree to assist with monitoring activities if 
requested and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Monitoring 
Plan requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB and Health Authority, per their guidelines. The 
site PI/all study staff is responsible for knowing and adhering to their IRB and Health Authority (as 
required) requirements. 
11.4 Auditing 
For the purpose of compliance with ICH GCP and regulatory agency guidelines, it may be 
necessary for Sponsor-authorized Quality Assurance personnel and/or authorized personnel from 
an external regulatory agency to conduct an audit or inspection of the investigational site.  The 
purpose of an audit is to assess the quality of data with regard to accuracy, adequacy and 
consistency, and to assure that studies are in accordance with the guidelines.  Having the highest 
quality data from studies is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by ICH GCP to be 
maintained by each site; drug storage, dispensing and return; all trial-related supplies; and source 
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documents against the CRFs to assure the adequacy and accuracy of the information which has 
been recorded, including the verification of any AEs which have occurred. The auditors or 
inspectors may also review site SOPs (where applicable), training records, site facilities and other 
trial related systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
12 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with ICH GCP, the ethical principles that have 
their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
Review 
The protocol and required trial related documents will be reviewed by the sites respective 
IEC/IRB.  The trial will not start until the IEC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, plus 
any other trial related documents required for review.  The IEC/IRB shall be constituted and shall 
operate in accordance with International ICH GCP, the ethical principles that have their origin in 
the Declaration of Helsinki. The Investigator will maintain an accurate and complete record of all 
submissions made to, and responses from the IRB/IEC.  The records should be filed in the 
Investigator’s Trial File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for the purpose of determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
considered to be part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary. The investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same IEC/IRB responsible for approval of this protocol.  Each 
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informed consent form shall include the elements required by the ICH GCP and must adhere to 
the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
ICF. 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the IEC/IRB approved written informed consent form 
will be signed and dated by both the participant and the person obtaining consent (Investigators 
or designees), and by any other parties required by the IEC/IRB. Ongoing participants must be 
re-consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative.  Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s 
medical record. 
The monitor will inspect the original completed consent form(s) for all participants 
12.5 Confidentiality  
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with ICH GCP, applicable local 
legislation/regulations.  Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the Sponsor or designees. 
13 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible IEC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors. (30)  
Because the Study is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Study must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Study must be submitted for 
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publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
14 Protocol Amendment Policy 
Any change to the protocol will be effected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the IEC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, IEC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant Authorities 
and/or IEC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the IEC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
15 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the Global Alliance for TB Drug Development (TB Alliance).  The TB Alliance 
is a not for profit, product development partnership accelerating the discovery and development 
of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, 
be compatible with antiretroviral therapies for those HIV-TB participants currently on such 
therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The Sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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16 References  
1. “A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis”. ClinicalTrials.gov, 25 
January 2017. https://www.clinicaltrials.gov/ct2/show/NCT02333799 
2. Bonilla CA, Crossa A, Jave HO, Mitnick CD, Jamanca RB, Herrera C, Ascencios L, 
Mendoza A, Bayona J, Zignol M and Jaramillo E (2008).  “Management of Extensively 
Drug-Resistant Tuberculosis in Peru: Cure Is Possible”. PLoS One 3(8): e2957. 
3. Cox H, Ford, N. “Linezolid for the treatment of complicated drug-resistant tuberculosis: a 
systematic review and meta-analysis” INT J TUBERC LUNG DIS 16(4):447–454, 2012.  
4. Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, van Niekerk C, 
Erondu N, Ginsberg AM, Becker P and Spigelman MK (2012). “Phase II Dose-Ranging 
Trial of the Early Bactericidal Activity of PA-824”. Antimicrobial Agents and Chemotherapy; 
56(6): 3027-3031.  
5. Bedaquiline (TMC207) Investigator’s Brochure, Janssen Research and Development., 
Edition 9, 09 October 2015.  
6. Investigator’s Brochure Pretomanid (PA-824), Global Alliance for TB Drug Development., 
Version 17, 22 December 2016.  
7. Keshavjee S, Gelmanova IY, Shin SS, Mishushtin SP, Andreev YG, Atwood S, Furin JJ 
and Miller A (2012). “Hepatotoxicity during treatment for multidrug-resistant tuberculosis: 
occurrence, management and outcome”. Int J Tuberc Lung Dis 16(5):596-603.   
8. Leach KL, Brickner SJ, Noe MC, Miller PF. "Linezolid, the first oxazolidinone antibacterial 
agent" Ann NY Acad Sci. 2011 Mar; 1222:49-54. 2011.  
9. Lee, et al. "Linezolid for treatment of chronic extensively drug-resistant tuberculosis" N 
Engl J Med. 2012 Oct 18; 367(16):1508-18. 
10. Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, 
Reynolds RC, and Orme IM. “Preclinical Testing of the Nitroimidazopyran PA-824 for 
Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models” 
Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301. 
11. Lytvynenko N, Cherenko S, Feschenko Y, Pogrebna M, Senko Y, Barbova A, Manzi M, 
Denisiuk O, Ramsay A and Zachariah R (2014). “Management of multi and extensively 
drug resistant tuberculosis in Ukraine: how well are we doing?” IUALTD Public Health 
Action 4(3): S67-S72. 
12. Manjunatha U, Boshoff HI, Berry CE. The mechanism of action of PA-824: novel insights 
from transcriptional profiling. Commun Integr Biol. 2009; 2(3):215-218. 
13. Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton, JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci USA. 2006; 103(2):431-436. 
14. McLeay SC, Vis P, van Heeswijk RPG and Green B (2014). “Population Pharmacokinetics 
of Bedaquiline (TMC207), a Novel Antituberculosis Drug”. Antimicrobial Agents and 
Chemotherapy 58(9): 5315-5324. 
15. Mdluli K, Nuermberger, E. “Pre-Clinical Drug Combination Studies to Identify Novel 
Regimens for TB”. In: Recent Advances in TB Drug Development symposium, 40th Union 
World Conference, International Union Against TB and Lung Disease, Cancun, Mexico, 
2009. 
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16. Mdluli K, Nuermberger E, Taylor K, Williams N, Koen A, Khisimuzi E, Rokeya T, Si-Yang 
L, Peloquin C, Dinesh C. “Sterilizing activity of novel TMC207- and PA-824-containing 
regimens in a murine model of tuberculosis” Antimicrobial Agents and Chemotherapy 
2011; 55: 5485-5492. 
17. Migliori GB, Sotgiu G, Gandhi NR, Falzon D, DeRiemer K, Centis R, Hollm-Delgado MG, 
Palmero D, Perez-Guzman C, Vargas MH, D’Ambrosio L, Spanevello A, Bauer M, Chan 
ED, Schaaf HS, Keshavjee S, Holtz TH, Menzies D and “The Collaborative Group for 
Meta-Analysis of Individual Patient Data in MDR-TB” (2013). “Drug resistance beyond 
XDR-TB: results from a large individual patient data meta-analysis”. Eur Respir J. 42(1): 
169-179.  
18. Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006; 50(8):2621-2625. 
19. Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal, I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 2008; 
52(4):1522-1524. 
20. Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005; 172(11):1452-1456. 
21. O’Donnell MR, Padayatchi N, Master I, Osburn G and Horsbaugh CR. “Improved Early 
Results for Patients with Extensively Drug Resistant Tuberculosis and HIV in South 
Africa”. Int J Tuberc Lung Dis. 13(7): 855-861. 
22. Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
23. Package Insert for South Africa, ZYVOXID® (linezolid), Pfizer Pharmaceuticals, May 
2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=1045. Date last accessed: 15 April 
15 2016.  
24. Package Insert, Lizomac™ 600 (linezolid), MacLeods Pharmaceutical, 2014. 
25. Package 
Insert, 
SIRTURO®, 
Janssen 
Therapeutics, 
December 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204384s006lbl.pdf. Date last 
accessed: 15 April 2016. 
26. Package 
Insert, 
ZYVOX®, 
Pfizer 
Pharmaceuticals, 
June 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021130s030,021131s029,02
1132s034lbl.pdf. Date last accessed: 15 April 2016.  
27. Park IN, et al. “Efficacy and tolerability of daily-half dose linezolid in patients with 
intractable multidrug-resistant tuberculosis.” B Antimicrobial Chemotherapy 2006; 58:701-
704. 
28. Pietersen E, et al. "Long-term outcomes of patients with extensively drug-resistant 
tuberculosis in South Africa: a cohort study" Lancet, 2014 Jan 16. pii: S0140-
6736(13)62675-6.  
29. Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, Vasilyeca I, 
Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, Van 
Baelen B, van Heeswijk RPG and Dannemann B (2016). “Bedaquiline safety data in a 
broad patient population treated for drug-resistant TB including XDR-TB (C209 study)”. 
Tuberculosis 47: 394-402.  
30. “Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in 
Medical Journals”, December 2016 update.  http://www.icmje.org/icmje-recommendations.pdf,  
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31. Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578.  
32. Schecter GF, et al.  “Linezolid Treatment for MDR-TB”. Clinical Infectious Diseases 2010; 
50:49-55. 
33. Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008; 
322(5906):1392-1395. 
34. Singla R. "Linezolid: an Effective, Safe and Cheap Drug for Patients Failing Multidrug-
resistant Tuberculosis Treatment in India" Eur Respir J. 2012 Apr; 39(4):956-62. doi: 
10.1183/09031936.00076811. Epub 2011 Sep 29. 
35. Stover, C. K., P. Warrener, D. R. VanDevanter, et al. 2000. “A small-molecule 
nitroimidazopyran drug candidate for the treatment of tuberculosis”. Nature 405:962–966. 
36. Tasneen R, Betoudji F, Tyagi S, et al.  Contributions of oxazolidinones to the efficacy of 
novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis.  
Antimicrob. Agents Chemother Posted Online 26 October 2015.  Dol:10.1128/AAC.01691-
15. 
37. Tasneen R, Tyagi S, Williams K, Grosset J, Nuermberger E. “Enhanced bactericidal 
activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of 
tuberculosis”. Antimicrob Agents Chemother. 2008; 52(10):3664-3668. 
38. Tato M, et al. "In vitro activity of linezolid against Mycobacterium tuberculosis complex, 
including multidrug-resistant Mycobacterium bovis isolates". Int. J. Antimicrob Agents 
2006 Jul; 28(1)75-8.  
39. Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”.  
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
40. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. Bactericidal 
activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2005; 49(6): 2289-2293. 
41. WHO Treatment of Tuberculosis Guidelines, 4th Edition. 2010.  
42. World Health Organization. Global Tuberculosis Report 2014, 19th ed. 2014. 
43. World Health Organization. Global Tuberculosis Report 2015, 20th ed. 2015. 
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Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
exact figure/100/scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at 
least 20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life-
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization 
or hospice care probable. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common Toxicity 
Criteria (CTC), and World Health Organization (WHO)) have been adapted for use by the 
Division of Microbiology and Infectious Diseases (DMID) and modified to better meet the 
needs of Patients in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low : 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low : 
<100 mg/dL 
High: 
>600 mg/dL 
Low : 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated w ith 
gross bleeding or 
w ith disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life-
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
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Hypocalcemia 
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life-
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life-
threatening arrhythmia 
Hyperbilirubinemia 
(w hen accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(w hen other liver 
function are in the  
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase  
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
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Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, w ith or 
w ithout clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment required 
acute treatment 
required; 
outpatienttreatm
ent or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension w ith 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable w ith oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock;   
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled w ith 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV 1 of peak 
flow  
requires treatment; 
normalizes w ith 
bronchodilator; FEV 1 
50% - 70% (of peak 
flow ) 
no normalization w ith 
bronchodilator;FEV 1 
25% - 50% of peak 
flow ; or  retractions 
present 
cyanosis: FEV 1 < 
25% of peak flow  
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea w ith normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
 
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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3-
4 loose stools/day 
or mild diarrhea 
last < 1 w eek 
moderate or 
persistent; 5-7 loose 
stools/day or 
diarrhea lasting >1 
w eek 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization   
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
sw allow ing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
sw allow  solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
 
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NEUROLOGICAL 
 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
w eakness no 
objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function 
objective 
w eakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment  required 
moderate 
discomfort; non-
narcotic analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
w ith symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment (mod 
decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or w rists) or 
loss of sensation of 
at least mod 
degree in multiple 
different body 
areas (i.e., upper 
and low er 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis;  or 
seizures 
 
 
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MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering w ith 
function 
moderate pain, 
analgesics and/or 
pain interfering w ith 
function but not w ith 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering w ith 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain w ith 
inflammation, 
erythema or joint 
sw elling – but not 
interfering w ith 
function 
moderate pain w ith 
inflammation, 
erythema or joint 
sw elling – interfering 
w ith function, but 
not w ith activities of 
daily living 
severe pain w ith 
inflammation, 
erythema or joint 
sw elling –and 
interfering w ith 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia w ith no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or w ith 
moderate 
impairment of 
activity 
severe muscle 
tenderness w ith 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected Stevens-
Johnson or  
necrosis requiring 
surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection 
Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 
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SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus w ithout rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial narcotic 
therapy 
intractable; requires 
repeated narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 50% 
> 48 hours 
normal activity 
decreased > 50% 
can’t w ork 
unable to care for 
self 
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Appendix 3:  Cardiovascular Safety 
 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 90 mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or 
Grade 4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
 
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Appendix 4:  Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms of 
disease.  
80 
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
Cares for self; unable to carry on normal activity or to 
do active work. 
70 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
60 
Requires considerable assistance and frequent medical 
care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109(22). 
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Appendix 5: Liver Toxicity Management  
Standard anti-TB chemotherapy is known to cause derangement of liver function tests in a 
substantial number of patients. In many cases this will be asymptomatic and self-limiting. In some 
cases, severe hepatitis and even fulminant liver failure and death can occur.  
In pre-marketing clinical trials of new drugs and regimens it is especially important to identify and 
carefully manage any trial participants who are at risk of progression to serious liver injury.  The 
observation of altered liver function to a degree that has a high risk of progressing to liver failure 
has been referred to informally as Hy’s Law;(31,39); this reflects that pure hepatocellular injury 
sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, Hy’s Law cases have the following three components:  
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo.  
2. Among trial participants showing such aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show elevation of serum total bilirubin (TBL) 
to >2x ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase 
(ALP)).  
3. No other reason can be found to explain the combination of increased AT and total bilirubin 
level (TBL), such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury.  
During the trial, liver function will be monitored regularly with clinical assessment and blood tests 
in study participants and this will assist in follow up laboratory measurements that can document 
either resolution of abnormalities or signal the potential for drug-induced liver injury (DILI).  In a 
clinical trial of new drugs and combinations it is especially important for investigators to follow 
closely any participants who have evidence of hepatic inflammation or potential toxicity. The 
following procedure describes the management of deranged liver function tests in study 
participants. 
Procedure 
Blood tests for liver function will be taken routinely at screening (Day -14 to -1) and at the specific 
time points designated in the protocol, and at Early Withdrawal.  If at any other visit the clinician 
suspects derangement of liver function, e.g. the participant describes nausea and vomiting, right 
upper abdominal pain or is jaundiced, blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of hepatitis or hepatic impairment and any 
potentially contributing causes.  
Suspected liver toxicity (or elevated liver enzymes detected in the absence of symptoms) must 
be taken seriously and detailed guidance will be provided in a separate document “ZeNix 
Hepatotoxicity Management Guideline”. Investigators should refer to this document as a guide to 
management in cases of suspected or proven liver toxicity.  Importantly, the trial Medical Monitor 
is available to provide further assistance if there is any uncertainty or additional questions. 
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The laboratory source (print-out of any results) should be stored alongside or transcribed into the 
clinical source document. Each abnormal value should be marked as clinically significant (CS) or 
non-clinically significant (NCS); the assessment of significance is at the discretion of the 
investigator. All clinically significant abnormal results must be recorded as Adverse Events in the 
eCRF and graded clinically as per the DMID adult toxicity table grading, (Appendix 2).  
Assessments and decision making for elevations in aminotransferase values or bilirubin of various 
levels of concern are detailed below: 
Elevated liver enzymes considered of clinical significance, but not accompanied by other signs 
and symptoms, should be reported as an adverse event and should usually be recorded as 
elevated liver enzymes. If the term "hepatitis" is used, the Safety Data Manager will question the 
site for additional evidence to support the diagnosis, such as clinical signs and serological or 
biopsy data. While a liver biopsy is not required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for cases where there is supportive evidence 
beyond a liver enzyme abnormality. However, if the investigator will confirm the diagnosis of 
hepatitis just on the basis of clinical signs and laboratory values the diagnosis will be accepted. 
Should other symptoms or signs be present, these should also be recorded as adverse events. 
Restarting Medication 
Liver function tests that are improving should be repeated regularly, such as every 3 days for the 
first week then once a week until they return to near baseline values for the participant. Manage 
the participant symptomatically as required using medications that are not potentially hepatotoxic. 
Infection control issues must be carefully managed whilst TB medications are being withheld, 
especially if the participant is still culture positive for acid fast bacilli. 
If medication has been temporarily stopped, once the liver function values have decreased 
substantially a decision must be made about further TB management.  This will be dependent on 
the clinical context and a decision must be made in discussion with the Sponsor Medical Monitor. 
Treatment can only be restarted if the trial Medical Monitor is in agreement with the plan. In all 
cases treatment should be recommenced under close supervision for any evidence of recurrent 
liver function abnormalities.  
If there is a further significant elevation of hepatic enzymes or bilirubin or symptoms of clinical 
concern after resumption of study medication, the study medication should be withdrawn 
permanently. Participants who permanently discontinue study medication should be managed as 
clinically indicated according to local National TB Programme guidelines. The Sponsor Medical 
Monitor can be contacted for further advice when referring to the National Treatment Program. 
The trial Medical Monitor is available to assist the Investigators in both the management of liver 
toxicity and decisions regarding the holding or re-introduction of trial medication. Investigators 
must involve the Medical Monitor in any decisions regarding medication hold or re-start, and there 
should always be a low threshold for contacting the Medical Monitor in cases of elevated liver 
enzymes. 
Refer to ZeNix Hepatotoxicity Management Guideline for further details. 
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Page 1 of 96 
CONFIDENTIAL  
 
Protocol Number 
NC-007-(B-Pa-L) 
Title: 
A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid 
plus bedaquiline and pretomanid in participants with pulmonary 
infection of either extensively drug-resistant tuberculosis (XDR-
TB), pre-XDR-TB or treatment intolerant or non-responsive multi-
drug resistant tuberculosis (MDR-TB). 
Drug(s)/Combination(s): Bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Amendment 
Version/Date:  
 
 
Version 2.0 MDA dated 10 March 2020 (incorporating Protocol 
V2.0 dated 13 Jun 2018, Country Specific Protocol Amendment for 
Moldova V1.0 dated 13 Jun 2018 and Protocol Amendment 2.0 
dated 10 March 2020). 
Protocol Name: 
ZeNix 
 
 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version  V2.0 MDA / 10 MAR 2020 
Protocol Name: ZeNix 
 
 
 
CONFIDENTIAL 
Page 2 of 96 
PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Date:   Version 2.0 MDA dated 10 March 2020 (incorporating Protocol V2.0 dated 
13 Jun 2018, Country Specific Protocol Amendment for Moldova V1.0 
dated 13 Jun 2018 and Protocol Amendment 2.0 dated 10 March 2020). 
Protocol Name: ZeNix 
SPONSOR  
I agree to the terms of this trial protocol. 
 
 
 
 
 
Signature of Senior Medical Officer 
 
Printed Name 
 
 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone 646-616-8671 
email: daniel.everitt@tballiance.org 
Date 
 
LEAD INVESTIGATOR 
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and local 
regulations. 
 
 
 
 
Signature  
 
Printed Name 
 
 
 
Date 
 
 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version  V2.0 MDA / 10 MAR 2020 
Protocol Name: ZeNix 
 
 
 
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Page 3 of 96 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-resistant 
tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug 
resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Date:  Version 2.0 MDA dated 10 March 2020 (incorporating Protocol V2.0 dated 13 
Jun 2018, Country Specific Protocol Amendment for Moldova V1.0 dated 13 
Jun 2018 and Protocol Amendment 2.0 dated 10 March 2020). 
 
Protocol Name: ZeNix 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix
1.1 
Synopsis Summary ...................................................................................................10 
1.2 
Synopsis Flowchart...................................................................................................15 
2 
Introduction and Rationale .............................................................................................. 20 
2.1 
Trial Rationale ..........................................................................................................21 
2.1.1 
Trial Design Rationale........................................................................................21 
2.1.2 
Trial Drug Rationale ...........................................................................................21 
2.1.3 
Pretomanid ........................................................................................................23 
2.1.4 
Linezolid ............................................................................................................23 
2.2 
Agents to be Studied ................................................................................................24 
2.2.1 
Bedaquiline .......................................................................................................24 
2.2.2 
Pretomanid ........................................................................................................27 
2.2.3 
Linezolid ............................................................................................................33 
2.3 
Regimens to be Studied............................................................................................38 
2.3.1 
Non-Clinical Studies ..........................................................................................38 
2.3.2 
Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or Linezolid ...40 
2.4 
Overall Benefit/Risk Assessment...............................................................................43 
3 
Trial Objectives .............................................................................................................. 44 
3.1 
Primary Objectives....................................................................................................44 
4 
Trial Design .................................................................................................................... 44 
4.1 
Summary of Trial Design...........................................................................................44 
4.2 
Treatment Plan: Schedule of Assessments ...............................................................44 
5 
Trial Population .............................................................................................................. 45 
5.1 
Inclusion Criteria .......................................................................................................46 
5.2 
Exclusion Criteria......................................................................................................47 
5.3 
Restrictions ..............................................................................................................50 
5.3.1 
Prior and Concomitant Medications and Other Treatments .................................50 
5.3.2 
Recommendations for Concomitant use of Anti-Malarials ...................................51 
5.3.3 
Antiretroviral Therapy.........................................................................................51 
5.3.4 
Other Restrictions ..............................................................................................52 
5.4 
Trial Discontinuation and Visits .................................................................................52 
5.4.1 
Treatment Discontinuation and Early Withdrawal ................................................52 
1 
Synopsis .......................................................................................................................... 10 
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5.4.2 
Early Withdrawal Follow-up................................................................................53 
5.4.3 
Unscheduled Visits ............................................................................................53 
5.4.4 
Lost to Follow-up ...............................................................................................54 
5.4.5 
Early Withdrawal due to TB................................................................................54 
5.5 
Participant Progress Definitions ................................................................................55 
5.6 
Trial Stopping Rules .................................................................................................55 
6 
Treatment ..........................................................................................................................55 
6.1 
IMP Administration....................................................................................................55 
6.2 
Participant Compliance .............................................................................................56 
6.3 
Treatment Modification(s) .........................................................................................57 
6.4 
IMP Packaging and Labelling ....................................................................................57 
6.5 
Method of Treatment Assignment..............................................................................58 
6.6 
Blinding and Procedures for Breaking the Blind .........................................................59 
6.7 
Handling, Storage and Accountability ........................................................................59 
7 
Trial Variables and Procedures ....................................................................................... 60 
7.1 
Demographic and Background Variables and Procedures .........................................60 
7.2 
Efficacy Variables and Procedures ............................................................................61 
7.3 
Safety and Tolerability Assessments .........................................................................61 
7.4 
PK Variables and Procedures ...................................................................................63 
7.5 
Mycobacteriology Characterization Variable and Procedures .....................................63 
8 
Adverse Events .............................................................................................................. 64 
8.1 
Definitions ................................................................................................................64 
8.1.1 
Adverse Event (AE) ...........................................................................................64 
8.1.2 
Serious Adverse Event (SAE) ............................................................................64 
8.1.3 
Attribution/Causality ...........................................................................................64 
8.1.4 
Severity .............................................................................................................65 
8.2 
Reporting .................................................................................................................66 
8.2.1 
Follow up of Adverse Events ..............................................................................66 
8.2.2 
Clinical Laboratory Adverse Events ....................................................................67 
8.2.3 
Disease under Study .........................................................................................67 
8.2.4 
Overdose ..........................................................................................................68 
8.2.5 
Drug Interaction .................................................................................................68 
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8.2.6 
Pregnancy .........................................................................................................68 
8.3 
Monitoring for Specific Toxicities ...............................................................................68 
8.3.1 
Neurological ......................................................................................................69 
8.3.2 
ALT, AST and Alkaline Phosphatase elevations: ................................................69 
8.3.3 
Lipase ...............................................................................................................69 
8.3.4 
Musculoskeletal System and Cardiac Muscle .....................................................69 
8.3.5 
Cardiac Rhythm Disturbances............................................................................69 
8.3.6 
Monitoring Linezolid Toxicities............................................................................70 
8.4 
Safety Monitoring by Data Monitoring Committee ......................................................71 
9 
Statistical Analysis.......................................................................................................... 72 
9.1 
Analysis Population ..................................................................................................72 
9.2 
Sample Size .............................................................................................................72 
9.3 
Interim Analyses .......................................................................................................73 
9.4 
Primary and Secondary Endpoint Analysis ................................................................73 
9.5 
Safety and Tolerability Analysis.................................................................................73 
9.6 
Pharmacokinetics .....................................................................................................75 
9.7 
Pharmacokinetics/Pharmacodynamics ......................................................................75 
10 Records Management .................................................................................................... 75 
10.1 Data Collection .........................................................................................................75 
10.2 Source Documents ...................................................................................................76 
10.3 File Management at the Trial Centre .........................................................................76 
10.4 Records Retention at the Trial Centre .......................................................................76 
11 Quality Control and Assurance........................................................................................ 76 
11.1 Site Procedures ........................................................................................................76 
11.2 Monitoring ................................................................................................................77 
11.3 Protocol Deviations ...................................................................................................77 
11.4 Auditing ....................................................................................................................77 
12 Ethics and Regulatory .................................................................................................... 78 
12.1 Basic Principles ........................................................................................................78 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review .............78 
12.3 Regulatory Authorities...............................................................................................78 
12.4 Informed Consent .....................................................................................................78 
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Protocol Name: ZeNix 
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12.5 Confidentiality ...........................................................................................................79 
13 Publication Policy ........................................................................................................... 79 
14 Protocol Amendment Policy ............................................................................................ 80 
15 Sponsor, Financial Aspects, Insurance and Indemnity ..................................................... 80 
16 References..................................................................................................................... 81 
Appendix 1: 
The IUATLD Scale ........................................................................................ 84 
Appendix 2: 
Division of Microbiology and Infectious Disease (DMID) Toxicity Table ........... 85 
Appendix 3: 
 Cardiovascular Safety................................................................................... 93 
Appendix 4: 
 Karnofsky Performance Status Scale Definitions Rating (%) Criteria .............. 94 
Appendix 5: 
Liver Toxicity Management ............................................................................ 95 
TABLES 
Table 1: 
ADRs C208 Stage 1 and Stage 2 ........................................................................26 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies .......................................28 
Table 3: 
Murine Lung CFU counts during Treatment with Linezolid .......................................34 
Table 4: 
Murine Relapse Data .........................................................................................39 
Table 5: 
Summary Statistics for EBA................................................................................40 
Table 6: 
NC-003 Efficacy Results: Daily BAlog ..................................................................41 
Table 7: 
NC-003 Safety Data ..........................................................................................41 
Table 8: 
Treatment Groups .............................................................................................44 
Table 9: 
Follow-up Visits Required for Early Withdrawal Participants.....................................53 
Table 10:  
Investigational Medicinal Product Details ..............................................................56 
Table 11:  
Adverse Events Attribution/Causality Ratings ........................................................65 
Table 12: 
Definitions for Adverse Event Severity Gradings ....................................................65 
FIGURES 
Figure 1: 
Log10 CFU Counts in Lungs .....................................................................................28 
Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010......................................31 
Figure 3: 
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin CL-001............35 
Figure 4: 
Trial Schematic .......................................................................................................45 
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Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
Abacavir 
ADR 
Adverse drug reactions 
AE  
Adverse event  
AIDS 
Acquired immune deficiency syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AREDS2 Age related eye disease scale 2 
ART 
Anti-retroviral therapy 
AST 
Aspartate amino transferase 
AT 
Amino transferase 
AUCτ 
Area under curve over a dosing interval 
B 
Bedaquiline 
BMI 
Body mass index 
bpm 
Beats per minute 
BPNS 
Brief peripheral neuropathy scale 
C 
Clofazimine 
CFU 
Colony forming units 
CK(-MB) 
Creatine kinase (-MB isoenzyme) 
C(max), 
(min) 
Plasma concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine phosphokinase 
CS 
Clinically significant 
Ctrough 
Plasma concentration trough 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of microbiology and infection disease 
DNA 
Deoxyribonucleic acid 
DOH 
Department of health 
DILI 
Drug induced liver injury 
DSMC 
Data safety monitoring committee 
DST 
Drug susceptibility testing 
E 
Ethambutol 
EBA 
Early bactericidal activity 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
Electronic case report form 
FQ  
Fluoroquinolone 
FTC 
Emtricitabine 
g/L 
Grams per liter 
GI 
Gastrointestinal 
GCP  
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMR 
Geometric mean ratio 
H 
Isoniazid 
hERG 
Human ether-à-go-go related gene 
HIV  
Human immunodeficiency virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product 
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IRB 
Institutional review board 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IXRS 
Interactive Voice and Web Response System 
kg 
Kilogram 
/L 
Liter 
L 
Linezolid 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
M 
Moxifloxacin 
MAO(I) 
Monoamine oxidase (Inhibitor) 
MBD 
Minimum bactericidal dose 
MIC 
Minimum inhibitory concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi drug resistant tuberculosis 
MGIT 
Mycobacterial growth inhibiting tube 
mITT 
Modified intent to treat 
mL 
Milliliter 
ms 
Millisecond 
NCS 
Not clinically significant 
NEJM 
New England Journal of Medicine 
NVP 
Nevirapine 
NO 
Nitric oxide 
NOAEL 
No observed adverse effect level 
NRTI 
(Triple) nuleosidase reverse transcriptase inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
QD 
Once daily 
R 
Rifampicin 
S 
Streptomycin 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SIRE 
Streptomycin isoniazid rifampicin ethambutol 
SOC 
System organ class 
TB 
Tuberculosis 
TBL 
Serum total bilirubin 
TDF 
Tenofovir 
TEAE 
Treatment emergent adverse events 
T>MIC 
Time above minimum inhibitory concentration 
t.i.w. 
Three times a week 
(BA) TTP (Bacteriocidal activity) time to positivity  
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
XDR-TB 
Extensively drug resistant tuberculosis 
μg 
Microgram 
Z 
Pyrazinamide 
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1 
Synopsis 
1.1 Synopsis Summary 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Number/Title: 
NC-007: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB) 
Treatment Indication: 
Pulmonary XDR-TB, pre-XDR-TB, and treatment intolerant or non-responsive 
MDR-TB 
Trial Objective: 
To evaluate the efficacy, safety and tolerability of various doses and durations 
of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in 
participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment 
intolerant or non-responsive MDR-TB. 
Trial Design: 
A phase 3, multi-center, partially-blinded, randomized clinical trial in four parallel 
treatment groups. Bedaquiline and pretomanid treatment will not be blinded.  
Linezolid treatment dose and duration will be double-blinded. 
 
Participants will have a screening period of up to 14 days and will be 
randomized to receive one of the 4 active treatment arms. Participants will be 
randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
voice and web response system (IXRS) which will utilize a randomization 
system using stratification with a random element to allocate participants evenly 
across the arms by HIV status and type of TB.   
 
Each participant will receive 26 weeks of treatment.  If participant’s sputum 
sample is culture positive between the week 16 and week 26 treatment visits 
and their clinical condition suggests they may have an ongoing TB infection, 
Investigator may consider extending current treatment to 39 weeks.   If the 
culture results between week 16 and week 26 are contaminated, missing or 
considered an isolated positive without clinical significance, available culture 
results should be used to make this decision. All decisions regarding treatment 
extension should be discussed with and approved by the Sponsor Medical 
Monitor before implementation. 
 
Participants will be followed for 78 weeks after end of treatment. 
Patient Population: 
A total of up to 180 participants, male and female, aged 18 and over Sponsor 
may consider replacement of late screen failure and un-assessable (as 
detailed in the statistical analysis plan) participants. 
Test product, Dose and 
Mode of Administration: 
The regimen will be supplied as the following: 
 
Product 
Tablet Strength 
Abbreviation  
Bedaquiline 
100 mg  
(B) 
Pretomanid 
200 mg  
(Pa) 
Linezolid (scored) 
 
 
600 mg 
(L) 
Placebo Linezolid 
(scored) 
placebo 
(L) 
Linezolid 600 mg half 
tablet (pre-cut) 
300 mg 
(L) 
 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 11 of 96 
Placebo linezolid half 
tablet (pre-cut) 
placebo 
(L) 
 
Linezolid treatment will be supplied as 2 rows of full tablets (active or 
placebo) and one row of half-tablets (active or placebo) to allow for all 
possible dosing options while maintaining the blind.  
 
Instructions for Dosing: 
Treatment will be administered orally, once daily, with a full glass of water and 
a meal in the following dosing schemes (treatment arms): 
 
Participants will receive the following: 
• 
Bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 
18 weeks plus;  
• 
Pretomanid 200 mg once daily for 26 weeks plus; 
• 
Linezolid- participants will be randomly assigned to receive one of the 
following four blinded linezolid treatment doses and durations:  
Linezolid 1200 mg daily for 26 weeks 
• 
2 linezolid 600 mg active tablets once daily for 26 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
 
Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
• 
2 linezolid 600 mg active tablets once daily for 9 weeks  
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
Linezolid 600 mg daily for 26 weeks 
• 
1 linezolid 600 mg active tablet once daily for 26 weeks 
• 
1 placebo linezolid tablet once daily for 26 weeks  
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
 
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid tablet for 9 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
  
Treatment Modifications: 
The above treatment schemes may require modification due to toxicities as 
noted below. All dose modifications should be discussed with the Sponsor 
Medical Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be informed 
within 24 hours of the change if not discussed prior to implementation 
 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 12 of 96 
In the event of linezolid specific toxicities, the following should be considered 
and implemented per guidance in the monitoring and safety for specific 
toxicities section (8.3) of protocol:   
 
• 
Blinded one step reductions (maximum 2 steps) in the dose of linezolid 
managed by the IXRS as per instructions in pharmacy manual and/or 
IXRS user manual.  
o 1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or   
o 600 mg QD to 300 mg QD, 300mg QD to placebo  
• 
Temporary pause of linezolid. 
• 
Permanent discontinuation of linezolid. 
• 
Participants who have a linezolid reduction can go back to a higher dose 
(1 step or 2 steps) post discussion with and approval by the Sponsor 
Medical Monitor. 
 
For participants experiencing suspected drug related toxicities due to other 
drugs in the regimen (B-Pa), the full regimen may be halted for up to 35 
consecutive days.  
 
Interruptions/pauses of all Investigational Medicinal Product (IMP) must not 
exceed 8 weeks (56 days) cumulatively.  
 
When treatment is extended to 39 weeks, interruptions/pauses of all IMP must 
not exceed 13 weeks (91 days) cumulatively. 
 
When the total of missed dosing days of the prescribed regimen and/or 
pauses is greater than 7 days, the same number of missed doses should be 
dispensed/treatment extended to make up for the total missed doses. 
 
At no time should the participant be treated with a single agent. 
 
Every effort should be made for participants to receive a total of 9 weeks of 
linezolid, even if pauses are required 
Criteria for Evaluation: 
Primary Endpoint: 
Incidence of bacteriologic failure or relapse, or clinical failure at 26 weeks after the end of treatment. 
 
Abbreviated Definitions, full definitions will be described in the Statistical Analysis Plan (SAP): 
• 
Bacteriologic failure: During the treatment period, failure to attain or maintain culture conversion to 
negative. 
• 
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative 
status, with culture conversion to positive status with a strain of Mycobacterium tuberculosis (MTB) 
genetically identical to the infecting strain at baseline.  
• 
Clinical failure: A change from protocol-specified TB treatment to a new regimen before end of 
protocol specified treatment due to treatment failure, retreatment for TB during follow up, or TB-
related death. 
Note: 
• 
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days 
apart. 
• 
Participants who are documented at a visit as unable to produce sputum and who are clinically 
considered to be responding well to treatment will be considered to be culture negative at that visit. 
 
Further details of definitions to be provided in the SAP. 
 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
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Page 13 of 96 
Secondary Endpoints: 
• 
Incidence of bacteriologic failure or relapse, or clinical failure through follow up until 78 weeks after 
the end of treatment. 
• 
Time to sputum culture conversion to negative status through the treatment period. 
• 
Proportion of participants with sputum culture conversion to negative status at weeks 4, 6, 8, 12, 16 
and end of treatment. 
• 
Change from baseline TB symptoms. 
• 
Change from baseline in Patient Reported Health Status. 
• 
Change from baseline weight. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations of bedaquiline and its M2, pretomanid and linezolid from sparse sampling (see Table 
1.2) will be measured and used to update population PK models for bedaquiline and its M2 metabolite, 
pretomanid, and linezolid to further evaluate the effects of covariates on model parameters in this study 
population. PK data from the current trial may be combined with prior data (e.g., from the NiX-TB trial) to 
enhance this population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between drug 
exposure and efficacy and safety endpoints.   
 
Safety and Tolerability: 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
• 
All-cause mortality. 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by, drug relatedness 
and seriousness, leading to early withdrawal from treatment, leading to pauses of linezolid, leading 
to linezolid reductions and leading to death.   
• 
Quantitative and qualitative clinical laboratory result measurements, including observed and change 
from baseline.  
• 
Quantitative and qualitative electrocardiogram (ECG) results read by a central cardiology service, 
including observed and change from baseline. 
• 
Descriptive statistics of ophthalmology slit lamp examination data (age related eye disease study 2 
[AREDS2]) lens opacity classification and grading). Categorical data for lens opacity will be 
summarized in a frequency table for the right and left eye, respectively, including observed and 
change from baseline. 
• 
Changes in ophthalmic exam for visual acuity and color vision, including observed and change from 
baseline. 
• 
Changes noted in peripheral neuropathy signs and symptoms, including observed and change from 
baseline. 
 
Mycobacteriology Assessments: 
Sputum samples will be obtained at all scheduled visits.  The following tests will be performed.   
• 
Smear microscopy for acid-fast bacilli (AFB); 
• 
Liquid Culture (MGIT), followed by a speciation test to detect presence or absence of MTB and 
obtain time to positivity (TTP); 
• 
GeneXpert, Hain Genotype MTBDRplus or an alternative molecular to confirm MTB and rifamycin 
resistance. 
• 
Minimum Inhibitory concentration (MIC) of bedaquiline, pretomanid and linezolid; 
• 
Drug Susceptibility Testing (DST) in liquid culture for rifampicin, isoniazid, streptomycin, ethambutol, 
pyrazinamide and second line TB drugs including fluoroquinolones and injectable; 
• 
Genotyping. 
 
Details on the testing and the collection and timing of samples are in sections 1.2 and 7.2 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 14 of 96 
Statistical Methods: 
A general description of the statistical methods planned for the primary efficacy outcome is outlined below. 
Specific details will be provided in the SAP. 
 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT).  We will 
evaluate the hypothesis, separately for each of the experimental B-Pa-L treatment arms, that the incidence 
of bacteriologic and clinical cure at 26 weeks after the end of therapy is greater than 50%.   
 
The incidence will be estimated from the binomial proportion for participants with success criteria based on 
the lower bound of the confidence interval for this proportion being greater than 50%. 
 
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as the target, 
because it is above the entire range of the historical control for cure of XDR-TB and because a cure rate of 
50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a shortened, simplified, all oral, 
inexpensive and safer regimen would clearly represent an important therapeutic advancement.  
 
The primary analysis population will include both XDR and non-XDR participants (up to 45 per arm).  A 
secondary analysis will be restricted to the XDR participants only (30 per arm).   A sample size of 30-45 per 
arm will provide more than 90% power to demonstrate that the lower bound of the 95% confidence interval 
of this estimate is greater than 50%, using a 2-sided 5% significance level. This assumes that the true cure 
rate is 80 percent.   
 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 6 months) with the 
L1200 2 months and L600 26 weeks only being tested if L1200 26 weeks is a success.  Similarly, L600 9 
weeks will only be tested if L600 26 weeks is a success.  A Bonferroni adjustment will be made for 
comparing the L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025.  For these 
comparisons the lower bound of the 97.5% confidence interval will need to exceed 50% for success.   
 
Both a Modified Intent to Treat (mITT) and a Per Protocol (PP) analysis for each arm will be conducted.  No 
formal statistical pairwise comparisons between the arms will be performed.   
Trial Duration: 
~4 Years (An enrolment period of approximately 24 months plus 14 days pre-treatment plus 6 months 
treatment period plus 18 months post treatment follow-up). 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 15 of 96 
1.2 Synopsis Flowchart 
Period Screeninga 
Treatment 
 Visits every 3 
weeks if 
treatment 
extendedb 
End of OR Early 
Withdrawal from 
Treatmentc 
Post Treatment Follow-up 
Time of Visit 
Up to 14 days 
prior to first 
dose 
Day 1 
Week  1 
Week  2 
Week 3 
Week  4 
Week 5 
Week  6 
Week 7  
Week  8 
Week 10 
Week 12 
Week 14 
Week  16 
Week 18 
Week 20 
Week 23 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks/EWc 
Visit Window q 
N/A 
+/- 3 days 
+/- 5 days 
+/- 7 days 
Post last 
dose IMP 
+7 days 
+/-  14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Trtmnt/Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusiond 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Statuse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 Count and Viral Loadf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest X-Rayg  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Testh 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Patient Reported Health Status 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Slit Lamp Exam i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
X 
 
 
 
 
 
Ophthalmic Exam j 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X X X 
Single 12-LeadECGk 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X   
 
 
 
 
X 
 
 
 
 
 
 
 
 
Limited Physical Exam l 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X X 
X X 
Full Physical Exam l 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Laboratory Safety Tests 
(includes Full Blood Count)m 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Full Blood Count 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Study Medication/Compliancen 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PK Samplingo 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Xo 
 
 
 
 
 
 
 
 
Early Morning & Spot Sputum r 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Peripheral Neuropathy 
Assessment 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
Investigator Assessmentp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
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Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
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Page 16 of 96 
 
GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
 
a. 
Screening: Screening assessments can occur on different days within 14 days prior to Day 
1 dosing (randomization). If a participant fails screening, a full re-screen may occur at a later 
date.  All screening procedures must be repeated at re-screen visit, with the exception of the 
slit lamp examination, which can be used from a previous screening if within 8 weeks of 
anticipated randomization. 
b. 
Visit Schedule: If the duration of treatment is extended (see section 6.3, Treatment 
Modifications for details), unscheduled visits should be added every 3 weeks (+/- 7 days).   
1. End of treatment visit (final treatment visit) should be done within 7 days AFTER the 
last dose of IMP.  
2. If participant completes 26 weeks of therapy at week 33 due to full regimen pauses, 
an EXAMPLE of visit scheduling would be weeks 26, 29 and 33 (3 weeks from week 
29 plus 7-day window). In this scenario, the week 33 visit would be the end of treatment 
visit and should be completed within 7 days after last dose. 
3. If participant completes treatment at week 39 due to treatment extension, an example 
of visit scheduling would be visits at weeks 26, 29, 32, 35 and 39/End of treatment (3 
weeks plus 7-day window).  
4. Follow-up visits should be scheduled based on timing of last dose of IMP (e.g., 4-week 
follow-up to be scheduled 4 weeks after last dose of IMP). 
c. 
Follow-up Visits Early Withdrawal Participants: Once a participant has been discontinued, 
they will be required to attend an Early Withdrawal visit. If participant: 
1. Received/took < 14 doses, no additional follow-up visits are required.   
2. Received 15 or more doses and is withdrawn during treatment, follow-up after end of 
treatment/EW visit at week 12, week 26 (if not already performed) and week 78 are 
required. The week 12 visit will only require the ophthalmologic exams. The week 26 
and 78 follow-up visits will be to collect Serious Adverse Event (SAE) information 
(including verification of survival) and patient reported TB outcome information only 
and may be telephonic, a home or a site visit. This includes participants who are 
withdrawn from the trial due to meeting the treatment failure endpoint. Participant may 
need to return for visits to collect sputum samples to determine outcome status. 
3. For participants who are withdrawn during post treatment follow-up, site should 
perform study procedures required for week 78 post treatment follow-up visit. If 
participant will not return for visit, site should obtain information on SAE and patient 
reported TB outcome as noted above in no 2. 
d. 
Inclusion/Exclusion: to be confirmed at screening and prior to randomization.  
e. 
HIV testing: If HIV status is a confirmed known positive, repeated HIV test is not needed 
provided that a documented HIV test result (ELISA, Western Blot or Electro-
Chemiluminescence) is available. If HIV status is unknown or suspected negative, HIV test 
will be requested. If an ELISA and/or Western Blot and/or Electro-Chemiluminescence based 
HIV test was performed within 4 weeks prior to screening, it should not be repeated if 
documentation of testing method and negative HIV results can be provided. Repeated HIV 
testing, during the Screening period is permitted for indeterminate HIV results. 
f. 
CD4 count and viral load:  Required for all HIV-positive participants, viral load and CD4 
required at screening, CD4 will be tested at end of treatment or early withdrawal from 
treatment visit. 
g. 
Chest X-Ray: A chest x-ray (digital image) within 6 months prior to or at screening, will be 
obtained and read locally by Investigator or designee. Digital images will be provided to 
Sponsor, this process will be described in a separate document, the Radiology Manual. 
h. 
Urine Pregnancy: Women of child-bearing potential only, whether they are sexually active or 
not.   
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 17 of 96 
i. 
Slit-Lamp Exam: Slit Lamp examination will be performed by an Ophthalmologist with 
AREDS2 training: 
1. For participants who receive < 14 doses of IMP, exam at: Screening only. 
2. For participants who receive 15 days to < 12 weeks of treatment, exams at: Screening 
and the 12-week post treatment follow-up visit. 
3. Participants who complete > 12 weeks of treatment exams at: Screening, End of 
Treatment or Early Withdrawal and the 12-week post treatment follow-up. 
j. 
Ophthalmic Exam: to include Ophthalmologic Medical history at Screening; All exams to 
include Visual Acuity (distance testing) and Colour Vision assessment.   Can be done by any 
trained study staff throughout study.  Screening exam must be done by Ophthalmologist in 
addition to trained study staff that will perform exams throughout the study. 
k. 
Single 12-Lead ECG: When possible, should be performed at approximately the same time 
of day (+/- 1 hours) and in the same fed/fasted state throughout the trial (e.g. 4 hours after 
lunch). Central ECG analysis will be performed. Central reading of screening results will be 
used to determine eligibility. 
l. 
Physical Exam:  Limited Physical exams should include weight and a gross neurological, 
pulmonary, cardiovascular and abdominal exam. Height will only be collected as part of full 
exam at screening. 
m. Safety Laboratory Assessments/Urine Drug Screen: The Safety Laboratory sampling 
methodology and requirements will be described in a separate document, the Laboratory 
Manual, which will be provided prior to the trial start. The following analyses will be performed: 
• 
Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential, platelet count).  
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK).  GGT will be done at screening. 
• 
When managing participants with elevated liver enzymes at an unscheduled visit, the 
Investigator can request additional tests, in addition to the repeated LFT [e.g. 
Gamma Glutamyl Transferase, screening for hepatitis A, B, C; to assist in ruling out 
other causes of abnormal liver test (e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection). 
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis. 
• 
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates, 
benzodiazepines, barbiturates, at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 2.  Positive results will not automatically 
exclude participant from the trial. 
n. 
Study Medication/Compliance: Study medication administration will be supervised per local 
site practice to assure compliance to regimen. 
o. 
PK Sampling:   The dates and times of the two doses of IMP taken prior to all pre-dose PK 
samples will be collected in the eCRF.    
Specific PK blood draws will be obtained as follows (pre-dose to be done after ECGs): 
1. Day 1; pre-dose (within 2 hours prior to dosing) 
2. Week 2: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
3. Week 8: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
4. Week 12: pre-dose (within 2 hours prior to dosing)  
5. Week 20 or at early withdrawal if prior to week 20: pre-dose (within 2 hours prior to 
dosing) and 2–3 hours post-dose 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 18 of 96 
• When participant is discharged and seen as an outpatient, site should make every effort to 
collect 6-8 hour sample at week 8 when operationally and logistically feasible.  
• Hospitalization information (e.g. discharge date) will be collected in the eCRF. 
• If the full regimen or linezolid is paused, PK sampling should be delayed until full regimen 
or linezolid are resumed. 
• PK sampling should be completed even if the participant’s linezolid dose has been 
lowered or linezolid has been permanently discontinued.  
• Sites may bring participant back at a scheduled or unscheduled visit (can occur outside of 
visit windows) to collect PKs to ensure draw is done when IMP is administered.  
p. 
Investigator Assessment: Principal Investigator to review participant status and assess 
whether TB treatment at current visit is considered a “success” or “failure”.  If considered a 
failure, should specify if based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. To be completed at 26 and 78 week post treatment follow-up visits and at any 
time Investigator determines that participant fulfills criteria for outcome of treatment failure. 
q. 
Visit Windows: the windows noted on the flowchart for timing of visit also apply to timing 
within a visit.  For example, procedures that are difficult to schedule such as ophthalmology 
exams, should be scheduled within +/- 3 days of scheduled visit from Day 1 to Week 8 or +/- 
14 days within scheduled visit at the week 12 post treatment follow-up visit.  Sites should 
make every effort to ensure all other procedures are done on the same day when possible. 
r. 
Sputum Sampling: 
Visit 
 
Sample 
Tests 
EMS 
SPOT 
ISOLATE* 
 AFB Smear  
microscopy  
MGIT culture, 
speciation 
Molecular 
testing 
MIC:  
B, Pa, L 
MGIT DST  
 
Genotyping 
Extended 
DST (paired 
with baseline 
isolate) 
Screening  
(Day -14 to -1) 
 
 
 
 
S 
S 
S 
  
  
  
 
Baseline (Day 1) 
or 1st positive 
between screening 
and wk4 if Day 1 
negative or 
contaminated  
 
 
 
  
  
  
C 
C 
C 
L (when 
applicable, with 
isolate below) 
All Visits Post 
Screening 
 
 
 
  
S 
  
  
  
  
 
1st positive for MTB 
at/after week 16 for 
participant not 
responding to 
therapy and/or 1st 
positive during 
follow-up for 
potential new 
infection 
 
 
 
 
 
S 
C 
C 
C 
L 
C –   Central Mycobacteriology Laboratory (specialized facility) 
S –   Study Mycobacteriology Laboratory (facility that receives sputum samples directly from site) 
L –   Lab (as applicable per Country) that performs extended DST beyond panel at Central lab 
*Preferably from EMS Sample w hen available.  Alternate isolate can be requested if initial one is 
contaminated, or the test needs to be repeated. 
 
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Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
Page 19 of 96 
SPUTUM SAMPLES GENERAL: If EMS (early morning sputum) is not available, site should 
make every attempt to collect two spot samples at least 30 minutes apart.  
 
PRE-SCREENING SAMPLES: If consent granted by participant, and when applicable, site can 
request pre-screening culture/isolate/DNA from current TB diagnosis/disease course to be sub-
cultured and shipped and/or tested: 
• 
at the study lab if/when those samples could support inclusion in trial.  
• 
at the study/central lab for relevant participants with no baseline (no positive cultures from 
screening through week 4). 
 
MOLECULAR TESTING:  
• 
At Screening: GeneXpert, Hain MTBDRplus or equivalent to determine MTB complex and 
Rifampicin resistance. 
• 
Positive MTB at/after week 16: Hain MTBDRplus and HainMTBRsl 
 
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including but not limited to 
fluoroquinolones and injectables. 
 
STORAGE: MTB isolates from all positive cultures to be stored at the study laboratory until trial 
closure for the applicable study tests. The cultures as well as the extracted MTB DNA from the 
applicable baseline and follow-up isolates will also be stored at the central lab for potential further 
work to validate new assay tools for 5 years after trial closure. 
 
CENTRAL LAB: Results from testing at central lab (MIC, DST and genotyping) will not routinely 
be provided to sites.  In the event that results are necessary to determine appropriate participant 
treatment, Sponsor will provide available drug susceptibility results to the site. Genotyping will be 
performed on paired DNA extracts to determine if the participant was a relapse or reinfection (See 
SAP for details). 
 
EXTENDED DST TESTING: Paired isolates from baseline and at/after week 16 should be 
shipped to a relevant lab (as applicable/available per Country) for DST extending beyond the 
panel of drugs tested at the central lab.  Extended results will be provided to the site to inform 
appropriate participant treatment.   
 
 
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2 
Introduction and Rationale 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is now the world’s leading infectious 
disease killer and is responsible for more deaths than HIV.(43) It is the leading cause of death 
among HIV-infected individuals, and there is more TB in the world today than at any other time in 
history. As a result of poor treatment adherence, in addition to primary transmission, drug 
resistance is becoming more common and fears of an epidemic with strains of extensively drug-
resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs and regimens for TB 
are needed for the growing number of patients with XDR TB.  
Outcomes of treatment for XDR-TB using the best available treatments have traditionally been 
very poor.  The best treatment historically has been to use available second line drugs individually 
tailored based on drug susceptibility testing in an inpatient setting to assure adherence with 
treatment lasting from 24 months to much longer for patients without culture conversion.  The 
most detailed report using this approach with long term follow-up prior to the use of linezolid, 
bedaquiline or delamanid in regimens has come from South Africa, where the HIV co-infection 
rate among patients with XDR-TB ranges from 40 to 70%.  A cohort study of 107 patients with 
XDR-TB found cure or completion of therapy at 24 months to be 16%, with 46% having died.(28)  
In another report from South Africa of 114 patients with XDR-TB, 22% completed treatment 
successfully.(21)  The largest evaluation of treatment outcomes was noted in the WHO 2014 annual 
tuberculosis report of 1269 patients in 40 countries, where 22% of patients with XDR-TB 
completed treatment successfully and 35% died.(42) A meta-analysis of 397 patients with XDR-TB 
from 31 centers, with HIV coinfection <10%, reported 32% treatment success.(17)  Reports of the 
outcome of XDR-TB treatment from Peru (43 patients, 42% treatment success)(2) and Ukraine 
(114 patients, 22% treatment success)(11) have been similar.  Based on these reports, the success 
of traditionally available drug therapies for treating XDR-TB infection is substantially less than 
50% and in the most detailed and largest reports is less than 25%. 
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with XDR-TB might be improved when added to background regimens. Experience 
recently published from the C209 uncontrolled study of bedaquiline given on a background of 
multiple drugs notes that the subset of 38 patients with XDR-TB had rates of sputum culture 
conversion to negative of 62.2%.(29) However, in this study only one patient with XDR-TB was co-
infected with HIV. All participants were required to have Mycobacterium tuberculosis (MTB) 
isolates susceptible to at least 3 drugs at enrolment, and patients had a median of only 5.4 months 
of treatment-free follow-up. This study added bedaquiline for 6 months to a background regimen 
of many drugs given for 18 months or longer. 
While treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR-
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.(43)  This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% 
died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information.   
With such poor historical outcomes for patients with XDR-TB and with the complexity, expense 
and toxicity of treatments for all forms of drug resistant TB, novel drug combinations are 
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desperately needed to improve treatment outcomes. Linezolid was identified in a small study as 
a potentially efficacious drug in patients with XDR-TB when added to a failing regimen(9) and this 
drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of three drugs for which there is little, if any, pre-existing resistance 
among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]), there is the opportunity 
to evaluate a new regimen that may be administered orally once daily to treat patients with XDR-
TB. Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, it is 
hypothesized in the design of the ongoing Nix-TB clinical study that patients with pulmonary XDR-
TB may have relapse-free cure after as little as 6 months’ treatment with the B-Pa-L regimen. 
Therefore, since 2015, the TB Alliance has sponsored a study with a 6 month treatment duration 
with the B-Pa-L regimen in participants with XDR-TB or MDR TB not responsive to or intolerant 
to therapy (the Nix-TB study).(1) 
A key advantage of this regimen over standard of care for MDR-TB as well as XDR-TB is that this 
is an all-oral daily regimen for 6 months of treatment in comparison to standard regimens of 6-8 
drugs over 9-30 months of treatment that includes daily injections for a minimum of 6 months. 
The NC-007 trial takes this regimen into a randomized Phase 3 trial to optimize the dosing scheme 
for linezolid and the benefit relative to risk, and to expand the patient population to include 
individuals with pre-XDR TB. 
The information presented below first details the trial rationale, then key preclinical information 
and human efficacy and safety information for each of the drugs in the regimen and then presents 
preclinical and clinical data to support the combination of these drugs in a regimen to treat patients 
with XDR, pre-XDR and MDR treatment intolerant/failure-TB. 
2.1 Trial Rationale 
2.1.1 Trial Design Rationale 
This trial will provide a regimen containing 3 drugs against which there is no expected MTB 
resistance in the community for patients with limited treatment options while simultaneously 
gathering important efficacy and safety data on a regimen that could potentially treat all strains of 
MTB. Data from previous trials shows that the combination of B-Pa is well tolerated and has the 
potential to shorten treatment in patients who are susceptible to the drugs. The ongoing Nix-TB 
trial has shown that the B-Pa-L regimen has manageable toxicity and encouraging efficacy as an 
all oral 6 month regimen administered to patients with XDR-TB. This current trial will provide 
important information on the toxicity and efficacy of the regimen under alternate doses and 
durations of linezolid to optimize the dosing scheme for the best benefit to risk balance. 
2.1.2 Trial Drug Rationale 
2.1.2.1 Bedaquiline  
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this study bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 18 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
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combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 study that administered bedaquiline 200 mg daily over 8 weeks, and 
by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
The NC-005 study allows the efficacy and safety to be compared for treatment arms that dosed 
bedaquiline at the currently registered dose and at 200 mg daily for the 8 weeks of the trial.  Briefly, 
Study NC-005 evaluated a regimen in patients with drug susceptible pulmonary TB given 
bedaquiline with pretomanid and pyrazinamide over an 8 week period.  One arm was to enroll 60 
patients who were to be given this regimen with bedaquiline dosed as approved for marketing 
(referred to as the B (loading dose/t.i.w.) PaZ arm), and another 60 patients were to be enrolled 
who would be given the regimen with bedaquiline dosed at 200 mg daily (referred to as the B 
(200mg) PaZ arm).  Another group of patients with DS TB were randomized to treatment with 
standard HRZE therapy.  Patients with MDR-TB were given the regimen with bedaquiline dosed 
at 200 mg daily in addition to moxifloxacin (referred to as the B (200 mg) MPaZ MDR-TB arm).  
The primary endpoint was The Bactericidal Activity (BATTP (0‐56)) as determined by the rate of 
change in time to sputum culture positivity (TTP) over 8 weeks of treatment in the Mycobacterial 
Growth Indicator Tube system, represented by the model‐fitted log (TTP) results as calculated by 
the regression of the observed log (TTP) results over time.  The assessments of safety and 
tolerability included the incidence of Treatment Emergent Adverse Events (TEAEs) presented by 
severity (DMID Grade), by drug relatedness and seriousness, and for those leading to early 
withdrawal and leading to death, by group.  In addition, quantitative and qualitative clinical 
laboratory result measurements were evaluated, including group summaries of observed values 
and changes from baseline.  Pharmacokinetics for all participants included pre-dose samples on 
9 days during and one day following dosing with the regimen.  Fifteen PK Sub‐study participants 
in each treatment arm had in addition intense PK sampling on Days 14 and 56. 
Efficacy of bedaquiline 200 mg daily dose vs the marketed dosing scheme over 8 weeks 
In the efficacy analysis of the NC-005 trial, based on liquid media collected from overnight sputum 
samples, the B(200 mg)MPaZ MDR-TB treatment group showed the highest bactericidal activity 
over the 8-week treatment period, followed by that of B(200 mg)PaZ, B(loading dose/t.i.w.)PaZ 
and then HRZE. It appears clear that the daily dosing regimen for bedaquiline provided at least 
as good a result in the primary efficacy analysis as the registered dosing scheme for bedaquiline.   
Safety of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
Adverse events, including serious adverse events and Grade III/IV adverse events were similar 
among groups.  In particular, the mean change from baseline in the corrected QTc intervals was 
numerically less in the participants given bedaquiline daily than in the participants given 
bedaquiline with the labelled dosing scheme.  Measures of potential hepatic toxicity, including 
participants with greater than 3 fold or 10 fold elevations in aminotransferase levels, were 
numerically greater in participants given the labelled dosing scheme than subjects given daily 
doses of bedaquiline.   
Pharmacokinetics of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
A population PK model published by McLeay in 2014 was used with PK data from Study NC-005 
to simulate the expected bedaquiline exposures when dosed at 200 mg daily followed by 100 mg 
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daily for the remainder of the study in comparison to the labelled dosing scheme with bedaquiline 
administered for 6 months.(14)  The key findings from the simulations of the proposed dosing 
scheme for NC-007 of bedaquiline administered 200 mg daily over 8 weeks followed by 100 mg 
daily for an additional 16 weeks are: 
• 
The exposures of the proposed dosing scheme (Cmax, mean or trough) are not expected to exceed 
the exposures associated with the labelled scheme on Day 14 at the end of the 400 mg daily 
dose.  With the labelled dosing scheme, the highest exposures are on Day 14 at the end of 
the 400 mg daily loading dose. 
• 
The average daily exposures with the proposed dosing scheme over 6 months are within (or 
not substantially different from) the range of exposures over 6 months of the labelled dosing 
scheme. 
• 
The cumulative exposure, in terms of AUC over time, is similar between the proposed dosing 
scheme and the labelled scheme 
2.1.3 Pretomanid 
Pretomanid has demonstrated good microbicidal activity at the 200mg daily dose as monotherapy 
in studies PA-824-CL-007 and PA-824-CL-010, in combination with either bedaquiline or 
pyrazinamide over 14 days in the early bacteriocidal activity (EBA) Study NC-001-(B-M-Pa-Z), in 
combination with either bedaquiline and/or pyrazinamide and/or clofazimine over 14 days in the 
EBA Study NC-003-(B-C-Pa-Z), and in combination with bedaquiline and linezolid over 6 months 
in the Nix-TB study.  In the EBA Study PA-824-CL-010 the 100mg dose demonstrated similar 
microbicidal activity to the 150 and the 200mg daily dose over 14 days. The Phase 2 trial NC-
002-(M-Pa-Z) evaluated this regimen at doses of pretomanid of both 100 mg and 200 mg relative 
to the HRZE control.   In this trial the efficacy results were similar between participants treated 
with 100 mg/day and 200 mg/day of pretomanid in the regimen, although for the primary endpoint, 
reduction in colony forming units of MTB from sputum, only the 200 mg/day dose group was 
statistically significantly better than the group randomized to standard HRZE therapy.  Safety was 
also similar between the groups, although the 200 mg/day group had more grade 2 adverse 
events than either the 100 mg/day group or the HRZE control group.  Because sterilizing relapse-
free cure of TB in patients with XDR-TB may ultimately require a regimen with higher drug 
exposures, the 200mg dose was chosen for evaluation in the Nix-TB study of the B-Pa-L regimen.  
The manageable toxicity of the regimen and very encouraging efficacy in the Nix-TB trial support 
taking the 200 mg dose of pretomanid forward in the NC-007 trial. 
2.1.4 Linezolid 
The standard dose of linezolid for a multitude of indications is 400mg or 600mg BID.  Doses of 
linezolid used to treat pulmonary TB in reported observational trials and case series range from 
300 mg to 1200 mg per day over periods of up to 20 months of treatment.  While the development 
of adverse events is generally higher with higher doses, the adverse events often ameliorate with 
a reduction of the dose or discontinuation of drug for several weeks and then reintroduction at a 
lower dose.  No controlled trials have clearly identified differences in anti-TB effect across a range 
of doses over long term treatment of TB. 
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In this trial, each arm will vary the linezolid dosing to identify the optimal ratio of efficacy to adverse 
events as noted below. The 4 arms, to which participants will be randomly assigned in a blinded 
manner, are: 
• 
Linezolid 1200 mg orally once daily for 26 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
• 
Linezolid 1200 mg orally once daily for the first 9 weeks, with the ability to interrupt or 
reduce the dose if needed based on toxicity.  
• 
Linezolid 600 mg orally once daily for 26 weeks, with the ability to interrupt or reduce the 
dose if needed based on toxicity. 
• 
Linezolid 600 mg orally once daily for the first 9 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
These dosing schemes for linezolid are chosen based on clinical experience in the Nix-TB trial, 
the company’s linezolid early bactericidal activity (EBA) study findings in the Lin CL-001 study, 
and preclinical data in the mouse model of infection. While the EBA study showed that a modestly 
greater bactericidal effect over 14 days at the highest 1200 mg daily dose (see further details 
below in Section 2.2.3), this dose appears to be associated in the Nix-TB trial and in published 
literature with a greater incidence of unwanted neuropathic and myelosuppressive effects than 
the 600 mg daily dose. While a full 6 months of linezolid therapy in the regimen may give greater 
culture conversion and avoid relapse, the mouse model found that linezolid dosing of only 1 or 2 
months, when B and Pa were given continuously for a total of 3 months, maximized relapse-free 
cure; in other words, similar to pyrazinamide in the present first line HRZE therapy, more than 2 
months of linezolid when combined with B and Pa does not increase relapse-free cure in the 
mouse model. Thus, the 4 treatment arms in this study will give randomized comparative 
information about the optimal duration and dose of linezolid in the regimen relative to efficacy and 
toxicity.  
The decision to give linezolid as a single daily dose is based on the results of the linezolid EBA 
study that showed over 14 days that similar bactericidal activity was noted whether the drug was 
given as a single daily dose or divided in to 2 doses. A single daily dose will ultimately enhance 
patient adherence and will reduce the total time the drug concentration is greater than the 
calculated concentration associated with mitochondrial toxicity (which we hypothesize to be the 
likely mechanism for the toxicities of peripheral neuropathy and myelosuppression). 
2.2 Agents to be Studied 
2.2.1 Bedaquiline 
Bedaquiline is being developed as part of combination therapies for pulmonary TB due to MDR-
TB and approved in 2012 in the USA under the provisions of accelerated approval regulations. 
Bedaquiline received conditional Marketing Authorization in the EU in 2014 and is approved in 
over 40 countries (EU countries counted individually). The approved indication may vary per 
country. Bedaquiline is marketed under the trade name SIRTUROTM.  Bedaquiline has a novel 
mechanism of action as it specifically inhibits mycobacterial ATP synthase, an enzyme that is 
essential for the generation of energy in MTB The inhibition of ATP synthase leads to bactericidal 
effects for both replicating and non-replicating tubercle bacilli. 
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In the placebo-controlled Phase 2b study C208 conducted in newly-diagnosed patients with 
sputum smear-positive pulmonary MDR-TB (including pre-XDR-TB), the addition of bedaquiline 
to a preferred background regimen of MDR-TB treatment resulted in a decreased time to culture 
conversion and improved culture conversion rates compared to placebo. Median time to culture 
conversion according to the primary analysis method was 83 days for the bedaquiline group 
compared to 125 days for the placebo group (p<0.0001; hazard ratio, 95% CI: 2.44 [1.57; 3.80]). 
The proportion of patients in the mITT population with sputum culture conversion after 24 weeks 
of treatment with bedaquiline or placebo in combination with background regimen (with patients 
who discontinued considered as non-responders), was 52/66 (78.8%) in the bedaquiline group 
and 38/66 (57.6%) in the placebo group. Durability of response seen in the bedaquiline treatment 
group was supported by the results at Week 120. The proportion of responders (with patients who 
discontinued considered as non-responders) at Week 120 was 41/66 (62.1%) in the bedaquiline 
group and 29/66 (43.9%) in the placebo group. 
In the Phase 2b, open-label study C209, conducted in 233 patients with sputum smear positive 
pulmonary MDR-TB, the median time to sputum culture conversion excluding patients with DS-TB 
and those that did not have a positive sputum culture at screening and/or baseline (mITT; 205 
patients), was 57 days. At Week 24, 163 of 205 (79.5%) patients responded to bedaquiline 
treatment as determined by sputum culture conversion rates. Conversion rates at Week 24 were 
highest (87.1%; 81/93) in patients with MDR-TB resistant to only RMP and INH, 77.3% (34/44) in 
pre-XDR-TB patients and lowest (54.1%; 20/37) in XDR-TB patients. 
The average terminal half-life of bedaquiline, is about 5.5 months. After reaching Cmax, however, 
there is initially a fairly rapid reduction in plasma bedaquiline concentrations over the dosing 
interval (with an estimated half-life of about 13 hours). Four weeks after ceasing bedaquiline 
intake, the mean bedaquiline concentrations were reduced by approximately 40% compared to 
the end of the bedaquiline treatment period in the C208 study. Administration of bedaquiline with 
food increased the relative bioavailability by about 2-fold compared to administration under fasted 
conditions. It is therefore recommended to take bedaquiline with food to enhance its oral 
bioavailability. 
CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline. Drug-
drug interaction (DDI) studies have showed reduced exposure to bedaquiline during combination 
with a strong or moderate inducer of CYP3A4 metabolism (i.e., rifampicin) and increased 
exposure during combination with a strong or moderate inhibitor of CYP3A4 metabolism (i.e., 
ketoconazole). Potential drug interactions with anti-retroviral drugs have been evaluated in three 
studies.  In an interaction study of single-dose bedaquiline and multiple-dose Lopinavir/ritonavir, 
exposure (AUC) to bedaquiline was increased by 22% (90% CI: 11-34). Co-administration of 
single-dose bedaquiline and multiple-dose nevaripine did not result in clinically relevant changes 
in the exposure to bedaquiline. Co-administration of a single dose of bedaquiline and multiple-
dose efavirenz (EFV) resulted in approximately a 20% decrease in the AUCinf  of bedaquiline with 
no alteration in the Cmax.  Modeling based on the data from this DDI study predicts average steady-
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state concentrations of bedaquiline and M2 to be reduced by 52% with chronic co-administration 
of bedaquiline and EFV.(5)  
Safety of Bedaquiline 
The Investigator’s Brochure for bedaquiline provides detailed safety information.5 
Data were used from 14 completed clinical studies to identify Adverse Drug Reactions (ADRs) 
according to the ICH guideline entitled, E6: Good Clinical Practice, Consolidated Guideline (ICH, 
1996): “…all noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. The phrase “responses to a medicinal product” means that 
a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out." 
The ADRs were identified from the pooled safety database of reported AEs in the Phase 2b clinical 
studies with bedaquiline, based upon a systematic well-documented approach and are presented 
for study C208 below in Table 1.  None of the ADRs reported in the controlled studies during the 
Investigational Treatment phase were considered serious. 
Table 1: 
ADRs C208 Stage 1 and Stage 2 
Adverse Drug Reactions (ADRs) in the Controlled Studies (C208 Stage 1 and Stage 2)  
During the Investigational Treatment Phase 
ADR (Grouped term), n (%) 
Frequency 
Any BDQ 
N=102 
Any Placebo 
N=105 
Nervous system disorders 
Headache 
Very Common 
24 (23.5) 
12 (11.4) 
Dizziness 
Very Common 
13 (12.7) 
12 (11.4) 
Cardiac disorders 
ECG QT prolonged 
Common 
3 (2.9) 
4 (3.8) 
Gastrointestinal disorders 
Nausea 
Very Common 
36 (35.3) 
27 (25.7) 
Vomiting 
Very Common 
21 (20.6) 
24 (22.9) 
Diarrhea 
Common 
6 (5.9) 
12 (11.4) 
Hepatobiliary disorders 
Transaminases increaseda 
Common 
7 (6.9) 
1 (1.0) 
Musculoskeletal and connective tissue disorders 
Arthralgia 
Very Common 
30 (29.4) 
21 (20.0) 
Myalgia 
Common 
6 (5.9) 
7 (6.7) 
 
a. 
Different AE preferred terms (i.e., transaminases increased, aspartate aminotransferase [AST] increased, 
alanine aminotransferase [ALT] increased, hepatic enzyme increased, and hepatic function abnormal) contribute 
to this ADR, w hile for the other ADRs the ADR is the preferred term. 
 
Of note, 13 deaths occurred in the C208 Stage 2 study: 10 subjects (12.7%) in the bedaquiline 
group and 3 subjects (3.7%) in the placebo group experienced an SAE leading to death. One 
death (alcohol poisoning) occurred during administration of bedaquiline. The median time to death 
for the remaining 9 subjects was 344 days after last intake of bedaquiline. One of the 10 deaths 
in the bedaquiline treatment group and 1 of the 3 deaths in the placebo group occurred after the 
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Week 120 window. In the bedaquiline group, the most common cause of death as reported by the 
investigator was TB or TB-related illness (5 subjects). For all deaths due to TB, the subject’s last 
microbiological outcome was either failure to convert or relapse. The causes of death in the 
remaining bedaquiline subjects varied. The investigator considered all the SAEs leading to death 
not or doubtfully related to bedaquiline/placebo. The imbalance in deaths is unexplained. In 
addition, no discernible pattern between death and sputum culture conversion, relapse, sensitivity 
to other drugs used to treat TB, HIV status, or severity of disease was observed.  
During clinical studies with bedaquiline a prolongation of QTc interval on the ECG was observed.  
Consequently, bedaquiline treatment initiation is not recommended in patients with, personal or 
family history of prolonged QT intervals, or additional risk factors for Torsades de Pointes. 
Detailed criteria are noted in Section 5.2 Exclusion Criteria. 
Increases in transaminases were seen in clinical studies during administration of bedaquiline in 
combination with a background regimen. Based on a review confirmed by an external 
hepatologist, it was concluded that bedaquiline has a signal for liver injury manifested by 
increases in AST and to a lesser extent ALT. Transaminase elevations are not unexpected given 
the number of other hepatotoxic drugs in the background regimens in clinical trials based on the 
publication by Keshavjee, which describes a 16.5% incidence of hepatotoxicity during MDR-TB 
treatment. (7) 
2.2.2 Pretomanid 
As detailed in the Investigator’s Brochure(6), pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti-
tuberculosis activity and a unique mechanism of action(35). Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB(10), and in vivo activity in a mouse model of tuberculosis(10, 
35).  
2.2.2.1 Pharmacology 
2.2.2.1.1 Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro studies demonstrated that pretomanid was active against actively growing 
drug-sensitive and drug-resistant MTB strains as well as against non-replicating MTB The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be similar to the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 
0.25 µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against 
drug-resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity. (6) 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO), (33) although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling studies also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.(12,13) 
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2.2.2.1.2 Key Non-Clinical Studies of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse studies.(18,19,20,36,40) In a mouse model of established TB, 
the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 
22 days after inhalation infection with H37Rv MTB is shown in Figure 1. In this model, the 
minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the 
development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum 
bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony forming units 
(CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 
100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
Figure 1: 
Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
2.2.2.2 Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology studies, 
in repeat-dose toxicity studies in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity studies, and in fertility and teratology studies in rats and rabbits.  
In the repeat-dose toxicity studies, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week study in rats, 50 mg/kg/day in a 13-week study in monkeys and 
<25 mg/kg/day (based on findings of thickening of the GI tract at all doses) in a 9-month study in 
monkeys. The major findings in safety and toxicity studies are listed below in Table 2 and are 
detailed in the Investigator’s Brochure .(6) 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
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repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development studies indicate no effects of PA-824 on fetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology studies and a Segment I fertility study. In this fertility study, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed study in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week study in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
study in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the electrocardiogram (ECG) as a prolonged QT interval corrected for heart 
rate (QTc). Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. 
Following a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation 
ranged from 21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-
administration of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog 
did not result in any greater effect on the QT interval than with either agent alone. After 
repeated daily doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
2.2.2.3 Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 studies with healthy adult 
male and female subjects, with 163 subjects receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 studies sponsored by the NIH included a Thorough QT study and a study 
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of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the 
studies are in the Investigator’s Brochure. 
2.2.2.3.1 Pharmacokinetics 
Several Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200 mg dose that increases total 
exposure by 88%. Interaction studies with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Study CL-006 was an open-label, fixed-sequence drug-drug 
interaction study to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs metabolised 
by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had 
minimal effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by 
measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax), area under the 
curve to the last available time point (AUC0-t), and area under the curve extrapolated to infinity 
(AUC0-inf ). The Cmax and AUC values for midazolam after co-administration with pretomanid 
were approximately 85% of those observed after treatment with midazolam alone. Furthermore, 
midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and half-life (t1/2) 
values were not different in the presence or absence of pretomanid. Therefore, 14 days’ dosing 
with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH sponsored this 
drug interaction study with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy subjects. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for the maximum concentration (Cmax) was 0.71, the GMR for the 24-hour area 
under the time-concentration curve (AUC0-24h) was 0.65, and the GMR for the trough 
concentration (Cmin) was 0.54. Concentrations of EFV when given with pretomanid versus given 
alone were similar. Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg 
once daily for 7 days, then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 
days, then LPV/r + pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + 
pretomanid, washout, then pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid 
alone from 16 PK-evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and 
for Cmin was 0.78. In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg 
for 7 days, then pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin 
versus pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and 
Cmin were 0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for maximum concentration (Cmax), area under the concentration-time curve (AUC0-
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24h), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz; 13%, 17%, 
and 21% with LPV/r; and 53%, 66%, and 85% with rifampin, respectively. 
2.2.2.3.2 Pretomanid Clinical Efficacy 
The first two Phase 2 studies to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first study (CL-007) demonstrated 
good EBA, but all doses in this study (200 to 1200 mg/day) had the same activity. The second 
study (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA 
was seen at a dose of 100 mg/day over 14 days (4) (Figure 2). 
Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010 
 
CFU = colony-forming unit; PA-824 = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Studies of Pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below in Section 2.3.2.  
2.2.2.3.3 Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure(6) provides detailed safety information. 
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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Across the 16 clinical studies with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy subjects across the 10 Phase 1 studies and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
studies.  Among the 289 healthy Subjects, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 1200 
mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical studies completed to date indicates pretomanid 
is well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these studies, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical studies completed to date as likely caused by 
pretomanid is blood creatinine increased.  A study of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close surveillance 
and careful management of participants who have elevations in aminotransferases and/or 
bilirubin. Serious liver injury, including death in 3 participants taking a combination of 
pretomanid, pyrazinamide and moxifloxacin, has occurred during clinical studies and the risk 
of liver injury may be higher for participants taking a combination of PA-824 and pyrazinamide 
than it is for the standard HRZE treatment. Therefore, close monitoring of liver function is 
required for participants who are administered PA-824, especially when combined with 
pyrazinamide.  Administration of the regimen of PaMZ has been associated with death in 3 
participants associated with hepatic injury. Furthermore, the HRZE control regimen, and both 
pyrazinamide and moxifloxacin, has been associated with drug induced liver injury and in rare 
cases hepatic necrosis.  Consequently, hepatic safety will be under close surveillance in all 
clinical studies. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human studies that involve exposure to pretomanid longer than 
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14 days.  These examinations will be conducted at baseline, near the end of the dosing period 
and 3 months after the end of study drug exposure.  These examinations are to follow up on 
the finding of cataracts in rats exposed to pretomanid in clinical studies. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple time 
points during the study.  Although the Thorough QT Study in healthy subjects found that 
pretomanid did not increase corrected QT intervals in a clinically meaningful way and did not 
add to the known effect of moxifloxacin, the ECGs will be carefully monitored during Phase 3.  
All ECGs will be interpreted and conduction intervals will be confirmed by a central cardiology 
service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Study NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology studies have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 study for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology studies found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 studies have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 studies) or FSH values (3 studies) at baseline and after daily 
dosing of regimens containing pretomanid in various combinations with moxifloxacin, 
pyrazinamide and bedaquiline.  A review of data from the 3 studies by an independent 
reproductive endocrine expert concluded that, based on the hormone evaluations to date, there 
is no evidence that PA-824 is a testicular toxicant in men at the doses and exposure times 
evaluated. 
2.2.3 Linezolid 
Linezolid is a synthetic antibacterial agent of the oxazolidanone class approved in many countries 
around the world for drug-resistant, gram-positive bacterial infections, including gram positive 
organisms such as Staphylococcus aureus, coagulase negative Staphlococcus and Enterococcal 
infections.  The recommended dose for these infections is 600 mg twice daily for up to 28 days of 
therapy.(23,24,26) Antimicrobial effects likely come from inhibition of protein synthesis in the 
ribosomes of the infecting organism.(8)  Resistance of MTB to linezolid is rare, as this drug has 
not been widely used to treat tuberculosis.  In a recent study using linezolid to treat patients with 
XDR-TB in Korea, none of 41 patients had resistance to linezolid at baseline.(9) 
Preclinical in vitro data shows linezolid is active against MTB, including MDR strains with minimum 
inhibitory concentrations (MICs) that range from 0.125-1 μg/mL.(38)  Recent studies of the 
bactericidal and sterilizing activity of linezolid in a mouse model of MTB infection have 
demonstrated linezolid alone causes marked reductions in lung colony forming units (CFUs) from 
mice following 1-3 months of therapy.(36) (Table 3, below) 
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Table 3: 
Murine Lung CFU counts during Treatment with Linezolid 
Monotherapy versus Standard Therapy 
 
Mean lung log10 CFU count (± S.D.) at: 
Regimen 
D0 
Month 1 
Month 2 
Month 3 
Untreated 
6.17 + 
0.27 
6.47 + 0.06 
 
 
2RHZ/4R
H 
 
3.47 + 0.37 
1.59 + 0.25 
0.50 + 0.51 
L 
 
4.97 + 0.26 
 
 
 
In recent years linezolid has been used to treat patients with MDR(28) and XDR-TB, although there 
have been no fully controlled trials of linezolid in a regimen for this indication.  The World Health 
Organization management guidelines place linezolid in Group 5 (“Agents with unclear role in 
treatment of drug resistant-TB”) in their groups of drugs to treat MDR-TB.(41) Over the past 10 
years small retrospective observational studies have reported good results when linezolid has 
been added to failing regimens for patients with MDR-TB.(9, 27, 34) The most compelling recent 
evidence linezolid may be of benefit to patients with XDR-TB was reported by Lee and colleagues 
from a study in S. Korea.(9)  Forty-one patients who had sputum culture–positive XDR-TB and who 
had not had a response to any available chemotherapeutic option during the previous 6 months 
were randomized to start linezolid at 600 mg daily or to delay therapy with linezolid at 600 mg 
daily for 2 months without changing their failing background regimen.  After confirmed sputum-
smear conversion, or at 4 months, patients underwent a second randomization to continued 
linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 
months.  Thirty four of 39 (87%) of the patients had a negative sputum culture within 6 months 
after linezolid had been added to their drug regimen.  As of the cutoff date prior to publication, of 
the 38 patients who received linezolid, 17 were still receiving the treatment per protocol, and 13 
had completed treatment, including 6 with no relapse during the treatment period, 4 with no 
relapse at the 6-month follow-up, and 3 with no relapse at the 12-month follow-up (end of study).  
While the standard dose of linezolid for short term use for severe bacterial infections is 600 mg 
bid, some clinicians and clinical trials using linezolid as Group 5 therapy to treat TB use only 300 
mg or 600 mg daily due to concerns about toxicity developing when used over a period of months 
(see below for a review of linezolid toxicity). (9)  However, there are no data to indicate what dose 
of linezolid is required or optimal to effectively treat TB infection.  Consequently, TB Alliance has 
recently conducted and completed an Early Bactericidal Activity trial to evaluate the use of 
linezolid over 14 days in patients with newly diagnosed DS Pulmonary TB in dosing schedules 
including 300 mg daily, 300 mg bid, 600 mg daily, 600 mg bid, 1200 mg daily, and HRZE at 
standard doses daily.  Preliminary unpublished in-house results using Bayesian mixed effects 
modelling have noted that there is a bactericidal effect of linezolid over 14 days that is substantial, 
but less than for the full HRZE regimen.  There is little difference between daily or twice daily 
dosing of the same total daily dose of drug, and there is a dose-response relationship between 
total daily dose and daily reductions in either total CFU counts on solid culture or increases in 
Time to Positivity in liquid culture (a decreased load of MTB is associated with an increase in Time 
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to Positivity).  Point estimates of the log of the daily increase in Time to Positivity over 14 days 
ranged from 2.278 for Linezolid 300 mg QD to 4.446 for linezolid 1200 mg QD, with the estimate 
of 6.860 for HRZE for reference. 
Figure 3:  
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin 
CL-001 
Bayesian Nonlinear Mixed Effects Regression Model: Posterior Estimates and 95% 
Bayesian Confidence Intervals 
 
HRZE = isoniazid, rifampin, pyrazinamide, and ethambutol 
2.2.3.1 Linezolid Clinical Safety 
Linezolid is currently marketed globally for a variety of acute infectious diseases and has been 
studied for the treatment of XDR-TB in several recent trials.(3,9) The following list of known and 
potential risks is based on the warnings and precautions and adverse reactions sections of the 
current package label.(23,24,26)  Of note, the approved indication for linezolid is for administration 
up to 28 days. 
 Warnings and Precautions 
• 
Linezolid should not be used in patients taking any medicinal product which inhibits 
monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking 
any such product. 
• 
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) 
has been reported in patients receiving linezolid. In cases where the outcome is known, 
when linezolid was discontinued, the affected hematologic parameters have risen toward 
pretreatment levels. Complete blood counts should be monitored weekly in patients who 
receive linezolid, particularly in those who receive linezolid for longer than two weeks, 
those with pre-existing myelosuppression, those receiving concomitant drugs that produce 
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bone marrow suppression or those with a chronic infection who have received previous or 
concomitant antibiotic therapy.  
•
Lactic acidosis has been reported with the use of linezolid. In reported cases, patients 
experienced repeated episodes of nausea and vomiting. Patients who develop recurrent 
nausea or vomiting, unexplained acidosis, or low bicarbonate level while 
receiving linezolid should receive immediate medical evaluation.
•
Spontaneous reports of serotonin syndrome associated with the co-administration of 
linezolid and serotonergic agents, including antidepressants such as selective 
serotonin reuptake inhibitors (SSRIs), have been reported.  Where administration of 
linezolid and concomitant serotonergic agents is clinically appropriate, patients 
should be closely observed for signs and symptoms of serotonin syndrome such as 
cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or 
symptoms occur physicians should consider discontinuation of either one or both 
agents. If the concomitant serotonergic agent is withdrawn, discontinuation 
symptoms can be observed (see package insert of the specified agent(s) for a 
description of the associated discontinuation symptoms).
•
Peripheral and optic neuropathy has been reported in patients treated with linezolid, 
primarily those patients treated for longer than the maximum recommended duration of 28 
days. In cases of optic neuropathy that progressed to loss of vision, patients were treated 
for extended periods beyond the maximum recommended duration. Visual blurring has 
been reported in some patients treated with linezolid for less than 28 days. If 
patients experience symptoms of visual impairment, such as changes in visual acuity, 
changes in color vision, blurred vision, or visual field defect, prompt ophthalmic 
evaluation is recommended. Visual function should be monitored in all patients 
taking linezolid for extended periods and in all patients reporting new visual symptoms 
regardless of length of therapy with linezolid. If peripheral or optic neuropathy occurs, 
the continued use of linezolid in these patients should be weighed against the 
potential risks.  Additional information on the neuropathies reported in recent studies 
of linezolid administered over prolonged periods to patients with TB infection is 
presented above in Section 2.2.3.
•
Convulsions have been reported in patients when treated with linezolid. In some of 
these cases, a history of seizures or risk factors for seizures was reported.
•
Postmarketing cases of symptomatic hypoglycemia have been reported in patients 
with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with 
linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been 
associated with hypoglycemic episodes in diabetic patients receiving insulin or 
hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia 
has not been established, diabetic patients should be cautioned of potential 
hypoglycemic reactions when treated with linezolid. 
In addition, the linezolid product label notes that there was an excess of abnormal liver function 
tests in comparator-controlled trials.  These abnormalities were noted in 0.4% of linezolid treated 
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patients in trials of skin and skin structure infections vs in 0.2% of clarithromycin treated patients, 
and in 1.6% of patients treated with linezolid versus 0.8% of patients with other treatments in trials 
of all other infections. 
Adverse events of linezolid long term therapy for Tuberculosis have been described in several 
literature reports. The most complete review is a meta-analysis by Cox which noted the proportion 
of adverse events necessitating treatment discontinuation was significantly different by dose: 
29.49% (95%CI 3.24–55.74) for ⩽600 mg daily vs. 60.75% (95%CI 42.69–78.81) for >600 mg 
daily (P = 0.05). (3) 
In a trial reported by Lee et al in S Korea(9), seven of 41 participants had myelosuppression, 
including anemia and neutropenia, primarily within the first 5 months, and only one participant 
withdrew due to anemia.  Six had clinically significant myelosuppression:  5 in 0-4 months and 1 
in 4-8 months, with 0 in 8-12 months. 
Peripheral and Optic Neuropathy:  
The linezolid product label notes these adverse events have been “ reported in patients, primarily 
those patients treated for longer than the maximum recommended duration of 28 days.  In cases 
of optic neuropathy that progressed to loss of vision, patients were treated for extended periods 
beyond the maximum recommended duration.  Visual function should be monitored in all patients 
taking ZVYOX for extended periods (>3 months) and in all patients reporting new visual 
symptoms, regardless of length of therapy.(26) 
In Lee, NEJM, 2012(9), the publication’s Supplemental Table 3 notes that 21 patients had clinically 
significant peripheral neuropathy spread over 12 months:  5 in months 0-4, 10 in months 4-8 and 
5 in months 8-12 (time of onset not noted for one).  Participants who developed any peripheral 
neuropathy had their dosing of linezolid interrupted, generally for several weeks, and then 
resumed at the lower dose of 300 mg/day (C. Barry, personal communication).  None of the 
participants withdrew from the study based on peripheral neuropathies.  At baseline, patients 
received visual acuity testing, contrast sensitivity and color vision tests. Seven cases were 
observed as having potential effects on vision; only two of 38 patients withdrew from study due to 
optic neuropathy.  For clinically significant optic neuropathy, one had this at 0-4 months, 2 at 4-8 
months and 3 at months 8-12.  Except for the 2 participants who withdrew from the study, the 
others resumed linezolid at the 300 mg dose after a hiatus of several weeks of treatment and 
completed the study with resolution of their visual acuity changes (C. Barry, personal 
communication). 
In the Schecter California Department of Health (DOH) review(32), peripheral neuropathy 
developed in 5 of 30 patients (no standardized monitoring), but only one withdrew from linezolid 
therapy.  One patient developed visual loss secondary to optic neuropathy after 10 months of 
linezolid therapy, but vision returned to normal 3-4 weeks after discontinuation. 
In Park, 2006(27), two patients of eight in the case series developed optic neuropathy after 8-9 
month and had linezolid discontinued; these patients also had peripheral neuropathy. After 
linezolid treatment was stopped, the optic neuropathy fully resolved after 2-3 months.  A total of 
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4 patients developed peripheral neuropathy at 4, 5, 8, 11 months; in the patients with optic 
neuropathy who stopped treatment, the peripheral neuropathic symptoms continued or improved 
only marginally. 
In Singla, 2012(34), two of 29 patients treated with linezolid, 600 mg daily over 12 months, stopped 
the drug because of peripheral neuritis (one patient) and optic neuritis (one patient).  The time 
course of these adverse events was not noted. 
2.3 Regimens to be Studied 
The regimen included in this study (B-Pa-L) has been selected based on the performance of the 
regimen in non-clinical pharmacology studies and on the combination of bedaquiline and 
pretomanid with other drugs in clinical studies NC-001 and NC-003.  In addition, improved 
treatment outcomes in XDR patients with the addition of linezolid to existing therapy provide 
support for combining linezolid with other drugs that have no pre-existing resistance.  Preliminary 
results from the ongoing Nix-TB clinical study demonstrate the encouraging potential of this 
regimen. 
This regimen has the potential to treat drug resistant strains of tuberculosis. This is an oral 
regimen, removing the need for injectables as part of drug resistant treatment, and is also 
projected to be markedly less expensive than current XDR-TB therapy. Treatment duration is 
anticipated to be shorter than current regimens for drug resistant TB, based on findings in mouse 
models of infection and the fact that all participants will be treated with three active drugs against 
TB for which there is no expected resistance.  
The key data supporting the use of the B-L-Pa regimen are described below. 
2.3.1 Non-Clinical Studies 
In the murine model of TB, addition of bedaquiline to HRZ results in accelerated clearance of MTB 
(5,36) when compared to HRZ alone. While the combination of bedaquiline and pretomanid in the 
murine model of TB in initial studies appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ(15) and in a subsequent study it was more 
active in the mouse model than HRZ.(16) Thus a novel regimen with bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance.   
Recent studies of the bactericidal and sterilising activity of linezolid in an animal model where 
mice were given high dose aerosol MTB infection have demonstrated that linezolid alone and in 
combination with bedaquiline and pretomanid causes marked reductions in lung CFUs from mice 
following 1 to 3 months of therapy (Table 4 below). Additionally, all mice treated daily with 
bedaquiline, pretomanid and linezolid (B-L-Pa) were cured of the infection after 3 months of 
therapy as evidenced by no MTB cultured from lungs when mice were sacrificed 3 months after 
the completion of therapy that lasted 3 months or more (Table 4, below). This is in contrast to the 
5-6 months required in previous studies to cure all mice when treated with the standard of care 
isoniazid, rifampicin and pyrazinamide (HRZ; note that typically ethambutol is not used in the 
mouse model of infection). Additional mouse studies were performed to determine whether 
shorter durations of linezolid, with continuation of the other drugs, would result in relapse-free 
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cure in the mouse (Table 4 below). Treatment with linezolid for only the first 4 to 8 weeks of a 
3-month treatment also resulted in relapse-free cure when lungs from the mice were cultured 
3 months after the completion of therapy.(37) 
Table 4: 
Murine Relapse Data 
Impact of Linezolid Treatment Duration on Lung Colony Forming Unit Counts 
Assessed during Treatment and Proportion of Mice Relapsing after Treatment 
Completion 
Proportion of mice relapsing after treatment for: 
Regimen 
2 months 
3 months 
2RHZ/RH* 
8/14 
(57%) 
BPa 
3/14 
(21%) 
3BPaL ** 
6/15 
(40%) 
0/15#† 
(0%) 
2BPaL/1BPa*** 
0/15#† 
(0%) 
1BPaL/2BPa 
9/15 
(60%) 
0/15#† 
(0%) 
#p = 0.11 vs. BPa; †p≤ 0.001 vs. RHZ 
*2RHZ/RH means 2 months on the full regimen and a third month on only RH 
**3BPaL means 3 months on the full regimen 
***2BPaL/1BPa means 2 months on the full regimen and a third month on only BPa 
****1BPaL/2Bpa means 1 month on the full regimen and a third month on only BPa 
B – bedaquiline, H-isoniazid, L-linezolid, Pa-pretomanid, R-rifampicin, Z-pyrazinamide 
 
In conclusion, linezolid increases the sterilising activity of the bedaquiline-pretomanid 
combination; no MTB could be cultured from the lungs of mice 3 months after cessation of 3 
months of treatment with the combination, in contrast to MTB cultured from 13 of 15 mice treated 
with the standard 2RHZ/4RH regimen over 3 months. In addition, limiting the duration of linezolid 
to the first month of treatment does not affect linezolid’s contribution to the sterilising activity of 
the regimen in the preclinical mouse study.   
Prior to the use of pretomanid in combination with bedaquiline in clinical study NC-001, a 
preclinical cardiovascular safety pharmacology study was conducted in unrestrained beagle dogs 
with both drugs to explore the potential for additive effects on QT prolongation induced by the 
combination.  Results indicate that administration of 100 mg/kg bedaquiline daily for 7 days 
causes a small increase in QTc interval by Day 6 in some animals that is not influenced by the 
addition of 100 mg/kg pretomanid on Day 7. The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the subcutaneous route of administration and not 
related to the plasma exposure.   
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2.3.2 Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or 
Linezolid 
2.3.2.1 Clinical Study NC-001 
Study NC-001 was a partially double-blind, randomized, parallel group study in adult male and 
female participants with newly diagnosed, uncomplicated, smear-positive, pulmonary TB. A total 
of 85 participants met study eligibility criteria and were randomly assigned to one of the six 
treatment groups. All study treatments were given once daily for 14 days. Substantial EBA activity 
was demonstrated across participants in all arms of the study and the daily reductions in cultured 
colony counts per mL of sputum are presented in Table 5 below. 
Table 5: 
Summary Statistics for EBACFU(0-14) 
Derived Using Bi-Linear Regression, Study NC-001 
Treatment Group 
N 
Daily Mean (SD)  
EBACFU(0-14) 
Pretomanid + pyrazinamide + moxifloxacin 
13 
0.23 (0.128) 
Pretomanid + pyrazinamide 
14 
0.15 (0.040) 
Pretomanid + bedaquiline  
15a 
0.11 (0.050) 
Bedaquiline alone 
14 
0.07 (0.068) 
Bedaquiline + pyrazinamide 
15 
0.13 (0.102) 
Rifafour e-275 
10 
0.14 (0.094) 
 
There were no Serious Adverse Events from the study among participants treated with 
pretomanid and bedaquiline.  Three participants in a bedaquiline-containing treatment arm were 
withdrawn: one participant on the bedaquiline only arm for a Grade 3 ALT and Gamma-Glutamyl 
Transferase (GGT) elevation (although the elevation occurred prior to the first dose of study 
medication), one on a bedaquiline plus pyrazinamide (weight banded) arm for a Grade 3 ALT 
and AST elevation, and one on a pretomanid and bedaquiline arm for to a Grade 3 ALT 
elevation. 
2.3.2.2 Clinical Study NC-003  
Efficacy 
In the 14 day EBA study NC-003 two monotherapy and four different combinations of bedaquiline, 
pretomanid, pyrazinamide and clofazimine were evaluated in DS-TB participants. Fifteen 
participants were randomized into 7 treatment arms: C, Z, B-Pa-Z-C, B-Pa-Z, B-Pa-C, B-Z-C, and 
HRZE control. This study demonstrated no EBA for the clofazimine monotherapy arm and modest 
EBA for the pyrazinamide monotherapy arm. However, all of the experimental regimens 
demonstrated EBA. In general, adding clofazimine to the various agents resulted in either no 
increase in EBA, or a decrease when compared to a similar regimen that did not include 
clofazimine. In this study, the experimental regimen with the best EBA was B-Pa-Z which 
demonstrated a rate of decrease in both logCFU and logTTP that was at least as good as the HRZE 
control. The daily logCFU results are presented in Table 6. Similar results were found when TTP 
was used to calculate the bactericidal activity over 14 days (BA(0-14)). 
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Table 6: 
NC-003 Efficacy Results: Daily BAlog CFU(0-14) 
Arm 
logCFU 
BPaZC 
.124 
BPaZ 
.180 
BPaC 
.086 
BZC 
.098 
Z 
.036 
C 
-.025 
Rifafour 
.152 
Safety 
Generally, the regimens in this study were well tolerated. Table 7 provides a list of the overall 
safety findings. The only SAE experienced in the study was in a participant in the clofazimine 
monotherapy arm. Otherwise, the rates of treatment emergent AEs (TEAEs) were similar across 
the treatment arms. One participant in the B-Pa-Z arm was withdrawn from the study due an 
adverse event of increased liver function tests (alanine aminotransferase (ALT), AST and GGT).  
Table 7: 
NC-003 Safety Data 
 
BPaZ
C 
BPaZ 
BPa
C 
BZC 
Z 
C 
HRZ
E 
Total 
N 
15 
15 
15 
15 
15 
15 
15 
105 
Participants with: 
TEAEs 
11 
9 
8 
10 
10 
9 
8 
65 
TEAEs leading to death: 
Serious TEAEs 
 
 
 
 
 
1 
 
1 
TEAES leading to early withdrawal 
 
1 
 
 
 
 
 
1 
TEAEs leading to discontinuation 
of study drug 
 
1 
 
 
 
 
 
1 
Drug-related TEAES 
8 
5 
7 
3 
5 
6 
5 
39 
Serious, drug-related TEAEs 
 
 
 
 
 
 
 
 
Grade III AEs 
 
2 
1 
2 
 
1 
 
6 
Grade IV AEs 
 
1 
1 
 
 
 
 
2 
Grade II/IV AEs 
 
2 
1 
2 
 
1 
 
6 
 
QT Prolongation 
Because bedaquiline and clofazimine are both known to prolong the QT interval, intensive ECG 
monitoring was included in the study endpoints. The mean change from baseline in QTcB and 
QTcF tended to be larger at 5 hours than at 10 hours post-dose in the (B-Pa-Z-C) arm and in the 
(B-Pa-C) arm.  No QTcB or QTcF ≥500 ms were reported.  An increase from baseline to Visit 5 
and subsequent visits of ≥60 ms in QTcB was reported for 2 participants in the (B-Pa-C) arm and 
for 1 participant in the clofazimine alone arm.  An increase from baseline to Visit 5 and subsequent 
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visits of ≥60 msec in QTcF was reported for 4 participants in the (B-Pa-C) arm and for 1 participant 
in the clofazimine alone arm.  For both QTcB and QTcF, the (B-Pa-Z-C) arm and the (B-Pa-C) 
arm showed the largest increase from baseline. Clofazimine will not be used in any treatment 
arms in the NC-007 study. 
2.3.2.3 The Nix-TB Study  
The NiX-TB Study is an ongoing open-label study assessing the safety and efficacy of bedaquiline 
plus linezolid plus pretomanid in participants with pulmonary infection of either XDR-TB or 
treatment intolerant/non-responsive MDR-TB. The study regimen includes: bedaquiline 400 mg 
once daily for 2 weeks then 200 mg 3 times per week plus pretomanid 200 mg once daily plus 
linezolid 600 mg twice daily amended (22 Jan 2016 protocol) to 1200 mg once daily. Treatment 
duration is 6 months, although if participants are still culture positive at month 4, there is the option 
to extend treatment to 9 months or withdraw. The primary endpoint is the incidence of 
bacteriologic failure or relapse or clinical failure through follow-up until 6 months after the end of 
treatment. Secondary Endpoints include: incidence of bacteriologic failure or relapse or clinical 
failure through follow-up until 24 months after the end of treatment as a confirmatory analysis, 
time to sputum culture conversion to negative status through the treatment period, and the 
proportion of participants with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 
end of treatment. In addition, linezolid dosing (actual) and efficacy will be explored and changes 
from baseline will be evaluated for TB symptoms, Patient Reported Health Status, body weight, 
and measures of safety. 
Efficacy Experience to Date:   
Sixty-nine participants have been enrolled as of February 1, 2017, at 2 sites in South Africa. Forty-
nine percent of the participants are HIV positive, 79% have XDR-TB and 21% have MDR 
intolerant or resistant to prior therapy.  Forty have completed the 6 months of therapy with the 
drug regimen and 31 have been followed to the primary endpoint at 6 months after treatment. All 
surviving patients were culture negative by 4 months, with 74% negative at 8 wks. As of February 
1, 2017, there has been 1 microbiological relapse during follow up after drug therapy and 1 
participant has had a new infection during follow-up with Drug Sensitive TB.  This study will 
continue to enrol participants until the NC-007 study is initiated. 
Safety of the B-Pa-L Regimen in the Nix-TB Study:  As of December 2016, four participants have 
died in the study. The causes of death have varied and include: 2 with multi-organ disseminated 
TB who died within the first 5 weeks of therapy, 1 who had a gastrointestinal bleed and 1 with 
multi-organ failure and disseminated TB on autopsy. No deaths or SAEs have been caused by 
hepatic injury. No participants have been withdrawn from the study except for the 4 who died.  
The expected linezolid toxicities of peripheral neuropathy and myelosuppression were common 
but manageable.  Seventy-one percent of participants had at least one linezolid dose pause (22% 
of all participants due to myelosuppression and 28% due to peripheral neuropathy), during the 6 
months of treatment. One had peak ALT and AST > 3 X ULN and total bili > 2X ULN, but these 
improved and treatment restarted without a recurrence.  There were 7 cases of grade 3 or 4 
transaminitis and all resolved and allowed the study regimen to be continued. There were no 
cases of optic neuritis. While participants have required close surveillance for signs and 
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symptoms of neuropathies and bone marrow suppression, these toxicities have been 
manageable.  
2.4 Overall Benefit/Risk Assessment 
The recent report of the long term outcome of patients with XDR-TB treated in S. Africa highlighted 
the very poor prognosis for patients with this disease.  After 60 months of follow up 73% of 107 
patients had died and only 11% had a favourable outcome(28).  These patients have infection with 
MTB resistant to many/most of the available drugs to treat tuberculosis.  Patients with XDR-TB 
have limited treatment options due to their resistance profile, and the drugs that are typically used 
in Standard of Care have many side effects, some are administered as injectables and have poor 
treatment outcomes in XDR-TB.  Similarly, patients with Pre-XDR-TB and patients with MDR-TB 
who are failing or are intolerant to treatment have traditionally poor outcomes and are a challenge 
to treat. While treatment success for MDR-TB is better than for XDR-TB, overall success in 
treating MDR-TB is still approximately 50% according to the World Health Organization 2015 
Global TB Report.(43) and it would be lower for patients failing or not able to take an optimal 
traditional regimen.  This trial provides an opportunity to treat these high-need patients with three 
active drugs, for which there is no or minimal pre-existing resistance, in a very closely controlled 
and monitored clinical trial setting with the opportunity to define the optimal dosing scheme for 
linezolid.  Participants will be monitored closely and regular reviews of safety and efficacy will be 
made by the Data Safety Monitoring Committee (DSMC).  Preliminary results of the ongoing Nix-
TB trial from patients with XDR-TB and who are failing or intolerant to treatment of MDR-TB 
demonstrate that this regimen has the potential to give relapse-free cure of XDR-TB with a simple 
regimen in a much shorter period of time than currently required by the available drugs used in 
the best standard of care.  Preclinical studies of this regimen in a murine model of infection 
demonstrated relapse free cure of MTB in half the time (3 vs 6 months) required by standard HRZ 
therapy.  Clinical studies of linezolid alone and pretomanid and bedaquiline alone and in 
combination have demonstrated activity against TB infection. 
These three drugs have not been used in combination in humans prior to the Nix-TB trial, and 
thus their combined toxicity profile is emerging.  The greatest risks of key concern for participants 
in this trial from linezolid are from the adverse events of myelosuppression and peripheral and 
optic neuropathy.  Participants will be closely monitored with full blood counts, vision 
examinations, and screening for peripheral neuropathy.  The investigator may interrupt dosing of 
either linezolid or linezolid with pretomanid and bedaquiline if adverse events of concern develop, 
and a resumption of the drugs, with linezolid at the same or at a lower dose, may be made 
cautiously.  Participants will be under close surveillance for hepatotoxicity, as that risk for 
pretomanid and bedaquiline is not yet well characterized.   
Overall the benefit-risk balance justifies evaluating the B-Pa-L regimen in this study, with the 
cautious surveillance in place, to treat patients with XDR-TB who have few options for a 
successful outcome. 
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3 
Trial Objectives  
3.1 Primary Objectives 
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus 
bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary 
XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
4 
Trial Design 
4.1 Summary of Trial Design 
This is a Phase 3, multi-center, partially-blinded, randomized clinical trial conducted in 4 treatment 
groups.  Participants, trial investigators and staff, including laboratory staff, will be blinded to dose 
and scheduled duration of linezolid.   Bedaquiline and pretomanid dosing will not be blinded. 
The trial will be performed at multiple centers located in South Africa, Eastern Europe and Russia.  
A total of 180 XDR-TB and Pre-XDR/MDR intolerant or non-responsive participants who meet all 
of the inclusion criteria and none of the exclusion criteria, aged 18 and over, will be randomized 
to receive one of the 4 active treatment arms. Participants will be randomized to one of the four 
regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will 
utilize a randomization system using stratification with a random element to allocate participants 
evenly across the arms by HIV status and type of TB after they have given written, informed 
consent and met all eligibility criteria.  
Each participant will receive 26 weeks of treatment. If participant’s sputum sample is culture 
positive between the week 16 and week 26 treatment visits and their clinical condition suggests 
they may have an ongoing TB infection, Investigator may consider extending current treatment 
to 39 weeks.   If the culture results between week 16 and week 26 are contaminated, missing or 
considered an isolated positive without clinical significance, available culture results should be 
used to make this decision. All decisions regarding treatment extension should be discussed with 
and approved by the Sponsor Medical Monitor before implementation. Participants will be 
followed for 78 weeks after end of treatment. 
 
4.2 Treatment Plan: Schedule of Assessments 
• 
Screening Period- Screening Visit up to 14 days prior to Treatment 
• 
Treatment Period- Day 1 to Week 26. Additional visits every 3 weeks until last dose when 
dosing extended due to pauses or positive culture at Week 16  
• 
Follow-up Period- 4 Week post end of treatment follow-up Visit to 78 Week post end of 
treatment follow-up Visit 
Refer to: 
• 
Trial Flow Chart (Section 1.2) for the timing of all procedures and laboratory 
samples to done at each visit.   
• 
Trial Procedures (Section 7) for details regarding specific procedures or 
laboratory tests. 
Participants will receive oral daily dosing. They will be randomized to one of the following arms: 
 
Table 8: 
Treatment Groups 
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Treatment Group 
No of Participants 
1 
Linezolid 1200 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
2 
Linezolid 1200 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
3 
Linezolid 600 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
4 
Linezolid 600 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
 
Figure 4: 
Trial Schematic 
 
26 Weeks of Treatment* 
 
Weeks 1-9 
Weeks 10-26 
1 
1200 mg Linezolid QD 
 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
Primary Endpoint 
follow-up for relapse-
free cure 26 weeks 
after end of treatment 
 
Full follow up 78 
weeks after end of 
treatment 
2 
1200 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100mg QD week 9 
Pretomanid 200 mg QD 
1200 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
3 
600 mg Linezolid QD 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
4 
600 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
600 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
Participants will be randomized to 1 of the 4 groups listed above.  
N = 45 Participants per group for a total of 180. 30 XDR-TB participants per group    
* Treatment will be extended to 39 weeks for participants who have a positive culture at week 16  
 
5 
Trial Population 
Participants must meet all inclusion and no exclusion criteria within the screening period.  Re-
testing for laboratory or ECG parameters is allowed within the 14-day screening period. Sponsor 
may consider replacement of late screen failure and un-assessable (as detailed in the statistical 
analysis plan) participants. 
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5.1 Inclusion Criteria 
Participants are required to meet all of the following inclusion criteria during the screening period 
in order to be randomized. 
1. Provide written, informed consent prior to all trial-related procedures (including any 
additional consent required for participants considered as minors per applicable regulatory 
authority or ethics committee). 
2. Willingness and ability to attend scheduled follow-up visits and undergo study 
assessments. 
3. HIV testing (if an HIV test was performed within 1 month prior to screening, it should not 
be repeated as long as a documented  result can be provided [ELISA and/or Western Blot 
and/or Electro-Chemiluminescence].  If HIV status is a confirmed known positive, repeated 
HIV test is not needed if ELISA and/or Western Blot and/or Electro-Chemiluminescence 
documentation of presence of HIV infection is available. 
4. Male or female, aged 18 years or older.  
 
Disease Characteristics: 
 
5. Participants with one of the following pulmonary TB conditions: 
a. 
 XDR-TB with  
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
documented resistance to rifamycins, a fluoroquinolone AND an injectable 
during the current TB diagnosis/disease course any time prior to or during 
screening period (may be sensitive or resistant to isoniazid);  
b. 
Pre-XDR-TB with 
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based molecular test within 3 months prior to or at 
screening and; 
ii. 
documented resistance to rifamycins, and to a fluoroquinolone OR an 
injectable during the current TB diagnosis/disease course any time prior to 
or during screening period (may be sensitive or resistant to isoniazid); 
c. 
MDR-TB with 
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected results within 3 months prior to screening or 
MTB confirmed in sputum based on molecular test within 3 months prior to 
or at screening and; 
ii. 
documented 
resistance to 
rifamycins 
during 
the 
current 
TB 
diagnosis/disease course any time prior to or during screening period (may 
be sensitive or resistant to isoniazid) and; 
iii. 
with documented non-response to treatment with the best available regimen 
for 6 months or more prior to enrolment who in the opinion of the Investigator 
have been adherent to treatment and will be adherent to study regimen.   
d. 
MDR-TB with  
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected within 3 months prior to screening or MTB 
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confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
documented 
resistance to 
rifamycins 
during 
the 
current 
TB 
diagnosis/disease course any time prior to or during screening period (may 
be sensitive or resistant to isoniazid) and; 
iii. 
who are unable to continue second line drug regimen due to a documented 
intolerance to: 
a. PAS, ethionamide, aminoglycosides or fluoroquinolones or ; 
b. Current treatment not listed above that renders participant eligible for 
the study in the Investigator’s opinion.  
6. Chest X-Ray within 6 months prior to or at screening, obtained and read locally by 
investigator or designee with results consistent with pulmonary TB in the opinion of the 
Investigator. 
 
Contraception: 
7. Be of non-childbearing potential or using effective methods of birth control, as defined 
below: 
 
Non-childbearing potential: 
a. Participant - not heterosexually active or practices sexual abstinence; or  
b. Female participant or male participant’s female sexual partner - bilateral 
oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months; 
or  
c. Male participant or female participant’s male sexual partner - vasectomised or 
has had a bilateral orchidectomy at least three months prior to screening. 
 
Effective birth control methods:                                                        
a. Double barrier method which can include a male condom, diaphragm, cervical cap, 
or female condom; or  
b. Female participant: Barrier method combined with hormone-based contraceptives 
or an intra-uterine device for the female participant; 
c. Male participant’s female sexual partner: Double barrier method or hormone based 
contraceptives or an intra-uterine device for the female partner. 
 
And are willing to continue practicing birth control methods throughout treatment and for 6 
months  (female participants) and 12 weeks (male participants) after the last dose of study 
medication. 
 
Note: Hormone based contraception alone may not be reliable when taking IMP; 
therefore, hormone-based contraceptives alone cannot be used by female participants 
to prevent pregnancy. 
 
5.2 Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria during 
the screening period: 
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Medical History and Concurrent Conditions 
1. Any condition in the Investigator’s opinion (i.e., an unstable disease such as 
uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended 
treatment, cancer that could affect survival through the protocol-specified follow up 
period), where participation in the trial would compromise the well-being of participant 
or prevent, limit or confound protocol specified assessments.  
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations.  
3. In the judgment of the Investigator, the participant is not expected to survive for more 
than 6 months. 
4. Karnofsky score < 60 at screening. 
5. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal 
Products or related substances. 
6. Body mass index (BMI) < 17 kg/m2 
7. TB infection with historic DST or MIC results with values suggesting likely resistance 
to pretomanid, delamanid, linezolid or bedaquiline; the Sponsor Medical Monitor must 
be consulted to help interpret any available historic results. 
8. Participants who, upon the evaluation of their pulmonary disease, are expected to 
require a surgical procedure. 
9. Having participated in other clinical studies with dosing of investigational agents within 
8 weeks prior to screening or currently enrolled in an investigational study that includes 
treatment with medicinal agents.  Participants who are participating in observational 
studies or who are in a follow up period of a trial that included drug therapy may be 
considered for inclusion. 
10. Participants with any of the following at Screening: 
• 
QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be 
discussed with and approved by the Sponsor Medical Monitor before enrolment. 
(Per measurements and reading done from screening central ECG.) 
• 
Heart failure 
• 
A personal or family history of congenital QT prolongation 
• 
A history of or known, untreated, ongoing hypothyroidism 
• 
A history of or ongoing bradyarrhythmia 
• 
A history of Torsade de Pointe 
11. Females who have a positive pregnancy test at Screening or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the study or within 6 
months of cessation of treatment.  Males planning to conceive a child during the study 
or within 6 months of cessation of treatment. 
12. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, 
participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the 
course of the study, in the opinion of the Investigator. 
 
Previous and Concomitant Therapy 
13. Known (during screening) requirement for future Concomitant (during treatment) use 
of any prohibited and/or avoided medications noted in section 5.3. 
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14. Prior use of Monoamine Oxidase Inhibitors (MAOIs) within 2 weeks of randomization.  
15. Prior use of serotonergic antidepressants within 3 days of randomization if Investigator 
foresees potential risks for serotonin syndrome when combined with linezolid.  
16. Participants who have received more than 2 weeks of bedaquiline, linezolid or 
delamanid prior to first dose of IMP. 
17. Participants with newly diagnosed tuberculosis and HIV that require initiation of 
appropriate HIV therapy before participant has received at least 2 weeks of an anti-
tuberculosis regimen.  
18. HIV infected participants with planned continued use of zidovudine, stavudine or 
didanosine. The antiretroviral therapy (ART) booster cobicistat should not be used. 
Please reference restrictions Section 5.3.3 Antiretroviral Therapy, for guidance on 
ART treatment during the treatment period.  
 
Diagnostic and Laboratory Abnormalities 
 
19. Participants with any of the following toxicities at Screening (labs may be repeated 
during screening period) as defined by the enhanced Division of Microbiology and 
Infectious Disease (DMID) adult toxicity table (November 2007): 
 
a. Viral load >1000 copies/mL (Unless newly diagnosed HIV and not yet on ART who 
otherwise qualify for participation); 
b. CD4+ count < 100 cells/µL (HIV positive participants); 
c. Serum potassium less than the lower limit of normal for the laboratory; 
d. Hemoglobin < 9.0 g/dL or < 90 g/L; 
e. Platelets <100,000/mm3 or < 100 x 10^9/L; 
f. Absolute neutrophil count (ANC) < 1500/ mm3 or < 1.5 x 10^9/L; 
g. Aspartate aminotransferase (AST)  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor Medical Monitor 
h. Alanine aminotransferase  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor medical monitor; 
i. Total bilirubin 
• 
greater than 1.5 x ULN to be excluded; 
• 
1-1.5 x ULN must be discussed with and approved by the Sponsor Medical 
Monitor  
j. Direct bilirubin 
• 
Greater than ULN to be excluded 
k. Serum creatinine level greater than 1.5 times upper limit of normal 
l. Albumin <3.0 g/dl or < 30 g/L  
 
All inclusion and no exclusion criteria must be met.  If no single variable/value is outside of the 
ranges of acceptability, but when multiple values are close to the limits and/or whenever the 
Investigator has reason to suspect that there might be a health problem (other than TB), enrolment 
should only be considered after discussing the case with the Sponsor Medical Monitor. 
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No protocol waivers will be granted by the TB Alliance. 
 
5.3 Restrictions 
5.3.1 Prior and Concomitant Medications and Other Treatments 
Concomitant medications should be kept to a minimum during the treatment period of the trial.  
However, if concomitant medications are necessary for the participant’s welfare and are unlikely 
to interfere with the IMP, they may be given at the discretion of the Investigator.  For any 
concomitant medications given as a treatment for a new condition or a worsening of an existing 
condition occurring after signing of the Informed Consent Form, the condition must be 
documented on the Adverse Event pages of the electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be consulted and reviewed 
carefully.  The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected to prevent any potentially serious and/or life-threatening drug 
interactions. 
The following concomitant medications are prohibited during the treatment period and during the 
14 days after treatment completion: 
• 
Medicinal products used to treat pulmonary TB:  including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and metronidazole. 
• 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). (e.g., phenelzine, 
isocarboxazid) 
The following concomitant medications should be avoided during the treatment period and during 
the 14 days after treatment completion to avoid possible drug interactions with the IMP. Use of 
any of the following must be discussed and approved by the Sponsor Medical Monitor prior to 
use: 
• 
Concomitant use of any drug known to prolong QTc interval (including but not limited to 
amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, 
clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, 
pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).  
• 
Treatment with fluoroquinolones (as they are known prolong QTc), are strongly 
discouraged in the trial. They should only be used to treat intercurrent non-TB infections 
and if the benefit of treatment outweighs the risk of prolonged QTc.   
• 
Concomitant use of any drug known to induce significant myelosuppression 
• 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: ketoconazole, 
voriconazole, itraconazole, fluconazole; ketolids such as telithromycin; and macrolide 
antibiotics other than azithromycin) for more than 3 consecutive days; 
• 
The systemic use of CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, 
St. John’s wort, rifamycins and systemic dexamethasone.  
• 
Concomitant use of serotonergic antidepressants should be avoided if possible as 
participants on these agents and linezolid are at risk for serotonin syndrome.  
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• 
Caution should be used in treating diabetic patients receiving insulin or oral hypoglycemic 
agents as cases have been reported of hypoglycemic reactions when patients on these 
agents have been treated with linezolid. 
The following concomitant medications which are known to be hepatotoxic should be avoided as 
much as possible during screening and throughout the treatment period.  If there are concerns 
about the co-administration of  hepatoxic drugs, discussion with the Sponsor Medical Monitor is 
encouraged (including but not limited to acetaminophen/paracetamol,  acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, augmentin/co-
amoxiclav, azathioprine, baclofen, bumetanide, captopril, carbamazepine, celecoxib, 
chlorpromazine, chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-trimoxazole, 
darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, fosamprenavir, 
furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, 
loperamide, losartan, methotrexate, metolazone, mirtazepine, nitrofurantoin, omeprazole, other 
non-steroidal anti-inflammatory drugs, paroxetine, phenobarbital, phenothiazines, phenytoin, 
pravastatin, probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, simeprevir, 
simvastatin, sodium valproate, sotalol, sulfasalazine, sumatriptan, tamsulosin, terbinafine, 
tetracycline, theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, topiramate, trazodone, 
tricyclic antidepressants, trimethoprim, verapamil). 
5.3.2 Recommendations for Concomitant use of Anti-Malarials 
The following treatments for malaria are recommended for concomitant use with the IMP, should 
it be necessary: 
• 
Proguanil/atovaquone or  
• 
Artesunate plus sulfadoxine-pyrimethamine  
 
These recommendations are based on the potential for QT prolongation by bedaquiline and many 
anti-malarials. Due to the extended half-life of bedaquiline commencing anti-malarial treatment 
containing drugs that could prolong the QT interval, shortly after discontinuing bedaquiline, is not 
recommended. 
5.3.3 Antiretroviral Therapy 
For HIV infected participants, to avoid potentiating known key toxicities of linezolid (neuropathy 
and myelosuppression), the following antiretroviral therapies should not be used during the 
treatment period: zidovudine, stavudine, didanosine.  
The ART booster cobicistat should not be used. 
Only the following types of antiretroviral therapy (ART) are permissible during administration of 
regimens: 
• 
Nevirapine based regimen consisting of NVP in combination with any two NRTIs TDF/ABC 
and FTC/3TC.  
• 
Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any 
two NRTIs TDF/ABC and FTC/3TC. 
• 
Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC. 
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• 
In patients who have viral load suppressed on efavirenz at the time of screening, their 
ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. If possible, 
the same nucleoside backbone should be used. 
 
The investigator must assess the risks and benefits of these antiretroviral regimens in the 
context of co-infection with TB acknowledging the following caveats: 
• 
Triple NRTI is generally not considered optimal chronic ART; 
• 
Nevirapine based regimens are associated with higher ART failure in participants having 
or known to have previously had a viral load more than or equal to 100,000/ mL. 
5.3.4 Other Restrictions 
Large quantities of foods or beverages with high tyramine content should be avoided while taking 
linezolid.  Quantities of tyramine consumed should be less than 100mg per meal. Foods high in 
tyramine content include those that may have undergone protein changes by aging, fermentation, 
pickling, or smoking to improve flavour, such as aged cheeses (0 to 15 mg tyramine per ounce); 
fermented or air-dried meats (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 
ounces); soy sauce (5mg tyramine per 1 teaspoon). The tyramine content of any protein-rich food 
may be increased if stored for long periods or improperly refrigerated. 
Alcohol should be avoided while on IMP, especially in participants with impaired hepatic function. 
5.4 Trial Discontinuation and Visits 
5.4.1 Treatment Discontinuation and Early Withdrawal 
A participant must be withdrawn from the trial due to the following;  
• 
Pregnancy (unless female post visit for end of treatment/early withdrawal from treatment); 
• 
Investigator considers it for safety reasons in the best interest of the participant that he/she 
be discontinued, including a concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB treatment.  
• 
At the specific request of the Sponsor or termination of the trial by Sponsor; 
• 
Lost to follow-up 
• 
In the opinion of the investigator, fails to comply with the protocol, including non-
compliance to IMP. 
Participants may be withdrawn from the trial based on the following. The specific situation should 
be discussed with the Medical Monitor before withdrawing the patient. 
o Myco testing results from baseline (Screening through Week 4) indicate sensitivity  
to rifamycins; 
o Myco testing results from baseline (Screening through Week 4) with MICs that 
indicate likely resistance to bedaquiline, pretomanid or linezolid; 
All participants who discontinue trial treatment (but have not withdrawn consent) and received at 
least one dose of IMP will be requested to return for an early withdrawal visit and applicable safety 
Follow Up visits, as per flow chart (Section 1.2). 
A participant may discontinue from the trial at any time at his/her request (withdrawal of 
consent) or may be withdrawn at any time at the discretion of the investigator for safety, 
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behavioral compliance or administrative issues. When a participant withdraws consent from the 
trial, no additional follow-up visits will be performed.  
5.4.2 Early Withdrawal Follow-up 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made to 
complete the Early Withdrawal assessments.   
Once a participant has been withdrawn early from the trial, they will be requested to attend follow-
up visits as described in Table 9: 
Table 9: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EW visit 
Ophthalmology 
Examination at 
EWa 
Ophthalmology 
Examination  
 
12 week Post 
treatment follow-
up visita 
26 Week  
Post 
Treatment  
Follow-up 
Visit 
78 Week Post 
Treatment 
Follow-up 
Visit 
≤ 14 days 
NA 
NA 
NA 
NA 
15 days to      
≤ 12 weeks 
NA 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if not 
already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 12 weeks after the 
EWD visit date. 
The 26 and 78 week post treatment follow-up visits will be performed to collect SAE information 
(including verification of survival) and participant reported TB outcome information.  This visit may 
be telephonic, a home or a site visit.  
5.4.3 Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures, should be considered unscheduled regardless of the reason for the visit. The 
assessments which are undertaken as part of an Unscheduled visit should be as clinically 
indicated.  
The following situation/s require an unscheduled visit/s: 
• 
If cultures of both spot sputum samples are contaminated at the following visits, or if 
necessary, in order to help define a participant’s outcome status/assess culture status 
during follow-up, the participant should return for an unscheduled visit(s) to give additional 
samples or to document the participant is not able to produce sputum: 
  
• 
End of treatment visit 
• 
Week 26 post treatment follow-up visit 
• 
Post treatment follow-up visits from week 8 through week 65 (in addition to week 26 
follow-up) 
• 
End of Follow-up Period (week 78 post treatment completion visit) 
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• 
Early Withdrawal (if applicable). 
 
• 
At the end of 26 weeks and 78 weeks post treatment completion, to define outcome status, 
and to determine whether the participant has: 
• 
At least two sequential negative sputum culture results; or  
• 
At least two sequential positive sputum culture results; or  
• 
Has been unable to produce sputum after documentation of at least two negative 
sputum cultures with no intervening positive and are clinically asymptomatic. 
 
If they do not fall into one of the above categories, site should continue to collect sputum samples 
x 2 (one early morning and one spot at the research site or 2 spots samples at least 30 minutes 
apart, under the coaching and observation of the trial staff) at a minimum of 7 days or more apart 
until they fall into one of the above categories. 
 
5.4.4 Lost to Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants.  A 
minimum of three contact attempts (telephonic/home visit) will be made for participants who do 
not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant will be 
considered LTFU.  All attempts to contact the participant must be clearly documented in the 
participant’s source documents. 
5.4.5 Early Withdrawal due to TB 
Ultimately it is the investigator’s decision whether a participant should discontinue treatment due 
to a concern that the participant has symptomatic worsening TB and/or bacteriological 
failure/relapse.  
Discontinuation is usually not indicated by a single positive culture.  Should a participant have a 
single positive culture result after being negative, the investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether it 
is in the participant’s best interest that he/she be discontinued. Prior to discontinuation of a 
participant due to TB, the investigator must discuss the participant with the Sponsor Medical 
Monitor, unless the investigator cannot contact the Sponsor Medical Monitor and considers that 
discontinuation must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the Investigator decides to discontinue trial treatment for a participant due to TB, additional 
sputum samples may need to be collected in order to ensure the participant’s outcome status may 
be determined, details noted in trial flowchart (Section 1.2). 
All Early Withdrawal participants who are confirmed sputum positive (at least two sequential 
sputum positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to specialists who treat XDR-TB, pre-XDR TB or MDR-TB as 
applicable.  
 
 
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5.5 Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who is not randomized 
Completed 
Treatment / 
Completed FU* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued FU 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
FU** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* Note that this includes treatment failures who complete all applicable follow-up visits 
** Early Withdrawal 
5.6 Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific Investigational Site at any time, although this should 
only occur after consultation between involved parties.  Should this occur, the local and central 
Ethics Committee/Institutional review Board (EC/IRB) and Regulatory Authorities will be informed.  
Should the Trial/Investigational Site be closed prematurely, all trial materials (except 
documentation that has to remain stored at the Investigational Site) will be returned to the Sponsor 
or vendor.   The Investigator will retain all other documents until notification given by the Sponsor 
for destruction.  Participants currently on treatment will receive an appropriate regimen and all 
participants will be referred to a unit specializing in the treatment of XDR-TB, Pre-XDR-TB or 
MDR-TB as applicable. 
6 
Treatment 
6.1 IMP Administration  
 Treatment will be administered orally, once daily, with a full glass of water and a meal in the 
dosing schemes (treatment arms) outlined in Table 9. The study drug regimen should be 
initiated as specified below regardless of whether participant has received any of the allowed 
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prior exposure of bedaquiline or linezolid (up to 14 days), including a loading dose of 
bedaquiline. The Pharmacy Manual should be referenced for further details. 
Table 10: 
 Investigational Medicinal Product Details  
Treatment Group 
Active and Placebo 
Linezolid 1200 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 2 linezolid 600 mg active tablets once daily for 26 weeks 
• 1/2 (one half) placebo linezolid tablet once daily for 26 weeks  
Linezolid 1200 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9  
• 2 linezolid 600 mg active tablets once daily for 9 weeks  
• ½ (one half) placebo linezolid  tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid tablets once daily for 17 weeks 
• ½ (one half) placebo linezolid tablet once daily for 17 weeks 
Linezolid 600 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 1 linezolid 600 mg active tablet once daily for 26 weeks 
• 1 placebo linezolid tablet once daily for 26 weeks  
• ½ (one half) placebo linezolid tablet once daily for 26 weeks 
Linezolid 600 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9 
• 1 linezolid 600 mg active tablet once daily for 9 weeks 
• 1 placebo linezolid tablet for 9 weeks 
• ½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolidtablets once daily for 17 weeks 
• ½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
6.2 Participant Compliance 
During site clinic visits or hospitalization, the IMP will be administered by the 
Investigator/designated site personnel. During the study, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully trained on how IMP is to be taken. When 
possible, participants will be checked for IMP compliance by the Investigators or trial 
personnel/National TB Treatment Program personnel via the hand-and-mouth procedure (both 
the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP).  Additionally, participant cards/bottles will be checked for unused tablets at 
each visit during the treatment period  
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6.3 Treatment Modification(s) 
All treatment modifications should be discussed with the Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required urgently for a safety concern; the 
Medical Monitor should be informed within 24 hours of the change if not discussed prior to 
implementation.  
In the event of linezolid specific toxicities, the following should be considered and implemented 
per guidance in the monitoring and safety for specific toxicities section of protocol (8.3): 
• 
Blinded one step reductions (maximum 2 steps) in the dose of linezolid managed by the 
IXRS as per instructions in pharmacy manual and/or IXRS user manual 
o 1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or;  
o 600 mg QD to 300 mg QD, 300mg QD to placebo).  
• 
Temporary pause of linezolid  
• 
Permanent discontinuation of linezolid. 
• 
Participants who have a linezolid reduction can go back to a higher dose (1 step or 2 
steps) post discussion with and approval by the Sponsor Medical Monitor. 
Participants experiencing suspected drug related toxicities due to other drugs in the regimen (B-
Pa), the full regimen may be halted for up to 35 consecutive days.  
Interruptions/pauses of the full regimen must not exceed 8 weeks (56 days) cumulatively.   
If participant’s sample is culture positive between the week 16 and week 26 treatment visits and 
their clinical condition suggests they may have an ongoing TB infection, Investigator may consider 
the option to extend  the treatment to which the participant is randomized to 39 weeks. If the 
culture results between week 16 and week 26 are contaminated, missing or considered an 
isolated positive without clinical significance, available culture results should be used to make this 
decision. All decisions regarding treatment extension should be discussed with and approved by 
the Sponsor Medical Monitor before implementation.  
When treatment extended to 39 weeks, pauses of the full regimen must not exceed 13 weeks (91 
days) cumulatively. 
When the total of missed dosing days of the prescribed regimen and/or pauses is greater than 7 
days, the same number of missed doses should be dispensed/treatment extended to make up for 
the total missed doses. 
At no time should the participant be treated with a single agent. 
Every effort should be made for participants to receive a total of at least 9 weeks of linezolid, even 
if pauses are required. 
6.4 IMP Packaging and Labelling 
The complete formulations of the IMP bedaquiline and pretomanid are found in the respective 
Investigator Brochures(5,6). The complete formulations of linezolid are found in the Package 
Inserts(23,24,26).  
The IMP will be packaged as follows: 
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• 
Bedaquiline: Bottles containing: 
o 200 mg QD dose- 28 tablets- bedaquiline 100 mg 
o 100mg QD dose- 14 tablets- bedaquiline 100 mg  
• 
Pretomanid: Blister card containing 14 tablets- pretomanid 200 mg  
• 
Linezolid: Blister Card containing 7 days of dosing as follows: 
o 1200 mg QD Dose  
 
2 blister strips of 7 tablets each (14 tablets) containing active linezolid 600 
mg   
 
1 blister strip of 7 half tablets containing placebo linezolid  
o 600 mg QD Dose:  
 
1 blister strip of 7 tablets containing active linezolid 600 mg   
 
1 blister strip of 7 tablets containing placebo linezolid  
 
1 blister strip of 7 half tablets containing placebo linezolid  
o 300 mg Dose (for reductions):  
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid  
 
1 blister strip of 7 half tablets containing active linezolid 300 mg  
o Placebo Linezolid Dose:  
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid  
 
1 blister strip of 7 half tablets containing placebo linezolid  
 
The packaging of each bottle/blister card will be labelled with, at a minimum, the following 
information: 
• 
Name of Sponsor. 
• 
Name of medication. 
• 
Dosage, quantity and method of administration for bedaquiline and 
pretomanid. 
• 
Potential dosage, quantity and method of administration for linezolid. 
• 
Reference/Lot Number. 
• 
The statement “For Clinical Trial Use Only”. 
• 
Space for completion of Name of Investigator and Site Number. 
• 
MedID: medication identification number  
• 
Storage conditions. 
• 
Period of Use. 
• 
The statement “Keep out of reach of children”. 
• 
Expiry Date. 
• 
Directions for use. 
• 
Space for completion of participant number and visit/date dispensed. 
6.5 Method of Treatment Assignment 
Participants will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
web/voice response system (IXRS) which will utilize a randomization system using stratification 
with a random element to allocate participants evenly across the arms by HIV status and type of 
TB.  Information & directions will be provided to each site via the IXRS user manual. 
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6.6 Blinding and Procedures for Breaking the Blind 
The blind for a participant must not be broken by the site or sponsor except in the case of a 
medical emergency, where treatment of a participant is influenced by the knowledge of what dose 
and duration of linezolid the participant is receiving. The investigator should discuss breaking the 
blind with the Sponsor Medical Monitor (or designee) prior to breaking the blind unless knowledge 
of treatment arm is required urgently for a safety concern. The Sponsor Medical Monitor should 
be informed of the blind break within 24 hours if not discussed prior. IXRS will be programmed 
with blind-breaking instructions, described in the user manual. The Sponsor reserves the right to 
break the blind to fulfil any regulatory requirements regarding reporting of SAEs. If a participant 
is unblinded, they are not required to be withdrawn from the study.  
 There will be three unblinded analyses which will contain results by linezolid treatment group in 
aggregate (see section 9.3). The first analysis will be after all participants have completed 26 
weeks of treatment and here sites, participants, and Sponsor staff will not be unblinded to 
individual linezolid treatment information. A limited number of statisticians will have access to 
individual linezolid treatment assignments.  
The blind for all individual participants will be broken for the primary endpoint analysis (the second 
unblinded analysis) once all clinical data and outcome parameters have been captured, no more 
data queries are pending, and the statistical analysis plan has been finalized. The third analysis 
will occur when all participants have completed 78 weeks of follow-up after end of treatment.   
 
6.7 Handling, Storage and Accountability  
The investigator or designee must confirm appropriate temperature conditions as per details on 
IMP labelling, have been maintained during transit for all trial treatment received and any 
discrepancies are reported and resolved before use of the trial treatment. 
Only participants enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Upon completion or termination of the trial, all unused 
and/or partially used IMPs must either be returned to Sponsor (or designated vendor) who will 
arrange for destruction or destroyed at site as agreed by Sponsor after final accountability has 
been confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising with 
respect to the trial medication. The Sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
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7 
Trial Variables and Procedures 
The trial flowchart in Section (1.2) should be referenced for timing and sequence of 
assessments. 
7.1 Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written informed consent. 
• 
Visit dates 
• 
Participant disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and treatment history (including past and current TB 
diagnosis, alcohol use and smoking) 
• 
Screening coached spot sputum samples: 
o Smear microscopy for acid-fast bacilli. 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB 
complex and rifamycin resistance. 
• 
Urine pregnancy test: women of child-bearing potential only, whether they are 
sexually active or not. 
• 
Serology: HIV,CD4 count and viral load.  
o If an HIV test was performed within 1 month prior to trial start, it should not be 
repeated as long as documentation of results can be provided (ELISA and/or 
Western Blot and/or Electro-Chemiluminescence). 
o Where required by regulatory authorities or ethics committees: 
 
Separate approval for this to be performed will be obtained from 
participants in the written informed consent process.  
o prior to HIV testing and on receipt of the results, participants will be 
counselled on HIV by trained counsellors if they have indicated as such on 
the HIV consent form. If requested by the participant, HIV counselling 
provided to the participant by the study site should be clearly documented in 
the participant’s medical records/source.  Participants have the right to 
decline to know or receive their HIV test results. This decision should be 
clearly documented in the participant’s medical records/source.   
• 
Karnofsky score (Appendix 4). 
• 
Chest X-Ray: A Chest X-Ray digital image will be obtained and read locally by the 
Investigator or designee.  Digital images will be provided to the Sponsor; this process 
will be documented in the Radiology Manual.  The Investigator is responsible for 
review and analysis for participant inclusion. 
• 
Method of birth control: male and female participants and their partners. 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
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7.2 Efficacy Variables and Procedures 
Two spot sputum samples are collected, one early morning brought from home or collected in the 
hospital ward and one spot collected at the research site under the coaching and observation of 
the trial staff or, if no early morning sample was provided, 2 samples collected on site at least 30 
minutes apart. The Mycobacteriology sampling methodology and requirements will be described 
in a separate document, the Laboratory Manual, which will be provided prior to the trial start.  
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the time to 
positivity (TTP) followed by a speciation test when applicable, to confirm MTB. 
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse; 
• 
Time to Sputum Culture Conversion; 
• 
Number of participants with Sputum Culture Conversion. 
Every effort is to be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favorable) result.  A participant 
who never achieves culture negative status due to inability to produce sputum, but has completed 
26 week /78 week post treatment completion follow-up and is without clinical or biological 
evidence of relapse, will be considered to have a favorable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (found in the Subject Questionnaires Guideline) will record 
participants’ ratings of the severity of common TB symptoms.  
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the trial flow chart. Patient Reported Health Status will be collected using the EQ-5D-5L 
Health Questionnaire (found in the Subject Questionnaires Guideline). This descriptive 
system consists of five health-related quality of life dimensions, each of which will be 
recorded using five levels of severity. Methodology: The Patient Reported Health Status 
methodology and requirements will be described in a separate document/guideline which 
will be provided prior to the trial start. 
 
7.3 Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
trial flow chart and assessed for evaluation of the safety endpoints: 
• 
Laboratory parameters. The Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, which will be provided prior to 
the trial start. The following analyses will be performed: 
o Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential, platelet count),  
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o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, 
calcium (corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, 
creatine phosphokinase (CPK).                  
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis.  
• 
12-lead Electrocardiogram (ECG): 
o Investigator assessment: normal, abnormal. 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected 
QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all 
participants and will be described in a separate document which will be 
provided prior to the trial start; 
 
Participants should be lying down (recumbent) for at least 5 minutes prior 
to each 12-lead ECG evaluation; 
 
ECGs are to be recorded for 10 seconds; 
 
All ECGs are to be performed in single. 
 
ECGs should be done before any labs when both included in a visit) 
 
For each participant, the ECGs should, to every extent possible, be 
collected at approximately the same time of day (+/- 1 hours) and in the 
same fed/fast state throughout the trial (e.g. 4 hours after lunch). 
• 
Vital signs: 
o Vital Signs, including weight (should be done before any labs) 
o Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 minutes of 
rest) using an appropriately sized cuff, and using the same type of sphygmomanometer, 
if possible by the same observer, at each relevant visit. 
o Heart rate (bpm). 
o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C). 
• 
Physical examination:  
o Height is measured at screening only. 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and abdominal) 
examinations will be performed and any clinically significant findings will be recorded.   
o Weight (kg) (in light clothing and with no shoes).  
o Using the observed variables weight and height, calculated body mass index (BMI) will be 
derived. 
• 
Ophthalmology slit lamp examination. To be done by an Ophthalmologist trained on AREDS2 
assessment. The ophthalmology slit lamp methodology and requirements will be described in 
a separate document, the Ophthalmology Guideline. The following analyses will be 
performed: AREDS2 opacity typing and grading. 
• 
Ophthalmic examination. The ophthalmic examinations can be performed by any trained study 
staff. The screening exams must be done by the trained site study staff AND an 
Ophthalmologist.  Methodology and requirements will be detailed in the Ophthalmology 
Guideline. 
• 
Ophthalmology History (Screening only); 
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• 
Visual Acuity Test – Corrected. Distance Vision; 
• 
Color Vision Assessment. 
• 
Adverse events. 
• 
Brief peripheral neuropathy screen (found in the Subject Questionnaires Guideline) will record 
ratings. 
• 
Investigator assessment:  
Principal Investigator to review participant status at specified visits in flow chart including any 
time Investigator determines that participant fulfills criteria for primary outcome of treatment 
failure. Investigator to assess whether TB treatment is considered a “success” or “failure”.  If 
considered a failure, should specify if based on bacteriology and/or clinical deterioration 
and/or radiological deterioration. 
7.4 PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Synopsis Flowchart 1.2) will be used to update 
population PK models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this trial population.  PK data from the 
current trial may be combined with prior data (e.g., from the NiX-TB trial) to enhance this 
population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T >MIC) for subsequent analyses exploring relationships between 
drug exposure and efficacy and safety endpoints.   
 
7.5 Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between Screening through Week 4; 
• 
If consent granted, and when applicable, Pre-screening culture/isolate to be sub cultured 
and shipped and/or tested: 
o At the study lab if/when samples could support inclusion in the trial 
o To the study/central lab for relevant participants/with no baseline (positive cultures 
from screening through Week 4)  
• 
When applicable, 1st positive for MTB at/after week 16 for participant not responding to 
therapy and/or 1st positive during follow-up for potential new infection. 
 
The MTB isolates will be processed at the central lab(s) for: 
• 
MIC against bedaquiline, pretomanid and linezolid;   
• 
Drug Susceptibility Testing in liquid culture for rifampicin, isoniazid, streptomycin, 
ethambutol, pyrazinamide and second line TB drugs including but not limited to 
fluoroquinolones, and injectables; 
• 
Genotyping. 
 
The MTB isolates will be processed at the central lab(s) for: Positive MTB at/after end of 
treatment: Hain MTBDRplus and HainMTBRsl 
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8 
Adverse Events 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; In general, 
hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event. 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalization, 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.   A “suspected 
transmission of infectious agent by a medicinal product” is also considered a serious adverse 
event under the SAE criterion “Other medically important condition”.   
8.1.3 Attribution/Causality 
• 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. 
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• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration will 
be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor/designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
Table 11: 
Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive.  The relationship in time is reasonable; 
therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event, which might be due to the use of the drug.  The 
relationship in time is suggestive, e.g., confirmed by dechallenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).   
 
8.1.4 Severity 
Table 12: 
Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
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Grade 
Severity Rating 
Definition 
GRADE 4 
Potentially Life-
Threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected from the signing of the ICF until the 78-week post treatment follow-up 
visit at the time points specified in the Flowchart (Section 1.2) and recorded in the case report 
from (CRF). The exception is early withdrawal participants who will only have SAEs collected from 
the time of their early withdrawal through the 78-week post treatment visit. 
Medical occurrences that begin after obtaining informed consent will be recorded as adverse 
events. If an adverse event started before signing of the informed consent, but is ongoing at trial 
start, it should be recorded as medical history.  If the pre-existing medical occurrence worsens 
during the trial, and adverse event will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the investigator.  
The Sponsor/investigator/designee will inform Regulatory Authorities and/or IEC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the IEC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in participants who have 
completed the trial. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the trial, and he/she considers the event to be 
reasonably related to the trial treatment or trial participation, the investigator must promptly notify 
the Sponsor, IEC/IRB and regulatory authorities on an expedited basis in accordance with local 
requirements and ICH guidelines for GCP. 
8.2.1 Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
Until the end of the follow-up period; and  
• 
Until all queries on these AEs have been resolved.   
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Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the treating physician.  If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor Medical Monitor. 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  Investigator should contact Sponsor/designee to discuss 
appropriate medical follow-up if consultation required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide Sponsor/representative with a copy of any post-mortem findings including 
histopathology. 
New or updated information on an SAE will be recorded in the originally completed CRF and 
submitted to Sponsor within 24 hours of the information becoming known per SAE reporting 
guidelines. 
8.2.2 Clinical Laboratory Adverse Events 
Changes in the results of the Clinical Laboratory assessment results which the Investigator feels 
are clinically significant will be reported as adverse events.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an adverse event. 
8.2.3 Disease under Study 
Symptoms of the disease under trial (Pulmonary Tuberculosis) experienced by the participant 
while on the trial will be assessed by the Investigator.  If the symptom has: 
• 
worsened while the participant is in the trial; and 
• 
the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event.  
If there is: 
• 
no change; and  
 
• 
the Investigator assesses the symptom as due to the participant’s TB; and  
• 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation.  
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
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8.2.4 Overdose 
Overdose of IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an Adverse Event, including if the taking of 
the suspect medicine led to suicidal intention and subsequent overdose of the suspect medicine, 
or other medication. In this case it will be recorded as an adverse event. If it does not lead to an 
Adverse Event, it will not be recorded as an AE and this will be noted in the participant’s source 
documentation. 
8.2.5 Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
Investigator will report to the Sponsor follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed for 6 months.   
All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following time-
periods: 
• 
During the trial 
• 
Within 6 months after last dose of IMP 
If pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow up will be performed 
unless contraindicated by the pregnancy. 
Pregnancy reporting will follow the same time lines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in preclinical toxicity 
studies Investigator’s Brochures(5,6) and Package Inserts.(23,24,25,26) Please reference section 6.3 
Treatment Modifications, which notes that all treatment modifications should be discussed with 
Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required 
urgently for a safety concern.  The Medical Monitor should be informed within 24 hours of the 
change if not discussed prior to implementation.   
AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization or until the end of the follow-up period and until all queries on these AEs 
have been resolved.  Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization. 
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
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these cases follow-up will be the responsibility of the treating physician. If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor Medical Monitor.  
 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours where possible. The recommendations for managing participants 
below assumes the laboratory abnormalities of concern have been confirmed. 
8.3.1 Neurological 
Participants with co-administration of a serotonergic agent, including anti-depressants, should be 
monitored closely for signs of serotonin syndrome.  The Investigator should determine whether 
the full regimen or the concomitant agent should be discontinued for those who experience signs 
or symptoms of serotonin syndrome such as cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
Linezolid and/or the full regimen should be paused for participants experiencing a seizure. The 
Sponsor Medical Monitor should be contacted to review details and discuss whether linezolid or 
full regimen should be resumed.  
8.3.2 ALT, AST and Alkaline Phosphatase elevations: 
The Investigator should refer to Appendix 5 – Liver Toxicity Management and to the ZeNix 
Hepatotoxicity Management Guideline to appropriately manage the participant for clinically 
significant elevations of AST, ALT or Alkaline Phosphatase. 
8.3.3 Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
Contact Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 4 elevations 
of lipase, Investigator should consider pausing the full regimen, pending further evaluation. 
8.3.4 Musculoskeletal System and Cardiac Muscle 
Myalgia 
Grade 2 (muscle tenderness at site other than sites of injection and/or venipuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
Participants with Grade 2 signs and symptoms should be followed closely. Participants with Grade 
3 or 4 signs and symptoms should be discussed with the Sponsor Medical Monitor to consider 
pausing trial medication, pending further evaluation. 
CPK 
For participants having elevations in CPK of potential clinical concern, the Investigator should 
check the CK-MB subunit, if high, consider pausing regimen and discuss with Sponsor Medical 
Monitor.  
8.3.5 Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
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Participants should be monitored closely.  The Investigator should discuss with the Sponsor 
Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artifacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen. 
8.3.6 Monitoring Linezolid Toxicities 
The following are guidelines for decisions to pause, reduce and to resume linezolid in response 
to the onset and resolution of known linezolid-specific toxicities.  These are guidelines, and 
decisions must be made in the context of the entire clinical status of the participant.  While the 
investigator may need to urgently interrupt dosing for potentially life threatening symptoms or 
laboratory findings, the Medical Monitor should be contacted and informed of any changes in 
dose within 24 hours.  Questions should be raised to the Sponsor’s Medical Monitor if the 
decision is not clear. 
8.3.6.1 Myelosuppression 
The hematologic parameters of hemoglobin and counts of Neutrophils and platelets are variable 
from measurement to measurement.  While decreases in any of these may be caused by linezolid 
toxicity, decreases of concern should be evaluated in the context of the participant’s full clinical 
status and alternate explanations.  Guidelines below are for situations of concern when it is 
considered likely that linezolid has caused the decrease. 
Anemia 
• 
Consider pausing linezolid if hemoglobin falls below 8 gm/dL or 80g/L (Grade 3) and 
significantly below baseline, or if hemoglobin falls > 25% of baseline. If it is clear that the 
anemia was caused by linezolid, consider resuming linezolid at half the dose when 
hemoglobin improves and linezolid is resumed.  
Leukopenia 
• 
Consider pausing linezolid if the Absolute Neutrophil Count (ANC) falls below 750/mm3  
or 0.75 x 10^9/L (Grade 3) and significantly below baseline.  Ideally confirm with a repeat 
test before making further decisions as ANCs can have diurnal and other variability. If it is 
clear that the leukopenia was caused by linezolid, consider resuming linezolid at half the 
dose when ANC improves and linezolid is resumed.  
Thrombocytopenia 
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• 
Consider pausing linezolid if platelets fall below 50,000/mm3 or 50 x 10^9/L (Grade 3) and 
significantly below baseline. Ideally confirm with a repeat test before making further 
decisions.  If it is clear that the thrombocytopenia was caused by linezolid, consider 
resuming linezolid at half the dose when platelets improves and linezolid is resumed. 
8.3.6.2 Peripheral Neuropathy 
The decision to reduce the dose, or to pause linezolid until symptoms improve is a judgment 
based on changes in signs and symptoms identified by the investigator and informed by 
discussion with the trial participant.  As general guidance, consider pausing and/or reducing 
linezolid when the grade of a neuropathy sign or symptom increases by a grade to grade two or 
greater.  If it is clear that linezolid caused the neuropathy, consider resuming linezolid at half the 
dose, when the neuropathy improves. 
8.3.6.3 Optic Neuropathy 
A participant with visual symptoms of concern or change in visual acuity of 2 lines or more or 
change in color vision of more than one plate should be referred to the site ophthalmologist for 
evaluation with a retinal examination.  Any changes as assessed by the ophthalmologist that raise 
concern that an optic neuropathy may be developing should be discussed with the medical 
monitor and linezolid should be paused.  If a likely or definite optic neuropathy is confirmed, 
linezolid should be permanently discontinued. 
8.3.6.4 Lactic Acidosis 
Lactic acidosis as a toxicity of linezolid should be considered if participants have gastrointestinal 
symptoms that are not explained by other more common causes of their symptoms.  Such 
participants should have lactate measured and, as indicated, a full evaluation of pH and 
bicarbonate. Note that lactate should not be measured in participants who have no symptoms of 
concern, as elevated asymptomatic lactate may be common and it is difficult to interpret the 
clinical relevance of this. Also evaluate whether any concomitant medications, such as anti-
retroviral therapies, may be associated with lactic acidosis and consider pausing them until the 
acidosis resolves. Consider pausing linezolid if a patient has GI symptoms and acidosis likely to 
be secondary to linezolid toxicity that is not otherwise explained. 
8.4 Safety Monitoring by Data Monitoring Committee 
A DSMC will be appointed for the trial. The primary responsibility of the DSMC will be to act in an 
advisory capacity to the Sponsor to safeguard the interests of trial participants by monitoring 
participant safety, assess participant risk versus benefit, and assess data quality and general 
evaluation of the trial progress. Its activities will be delineated in a DSMC charter that will define 
the membership, responsibilities and the scope and frequency of data reviews. The DSMC will 
operate on a conflict-free basis independently of the Sponsor and the trial team. It will comprise 
at least 3 voting members that include at least 2 clinicians and one statistician.  The DSMC may 
have an organizational meeting prior to commencement of the trial. The DSMC will have meetings 
where it will review unblinded data during a closed session. These meetings will be planned at 
regular intervals. The Sponsor or the DSMC may convene ad hoc meetings based on rates of 
SAEs and/or to review results of the futility analysis or if safety concerns arise during the trial.  
After its assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
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9 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 Analysis Population 
The primary analysis population will include both XDR and non-XDR (pre-XDR and MDR 
intolerant and non-responsive TB) participants (up to 45 per arm).  A secondary analysis will be 
restricted to the XDR participants only (30 per arm).    
A modified intent-to-treat (mITT) and a per-protocol (PP) analysis for each arm and analysis 
population will be conducted.    The mITT will be considered the primary analysis and will include 
all those in the ITT analysis with additional specific exclusions detailed in the statistical analysis 
plan (SAP). 
Other analyses will be performed (for sensitivity) including a full intent-to-treat (ITT) analysis with 
no exclusions, and an analysis excluding only those who were later found to be ineligible at 
baseline (based on data collected prior to randomization).    
The Safety analysis population will include data from all randomized participants who received at 
least one dose of IMP.  
Full details of all the analysis populations will be defined in the SAP. 
9.2 Sample Size 
The objective of this trial is to evaluate the efficacy, safety and tolerability of various doses and 
durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants 
with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
In order to fulfil this objective, it is planned to randomize 30 XDR-TB participants per treatment 
group and up to 15 pre-XDR and/or MDR intolerant/non-responsive -TB participants per group. A 
sample size of 30-45 per arm will provide more than 90% power to demonstrate that the lower 
bound of the 95% confidence interval of this estimate is greater than 50%, using a 2-sided 5% 
significance level. This assumes that the true cure rate is 80 percent.   
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as 
the target, because it is above the entire range of the historical control for cure of XDR-TB and 
because a cure rate of 50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a 
shortened, simplified, all oral, inexpensive and safer regimen would clearly represent an important 
therapeutic advancement. A standard-of-care control group cannot reasonably be included in the 
trial for several reasons.  1) Given that the regimens being tested contain B and L, these drugs 
would need to be excluded from the control group.  However, they are beginning to be used 
increasingly in XDR-TB, despite lack of firm evidence, but with positive anecdotal reports.  Asking 
patients in the control group to avoid these medications could present an ethical issue.  2) The 
success rate of standard-of-care treatment for XDR-TB, particularly without B and L (see below), 
and the risk and difficulty of its administration contrast markedly with the early findings of B-L-Pa 
in the Nix-TB trial.  It is unlikely that patients would sign informed consent to receive standard-of-
care treatment if there is an alternative, but even if they do there remains an ethical issue of 
comparing such a disadvantaged treatment with such an advantaged treatment.  3) The scientific 
validity of comparing a 12-month endpoint (B-L-Pa) with a 30- or 36-month endpoint (standard of 
care) would represent a significant challenge.   
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9.3 Interim Analyses 
No formal interim analyses are planned. However, there will be three planned unblinded 
analyses which will contain results by linezolid treatment group in aggregate as described 
below. The first analysis will be done after all participants have completed 26 weeks of 
treatment. The analysis will be on treatment safety events (mainly the specific toxicities 
described in section 8.3) and time to culture conversion (on treatment). The sites, participants, 
and Sponsor staff will not be unblinded to individual linezolid treatment information. A limited 
number of statisticians will have access to individual linezolid treatment assignments.  
The blind for all individual participants will be broken for the primary endpoint analysis (the 
second unblinded analysis) once all clinical data and outcome parameters for the primary 
endpoint have been captured, no more data queries are pending, and the statistical analysis 
plan has been updated accordingly.   
 
There will be three database locks, for the three planned unblinded data analyses generated for 
this trial:  
1. 
When all participants have completed 26 weeks of treatment   
2. 
When all participants have completed 26 weeks of follow-up after end of treatment.  
3. 
When all participants have completed 78 weeks of follow-up from after end of treatment.  
9.4 Primary and Secondary Endpoint Analysis 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT). 
A secondary analysis will be restricted to the XDR participants only (30 per arm). We will 
evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that 
the incidence of bacteriologic failure or relapse or clinical failure (including mortality) at 6 months 
(26 weeks) after the end of therapy is less than 50%.   
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and 
safety and to control the overall type I error rate the following analysis strategy will be adopted 
for both the primary and secondary analysis populations: 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 
weeks) with the L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a 
success.  Similarly, L600 9 weeks will only be tested if L600 26 weeks is a success.   A 
Bonferroni adjustment will be made for comparing the L1200 9 weeks and L600 26 weeks arms 
simultaneously, using p<0.025.  For these comparisons the lower bound of the 97.5% 
confidence interval will need to exceed 50% for success.   
No formal statistical pairwise comparisons between the arms will be performed. 
9.5 Safety and Tolerability Analysis 
• 
The incidence of all-cause mortality will be summarized. 
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• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake.  Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
• 
Cardiovascular Safety:  QT intervals will be adjusted using Fridericia’s correction and Bazett’s 
correction. QT/QTc values and changes from pre-dose (average of Screening and Day 1 
values) at each time point will be summarized using descriptive statistics by group and time 
of collection.  These will be presented as descriptive analyses, and no inferential tests will be 
carried out. 
o Post-baseline QT/QTc intervals will be classified into the following categories:   
 
QT/QTc < 450 msec 
 
450 msec < QT/QTc < 480 msec 
 
480 msec < QT/QTc < 500 msec 
 
QT/QTc > 500 msec   
o QTc changes from baseline will be classified into the following categories: 
 
increase < 30 msec,  
 
30 msec and < 60 msec, and  
 
increase > 60 msec.  
o Frequency counts will be used to summarize the number of participants at each 
time point according to the above categories. 
o ECG results will be classified as normal or abnormal (investigator assessment) 
and summarized using frequency counts by dose group and time of collection. 
• 
Ophthalmology: Descriptive statistics, including changes from baseline, will be summarized 
and listed by participant for ophthalmology slit lamp examination (age related eye disease 
study 2 [AREDS2] lens opacity classification and grading). Categorical data for lens opacity 
will be summarized in a frequency table for the right and left eye, respectively.  
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• 
Visual acuity and color vision:   Descriptive statistics, including changes from baseline, will be 
summarized and listed by participant for both Visual Acuity and Color Assessments. 
Categorical data for changes in visual acuity and color vision from baseline will be summarized 
in a frequency table for the right and left eye, respectively.  
• 
Descriptive statistics of neuropathy data derived from Brief Peripheral Neuropathy Screen. 
Categorical data for observed signs and symptoms of neuropathy will be summarized in 
frequency tables, including changes in signs and symptoms from baseline.  
• 
Other safety variables: Laboratory Parameters, Physical Examination, Vital signs (see 
Appendix 3), Concomitant medication, ophthalmic examination and peripheral neuropathy.  
Descriptive summary statistics will be presented. The incidence of liver related laboratory 
abnormalities will be explored. 
9.6 Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update population pharmacokinetic 
(PopPK) models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study trial population, and to derive 
individual exposure metrics for use in exposure-response analyses. PK data from the current trial 
may be combined with prior data (e.g., from the NiX-TB trial) to enhance this population PK 
analysis. Detailed plans for the PopPK analysis will be outlined in a separate modeling plan, and 
results will be reported in separate modeling report. 
9.7 Pharmacokinetics/Pharmacodynamics 
For each analyte, the PopPK model will be used to derive individual exposure metrics such as 
steady-state Ctrough, Cmax, AUCτ, and time-above-minimum-inhibitory-concentration (T>MIC), 
or alternative individual summaries of these metrics over the treatment period to account for dose 
adjustments and interruptions as appropriate. Relationships between such exposure metrics and 
efficacy and safety endpoints will be explored graphically and by model-based analyses as 
appropriate. Planning details and results will be included in the separate modeling plan and report. 
10 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants specific eCRF pages will be 
completed as described in the eCRF Completion Guidelines.  For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
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10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-Patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator has 
to 
permit 
trial 
related 
monitoring, audits, 
Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-Patient records while participants is on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial center files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection subsequent to trial completion.  The essential documents should be retained for 
not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify Sponsor/designees 
prior to destroying any records pertaining to the trial. 
11 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, ICH GCP, and the ethical principles that have their origin in the Declaration of 
Helsinki.  
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures, where available will be adhered to for all clinical and 
bioanalytical activities relevant to the quality of the trial.  Participant compliance will be monitored 
throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-investigators. Written 
IEC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements 
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11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, ICH GCP, the ethical principles that have their origin in the Declaration of 
Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for the purpose of monitoring various aspects of the trial, and to assure appropriate conduct of 
the trial in accordance with ICH GCP.  Visits will take place usually within a predetermined interval, 
but this may vary during the course of the trial.  The Investigator and site staff will allow the trial 
monitor and authorized representatives of the Sponsor to (1) inspect all CRFs, written informed 
consent documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs (where applicable), training records, facilities and 
other trial related systems/processes, and (2) access clinical supplies, dispensing and storage 
areas.  The Investigator and site staff should also (1) agree to assist with monitoring activities if 
requested and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Monitoring 
Plan requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB and Health Authority, per their guidelines. The 
site PI/all study staff is responsible for knowing and adhering to their IRB and Health Authority (as 
required) requirements. 
11.4 Auditing 
For the purpose of compliance with ICH GCP and regulatory agency guidelines, it may be 
necessary for Sponsor-authorized Quality Assurance personnel and/or authorized personnel from 
an external regulatory agency to conduct an audit or inspection of the investigational site.  The 
purpose of an audit is to assess the quality of data with regard to accuracy, adequacy and 
consistency, and to assure that studies are in accordance with the guidelines.  Having the highest 
quality data from studies is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by ICH GCP to be 
maintained by each site; drug storage, dispensing and return; all trial-related supplies; and source 
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documents against the CRFs to assure the adequacy and accuracy of the information which has 
been recorded, including the verification of any AEs which have occurred. The auditors or 
inspectors may also review site SOPs (where applicable), training records, site facilities and other 
trial related systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
12 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with ICH GCP, the ethical principles that have 
their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
Review 
The protocol and required trial related documents will be reviewed by the sites respective 
IEC/IRB.  The trial will not start until the IEC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, plus 
any other trial related documents required for review.  The IEC/IRB shall be constituted and shall 
operate in accordance with International ICH GCP, the ethical principles that have their origin in 
the Declaration of Helsinki. The Investigator will maintain an accurate and complete record of all 
submissions made to, and responses from the IRB/IEC.  The records should be filed in the 
Investigator’s Trial File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for the purpose of determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
considered to be part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary. The investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same IEC/IRB responsible for approval of this protocol.  Each 
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informed consent form shall include the elements required by the ICH GCP and must adhere to 
the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
ICF. 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the IEC/IRB approved written informed consent form 
will be signed and dated by both the participant and the person obtaining consent (Investigators 
or designees), and by any other parties required by the IEC/IRB. Ongoing participants must be 
re-consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative.  Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s 
medical record. 
The monitor will inspect the original completed consent form(s) for all participants 
12.5 Confidentiality  
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with ICH GCP, applicable local 
legislation/regulations.  Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the Sponsor or designees. 
13 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible IEC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors. (30)  
Because the Study is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Study must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Study must be submitted for 
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publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
14 Protocol Amendment Policy 
Any change to the protocol will be effected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the IEC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, IEC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant Authorities 
and/or IEC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the IEC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
15 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the Global Alliance for TB Drug Development (TB Alliance).  The TB Alliance 
is a not for profit, product development partnership accelerating the discovery and development 
of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, 
be compatible with antiretroviral therapies for those HIV-TB participants currently on such 
therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The Sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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16 References  
1. “A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis”. ClinicalTrials.gov, 25 
January 2017. https://www.clinicaltrials.gov/ct2/show/NCT02333799 
2. Bonilla CA, Crossa A, Jave HO, Mitnick CD, Jamanca RB, Herrera C, Ascencios L, 
Mendoza A, Bayona J, Zignol M and Jaramillo E (2008).  “Management of Extensively 
Drug-Resistant Tuberculosis in Peru: Cure Is Possible”. PLoS One 3(8): e2957. 
3. Cox H, Ford, N. “Linezolid for the treatment of complicated drug-resistant tuberculosis: a 
systematic review and meta-analysis” INT J TUBERC LUNG DIS 16(4):447–454, 2012.  
4. Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, van Niekerk C, 
Erondu N, Ginsberg AM, Becker P and Spigelman MK (2012). “Phase II Dose-Ranging 
Trial of the Early Bactericidal Activity of PA-824”. Antimicrobial Agents and Chemotherapy; 
56(6): 3027-3031.  
5. Bedaquiline (TMC207) Investigator’s Brochure, Janssen Research and Development., 
Edition 9, 09 October 2015.  
6. Investigator’s Brochure Pretomanid (PA-824), Global Alliance for TB Drug Development., 
Version 17, 22 December 2016.  
7. Keshavjee S, Gelmanova IY, Shin SS, Mishushtin SP, Andreev YG, Atwood S, Furin JJ 
and Miller A (2012). “Hepatotoxicity during treatment for multidrug-resistant tuberculosis: 
occurrence, management and outcome”. Int J Tuberc Lung Dis 16(5):596-603.   
8. Leach KL, Brickner SJ, Noe MC, Miller PF. "Linezolid, the first oxazolidinone antibacterial 
agent" Ann NY Acad Sci. 2011 Mar; 1222:49-54. 2011.  
9. Lee, et al. "Linezolid for treatment of chronic extensively drug-resistant tuberculosis" N 
Engl J Med. 2012 Oct 18; 367(16):1508-18. 
10. Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, 
Reynolds RC, and Orme IM. “Preclinical Testing of the Nitroimidazopyran PA-824 for 
Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models” 
Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301. 
11. Lytvynenko N, Cherenko S, Feschenko Y, Pogrebna M, Senko Y, Barbova A, Manzi M, 
Denisiuk O, Ramsay A and Zachariah R (2014). “Management of multi and extensively 
drug resistant tuberculosis in Ukraine: how well are we doing?” IUALTD Public Health 
Action 4(3): S67-S72. 
12. Manjunatha U, Boshoff HI, Berry CE. The mechanism of action of PA-824: novel insights 
from transcriptional profiling. Commun Integr Biol. 2009; 2(3):215-218. 
13. Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton, JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci USA. 2006; 103(2):431-436. 
14. McLeay SC, Vis P, van Heeswijk RPG and Green B (2014). “Population Pharmacokinetics 
of Bedaquiline (TMC207), a Novel Antituberculosis Drug”. Antimicrobial Agents and 
Chemotherapy 58(9): 5315-5324. 
15. Mdluli K, Nuermberger, E. “Pre-Clinical Drug Combination Studies to Identify Novel 
Regimens for TB”. In: Recent Advances in TB Drug Development symposium, 40th Union 
World Conference, International Union Against TB and Lung Disease, Cancun, Mexico, 
2009. 
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16. Mdluli K, Nuermberger E, Taylor K, Williams N, Koen A, Khisimuzi E, Rokeya T, Si-Yang 
L, Peloquin C, Dinesh C. “Sterilizing activity of novel TMC207- and PA-824-containing 
regimens in a murine model of tuberculosis” Antimicrobial Agents and Chemotherapy 
2011; 55: 5485-5492. 
17. Migliori GB, Sotgiu G, Gandhi NR, Falzon D, DeRiemer K, Centis R, Hollm-Delgado MG, 
Palmero D, Perez-Guzman C, Vargas MH, D’Ambrosio L, Spanevello A, Bauer M, Chan 
ED, Schaaf HS, Keshavjee S, Holtz TH, Menzies D and “The Collaborative Group for 
Meta-Analysis of Individual Patient Data in MDR-TB” (2013). “Drug resistance beyond 
XDR-TB: results from a large individual patient data meta-analysis”. Eur Respir J. 42(1): 
169-179.  
18. Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006; 50(8):2621-2625. 
19. Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal, I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 2008; 
52(4):1522-1524. 
20. Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005; 172(11):1452-1456. 
21. O’Donnell MR, Padayatchi N, Master I, Osburn G and Horsbaugh CR. “Improved Early 
Results for Patients with Extensively Drug Resistant Tuberculosis and HIV in South 
Africa”. Int J Tuberc Lung Dis. 13(7): 855-861. 
22. Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
23. Package Insert for South Africa, ZYVOXID® (linezolid), Pfizer Pharmaceuticals, May 
2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=1045. Date last accessed: 15 April 
15 2016.  
24. Package Insert, Lizomac™ 600 (linezolid), MacLeods Pharmaceutical, 2014. 
25. Package 
Insert, 
SIRTURO®, 
Janssen 
Therapeutics, 
December 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204384s006lbl.pdf. Date last 
accessed: 15 April 2016. 
26. Package 
Insert, 
ZYVOX®, 
Pfizer 
Pharmaceuticals, 
June 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021130s030,021131s029,02
1132s034lbl.pdf. Date last accessed: 15 April 2016.  
27. Park IN, et al. “Efficacy and tolerability of daily-half dose linezolid in patients with 
intractable multidrug-resistant tuberculosis.” B Antimicrobial Chemotherapy 2006; 58:701-
704. 
28. Pietersen E, et al. "Long-term outcomes of patients with extensively drug-resistant 
tuberculosis in South Africa: a cohort study" Lancet, 2014 Jan 16. pii: S0140-
6736(13)62675-6.  
29. Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, Vasilyeca I, 
Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, Van 
Baelen B, van Heeswijk RPG and Dannemann B (2016). “Bedaquiline safety data in a 
broad patient population treated for drug-resistant TB including XDR-TB (C209 study)”. 
Tuberculosis 47: 394-402.  
30. “Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in 
Medical Journals”, December 2016 update.  http://www.icmje.org/icmje-recommendations.pdf,  
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31. Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578.  
32. Schecter GF, et al.  “Linezolid Treatment for MDR-TB”. Clinical Infectious Diseases 2010; 
50:49-55. 
33. Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008; 
322(5906):1392-1395. 
34. Singla R. "Linezolid: an Effective, Safe and Cheap Drug for Patients Failing Multidrug-
resistant Tuberculosis Treatment in India" Eur Respir J. 2012 Apr; 39(4):956-62. doi: 
10.1183/09031936.00076811. Epub 2011 Sep 29. 
35. Stover, C. K., P. Warrener, D. R. VanDevanter, et al. 2000. “A small-molecule 
nitroimidazopyran drug candidate for the treatment of tuberculosis”. Nature 405:962–966. 
36. Tasneen R, Betoudji F, Tyagi S, et al.  Contributions of oxazolidinones to the efficacy of 
novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis.  
Antimicrob. Agents Chemother Posted Online 26 October 2015.  Dol:10.1128/AAC.01691-
15. 
37. Tasneen R, Tyagi S, Williams K, Grosset J, Nuermberger E. “Enhanced bactericidal 
activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of 
tuberculosis”. Antimicrob Agents Chemother. 2008; 52(10):3664-3668. 
38. Tato M, et al. "In vitro activity of linezolid against Mycobacterium tuberculosis complex, 
including multidrug-resistant Mycobacterium bovis isolates". Int. J. Antimicrob Agents 
2006 Jul; 28(1)75-8.  
39. Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”.  
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
40. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. Bactericidal 
activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2005; 49(6): 2289-2293. 
41. WHO Treatment of Tuberculosis Guidelines, 4th Edition. 2010.  
42. World Health Organization. Global Tuberculosis Report 2014, 19th ed. 2014. 
43. World Health Organization. Global Tuberculosis Report 2015, 20th ed. 2015. 
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Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
exact figure/100/scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at 
least 20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life-
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization 
or hospice care probable. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common Toxicity 
Criteria (CTC), and World Health Organization (WHO)) have been adapted for use by the 
Division of Microbiology and Infectious Diseases (DMID) and modified to better meet the 
needs of Patients in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low : 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low : 
<100 mg/dL 
High: 
>600 mg/dL 
Low : 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated w ith 
gross bleeding or 
w ith disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life-
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
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Hypocalcemia 
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life-
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life-
threatening arrhythmia 
Hyperbilirubinemia 
(w hen accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(w hen other liver 
function are in the  
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase  
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
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Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, w ith or 
w ithout clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment required 
acute treatment 
required; 
outpatienttreatm
ent or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension w ith 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable w ith oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock;   
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled w ith 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV 1 of peak 
flow  
requires treatment; 
normalizes w ith 
bronchodilator; FEV 1 
50% - 70% (of peak 
flow ) 
no normalization w ith 
bronchodilator;FEV 1 
25% - 50% of peak 
flow ; or  retractions 
present 
cyanosis: FEV 1 < 
25% of peak flow  
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea w ith normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
 
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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3-
4 loose stools/day 
or mild diarrhea 
last < 1 w eek 
moderate or 
persistent; 5-7 loose 
stools/day or 
diarrhea lasting >1 
w eek 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization   
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
sw allow ing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
sw allow  solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
 
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NEUROLOGICAL 
 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
w eakness no 
objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function 
objective 
w eakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment  required 
moderate 
discomfort; non-
narcotic analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
w ith symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment (mod 
decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or w rists) or 
loss of sensation of 
at least mod 
degree in multiple 
different body 
areas (i.e., upper 
and low er 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis;  or 
seizures 
 
 
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MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering w ith 
function 
moderate pain, 
analgesics and/or 
pain interfering w ith 
function but not w ith 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering w ith 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain w ith 
inflammation, 
erythema or joint 
sw elling – but not 
interfering w ith 
function 
moderate pain w ith 
inflammation, 
erythema or joint 
sw elling – interfering 
w ith function, but 
not w ith activities of 
daily living 
severe pain w ith 
inflammation, 
erythema or joint 
sw elling –and 
interfering w ith 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia w ith no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or w ith 
moderate 
impairment of 
activity 
severe muscle 
tenderness w ith 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected Stevens-
Johnson or  
necrosis requiring 
surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection 
Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 
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CONFIDENTIAL 
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SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus w ithout rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial narcotic 
therapy 
intractable; requires 
repeated narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 50% 
> 48 hours 
normal activity 
decreased > 50% 
can’t w ork 
unable to care for 
self 
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Appendix 3:  Cardiovascular Safety 
 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 90 mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or 
Grade 4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
 
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CONFIDENTIAL 
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Appendix 4:  Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms of 
disease.  
80 
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
Cares for self; unable to carry on normal activity or to 
do active work. 
70 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
60 
Requires considerable assistance and frequent medical 
care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109(22). 
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CONFIDENTIAL 
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Appendix 5: Liver Toxicity Management  
Standard anti-TB chemotherapy is known to cause derangement of liver function tests in a 
substantial number of patients. In many cases this will be asymptomatic and self-limiting. In some 
cases, severe hepatitis and even fulminant liver failure and death can occur.  
In pre-marketing clinical trials of new drugs and regimens it is especially important to identify and 
carefully manage any trial participants who are at risk of progression to serious liver injury.  The 
observation of altered liver function to a degree that has a high risk of progressing to liver failure 
has been referred to informally as Hy’s Law;(31,39); this reflects that pure hepatocellular injury 
sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, Hy’s Law cases have the following three components:  
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo.  
2. Among trial participants showing such aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show elevation of serum total bilirubin (TBL) 
to >2x ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase 
(ALP)).  
3. No other reason can be found to explain the combination of increased AT and total bilirubin 
level (TBL), such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury.  
During the trial, liver function will be monitored regularly with clinical assessment and blood tests 
in study participants and this will assist in follow up laboratory measurements that can document 
either resolution of abnormalities or signal the potential for drug-induced liver injury (DILI).  In a 
clinical trial of new drugs and combinations it is especially important for investigators to follow 
closely any participants who have evidence of hepatic inflammation or potential toxicity. The 
following procedure describes the management of deranged liver function tests in study 
participants. 
Procedure 
Blood tests for liver function will be taken routinely at screening (Day -14 to -1) and at the specific 
time points designated in the protocol, and at Early Withdrawal.  If at any other visit the clinician 
suspects derangement of liver function, e.g. the participant describes nausea and vomiting, right 
upper abdominal pain or is jaundiced, blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of hepatitis or hepatic impairment and any 
potentially contributing causes.  
Suspected liver toxicity (or elevated liver enzymes detected in the absence of symptoms) must 
be taken seriously and detailed guidance will be provided in a separate document “ZeNix 
Hepatotoxicity Management Guideline”. Investigators should refer to this document as a guide to 
management in cases of suspected or proven liver toxicity.  Importantly, the trial Medical Monitor 
is available to provide further assistance if there is any uncertainty or additional questions. 
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Protocol Version V2.0 MDA / 10 Mar 2020 
Protocol Name: ZeNix 
 
 
CONFIDENTIAL 
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The laboratory source (print-out of any results) should be stored alongside or transcribed into the 
clinical source document. Each abnormal value should be marked as clinically significant (CS) or 
non-clinically significant (NCS); the assessment of significance is at the discretion of the 
investigator. All clinically significant abnormal results must be recorded as Adverse Events in the 
eCRF and graded clinically as per the DMID adult toxicity table grading, (Appendix 2).  
Assessments and decision making for elevations in aminotransferase values or bilirubin of various 
levels of concern are detailed below: 
Elevated liver enzymes considered of clinical significance, but not accompanied by other signs 
and symptoms, should be reported as an adverse event and should usually be recorded as 
elevated liver enzymes. If the term "hepatitis" is used, the Safety Data Manager will question the 
site for additional evidence to support the diagnosis, such as clinical signs and serological or 
biopsy data. While a liver biopsy is not required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for cases where there is supportive evidence 
beyond a liver enzyme abnormality. However, if the investigator will confirm the diagnosis of 
hepatitis just on the basis of clinical signs and laboratory values the diagnosis will be accepted. 
Should other symptoms or signs be present, these should also be recorded as adverse events. 
Restarting Medication 
Liver function tests that are improving should be repeated regularly, such as every 3 days for the 
first week then once a week until they return to near baseline values for the participant. Manage 
the participant symptomatically as required using medications that are not potentially hepatotoxic. 
Infection control issues must be carefully managed whilst TB medications are being withheld, 
especially if the participant is still culture positive for acid fast bacilli. 
If medication has been temporarily stopped, once the liver function values have decreased 
substantially a decision must be made about further TB management.  This will be dependent on 
the clinical context and a decision must be made in discussion with the Sponsor Medical Monitor. 
Treatment can only be restarted if the trial Medical Monitor is in agreement with the plan. In all 
cases treatment should be recommenced under close supervision for any evidence of recurrent 
liver function abnormalities.  
If there is a further significant elevation of hepatic enzymes or bilirubin or symptoms of clinical 
concern after resumption of study medication, the study medication should be withdrawn 
permanently. Participants who permanently discontinue study medication should be managed as 
clinically indicated according to local National TB Programme guidelines. The Sponsor Medical 
Monitor can be contacted for further advice when referring to the National Treatment Program. 
The trial Medical Monitor is available to assist the Investigators in both the management of liver 
toxicity and decisions regarding the holding or re-introduction of trial medication. Investigators 
must involve the Medical Monitor in any decisions regarding medication hold or re-start, and there 
should always be a low threshold for contacting the Medical Monitor in cases of elevated liver 
enzymes. 
Refer to ZeNix Hepatotoxicity Management Guideline for further details. 
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Page 1 of 98 
CONFIDENTIAL  
Protocol Number 
NC-007-(B-Pa-L) 
Title: 
A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid 
plus bedaquiline and pretomanid in participants with pulmonary 
infection of either extensively drug-resistant tuberculosis (XDR-
TB), pre-XDR-TB or treatment intolerant or non-responsive multi-
drug resistant tuberculosis (MDR-TB). 
Drug(s)/Combination(s): Bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Version/Date: 
V 3.0 RUS dated 18 March 2020 (incorporating:  
Protocol RUS/BEL V1.0 dated 23 Feb 2017 and 
Country specific Amendment for Russia V1.0 dated 15 Nov 2017 
and Protocol Amendment 1 dated 13 June 2018 and Protocol 
Amendment 2 dated 10 Mar 2020 
Protocol Name: 
ZeNix 
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Protocol Version  V3.0 RUS / 18 MARCH 2020   
Protocol Name: ZeNix 
 
 
 
CONFIDENTIAL 
Page 2 of 98 
 
SPONSOR PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version/Date:  V3.0 RUS dated 18 March 2020, (incorporating  
Protocol RUS/BEL V1.0 dated 23 Feb 2017,  
Country specific Amendment for Russia V1.0 dated15 Nov 2017 
and Protocol Amendment 1 dated 13 June 2018 and Protocol 
Amendment 2 dated 10 Mar 2020) 
Protocol Name: ZeNix  
SPONSOR  
I agree to the terms of this trial protocol. 
 
 
 
Signature of Senior Medical Officer 
 
Printed Name 
 
 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone 646-616-8671 
email: daniel.everitt@tballiance.org 
Date 
 
 
 
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Protocol Version  V3.0 RUS / 18 MARCH 2020   
Protocol Name: ZeNix 
 
 
 
CONFIDENTIAL 
Page 3 of 98 
LEAD INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version/Date:  V3.0 RUS dated 18 March 2020, (incorporating  
Protocol RUS/BEL V1.0 dated 23 Feb 2017,  
Country specific Amendment for Russia V1.0 dated15 Nov 2017 
and Protocol Amendment 1 dated 13 June 2018 and Protocol 
Amendment 2 dated 10 Mar 2020) 
 
Protocol Name: ZeNix 
 
LEAD INVESTIGATOR 
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and local 
regulations. 
 
 
 
Signature  
 
Printed Name 
 
 
 
Date 
 
 
 
 
 
 
 
 
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Protocol Version  V3.0 RUS / 18 MARCH 2020   
Protocol Name: ZeNix 
 
 
 
CONFIDENTIAL 
Page 4 of 98 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline and 
pretomanid in participants with pulmonary infection of either extensively drug-resistant 
tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug 
resistant tuberculosis (MDR-TB). 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version/Date:   V3.0 RUS dated 18 March 2020, (incorporating  
Protocol RUS/BEL V1.0 dated 23 Feb 2017,  
Country specific Amendment for Russia V1.0 dated15 Nov 2017 
and Protocol Amendment 1 dated 13 June 2018 and Protocol 
Amendment 2 dated 10 Mar 2020) 
 
Protocol Name: ZeNix 
PRINCIPAL INVESTIGATOR 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
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Global Alliance for TB Drug Development 
Protocol Number: NC-007-(B-Pa-L) 
Protocol Version V3.0 RUS / 18 MARCH 2020 
Protocol Name: ZeNix  
1.1 
Synopsis Summary ...................................................................................................11 
1.2 
Synopsis Flowchart...................................................................................................16 
2 
Introduction and Rationale .............................................................................................. 21 
2.1 
Trial Rationale ..........................................................................................................22 
2.1.1 
Trial Design Rationale........................................................................................22 
2.1.2 
Trial Drug Rationale ...........................................................................................22 
2.1.3 
Pretomanid ........................................................................................................24 
2.1.4 
Linezolid ............................................................................................................24 
2.2 
Agents to be Studied ................................................................................................25 
2.2.1 
Bedaquiline .......................................................................................................25 
2.2.2 
Pretomanid ........................................................................................................28 
2.2.3 
Linezolid ............................................................................................................34 
2.3 
Regimens to be Studied............................................................................................39 
2.3.1 
Non-Clinical Studies ..........................................................................................39 
2.3.2 
Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or Linezolid ...41 
2.4 
Overall Benefit/Risk Assessment...............................................................................44 
3 
Trial Objectives .............................................................................................................. 45 
3.1 
Primary Objectives....................................................................................................45 
4 
Trial Design .................................................................................................................... 45 
4.1 
Summary of Trial Design...........................................................................................45 
4.2 
Treatment Plan: Schedule of Assessments ...............................................................45 
5 
Trial Population .............................................................................................................. 46 
5.1 
Inclusion Criteria .......................................................................................................47 
5.2 
Exclusion Criteria......................................................................................................48 
5.3 
Restrictions ..............................................................................................................51 
5.3.1 
Prior and Concomitant Medications and Other Treatments .................................51 
5.3.2 
Recommendations for Concomitant use of Anti-Malarials ...................................52 
5.3.3 
Antiretroviral Therapy.........................................................................................53 
5.3.4 
Other Restrictions ..............................................................................................53 
5.4 
Trial Discontinuation and Visits .................................................................................53 
5.4.1 
Treatment Discontinuation and Early Withdrawal ................................................53 
1 
Synopsis ........................................................................................................................ 11 
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5.4.2 
Early Withdrawal Follow-up................................................................................54 
5.4.3 
Unscheduled Visits ............................................................................................55 
5.4.4 
Lost to Follow-up ...............................................................................................55 
5.4.5 
Early Withdrawal due to TB................................................................................55 
5.5 
Participant Progress Definitions ................................................................................56 
5.6 
Trial Stopping Rules .................................................................................................57 
6 
Treatment ..........................................................................................................................57 
6.1 
IMP Administration....................................................................................................57 
6.2 
Participant Compliance .............................................................................................58 
6.3 
Treatment Modification(s) .........................................................................................58 
6.4 
IMP Packaging and Labelling ....................................................................................59 
6.5 
Method of Treatment Assignment..............................................................................60 
6.6 
Blinding and Procedures for Breaking the Blind .........................................................60 
6.7 
Handling, Storage and Accountability ........................................................................61 
7 
Trial Variables and Procedures ....................................................................................... 62 
7.1 
Demographic and Background Variables and Procedures .........................................62 
7.2 
Efficacy Variables and Procedures ............................................................................63 
7.3 
Safety and Tolerability Assessments .........................................................................63 
7.4 
PK Variables and Procedures ...................................................................................65 
7.5 
Mycobacteriology Characterization Variable and Procedures .....................................65 
8 
Adverse Events .............................................................................................................. 66 
8.1 
Definitions ................................................................................................................66 
8.1.1 
Adverse Event (AE) ...........................................................................................66 
8.1.2 
Serious Adverse Event (SAE) ............................................................................66 
8.1.3 
Attribution/Causality ...........................................................................................66 
8.1.4 
Severity .............................................................................................................67 
8.2 
Reporting .................................................................................................................68 
8.2.1 
Follow up of Adverse Events ..............................................................................68 
8.2.2 
Clinical Laboratory Adverse Events ....................................................................69 
8.2.3 
Disease under Study .........................................................................................69 
8.2.4 
Overdose ..........................................................................................................70 
8.2.5 
Drug Interaction .................................................................................................70 
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8.2.6 
Pregnancy .........................................................................................................70 
8.3 
Monitoring for Specific Toxicities ...............................................................................70 
8.3.1 
Neurological ......................................................................................................71 
8.3.2 
ALT, AST and Alkaline Phosphatase elevations: ................................................71 
8.3.3 
Lipase ...............................................................................................................71 
8.3.4 
Musculoskeletal System and Cardiac Muscle .....................................................71 
8.3.5 
Cardiac Rhythm Disturbances............................................................................71 
8.3.6 
Monitoring Linezolid Toxicities............................................................................72 
8.4 
Safety Monitoring by Data Monitoring Committee ......................................................73 
9 
Statistical Analysis.......................................................................................................... 74 
9.1 
Analysis Population ..................................................................................................74 
9.2 
Sample Size .............................................................................................................74 
9.3 
Interim Analyses .......................................................................................................75 
9.4 
Primary and Secondary Endpoint Analysis ................................................................75 
9.5 
Safety and Tolerability Analysis.................................................................................75 
9.6 
Pharmacokinetics .....................................................................................................77 
9.7 
Pharmacokinetics/Pharmacodynamics ......................................................................77 
10 Records Management .................................................................................................... 77 
10.1 Data Collection .........................................................................................................77 
10.2 Source Documents ...................................................................................................77 
10.3 File Management at the Trial Centre .........................................................................78 
10.4 Records Retention at the Trial Centre .......................................................................78 
11 Quality Control and Assurance........................................................................................ 78 
11.1 Site Procedures ........................................................................................................78 
11.2 Monitoring ................................................................................................................78 
11.3 Protocol Deviations ...................................................................................................79 
11.4 Auditing ....................................................................................................................79 
12 Ethics and Regulatory .................................................................................................... 80 
12.1 Basic Principles ........................................................................................................80 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review .............80 
12.3 Regulatory Authorities...............................................................................................80 
12.4 Informed Consent .....................................................................................................80 
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Protocol Name: ZeNix 
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12.5 Confidentiality ...........................................................................................................81 
13 Publication Policy ........................................................................................................... 81 
14 Protocol Amendment Policy ............................................................................................ 82 
15 Sponsor, Financial Aspects, Insurance and Indemnity ..................................................... 82 
16 References..................................................................................................................... 83 
Appendix 1: 
The IUATLD Scale ........................................................................................ 86 
Appendix 2: 
Division of Microbiology and Infectious Disease (DMID) Toxicity Table ........... 87 
Appendix 3: 
 Cardiovascular Safety................................................................................... 95 
Appendix 4: 
 Karnofsky Performance Status Scale Definitions Rating (%) Criteria .............. 96 
Appendix 5: 
Liver Toxicity Management ............................................................................ 97 
TABLES 
Table 1: 
ADRs C208 Stage 1 and Stage 2 ........................................................................27 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies .......................................29 
Table 3: 
Murine Lung CFU counts during Treatment with Linezolid .......................................35 
Table 4: 
Murine Relapse Data .........................................................................................40 
Table 5: 
Summary Statistics for EBA................................................................................41 
Table 6: 
NC-003 Efficacy Results: Daily BAlog ..................................................................42 
Table 7: 
NC-003 Safety Data ..........................................................................................42 
Table 8: 
Treatment Groups .............................................................................................45 
Table 9: 
Follow-up Visits Required for Early Withdrawal Participants.....................................54 
Table 10:  
Investigational Medicinal Product Details ..............................................................58 
Table 11:  
Adverse Events Attribution/Causality Ratings ........................................................67 
Table 12: 
Definitions for Adverse Event Severity Gradings ....................................................67 
FIGURES 
Figure 1: 
Log10 CFU Counts in Lungs .....................................................................................29 
Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010......................................32 
Figure 3: 
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin CL-001............36 
Figure 4: 
Trial Schematic .......................................................................................................46 
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CONFIDENTIAL 
Page 9 of 98 
Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
Abacavir 
ADR 
Adverse drug reactions 
AE  
Adverse event  
AIDS 
Acquired immune deficiency syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AREDS2 Age related eye disease scale 2 
ART 
Anti-retroviral therapy 
AST 
Aspartate amino transferase 
AT 
Amino transferase 
AUCτ 
Area under curve over a dosing interval 
B 
Bedaquiline 
BMI 
Body mass index 
bpm 
Beats per minute 
BPNS 
Brief peripheral neuropathy scale 
C 
Clofazimine 
CFU 
Colony forming units 
CK(-MB) 
Creatine kinase (-MB isoenzyme) 
C(max), 
(min) 
Plasma concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine phosphokinase 
CS 
Clinically significant 
Ctrough 
Plasma concentration trough 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of microbiology and infection disease 
DNA 
Deoxyribonucleic acid 
DOH 
Department of health 
DILI 
Drug induced liver injury 
DSMC 
Data safety monitoring committee 
DST 
Drug susceptibility testing 
E 
Ethambutol 
EBA 
Early bactericidal activity 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
Electronic case report form 
FQ  
Fluoroquinolone 
FTC 
Emtricitabine 
g/L 
Grams per liter 
GI 
Gastrointestinal 
GCP  
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMR 
Geometric mean ratio 
H 
Isoniazid 
hERG 
Human ether-à-go-go related gene 
HIV  
Human immunodeficiency virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
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Page 10 of 98 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IXRS 
Interactive Voice and Web Response System 
kg 
Kilogram 
/L 
Liter 
L 
Linezolid 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
M 
Moxifloxacin 
MAO(I) 
Monoamine oxidase (Inhibitor) 
MBD 
Minimum bactericidal dose 
MIC 
Minimum inhibitory concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi drug resistant tuberculosis 
MGIT 
Mycobacterial growth inhibiting tube 
mITT 
Modified intent to treat 
mL 
Milliliter 
ms 
Millisecond 
NCS 
Not clinically significant 
NEJM 
New England Journal of Medicine 
NVP 
Nevirapine 
NO 
Nitric oxide 
NOAEL 
No observed adverse effect level 
NRTI 
(Triple) nuleosidase reverse transcriptase inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
QD 
Once daily 
R 
Rifampicin 
S 
Streptomycin 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SIRE 
Streptomycin isoniazid rifampicin ethambutol 
SOC 
System organ class 
TB 
Tuberculosis 
TBL 
Serum total bilirubin 
TDF 
Tenofovir 
TEAE 
Treatment emergent adverse events 
T>MIC 
Time above minimum inhibitory concentration 
t.i.w. 
Three times a week 
(BA) TTP (Bacteriocidal activity) time to positivity  
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
XDR-TB 
Extensively drug resistant tuberculosis 
μg 
Microgram 
Z 
Pyrazinamide 
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1 
Synopsis 
1.1 Synopsis Summary 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
bedaquiline (B), pretomanid (Pa) and linezolid (L) 
Protocol Number/Title: 
NC-007: A Phase 3 partially-blinded, randomized trial assessing the safety 
and efficacy of various doses and treatment durations of linezolid plus 
bedaquiline and pretomanid in participants with pulmonary infection of either 
extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB) 
Treatment Indication: 
Pulmonary XDR-TB, pre-XDR-TB, and treatment intolerant or non-responsive 
MDR-TB 
Trial Objective: 
To evaluate the efficacy, safety and tolerability of various doses and durations 
of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in 
participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment 
intolerant or non-responsive MDR-TB. 
Trial Design: 
A phase 3, multi-center, partially-blinded, randomized clinical trial in four parallel 
treatment groups. Bedaquiline and pretomanid treatment will not be blinded.  
Linezolid treatment dose and duration will be double-blinded. 
 
Participants will have a screening period of up to 14 days and will be 
randomized to receive one of the 4 active treatment arms. Participants will be 
randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
voice and web response system (IXRS) which will utilize a randomization 
system using stratification with a random element to allocate participants evenly 
across the arms by HIV status and type of TB.   
 
Each participant will receive 26 weeks of treatment.  If participant’s  sputum 
sample is culture positive between the week 16 and week 26 treatment visits 
and their clinical condition suggests they may have an ongoing TB infection, 
Investigator may consider extending current treatment to 39 weeks.   If the 
culture results between week 16 and week 26 are contaminated, missing or 
considered an isolated positive without clinical significance, available culture 
results should be used to make this decision. All decisions regarding treatment 
extension should be discussed with and approved by  the Sponsor Medical 
Monitor before implementation. 
 
Participants will be followed for 78 weeks after end of treatment. 
Patient Population: 
A total of up to 180 participants, male and female, aged 18 and over Sponsor 
may consider replacement of late screen failure and un-assessable (as 
detailed in the statistical analysis plan) participants. 
Test product, Dose and 
Mode of Administration: 
The regimen will be supplied as the following: 
 
Product 
Tablet Strength 
Abbreviation  
Bedaquiline 
100 mg  
(B) 
Pretomanid 
200 mg  
(Pa) 
Linezolid (scored) 
 
 
600 mg 
(L) 
Placebo Linezolid 
(scored) 
placebo 
(L) 
Linezolid 600 mg half 
tablet (pre-cut) 
300 mg 
(L) 
 
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Protocol Version V3.0 RUS / 18 MARCH 2020  
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Page 12 of 98 
Placebo linezolid half 
tablet (pre-cut) 
placebo 
(L) 
 
Linezolid treatment will be supplied as 2 rows of full tablets (active or 
placebo) and one row of half-tablets (active or placebo) to allow for all 
possible dosing options while maintaining the blind.  
 
Instructions for Dosing: 
Treatment will be administered orally, once daily, with a full glass of water and 
a meal in the following dosing schemes (treatment arms): 
 
Participants will receive the following: 
• 
Bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 
18 weeks plus;  
• 
Pretomanid 200 mg once daily for 26 weeks plus; 
• 
Linezolid- participants will be randomly assigned to receive one of the 
following four blinded linezolid treatment doses and durations:  
Linezolid 1200 mg daily for 26 weeks 
• 
2 linezolid 600 mg active tablets once daily for 26 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
 
Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
• 
2 linezolid 600 mg active tablets once daily for 9 weeks  
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
Linezolid 600 mg daily for 26 weeks 
• 
1 linezolid 600 mg active tablet once daily for 26 weeks 
• 
1 placebo linezolid tablet once daily for 26 weeks  
• 
½ (one half) placebo linezolid tablet once daily for 26 weeks 
 
Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid tablet for 9 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid tablets once daily for 17 weeks 
• 
½ (one half) placebo linezolid tablet once daily for 17 weeks 
  
Treatment Modifications: 
The above treatment schemes may require modification due to toxicities as 
noted below. All dose modifications should be discussed with the Sponsor 
Medical Monitor prior to implementation, unless a pause or dose reduction is 
required urgently for a safety concern; the Medical Monitor should be informed 
within 24 hours of the change if not discussed prior to implementation 
 
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Protocol Version V3.0 RUS / 18 MARCH 2020 
Protocol Name: ZeNix 
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Page 13 of 98 
In the event of linezolid specific toxicities, the following should be considered 
and implemented per guidance in the monitoring and safety for specific 
toxicities section (8.3) of protocol:   
•
Blinded one step reductions (maximum 2 steps) in the dose of linezolid
managed by the IXRS as per instructions in pharmacy manual and/or
IXRS user manual.
o
1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or
o
600 mg QD to 300 mg QD, 300mg QD to placebo
•
Temporary pause of linezolid.
•
Permanent discontinuation of linezolid.
•
Participants who have a linezolid reduction can go back to a higher dose
(1 step or 2 steps) post discussion with and approval by the Sponsor
Medical Monitor.
For participants experiencing suspected drug related toxicities due to other 
drugs in the regimen (B-Pa), the full regimen may be halted for up to 35 
consecutive days.  
Interruptions/pauses of all Investigational Medicinal Product (IMP) must not 
exceed 8 weeks (56 days) cumulatively.  
When treatment is extended to 39 weeks, interruptions/pauses of all IMP must 
not exceed 13 weeks (91 days) cumulatively. 
When the total of missed dosing days of the prescribed regimen and/or 
pauses is greater than 7 days, the same number of missed doses should be 
dispensed/treatment extended to make up for the total missed doses. 
At no time should the participant be treated with a single agent. 
Every effort should be made for participants to receive a total of 9 weeks of 
linezolid, even if pauses are required 
Criteria for Evaluation: 
Primary Endpoint: 
Incidence of bacteriologic failure or relapse, or clinical failure at 26 weeks after the end of treatment. 
Abbreviated Definitions, full definitions will be described in the Statistical Analysis Plan (SAP): 
•
Bacteriologic failure: During the treatment period, failure to attain or maintain culture conversion to
negative.
•
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative
status, with culture conversion to positive status with a strain of Mycobacterium tuberculosis (MTB)
genetically identical to the infecting strain at baseline.
•
Clinical failure: A change from protocol-specified TB treatment to a new regimen before end of 
protocol specified treatment due to treatment failure, retreatment for TB during follow up, or TB-
related death.
Note: 
•
Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days 
apart.
•
Participants who are documented at a visit as unable to produce sputum and who are clinically 
considered to be responding well to treatment will be considered to be culture negative at that visit.
Further details of definitions to be provided in the SAP. 
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Protocol Version V3.0 RUS / 18 MARCH 2020 
Protocol Name: ZeNix 
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Page 14 of 98 
Secondary Endpoints: 
•
Incidence of bacteriologic failure or relapse, or clinical failure through follow up until 78 weeks after
the end of treatment.
•
Time to sputum culture conversion to negative status through the treatment period.
•
Proportion of participants with sputum culture conversion to negative status at weeks 4, 6, 8, 12, 16
and end of treatment.
•
Change from baseline TB symptoms.
•
Change from baseline in Patient Reported Health Status.
•
Change from baseline weight.
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations of bedaquiline and its M2, pretomanid and linezolid from sparse sampling (see Table 
1.2) will be measured and used to update population PK models for bedaquiline and its M2 metabolite, 
pretomanid, and linezolid to further evaluate the effects of covariates on model parameters in this study 
population. PK data from the current trial may be combined with prior data (e.g., from the NiX-TB trial) to 
enhance this population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T>MIC) for subsequent analyses exploring relationships between drug 
exposure and efficacy and safety endpoints.   
Safety and Tolerability: 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
•
All-cause mortality.
•
Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by, drug relatedness 
and seriousness, leading to early withdrawal from treatment, leading to pauses of linezolid, leading
to linezolid reductions and leading to death.
•
Quantitative and qualitative clinical laboratory result measurements, including observed and change
from baseline.
•
Quantitative and qualitative electrocardiogram (ECG) results read by a central cardiology service,
including observed and change from baseline.
•
Descriptive statistics of ophthalmology slit lamp examination data (age related eye disease study 2
[AREDS2]) lens opacity classification and grading). Categorical data for lens opacity will be
summarized in a frequency table for the right and left eye, respectively, including observed and
change from baseline.
•
Changes in ophthalmic exam for visual acuity and color vision, including observed and change from
baseline.
•
Changes noted in peripheral neuropathy signs and symptoms, including observed and change from
baseline.
Mycobacteriology Assessments: 
Sputum samples will be obtained at all scheduled visits.  The following tests will be performed.  
•
Smear microscopy for acid-fast bacilli (AFB);
•
Liquid Culture (MGIT), followed by a speciation test to detect presence or absence of MTB and
obtain time to positivity (TTP);
•
GeneXpert, Hain Genotype MTBDRplus or an alternative molecular to confirm MTB and rifamycin
resistance.
•
Minimum Inhibitory concentration (MIC) of bedaquiline, pretomanid and linezolid;
•
Drug Susceptibility Testing (DST) in liquid culture for rifampicin, isoniazid, streptomycin, ethambutol, 
pyrazinamide and second line TB drugs including fluoroquinolones and injectable;
•
Genotyping.
Details on the testing and the collection and timing of samples are in sections 1.2 and 7.2 
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Protocol Version V3.0 RUS / 18 MARCH 2020  
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Statistical Methods: 
A general description of the statistical methods planned for the primary efficacy outcome is outlined below. 
Specific details will be provided in the SAP. 
 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT).  We will 
evaluate the hypothesis, separately for each of the experimental B-Pa-L treatment arms, that the incidence 
of bacteriologic and clinical cure at 26 weeks after the end of therapy is greater than 50%.   
 
The incidence will be estimated from the binomial proportion for participants with success criteria based on 
the lower bound of the confidence interval for this proportion being greater than 50%. 
 
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as the target, 
because it is above the entire range of the historical control for cure of XDR-TB and because a cure rate of 
50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a shortened, simplified, all oral, 
inexpensive and safer regimen would clearly represent an important therapeutic advancement.  
 
The primary analysis population will include both XDR and non-XDR participants (up to 45 per arm).  A 
secondary analysis will be restricted to the XDR participants only (30 per arm).   A sample size of 30-45 per 
arm will provide more than 90% power to demonstrate that the lower bound of the 95% confidence interval 
of this estimate is greater than 50%, using a 2-sided 5% significance level. This assumes that the true cure 
rate is 80 percent.   
 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 6 months) with the 
L1200 2 months and L600 26 weeks only being tested if L1200 26 weeks is a success.  Similarly, L600 9 
weeks will only be tested if L600 26 weeks is a success.  A Bonferroni adjustment will be made for 
comparing the L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025.  For these 
comparisons the lower bound of the 97.5% confidence interval will need to exceed 50% for success.   
 
Both a Modified Intent to Treat (mITT) and a Per Protocol (PP) analysis for each arm will be conducted.  No 
formal statistical pairwise comparisons between the arms will be performed.   
Trial Duration: 
~4 Years (An enrolment period of approximately 24 months plus 14 days pre-treatment plus 6 months 
treatment period plus 18 months post treatment follow-up). 
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Protocol Version V3.0 RUS / 18 MARCH 2020  
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Page 16 of 98 
1.2 Synopsis Flowchart 
Period Screeninga 
Treatment 
 Visits every 3 
weeks if 
treatment 
extendedb 
End of OR Early 
Withdrawal from 
Treatmentc 
Post Treatment Follow-up 
Time of Visit 
Up to 14 days 
prior to first 
dose 
Day 1 
Week  1 
Week  2 
Week 3 
Week  4 
Week 5 
Week  6 
Week 7  
Week  8 
Week 10 
Week 12 
Week 14 
Week  16 
Week 18 
Week 20 
Week 23 
4 weeks 
8 weeks 
12 weeks 
26 weeks 
39 weeks 
52 weeks 
65 weeks 
78 weeks/EWc 
Visit Window q 
N/A 
+/- 3 days 
+/- 5 days 
+/- 7 days 
Post last 
dose IMP 
+7 days 
+/-  14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Trtmnt/Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusiond 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Statuse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 Count and Viral Loadf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Chest X-Rayg  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Testh 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Patient Reported Health Status 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Slit Lamp Exam i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
X 
 
 
 
 
 
Ophthalmic Exam j 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X X X 
Single 12-LeadECGk 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X   
 
 
 
 
X 
 
 
 
 
 
 
 
 
Limited Physical Exam l 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X X 
X X 
Full Physical Exam l 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Laboratory Safety Tests 
(includes Full Blood Count)m 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Full Blood Count 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Study Medication/Compliancen 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
PK Samplingo 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Xo 
 
 
 
 
 
 
 
 
Early Morning & Spot Sputum r 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X X 
X 
X 
X X X 
Peripheral Neuropathy 
Assessment 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
X 
 
X 
Investigator Assessmentp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
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GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
 
a. 
Screening: Screening assessments can occur on different days within 14 days prior to Day 
1 dosing (randomization). If a participant fails screening, a full re-screen may occur at a later 
date.  All screening procedures must be repeated at re-screen visit, with the exception of the 
slit lamp examination, which can be used from a previous screening if within 8 weeks of 
anticipated randomization. 
b. 
Visit Schedule: If the duration of treatment is extended (see section 6.3, Treatment 
Modifications for details), unscheduled visits should be added every 3 weeks (+/- 7 days).   
1. End of treatment visit (final treatment visit) should be done within 7 days AFTER the 
last dose of IMP.  
2. If participant completes 26 weeks of therapy at week 33 due to full regimen pauses, 
an EXAMPLE of visit scheduling would be weeks 26, 29 and 33 (3 weeks from week 
29 plus 7-day window). In this scenario, the week 33 visit would be the end of treatment 
visit and should be completed within 7 days after last dose. 
3. If participant completes treatment at week 39 due to treatment extension, an example 
of visit scheduling would be visits at weeks 26, 29, 32, 35 and 39/End of treatment (3 
weeks plus 7-day window).  
4. Follow-up visits should be scheduled based on timing of last dose of IMP (e.g., 4-week 
follow-up to be scheduled 4 weeks after last dose of IMP). 
c. 
Follow-up Visits Early Withdrawal Participants: Once a participant has been discontinued, 
they will be required to attend an Early Withdrawal visit. If participant: 
1. Received/took < 14 doses, no additional follow-up visits are required.   
2. Received 15 or more doses and is withdrawn during treatment, follow-up after end of 
treatment/EW visit at week 12, week 26 (if not already performed) and week 78 are 
required. The week 12 visit will only require the ophthalmologic exams. The week 26 
and 78 follow-up visits will be to collect Serious Adverse Event (SAE) information 
(including verification of survival) and patient reported TB outcome information only 
and may be telephonic, a home or a site visit. This includes participants who are 
withdrawn from the trial due to meeting the treatment failure endpoint. Participant may 
need to return for visits to collect sputum samples to determine outcome status. 
3. For participants who are withdrawn during post treatment follow-up, site should 
perform study procedures required for week 78 post treatment follow-up visit. If 
participant will not return for visit, site should obtain information on SAE and patient 
reported TB outcome as noted above in no 2. 
d. 
Inclusion/Exclusion: to be confirmed at screening and prior to randomization.  
e. 
HIV testing: If HIV status is a confirmed known positive, repeated HIV test is not needed 
provided that a documented HIV test result (ELISA, Western Blot or Electro-
Chemiluminescence) is available. If HIV status is unknown or suspected negative, HIV test 
will be requested. If an ELISA and/or Western Blot and/or Electro-Chemiluminescence based 
HIV test was performed within 4 weeks prior to screening, it should not be repeated if 
documentation of testing method and negative HIV results can be provided. Repeated HIV 
testing, during the Screening period is permitted for indeterminate HIV results. 
f. 
CD4 count and viral load:  Required for all HIV-positive participants, viral load and CD4 
required at screening, CD4 will be tested at end of treatment or early withdrawal from 
treatment visit. 
g. 
Chest X-Ray: A chest x-ray (digital image) within 6 months prior to or at screening, will be 
obtained and read locally by Investigator or designee. Digital images will be provided to 
Sponsor, this process will be described in a separate document, the Radiology Manual. 
h. 
Urine Pregnancy: Women of child-bearing potential only, whether they are sexually active or 
not.   
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i. 
Slit-Lamp Exam: Slit Lamp examination will be performed by an Ophthalmologist with 
AREDS2 training: 
1. For participants who receive < 14 doses of IMP, exam at: Screening only. 
2. For participants who receive 15 days to < 12 weeks of treatment, exams at: Screening 
and the 12-week post treatment follow-up visit. 
3. Participants who complete > 12 weeks of treatment exams at: Screening, End of 
Treatment or Early Withdrawal and the 12-week post treatment follow-up. 
j. 
Ophthalmic Exam: to include Ophthalmologic Medical history at Screening; All exams to 
include Visual Acuity (distance testing) and Colour Vision assessment.   Can be done by any 
trained study staff throughout study.  Screening exam must be done by Ophthalmologist in 
addition to trained study staff that will perform exams throughout the study. 
k. 
Single 12-Lead ECG: When possible, should be performed at approximately the same time 
of day (+/- 1 hours) and in the same fed/fasted state throughout the trial (e.g. 4 hours after 
lunch). Central ECG analysis will be performed. Central reading of screening results will be 
used to determine eligibility. 
l. 
Physical Exam:  Limited Physical exams should include weight and a gross neurological, 
pulmonary, cardiovascular and abdominal exam. Height will only be collected as part of full 
exam at screening. 
m. Safety Laboratory Assessments/Urine Drug Screen: The Safety Laboratory sampling 
methodology and requirements will be described in a separate document, the Laboratory 
Manual, which will be provided prior to the trial start. The following analyses will be performed: 
• 
Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential, platelet count).  
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK).  GGT will be done at screening. 
• 
When managing participants with elevated liver enzymes at an unscheduled visit, the 
Investigator can request additional tests, in addition to the repeated LFT [e.g. 
Gamma Glutamyl Transferase, screening for hepatitis A, B, C; to assist in ruling out 
other causes of abnormal liver test (e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection). 
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis. 
• 
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates, 
benzodiazepines, barbiturates, at Screening only. Investigator to utilize to determine 
whether participant meets Exclusion criteria 2.  Positive results will not automatically 
exclude participant from the trial. 
n. 
Study Medication/Compliance: Study medication administration will be supervised per local 
site practice to assure compliance to regimen. 
o. 
PK Sampling:   The dates and times of the two doses of IMP taken prior to all pre-dose PK 
samples will be collected in the eCRF.    
Specific PK blood draws will be obtained as follows (pre-dose to be done after ECGs): 
1. Day 1; pre-dose (within 2 hours prior to dosing) 
2. Week 2: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
3. Week 8: pre-dose (within 2 hours prior to dosing), 2–3 hours post-dose and 6–8 hours 
post-dose 
4. Week 12: pre-dose (within 2 hours prior to dosing)  
5. Week 20 or at early withdrawal if prior to week 20: pre-dose (within 2 hours prior to 
dosing) and 2–3 hours post-dose 
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Protocol Version V3.0 RUS / 18 MARCH 2020  
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• When participant is discharged and seen as an outpatient, site should make every effort to 
collect 6-8 hour sample at week 8 when operationally and logistically feasible.  
• Hospitalization information (e.g. discharge date) will be collected in the eCRF. 
• If the full regimen or linezolid is paused, PK sampling should be delayed until full regimen 
or linezolid are resumed. 
• PK sampling should be completed even if the participant’s linezolid dose has been 
lowered or linezolid has been permanently discontinued.  
• Sites may bring participant back at a scheduled or unscheduled visit (can occur outside of 
visit windows) to collect PKs to ensure draw is done when IMP is administered.  
p. 
Investigator Assessment: Principal Investigator to review participant status and assess 
whether TB treatment at current visit is considered a “success” or “failure”.  If considered a 
failure, should specify if based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. To be completed at 26 and 78 week post treatment follow-up visits and at any 
time Investigator determines that participant fulfills criteria for outcome of treatment failure. 
q. 
Visit Windows: the windows noted on the flowchart for timing of visit also apply to timing 
within a visit.  For example, procedures that are difficult to schedule such as ophthalmology 
exams, should be scheduled within +/- 3 days of scheduled visit from Day 1 to Week 8 or +/- 
14 days within scheduled visit at the week 12 post treatment follow-up visit.  Sites should 
make every effort to ensure all other procedures are done on the same day when possible. 
r. 
Sputum Sampling: 
Visit 
 
Sample 
Tests 
EMS 
SPOT 
ISOLATE* 
 AFB Smear  
microscopy  
MGIT culture, 
speciation 
Molecular 
testing 
MIC:  
B, Pa, L 
MGIT DST  
 
Genotyping 
Extended 
DST (paired 
with baseline 
isolate) 
Screening  
(Day -14 to -1) 
 
 
 
 
S 
S 
S 
  
  
  
 
Baseline (Day 1) 
or 1st positive 
between screening 
and wk4 if Day 1 
negative or 
contaminated  
 
 
 
  
  
  
C 
C 
C 
L (when 
applicable, with 
isolate below) 
All Visits Post 
Screening 
 
 
 
  
S 
  
  
  
  
 
1st positive for MTB 
at/after week 16 for 
participant not 
responding to 
therapy and/or 1st 
positive during 
follow-up for 
potential new 
infection 
 
 
 
 
 
S 
C 
C 
C 
L 
C –   Central Mycobacteriology Laboratory (specialized facility) 
S –   Study Mycobacteriology Laboratory (facility that receives sputum samples directly from site) 
L –   Lab (as applicable per Country) that performs extended DST beyond panel at Central lab 
*Preferably from EMS Sample w hen available.  Alternate isolate can be requested if initial one is 
contaminated, or the test needs to be repeated. 
 
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Protocol Version V3.0 RUS / 18 MARCH 2020  
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CONFIDENTIAL 
Page 20 of 98 
SPUTUM SAMPLES GENERAL: If EMS (early morning sputum) is not available, site should 
make every attempt to collect two spot samples at least 30 minutes apart.  
 
PRE-SCREENING SAMPLES: If consent granted by participant, and when applicable, site can 
request pre-screening culture/isolate/DNA from current TB diagnosis/disease course to be sub-
cultured and shipped and/or tested: 
• 
at the study lab if/when those samples could support inclusion in trial.  
• 
at the study/central lab for relevant participants with no baseline (no positive cultures from 
screening through week 4). 
 
MOLECULAR TESTING:  
• 
At Screening: GeneXpert, Hain MTBDRplus or equivalent to determine MTB complex and 
Rifampicin resistance. 
• 
Positive MTB at/after week 16: Hain MTBDRplus and HainMTBRsl 
 
LIQUID DST: for SIRE, Z and second line anti-TB drugs, including but not limited to 
fluoroquinolones and injectables. 
 
STORAGE: MTB isolates from all positive cultures to be stored at the study laboratory until trial 
closure for the applicable study tests. The cultures as well as the extracted MTB DNA from the 
applicable baseline and follow-up isolates will also be stored at the central lab for potential further 
work to validate new assay tools for 5 years after trial closure. 
 
CENTRAL LAB: Results from testing at central lab (MIC, DST and genotyping) will not routinely 
be provided to sites.  In the event that results are necessary to determine appropriate participant 
treatment, Sponsor will provide available drug susceptibility results to the site. Genotyping will be 
performed on paired DNA extracts to determine if the participant was a relapse or reinfection (See 
SAP for details). 
 
EXTENDED DST TESTING: Paired isolates from baseline and at/after week 16 should be 
shipped to a relevant lab (as applicable/available per Country) for DST extending beyond the 
panel of drugs tested at the central lab.  Extended results will be provided to the site to inform 
appropriate participant treatment.   
 
 
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2 
Introduction and Rationale 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is now the world’s leading infectious 
disease killer and is responsible for more deaths than HIV.(43) It is the leading cause of death 
among HIV-infected individuals, and there is more TB in the world today than at any other time in 
history. As a result of poor treatment adherence, in addition to primary transmission, drug 
resistance is becoming more common and fears of an epidemic with strains of extensively drug-
resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs and regimens for TB 
are needed for the growing number of patients with XDR TB.  
Outcomes of treatment for XDR-TB using the best available treatments have traditionally been 
very poor.  The best treatment historically has been to use available second line drugs individually 
tailored based on drug susceptibility testing in an inpatient setting to assure adherence with 
treatment lasting from 24 months to much longer for patients without culture conversion.  The 
most detailed report using this approach with long term follow-up prior to the use of linezolid, 
bedaquiline or delamanid in regimens has come from South Africa, where the HIV co-infection 
rate among patients with XDR-TB ranges from 40 to 70%.  A cohort study of 107 patients with 
XDR-TB found cure or completion of therapy at 24 months to be 16%, with 46% having died.(28)  
In another report from South Africa of 114 patients with XDR-TB, 22% completed treatment 
successfully.(21)  The largest evaluation of treatment outcomes was noted in the WHO 2014 annual 
tuberculosis report of 1269 patients in 40 countries, where 22% of patients with XDR-TB 
completed treatment successfully and 35% died.(42) A meta-analysis of 397 patients with XDR-TB 
from 31 centers, with HIV coinfection <10%, reported 32% treatment success.(17)  Reports of the 
outcome of XDR-TB treatment from Peru (43 patients, 42% treatment success)(2) and Ukraine 
(114 patients, 22% treatment success)(11) have been similar.  Based on these reports, the success 
of traditionally available drug therapies for treating XDR-TB infection is substantially less than 
50% and in the most detailed and largest reports is less than 25%. 
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with XDR-TB might be improved when added to background regimens. Experience 
recently published from the C209 uncontrolled study of bedaquiline given on a background of 
multiple drugs notes that the subset of 38 patients with XDR-TB had rates of sputum culture 
conversion to negative of 62.2%.(29) However, in this study only one patient with XDR-TB was co-
infected with HIV. All participants were required to have Mycobacterium tuberculosis (MTB) 
isolates susceptible to at least 3 drugs at enrolment, and patients had a median of only 5.4 months 
of treatment-free follow-up. This study added bedaquiline for 6 months to a background regimen 
of many drugs given for 18 months or longer. 
While treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR-
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.(43)  This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% 
died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information.   
With such poor historical outcomes for patients with XDR-TB and with the complexity, expense 
and toxicity of treatments for all forms of drug resistant TB, novel drug combinations are 
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desperately needed to improve treatment outcomes. Linezolid was identified in a small study as 
a potentially efficacious drug in patients with XDR-TB when added to a failing regimen(9) and this 
drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of three drugs for which there is little, if any, pre-existing resistance 
among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]), there is the opportunity 
to evaluate a new regimen that may be administered orally once daily to treat patients with XDR-
TB. Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, it is 
hypothesized in the design of the ongoing Nix-TB clinical study that patients with pulmonary XDR-
TB may have relapse-free cure after as little as 6 months’ treatment with the B-Pa-L regimen. 
Therefore, since 2015, the TB Alliance has sponsored a study with a 6 month treatment duration 
with the B-Pa-L regimen in participants with XDR-TB or MDR TB not responsive to or intolerant 
to therapy (the Nix-TB study).(1) 
A key advantage of this regimen over standard of care for MDR-TB as well as XDR-TB is that this 
is an all-oral daily regimen for 6 months of treatment in comparison to standard regimens of 6-8 
drugs over 9-30 months of treatment that includes daily injections for a minimum of 6 months. 
The NC-007 trial takes this regimen into a randomized Phase 3 trial to optimize the dosing scheme 
for linezolid and the benefit relative to risk, and to expand the patient population to include 
individuals with pre-XDR TB. 
The information presented below first details the trial rationale, then key preclinical information 
and human efficacy and safety information for each of the drugs in the regimen and then presents 
preclinical and clinical data to support the combination of these drugs in a regimen to treat patients 
with XDR, pre-XDR and MDR treatment intolerant/failure-TB. 
2.1 Trial Rationale 
2.1.1 Trial Design Rationale 
This trial will provide a regimen containing 3 drugs against which there is no expected MTB 
resistance in the community for patients with limited treatment options while simultaneously 
gathering important efficacy and safety data on a regimen that could potentially treat all strains of 
MTB. Data from previous trials shows that the combination of B-Pa is well tolerated and has the 
potential to shorten treatment in patients who are susceptible to the drugs. The ongoing Nix-TB 
trial has shown that the B-Pa-L regimen has manageable toxicity and encouraging efficacy as an 
all oral 6 month regimen administered to patients with XDR-TB. This current trial will provide 
important information on the toxicity and efficacy of the regimen under alternate doses and 
durations of linezolid to optimize the dosing scheme for the best benefit to risk balance. 
2.1.2 Trial Drug Rationale 
2.1.2.1 Bedaquiline  
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this study bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 18 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
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combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 study that administered bedaquiline 200 mg daily over 8 weeks, and 
by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
The NC-005 study allows the efficacy and safety to be compared for treatment arms that dosed 
bedaquiline at the currently registered dose and at 200 mg daily for the 8 weeks of the trial.  Briefly, 
Study NC-005 evaluated a regimen in patients with drug susceptible pulmonary TB given 
bedaquiline with pretomanid and pyrazinamide over an 8 week period.  One arm was to enroll 60 
patients who were to be given this regimen with bedaquiline dosed as approved for marketing 
(referred to as the B (loading dose/t.i.w.) PaZ arm), and another 60 patients were to be enrolled 
who would be given the regimen with bedaquiline dosed at 200 mg daily (referred to as the B 
(200mg) PaZ arm).  Another group of patients with DS TB were randomized to treatment with 
standard HRZE therapy.  Patients with MDR-TB were given the regimen with bedaquiline dosed 
at 200 mg daily in addition to moxifloxacin (referred to as the B (200 mg) MPaZ MDR-TB arm).  
The primary endpoint was The Bactericidal Activity (BATTP (0‐56)) as determined by the rate of 
change in time to sputum culture positivity (TTP) over 8 weeks of treatment in the Mycobacterial 
Growth Indicator Tube system, represented by the model‐fitted log (TTP) results as calculated by 
the regression of the observed log (TTP) results over time.  The assessments of safety and 
tolerability included the incidence of Treatment Emergent Adverse Events (TEAEs) presented by 
severity (DMID Grade), by drug relatedness and seriousness, and for those leading to early 
withdrawal and leading to death, by group.  In addition, quantitative and qualitative clinical 
laboratory result measurements were evaluated, including group summaries of observed values 
and changes from baseline.  Pharmacokinetics for all participants included pre-dose samples on 
9 days during and one day following dosing with the regimen.  Fifteen PK Sub‐study participants 
in each treatment arm had in addition intense PK sampling on Days 14 and 56. 
Efficacy of bedaquiline 200 mg daily dose vs the marketed dosing scheme over 8 weeks 
In the efficacy analysis of the NC-005 trial, based on liquid media collected from overnight sputum 
samples, the B(200 mg)MPaZ MDR-TB treatment group showed the highest bactericidal activity 
over the 8-week treatment period, followed by that of B(200 mg)PaZ, B(loading dose/t.i.w.)PaZ 
and then HRZE. It appears clear that the daily dosing regimen for bedaquiline provided at least 
as good a result in the primary efficacy analysis as the registered dosing scheme for bedaquiline.   
Safety of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
Adverse events, including serious adverse events and Grade III/IV adverse events were similar 
among groups.  In particular, the mean change from baseline in the corrected QTc intervals was 
numerically less in the participants given bedaquiline daily than in the participants given 
bedaquiline with the labelled dosing scheme.  Measures of potential hepatic toxicity, including 
participants with greater than 3 fold or 10 fold elevations in aminotransferase levels, were 
numerically greater in participants given the labelled dosing scheme than subjects given daily 
doses of bedaquiline.   
Pharmacokinetics of bedaquiline 200 mg daily dose vs the marketed dosing scheme  
A population PK model published by McLeay in 2014 was used with PK data from Study NC-005 
to simulate the expected bedaquiline exposures when dosed at 200 mg daily followed by 100 mg 
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daily for the remainder of the study in comparison to the labelled dosing scheme with bedaquiline 
administered for 6 months.(14)  The key findings from the simulations of the proposed dosing 
scheme for NC-007 of bedaquiline administered 200 mg daily over 8 weeks followed by 100 mg 
daily for an additional 16 weeks are: 
• 
The exposures of the proposed dosing scheme (Cmax, mean or trough) are not expected to exceed 
the exposures associated with the labelled scheme on Day 14 at the end of the 400 mg daily 
dose.  With the labelled dosing scheme, the highest exposures are on Day 14 at the end of 
the 400 mg daily loading dose. 
• 
The average daily exposures with the proposed dosing scheme over 6 months are within (or 
not substantially different from) the range of exposures over 6 months of the labelled dosing 
scheme. 
• 
The cumulative exposure, in terms of AUC over time, is similar between the proposed dosing 
scheme and the labelled scheme 
2.1.3 Pretomanid 
Pretomanid has demonstrated good microbicidal activity at the 200mg daily dose as monotherapy 
in studies PA-824-CL-007 and PA-824-CL-010, in combination with either bedaquiline or 
pyrazinamide over 14 days in the early bacteriocidal activity (EBA) Study NC-001-(B-M-Pa-Z), in 
combination with either bedaquiline and/or pyrazinamide and/or clofazimine over 14 days in the 
EBA Study NC-003-(B-C-Pa-Z), and in combination with bedaquiline and linezolid over 6 months 
in the Nix-TB study.  In the EBA Study PA-824-CL-010 the 100mg dose demonstrated similar 
microbicidal activity to the 150 and the 200mg daily dose over 14 days. The Phase 2 trial NC-
002-(M-Pa-Z) evaluated this regimen at doses of pretomanid of both 100 mg and 200 mg relative 
to the HRZE control.   In this trial the efficacy results were similar between participants treated 
with 100 mg/day and 200 mg/day of pretomanid in the regimen, although for the primary endpoint, 
reduction in colony forming units of MTB from sputum, only the 200 mg/day dose group was 
statistically significantly better than the group randomized to standard HRZE therapy.  Safety was 
also similar between the groups, although the 200 mg/day group had more grade 2 adverse 
events than either the 100 mg/day group or the HRZE control group.  Because sterilizing relapse-
free cure of TB in patients with XDR-TB may ultimately require a regimen with higher drug 
exposures, the 200mg dose was chosen for evaluation in the Nix-TB study of the B-Pa-L regimen.  
The manageable toxicity of the regimen and very encouraging efficacy in the Nix-TB trial support 
taking the 200 mg dose of pretomanid forward in the NC-007 trial. 
2.1.4 Linezolid 
The standard dose of linezolid for a multitude of indications is 400mg or 600mg BID.  Doses of 
linezolid used to treat pulmonary TB in reported observational trials and case series range from 
300 mg to 1200 mg per day over periods of up to 20 months of treatment.  While the development 
of adverse events is generally higher with higher doses, the adverse events often ameliorate with 
a reduction of the dose or discontinuation of drug for several weeks and then reintroduction at a 
lower dose.  No controlled trials have clearly identified differences in anti-TB effect across a range 
of doses over long term treatment of TB. 
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In this trial, each arm will vary the linezolid dosing to identify the optimal ratio of efficacy to adverse 
events as noted below. The 4 arms, to which participants will be randomly assigned in a blinded 
manner, are: 
• 
Linezolid 1200 mg orally once daily for 26 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
• 
Linezolid 1200 mg orally once daily for the first 9 weeks, with the ability to interrupt or 
reduce the dose if needed based on toxicity.  
• 
Linezolid 600 mg orally once daily for 26 weeks, with the ability to interrupt or reduce the 
dose if needed based on toxicity. 
• 
Linezolid 600 mg orally once daily for the first 9 weeks, with the ability to interrupt or reduce 
the dose if needed based on toxicity.  
These dosing schemes for linezolid are chosen based on clinical experience in the Nix-TB trial, 
the company’s linezolid early bactericidal activity (EBA) study findings in the Lin CL-001 study, 
and preclinical data in the mouse model of infection. While the EBA study showed that a modestly 
greater bactericidal effect over 14 days at the highest 1200 mg daily dose (see further details 
below in Section 2.2.3), this dose appears to be associated in the Nix-TB trial and in published 
literature with a greater incidence of unwanted neuropathic and myelosuppressive effects than 
the 600 mg daily dose. While a full 6 months of linezolid therapy in the regimen may give greater 
culture conversion and avoid relapse, the mouse model found that linezolid dosing of only 1 or 2 
months, when B and Pa were given continuously for a total of 3 months, maximized relapse-free 
cure; in other words, similar to pyrazinamide in the present first line HRZE therapy, more than 2 
months of linezolid when combined with B and Pa does not increase relapse-free cure in the 
mouse model. Thus, the 4 treatment arms in this study will give randomized comparative 
information about the optimal duration and dose of linezolid in the regimen relative to efficacy and 
toxicity.  
The decision to give linezolid as a single daily dose is based on the results of the linezolid EBA 
study that showed over 14 days that similar bactericidal activity was noted whether the drug was 
given as a single daily dose or divided in to 2 doses. A single daily dose will ultimately enhance 
patient adherence and will reduce the total time the drug concentration is greater than the 
calculated concentration associated with mitochondrial toxicity (which we hypothesize to be the 
likely mechanism for the toxicities of peripheral neuropathy and myelosuppression). 
2.2 Agents to be Studied 
2.2.1 Bedaquiline 
Bedaquiline is being developed as part of combination therapies for pulmonary TB due to MDR-
TB and approved in 2012 in the USA under the provisions of accelerated approval regulations. 
Bedaquiline received conditional Marketing Authorization in the EU in 2014 and is approved in 
over 40 countries (EU countries counted individually). The approved indication may vary per 
country. Bedaquiline is marketed under the trade name SIRTUROTM.  Bedaquiline has a novel 
mechanism of action as it specifically inhibits mycobacterial ATP synthase, an enzyme that is 
essential for the generation of energy in MTB The inhibition of ATP synthase leads to bactericidal 
effects for both replicating and non-replicating tubercle bacilli. 
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In the placebo-controlled Phase 2b study C208 conducted in newly-diagnosed patients with 
sputum smear-positive pulmonary MDR-TB (including pre-XDR-TB), the addition of bedaquiline 
to a preferred background regimen of MDR-TB treatment resulted in a decreased time to culture 
conversion and improved culture conversion rates compared to placebo. Median time to culture 
conversion according to the primary analysis method was 83 days for the bedaquiline group 
compared to 125 days for the placebo group (p<0.0001; hazard ratio, 95% CI: 2.44 [1.57; 3.80]). 
The proportion of patients in the mITT population with sputum culture conversion after 24 weeks 
of treatment with bedaquiline or placebo in combination with background regimen (with patients 
who discontinued considered as non-responders), was 52/66 (78.8%) in the bedaquiline group 
and 38/66 (57.6%) in the placebo group. Durability of response seen in the bedaquiline treatment 
group was supported by the results at Week 120. The proportion of responders (with patients who 
discontinued considered as non-responders) at Week 120 was 41/66 (62.1%) in the bedaquiline 
group and 29/66 (43.9%) in the placebo group. 
In the Phase 2b, open-label study C209, conducted in 233 patients with sputum smear positive 
pulmonary MDR-TB, the median time to sputum culture conversion excluding patients with DS-TB 
and those that did not have a positive sputum culture at screening and/or baseline (mITT; 205 
patients), was 57 days. At Week 24, 163 of 205 (79.5%) patients responded to bedaquiline 
treatment as determined by sputum culture conversion rates. Conversion rates at Week 24 were 
highest (87.1%; 81/93) in patients with MDR-TB resistant to only RMP and INH, 77.3% (34/44) in 
pre-XDR-TB patients and lowest (54.1%; 20/37) in XDR-TB patients. 
The average terminal half-life of bedaquiline, is about 5.5 months. After reaching Cmax, however, 
there is initially a fairly rapid reduction in plasma bedaquiline concentrations over the dosing 
interval (with an estimated half-life of about 13 hours). Four weeks after ceasing bedaquiline 
intake, the mean bedaquiline concentrations were reduced by approximately 40% compared to 
the end of the bedaquiline treatment period in the C208 study. Administration of bedaquiline with 
food increased the relative bioavailability by about 2-fold compared to administration under fasted 
conditions. It is therefore recommended to take bedaquiline with food to enhance its oral 
bioavailability. 
CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline. Drug-
drug interaction (DDI) studies have showed reduced exposure to bedaquiline during combination 
with a strong or moderate inducer of CYP3A4 metabolism (i.e., rifampicin) and increased 
exposure during combination with a strong or moderate inhibitor of CYP3A4 metabolism (i.e., 
ketoconazole). Potential drug interactions with anti-retroviral drugs have been evaluated in three 
studies.  In an interaction study of single-dose bedaquiline and multiple-dose Lopinavir/ritonavir, 
exposure (AUC) to bedaquiline was increased by 22% (90% CI: 11-34). Co-administration of 
single-dose bedaquiline and multiple-dose nevaripine did not result in clinically relevant changes 
in the exposure to bedaquiline. Co-administration of a single dose of bedaquiline and multiple-
dose efavirenz (EFV) resulted in approximately a 20% decrease in the AUCinf  of bedaquiline with 
no alteration in the Cmax.  Modeling based on the data from this DDI study predicts average steady-
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state concentrations of bedaquiline and M2 to be reduced by 52% with chronic co-administration 
of bedaquiline and EFV.(5)  
Safety of Bedaquiline 
The Investigator’s Brochure for bedaquiline provides detailed safety information.5 
Data were used from 14 completed clinical studies to identify Adverse Drug Reactions (ADRs) 
according to the ICH guideline entitled, E6: Good Clinical Practice, Consolidated Guideline (ICH, 
1996): “…all noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. The phrase “responses to a medicinal product” means that 
a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out." 
The ADRs were identified from the pooled safety database of reported AEs in the Phase 2b clinical 
studies with bedaquiline, based upon a systematic well-documented approach and are presented 
for study C208 below in Table 1.  None of the ADRs reported in the controlled studies during the 
Investigational Treatment phase were considered serious. 
Table 1: 
ADRs C208 Stage 1 and Stage 2 
Adverse Drug Reactions (ADRs) in the Controlled Studies (C208 Stage 1 and Stage 2)  
During the Investigational Treatment Phase 
ADR (Grouped term), n (%) 
Frequency 
Any BDQ 
N=102 
Any Placebo 
N=105 
Nervous system disorders 
Headache 
Very Common 
24 (23.5) 
12 (11.4) 
Dizziness 
Very Common 
13 (12.7) 
12 (11.4) 
Cardiac disorders 
ECG QT prolonged 
Common 
3 (2.9) 
4 (3.8) 
Gastrointestinal disorders 
Nausea 
Very Common 
36 (35.3) 
27 (25.7) 
Vomiting 
Very Common 
21 (20.6) 
24 (22.9) 
Diarrhea 
Common 
6 (5.9) 
12 (11.4) 
Hepatobiliary disorders 
Transaminases increaseda 
Common 
7 (6.9) 
1 (1.0) 
Musculoskeletal and connective tissue disorders 
Arthralgia 
Very Common 
30 (29.4) 
21 (20.0) 
Myalgia 
Common 
6 (5.9) 
7 (6.7) 
 
a. 
Different AE preferred terms (i.e., transaminases increased, aspartate aminotransferase [AST] increased, 
alanine aminotransferase [ALT] increased, hepatic enzyme increased, and hepatic function abnormal) contribute 
to this ADR, w hile for the other ADRs the ADR is the preferred term. 
 
Of note, 13 deaths occurred in the C208 Stage 2 study: 10 subjects (12.7%) in the bedaquiline 
group and 3 subjects (3.7%) in the placebo group experienced an SAE leading to death. One 
death (alcohol poisoning) occurred during administration of bedaquiline. The median time to death 
for the remaining 9 subjects was 344 days after last intake of bedaquiline. One of the 10 deaths 
in the bedaquiline treatment group and 1 of the 3 deaths in the placebo group occurred after the 
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Week 120 window. In the bedaquiline group, the most common cause of death as reported by the 
investigator was TB or TB-related illness (5 subjects). For all deaths due to TB, the subject’s last 
microbiological outcome was either failure to convert or relapse. The causes of death in the 
remaining bedaquiline subjects varied. The investigator considered all the SAEs leading to death 
not or doubtfully related to bedaquiline/placebo. The imbalance in deaths is unexplained. In 
addition, no discernible pattern between death and sputum culture conversion, relapse, sensitivity 
to other drugs used to treat TB, HIV status, or severity of disease was observed.  
During clinical studies with bedaquiline a prolongation of QTc interval on the ECG was observed.  
Consequently, bedaquiline treatment initiation is not recommended in patients with, personal or 
family history of prolonged QT intervals, or additional risk factors for Torsades de Pointes. 
Detailed criteria are noted in Section 5.2 Exclusion Criteria. 
Increases in transaminases were seen in clinical studies during administration of bedaquiline in 
combination with a background regimen. Based on a review confirmed by an external 
hepatologist, it was concluded that bedaquiline has a signal for liver injury manifested by 
increases in AST and to a lesser extent ALT. Transaminase elevations are not unexpected given 
the number of other hepatotoxic drugs in the background regimens in clinical trials based on the 
publication by Keshavjee, which describes a 16.5% incidence of hepatotoxicity during MDR-TB 
treatment. (7) 
2.2.2 Pretomanid 
As detailed in the Investigator’s Brochure(6), pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti-
tuberculosis activity and a unique mechanism of action(35). Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB(10), and in vivo activity in a mouse model of tuberculosis(10, 
35).  
2.2.2.1 Pharmacology 
2.2.2.1.1 Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro studies demonstrated that pretomanid was active against actively growing 
drug-sensitive and drug-resistant MTB strains as well as against non-replicating MTB The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be similar to the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 
0.25 µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against 
drug-resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity. (6) 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO), (33) although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling studies also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.(12,13) 
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2.2.2.1.2 Key Non-Clinical Studies of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse studies.(18,19,20,36,40) In a mouse model of established TB, 
the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 
22 days after inhalation infection with H37Rv MTB is shown in Figure 1. In this model, the 
minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the 
development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum 
bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony forming units 
(CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 
100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
Figure 1: 
Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
2.2.2.2 Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology studies, 
in repeat-dose toxicity studies in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity studies, and in fertility and teratology studies in rats and rabbits.  
In the repeat-dose toxicity studies, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week study in rats, 50 mg/kg/day in a 13-week study in monkeys and 
<25 mg/kg/day (based on findings of thickening of the GI tract at all doses) in a 9-month study in 
monkeys. The major findings in safety and toxicity studies are listed below in Table 2 and are 
detailed in the Investigator’s Brochure .(6) 
Table 2: 
Key findings of Pretomanid in Safety and Toxicity Studies 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
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repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development studies indicate no effects of PA-824 on fetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology studies and a Segment I fertility study. In this fertility study, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed study in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week study in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
study in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the electrocardiogram (ECG) as a prolonged QT interval corrected for heart 
rate (QTc). Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. 
Following a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation 
ranged from 21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-
administration of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog 
did not result in any greater effect on the QT interval than with either agent alone. After 
repeated daily doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
2.2.2.3 Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 studies with healthy adult 
male and female subjects, with 163 subjects receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 studies sponsored by the NIH included a Thorough QT study and a study 
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of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the 
studies are in the Investigator’s Brochure. 
2.2.2.3.1 Pharmacokinetics 
Several Phase 1 studies have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200 mg dose that increases total 
exposure by 88%. Interaction studies with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Study CL-006 was an open-label, fixed-sequence drug-drug 
interaction study to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs metabolised 
by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had 
minimal effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by 
measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax), area under the 
curve to the last available time point (AUC0-t), and area under the curve extrapolated to infinity 
(AUC0-inf ). The Cmax and AUC values for midazolam after co-administration with pretomanid 
were approximately 85% of those observed after treatment with midazolam alone. Furthermore, 
midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and half-life (t1/2) 
values were not different in the presence or absence of pretomanid. Therefore, 14 days’ dosing 
with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH sponsored this 
drug interaction study with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy subjects. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for the maximum concentration (Cmax) was 0.71, the GMR for the 24-hour area 
under the time-concentration curve (AUC0-24h) was 0.65, and the GMR for the trough 
concentration (Cmin) was 0.54. Concentrations of EFV when given with pretomanid versus given 
alone were similar. Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg 
once daily for 7 days, then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 
days, then LPV/r + pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + 
pretomanid, washout, then pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid 
alone from 16 PK-evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and 
for Cmin was 0.78. In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg 
for 7 days, then pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin 
versus pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and 
Cmin were 0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for maximum concentration (Cmax), area under the concentration-time curve (AUC0-
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24h), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz; 13%, 17%, 
and 21% with LPV/r; and 53%, 66%, and 85% with rifampin, respectively. 
2.2.2.3.2 Pretomanid Clinical Efficacy 
The first two Phase 2 studies to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first study (CL-007) demonstrated 
good EBA, but all doses in this study (200 to 1200 mg/day) had the same activity. The second 
study (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA 
was seen at a dose of 100 mg/day over 14 days (4) (Figure 2). 
Figure 2: 
Mean log Colony Forming Unit Values over Time Study CL-010 
 
CFU = colony-forming unit; PA-824 = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Studies of Pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below in Section 2.3.2.  
2.2.2.3.3 Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure(6) provides detailed safety information. 
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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Across the 16 clinical studies with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy subjects across the 10 Phase 1 studies and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
studies.  Among the 289 healthy Subjects, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 1200 
mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical studies completed to date indicates pretomanid 
is well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these studies, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical studies completed to date as likely caused by 
pretomanid is blood creatinine increased.  A study of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close surveillance 
and careful management of participants who have elevations in aminotransferases and/or 
bilirubin. Serious liver injury, including death in 3 participants taking a combination of 
pretomanid, pyrazinamide and moxifloxacin, has occurred during clinical studies and the risk 
of liver injury may be higher for participants taking a combination of PA-824 and pyrazinamide 
than it is for the standard HRZE treatment. Therefore, close monitoring of liver function is 
required for participants who are administered PA-824, especially when combined with 
pyrazinamide.  Administration of the regimen of PaMZ has been associated with death in 3 
participants associated with hepatic injury. Furthermore, the HRZE control regimen, and both 
pyrazinamide and moxifloxacin, has been associated with drug induced liver injury and in rare 
cases hepatic necrosis.  Consequently, hepatic safety will be under close surveillance in all 
clinical studies. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human studies that involve exposure to pretomanid longer than 
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14 days.  These examinations will be conducted at baseline, near the end of the dosing period 
and 3 months after the end of study drug exposure.  These examinations are to follow up on 
the finding of cataracts in rats exposed to pretomanid in clinical studies. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple time 
points during the study.  Although the Thorough QT Study in healthy subjects found that 
pretomanid did not increase corrected QT intervals in a clinically meaningful way and did not 
add to the known effect of moxifloxacin, the ECGs will be carefully monitored during Phase 3.  
All ECGs will be interpreted and conduction intervals will be confirmed by a central cardiology 
service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Study NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology studies have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 study for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology studies found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 studies have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 studies) or FSH values (3 studies) at baseline and after daily 
dosing of regimens containing pretomanid in various combinations with moxifloxacin, 
pyrazinamide and bedaquiline.  A review of data from the 3 studies by an independent 
reproductive endocrine expert concluded that, based on the hormone evaluations to date, there 
is no evidence that PA-824 is a testicular toxicant in men at the doses and exposure times 
evaluated. 
2.2.3 Linezolid 
Linezolid is a synthetic antibacterial agent of the oxazolidanone class approved in many countries 
around the world for drug-resistant, gram-positive bacterial infections, including gram positive 
organisms such as Staphylococcus aureus, coagulase negative Staphlococcus and Enterococcal 
infections.  The recommended dose for these infections is 600 mg twice daily for up to 28 days of 
therapy.(23,24,26) Antimicrobial effects likely come from inhibition of protein synthesis in the 
ribosomes of the infecting organism.(8)  Resistance of MTB to linezolid is rare, as this drug has 
not been widely used to treat tuberculosis.  In a recent study using linezolid to treat patients with 
XDR-TB in Korea, none of 41 patients had resistance to linezolid at baseline.(9) 
Preclinical in vitro data shows linezolid is active against MTB, including MDR strains with minimum 
inhibitory concentrations (MICs) that range from 0.125-1 μg/mL.(38)  Recent studies of the 
bactericidal and sterilizing activity of linezolid in a mouse model of MTB infection have 
demonstrated linezolid alone causes marked reductions in lung colony forming units (CFUs) from 
mice following 1-3 months of therapy.(36) (Table 3, below) 
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Table 3: 
Murine Lung CFU counts during Treatment with Linezolid 
Monotherapy versus Standard Therapy 
 
Mean lung log10 CFU count (± S.D.) at: 
Regimen 
D0 
Month 1 
Month 2 
Month 3 
Untreated 
6.17 + 
0.27 
6.47 + 0.06 
 
 
2RHZ/4R
H 
 
3.47 + 0.37 
1.59 + 0.25 
0.50 + 0.51 
L 
 
4.97 + 0.26 
 
 
 
In recent years linezolid has been used to treat patients with MDR(28) and XDR-TB, although there 
have been no fully controlled trials of linezolid in a regimen for this indication.  The World Health 
Organization management guidelines place linezolid in Group 5 (“Agents with unclear role in 
treatment of drug resistant-TB”) in their groups of drugs to treat MDR-TB.(41) Over the past 10 
years small retrospective observational studies have reported good results when linezolid has 
been added to failing regimens for patients with MDR-TB.(9, 27, 34) The most compelling recent 
evidence linezolid may be of benefit to patients with XDR-TB was reported by Lee and colleagues 
from a study in S. Korea.(9)  Forty-one patients who had sputum culture–positive XDR-TB and who 
had not had a response to any available chemotherapeutic option during the previous 6 months 
were randomized to start linezolid at 600 mg daily or to delay therapy with linezolid at 600 mg 
daily for 2 months without changing their failing background regimen.  After confirmed sputum-
smear conversion, or at 4 months, patients underwent a second randomization to continued 
linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 
months.  Thirty four of 39 (87%) of the patients had a negative sputum culture within 6 months 
after linezolid had been added to their drug regimen.  As of the cutoff date prior to publication, of 
the 38 patients who received linezolid, 17 were still receiving the treatment per protocol, and 13 
had completed treatment, including 6 with no relapse during the treatment period, 4 with no 
relapse at the 6-month follow-up, and 3 with no relapse at the 12-month follow-up (end of study).  
While the standard dose of linezolid for short term use for severe bacterial infections is 600 mg 
bid, some clinicians and clinical trials using linezolid as Group 5 therapy to treat TB use only 300 
mg or 600 mg daily due to concerns about toxicity developing when used over a period of months 
(see below for a review of linezolid toxicity). (9)  However, there are no data to indicate what dose 
of linezolid is required or optimal to effectively treat TB infection.  Consequently, TB Alliance has 
recently conducted and completed an Early Bactericidal Activity trial to evaluate the use of 
linezolid over 14 days in patients with newly diagnosed DS Pulmonary TB in dosing schedules 
including 300 mg daily, 300 mg bid, 600 mg daily, 600 mg bid, 1200 mg daily, and HRZE at 
standard doses daily.  Preliminary unpublished in-house results using Bayesian mixed effects 
modelling have noted that there is a bactericidal effect of linezolid over 14 days that is substantial, 
but less than for the full HRZE regimen.  There is little difference between daily or twice daily 
dosing of the same total daily dose of drug, and there is a dose-response relationship between 
total daily dose and daily reductions in either total CFU counts on solid culture or increases in 
Time to Positivity in liquid culture (a decreased load of MTB is associated with an increase in Time 
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to Positivity).  Point estimates of the log of the daily increase in Time to Positivity over 14 days 
ranged from 2.278 for Linezolid 300 mg QD to 4.446 for linezolid 1200 mg QD, with the estimate 
of 6.860 for HRZE for reference. 
Figure 3:  
Mean Early Bactericidal Activity Time to Positivity, Days 0 to 14, Study Lin 
CL-001 
Bayesian Nonlinear Mixed Effects Regression Model: Posterior Estimates and 95% 
Bayesian Confidence Intervals 
 
HRZE = isoniazid, rifampin, pyrazinamide, and ethambutol 
2.2.3.1 Linezolid Clinical Safety 
Linezolid is currently marketed globally for a variety of acute infectious diseases and has been 
studied for the treatment of XDR-TB in several recent trials.(3,9) The following list of known and 
potential risks is based on the warnings and precautions and adverse reactions sections of the 
current package label.(23,24,26)  Of note, the approved indication for linezolid is for administration 
up to 28 days. 
 Warnings and Precautions 
• 
Linezolid should not be used in patients taking any medicinal product which inhibits 
monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking 
any such product. 
• 
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) 
has been reported in patients receiving linezolid. In cases where the outcome is known, 
when linezolid was discontinued, the affected hematologic parameters have risen toward 
pretreatment levels. Complete blood counts should be monitored weekly in patients who 
receive linezolid, particularly in those who receive linezolid for longer than two weeks, 
those with pre-existing myelosuppression, those receiving concomitant drugs that produce 
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bone marrow suppression or those with a chronic infection who have received previous or 
concomitant antibiotic therapy.  
•
Lactic acidosis has been reported with the use of linezolid. In reported cases, patients 
experienced repeated episodes of nausea and vomiting. Patients who develop recurrent 
nausea or vomiting, unexplained acidosis, or low bicarbonate level while 
receiving linezolid should receive immediate medical evaluation.
•
Spontaneous reports of serotonin syndrome associated with the co-administration of 
linezolid and serotonergic agents, including antidepressants such as selective 
serotonin reuptake inhibitors (SSRIs), have been reported.  Where administration of 
linezolid and concomitant serotonergic agents is clinically appropriate, patients 
should be closely observed for signs and symptoms of serotonin syndrome such as 
cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or 
symptoms occur physicians should consider discontinuation of either one or both 
agents. If the concomitant serotonergic agent is withdrawn, discontinuation 
symptoms can be observed (see package insert of the specified agent(s) for a 
description of the associated discontinuation symptoms).
•
Peripheral and optic neuropathy has been reported in patients treated with linezolid, 
primarily those patients treated for longer than the maximum recommended duration of 28 
days. In cases of optic neuropathy that progressed to loss of vision, patients were treated 
for extended periods beyond the maximum recommended duration. Visual blurring has 
been reported in some patients treated with linezolid for less than 28 days. If 
patients experience symptoms of visual impairment, such as changes in visual acuity, 
changes in color vision, blurred vision, or visual field defect, prompt ophthalmic 
evaluation is recommended. Visual function should be monitored in all patients 
taking linezolid for extended periods and in all patients reporting new visual symptoms 
regardless of length of therapy with linezolid. If peripheral or optic neuropathy occurs, 
the continued use of linezolid in these patients should be weighed against the 
potential risks.  Additional information on the neuropathies reported in recent studies 
of linezolid administered over prolonged periods to patients with TB infection is 
presented above in Section 2.2.3.
•
Convulsions have been reported in patients when treated with linezolid. In some of 
these cases, a history of seizures or risk factors for seizures was reported.
•
Postmarketing cases of symptomatic hypoglycemia have been reported in patients 
with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with 
linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been 
associated with hypoglycemic episodes in diabetic patients receiving insulin or 
hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia 
has not been established, diabetic patients should be cautioned of potential 
hypoglycemic reactions when treated with linezolid. 
In addition, the linezolid product label notes that there was an excess of abnormal liver function 
tests in comparator-controlled trials.  These abnormalities were noted in 0.4% of linezolid treated 
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patients in trials of skin and skin structure infections vs in 0.2% of clarithromycin treated patients, 
and in 1.6% of patients treated with linezolid versus 0.8% of patients with other treatments in trials 
of all other infections. 
Adverse events of linezolid long term therapy for Tuberculosis have been described in several 
literature reports. The most complete review is a meta-analysis by Cox which noted the proportion 
of adverse events necessitating treatment discontinuation was significantly different by dose: 
29.49% (95%CI 3.24–55.74) for ⩽600 mg daily vs. 60.75% (95%CI 42.69–78.81) for >600 mg 
daily (P = 0.05). (3) 
In a trial reported by Lee et al in S Korea(9), seven of 41 participants had myelosuppression, 
including anemia and neutropenia, primarily within the first 5 months, and only one participant 
withdrew due to anemia.  Six had clinically significant myelosuppression:  5 in 0-4 months and 1 
in 4-8 months, with 0 in 8-12 months. 
Peripheral and Optic Neuropathy:  
The linezolid product label notes these adverse events have been “ reported in patients, primarily 
those patients treated for longer than the maximum recommended duration of 28 days.  In cases 
of optic neuropathy that progressed to loss of vision, patients were treated for extended periods 
beyond the maximum recommended duration.  Visual function should be monitored in all patients 
taking ZVYOX for extended periods (>3 months) and in all patients reporting new visual 
symptoms, regardless of length of therapy.(26) 
In Lee, NEJM, 2012(9), the publication’s Supplemental Table 3 notes that 21 patients had clinically 
significant peripheral neuropathy spread over 12 months:  5 in months 0-4, 10 in months 4-8 and 
5 in months 8-12 (time of onset not noted for one).  Participants who developed any peripheral 
neuropathy had their dosing of linezolid interrupted, generally for several weeks, and then 
resumed at the lower dose of 300 mg/day (C. Barry, personal communication).  None of the 
participants withdrew from the study based on peripheral neuropathies.  At baseline, patients 
received visual acuity testing, contrast sensitivity and color vision tests. Seven cases were 
observed as having potential effects on vision; only two of 38 patients withdrew from study due to 
optic neuropathy.  For clinically significant optic neuropathy, one had this at 0-4 months, 2 at 4-8 
months and 3 at months 8-12.  Except for the 2 participants who withdrew from the study, the 
others resumed linezolid at the 300 mg dose after a hiatus of several weeks of treatment and 
completed the study with resolution of their visual acuity changes (C. Barry, personal 
communication). 
In the Schecter California Department of Health (DOH) review(32), peripheral neuropathy 
developed in 5 of 30 patients (no standardized monitoring), but only one withdrew from linezolid 
therapy.  One patient developed visual loss secondary to optic neuropathy after 10 months of 
linezolid therapy, but vision returned to normal 3-4 weeks after discontinuation. 
In Park, 2006(27), two patients of eight in the case series developed optic neuropathy after 8-9 
month and had linezolid discontinued; these patients also had peripheral neuropathy. After 
linezolid treatment was stopped, the optic neuropathy fully resolved after 2-3 months.  A total of 
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4 patients developed peripheral neuropathy at 4, 5, 8, 11 months; in the patients with optic 
neuropathy who stopped treatment, the peripheral neuropathic symptoms continued or improved 
only marginally. 
In Singla, 2012(34), two of 29 patients treated with linezolid, 600 mg daily over 12 months, stopped 
the drug because of peripheral neuritis (one patient) and optic neuritis (one patient).  The time 
course of these adverse events was not noted. 
2.3 Regimens to be Studied 
The regimen included in this study (B-Pa-L) has been selected based on the performance of the 
regimen in non-clinical pharmacology studies and on the combination of bedaquiline and 
pretomanid with other drugs in clinical studies NC-001 and NC-003.  In addition, improved 
treatment outcomes in XDR patients with the addition of linezolid to existing therapy provide 
support for combining linezolid with other drugs that have no pre-existing resistance.  Preliminary 
results from the ongoing Nix-TB clinical study demonstrate the encouraging potential of this 
regimen. 
This regimen has the potential to treat drug resistant strains of tuberculosis. This is an oral 
regimen, removing the need for injectables as part of drug resistant treatment, and is also 
projected to be markedly less expensive than current XDR-TB therapy. Treatment duration is 
anticipated to be shorter than current regimens for drug resistant TB, based on findings in mouse 
models of infection and the fact that all participants will be treated with three active drugs against 
TB for which there is no expected resistance.  
The key data supporting the use of the B-L-Pa regimen are described below. 
2.3.1 Non-Clinical Studies 
In the murine model of TB, addition of bedaquiline to HRZ results in accelerated clearance of MTB 
(5,36) when compared to HRZ alone. While the combination of bedaquiline and pretomanid in the 
murine model of TB in initial studies appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ(15) and in a subsequent study it was more 
active in the mouse model than HRZ.(16) Thus a novel regimen with bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance.   
Recent studies of the bactericidal and sterilising activity of linezolid in an animal model where 
mice were given high dose aerosol MTB infection have demonstrated that linezolid alone and in 
combination with bedaquiline and pretomanid causes marked reductions in lung CFUs from mice 
following 1 to 3 months of therapy (Table 4 below). Additionally, all mice treated daily with 
bedaquiline, pretomanid and linezolid (B-L-Pa) were cured of the infection after 3 months of 
therapy as evidenced by no MTB cultured from lungs when mice were sacrificed 3 months after 
the completion of therapy that lasted 3 months or more (Table 4, below). This is in contrast to the 
5-6 months required in previous studies to cure all mice when treated with the standard of care 
isoniazid, rifampicin and pyrazinamide (HRZ; note that typically ethambutol is not used in the 
mouse model of infection). Additional mouse studies were performed to determine whether 
shorter durations of linezolid, with continuation of the other drugs, would result in relapse-free 
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cure in the mouse (Table 4 below). Treatment with linezolid for only the first 4 to 8 weeks of a 
3-month treatment also resulted in relapse-free cure when lungs from the mice were cultured 
3 months after the completion of therapy.(37) 
Table 4: 
Murine Relapse Data 
Impact of Linezolid Treatment Duration on Lung Colony Forming Unit Counts 
Assessed during Treatment and Proportion of Mice Relapsing after Treatment 
Completion 
Proportion of mice relapsing after treatment for: 
Regimen 
2 months 
3 months 
2RHZ/RH* 
8/14 
(57%) 
BPa 
3/14 
(21%) 
3BPaL ** 
6/15 
(40%) 
0/15#† 
(0%) 
2BPaL/1BPa*** 
0/15#† 
(0%) 
1BPaL/2BPa 
9/15 
(60%) 
0/15#† 
(0%) 
#p = 0.11 vs. BPa; †p≤ 0.001 vs. RHZ 
*2RHZ/RH means 2 months on the full regimen and a third month on only RH 
**3BPaL means 3 months on the full regimen 
***2BPaL/1BPa means 2 months on the full regimen and a third month on only BPa 
****1BPaL/2Bpa means 1 month on the full regimen and a third month on only BPa 
B – bedaquiline, H-isoniazid, L-linezolid, Pa-pretomanid, R-rifampicin, Z-pyrazinamide 
 
In conclusion, linezolid increases the sterilising activity of the bedaquiline-pretomanid 
combination; no MTB could be cultured from the lungs of mice 3 months after cessation of 3 
months of treatment with the combination, in contrast to MTB cultured from 13 of 15 mice treated 
with the standard 2RHZ/4RH regimen over 3 months. In addition, limiting the duration of linezolid 
to the first month of treatment does not affect linezolid’s contribution to the sterilising activity of 
the regimen in the preclinical mouse study.   
Prior to the use of pretomanid in combination with bedaquiline in clinical study NC-001, a 
preclinical cardiovascular safety pharmacology study was conducted in unrestrained beagle dogs 
with both drugs to explore the potential for additive effects on QT prolongation induced by the 
combination.  Results indicate that administration of 100 mg/kg bedaquiline daily for 7 days 
causes a small increase in QTc interval by Day 6 in some animals that is not influenced by the 
addition of 100 mg/kg pretomanid on Day 7. The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the subcutaneous route of administration and not 
related to the plasma exposure.   
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2.3.2 Clinical Studies of Pretomanid in a Regimen with Bedaquiline and/or 
Linezolid 
2.3.2.1 Clinical Study NC-001 
Study NC-001 was a partially double-blind, randomized, parallel group study in adult male and 
female participants with newly diagnosed, uncomplicated, smear-positive, pulmonary TB. A total 
of 85 participants met study eligibility criteria and were randomly assigned to one of the six 
treatment groups. All study treatments were given once daily for 14 days. Substantial EBA activity 
was demonstrated across participants in all arms of the study and the daily reductions in cultured 
colony counts per mL of sputum are presented in Table 5 below. 
Table 5: 
Summary Statistics for EBACFU(0-14) 
Derived Using Bi-Linear Regression, Study NC-001 
Treatment Group 
N 
Daily Mean (SD)  
EBACFU(0-14) 
Pretomanid + pyrazinamide + moxifloxacin 
13 
0.23 (0.128) 
Pretomanid + pyrazinamide 
14 
0.15 (0.040) 
Pretomanid + bedaquiline  
15a 
0.11 (0.050) 
Bedaquiline alone 
14 
0.07 (0.068) 
Bedaquiline + pyrazinamide 
15 
0.13 (0.102) 
Rifafour e-275 
10 
0.14 (0.094) 
 
There were no Serious Adverse Events from the study among participants treated with 
pretomanid and bedaquiline.  Three participants in a bedaquiline-containing treatment arm were 
withdrawn: one participant on the bedaquiline only arm for a Grade 3 ALT and Gamma-Glutamyl 
Transferase (GGT) elevation (although the elevation occurred prior to the first dose of study 
medication), one on a bedaquiline plus pyrazinamide (weight banded) arm for a Grade 3 ALT 
and AST elevation, and one on a pretomanid and bedaquiline arm for to a Grade 3 ALT 
elevation. 
2.3.2.2 Clinical Study NC-003  
Efficacy 
In the 14 day EBA study NC-003 two monotherapy and four different combinations of bedaquiline, 
pretomanid, pyrazinamide and clofazimine were evaluated in DS-TB participants. Fifteen 
participants were randomized into 7 treatment arms: C, Z, B-Pa-Z-C, B-Pa-Z, B-Pa-C, B-Z-C, and 
HRZE control. This study demonstrated no EBA for the clofazimine monotherapy arm and modest 
EBA for the pyrazinamide monotherapy arm. However, all of the experimental regimens 
demonstrated EBA. In general, adding clofazimine to the various agents resulted in either no 
increase in EBA, or a decrease when compared to a similar regimen that did not include 
clofazimine. In this study, the experimental regimen with the best EBA was B-Pa-Z which 
demonstrated a rate of decrease in both logCFU and logTTP that was at least as good as the HRZE 
control. The daily logCFU results are presented in Table 6. Similar results were found when TTP 
was used to calculate the bactericidal activity over 14 days (BA(0-14)). 
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Table 6: 
NC-003 Efficacy Results: Daily BAlog CFU(0-14) 
Arm 
logCFU 
BPaZC 
.124 
BPaZ 
.180 
BPaC 
.086 
BZC 
.098 
Z 
.036 
C 
-.025 
Rifafour 
.152 
Safety 
Generally, the regimens in this study were well tolerated. Table 7 provides a list of the overall 
safety findings. The only SAE experienced in the study was in a participant in the clofazimine 
monotherapy arm. Otherwise, the rates of treatment emergent AEs (TEAEs) were similar across 
the treatment arms. One participant in the B-Pa-Z arm was withdrawn from the study due an 
adverse event of increased liver function tests (alanine aminotransferase (ALT), AST and GGT).  
Table 7: 
NC-003 Safety Data 
 
BPaZ
C 
BPaZ 
BPa
C 
BZC 
Z 
C 
HRZ
E 
Total 
N 
15 
15 
15 
15 
15 
15 
15 
105 
Participants with: 
TEAEs 
11 
9 
8 
10 
10 
9 
8 
65 
TEAEs leading to death: 
Serious TEAEs 
 
 
 
 
 
1 
 
1 
TEAES leading to early withdrawal 
 
1 
 
 
 
 
 
1 
TEAEs leading to discontinuation 
of study drug 
 
1 
 
 
 
 
 
1 
Drug-related TEAES 
8 
5 
7 
3 
5 
6 
5 
39 
Serious, drug-related TEAEs 
 
 
 
 
 
 
 
 
Grade III AEs 
 
2 
1 
2 
 
1 
 
6 
Grade IV AEs 
 
1 
1 
 
 
 
 
2 
Grade II/IV AEs 
 
2 
1 
2 
 
1 
 
6 
 
QT Prolongation 
Because bedaquiline and clofazimine are both known to prolong the QT interval, intensive ECG 
monitoring was included in the study endpoints. The mean change from baseline in QTcB and 
QTcF tended to be larger at 5 hours than at 10 hours post-dose in the (B-Pa-Z-C) arm and in the 
(B-Pa-C) arm.  No QTcB or QTcF ≥500 ms were reported.  An increase from baseline to Visit 5 
and subsequent visits of ≥60 ms in QTcB was reported for 2 participants in the (B-Pa-C) arm and 
for 1 participant in the clofazimine alone arm.  An increase from baseline to Visit 5 and subsequent 
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visits of ≥60 msec in QTcF was reported for 4 participants in the (B-Pa-C) arm and for 1 participant 
in the clofazimine alone arm.  For both QTcB and QTcF, the (B-Pa-Z-C) arm and the (B-Pa-C) 
arm showed the largest increase from baseline. Clofazimine will not be used in any treatment 
arms in the NC-007 study. 
2.3.2.3 The Nix-TB Study  
The NiX-TB Study is an ongoing open-label study assessing the safety and efficacy of bedaquiline 
plus linezolid plus pretomanid in participants with pulmonary infection of either XDR-TB or 
treatment intolerant/non-responsive MDR-TB. The study regimen includes: bedaquiline 400 mg 
once daily for 2 weeks then 200 mg 3 times per week plus pretomanid 200 mg once daily plus 
linezolid 600 mg twice daily amended (22 Jan 2016 protocol) to 1200 mg once daily. Treatment 
duration is 6 months, although if participants are still culture positive at month 4, there is the option 
to extend treatment to 9 months or withdraw. The primary endpoint is the incidence of 
bacteriologic failure or relapse or clinical failure through follow-up until 6 months after the end of 
treatment. Secondary Endpoints include: incidence of bacteriologic failure or relapse or clinical 
failure through follow-up until 24 months after the end of treatment as a confirmatory analysis, 
time to sputum culture conversion to negative status through the treatment period, and the 
proportion of participants with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 
end of treatment. In addition, linezolid dosing (actual) and efficacy will be explored and changes 
from baseline will be evaluated for TB symptoms, Patient Reported Health Status, body weight, 
and measures of safety. 
Efficacy Experience to Date:   
Sixty-nine participants have been enrolled as of February 1, 2017, at 2 sites in South Africa. Forty-
nine percent of the participants are HIV positive, 79% have XDR-TB and 21% have MDR 
intolerant or resistant to prior therapy.  Forty have completed the 6 months of therapy with the 
drug regimen and 31 have been followed to the primary endpoint at 6 months after treatment. All 
surviving patients were culture negative by 4 months, with 74% negative at 8 wks. As of February 
1, 2017, there has been 1 microbiological relapse during follow up after drug therapy and 1 
participant has had a new infection during follow-up with Drug Sensitive TB.  This study will 
continue to enrol participants until the NC-007 study is initiated. 
Safety of the B-Pa-L Regimen in the Nix-TB Study:  As of December 2016, four participants have 
died in the study. The causes of death have varied and include: 2 with multi-organ disseminated 
TB who died within the first 5 weeks of therapy, 1 who had a gastrointestinal bleed and 1 with 
multi-organ failure and disseminated TB on autopsy. No deaths or SAEs have been caused by 
hepatic injury. No participants have been withdrawn from the study except for the 4 who died.  
The expected linezolid toxicities of peripheral neuropathy and myelosuppression were common 
but manageable.  Seventy-one percent of participants had at least one linezolid dose pause (22% 
of all participants due to myelosuppression and 28% due to peripheral neuropathy), during the 6 
months of treatment. One had peak ALT and AST > 3 X ULN and total bili > 2X ULN, but these 
improved and treatment restarted without a recurrence.  There were 7 cases of grade 3 or 4 
transaminitis and all resolved and allowed the study regimen to be continued. There were no 
cases of optic neuritis. While participants have required close surveillance for signs and 
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symptoms of neuropathies and bone marrow suppression, these toxicities have been 
manageable.  
2.4 Overall Benefit/Risk Assessment 
The recent report of the long term outcome of patients with XDR-TB treated in S. Africa highlighted 
the very poor prognosis for patients with this disease.  After 60 months of follow up 73% of 107 
patients had died and only 11% had a favourable outcome(28).  These patients have infection with 
MTB resistant to many/most of the available drugs to treat tuberculosis.  Patients with XDR-TB 
have limited treatment options due to their resistance profile, and the drugs that are typically used 
in Standard of Care have many side effects, some are administered as injectables and have poor 
treatment outcomes in XDR-TB.  Similarly, patients with Pre-XDR-TB and patients with MDR-TB 
who are failing or are intolerant to treatment have traditionally poor outcomes and are a challenge 
to treat. While treatment success for MDR-TB is better than for XDR-TB, overall success in 
treating MDR-TB is still approximately 50% according to the World Health Organization 2015 
Global TB Report.(43) and it would be lower for patients failing or not able to take an optimal 
traditional regimen.  This trial provides an opportunity to treat these high-need patients with three 
active drugs, for which there is no or minimal pre-existing resistance, in a very closely controlled 
and monitored clinical trial setting with the opportunity to define the optimal dosing scheme for 
linezolid.  Participants will be monitored closely and regular reviews of safety and efficacy will be 
made by the Data Safety Monitoring Committee (DSMC).  Preliminary results of the ongoing Nix-
TB trial from patients with XDR-TB and who are failing or intolerant to treatment of MDR-TB 
demonstrate that this regimen has the potential to give relapse-free cure of XDR-TB with a simple 
regimen in a much shorter period of time than currently required by the available drugs used in 
the best standard of care.  Preclinical studies of this regimen in a murine model of infection 
demonstrated relapse free cure of MTB in half the time (3 vs 6 months) required by standard HRZ 
therapy.  Clinical studies of linezolid alone and pretomanid and bedaquiline alone and in 
combination have demonstrated activity against TB infection. 
These three drugs have not been used in combination in humans prior to the Nix-TB trial, and 
thus their combined toxicity profile is emerging.  The greatest risks of key concern for participants 
in this trial from linezolid are from the adverse events of myelosuppression and peripheral and 
optic neuropathy.  Participants will be closely monitored with full blood counts, vision 
examinations, and screening for peripheral neuropathy.  The investigator may interrupt dosing of 
either linezolid or linezolid with pretomanid and bedaquiline if adverse events of concern develop, 
and a resumption of the drugs, with linezolid at the same or at a lower dose, may be made 
cautiously.  Participants will be under close surveillance for hepatotoxicity, as that risk for 
pretomanid and bedaquiline is not yet well characterized.   
Overall the benefit-risk balance justifies evaluating the B-Pa-L regimen in this study, with the 
cautious surveillance in place, to treat patients with XDR-TB who have few options for a 
successful outcome. 
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3 
Trial Objectives  
3.1 Primary Objectives 
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus 
bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary 
XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
4 
Trial Design 
4.1 Summary of Trial Design 
This is a Phase 3, multi-center, partially-blinded, randomized clinical trial conducted in 4 treatment 
groups.  Participants, trial investigators and staff, including laboratory staff, will be blinded to dose 
and scheduled duration of linezolid.   Bedaquiline and pretomanid dosing will not be blinded. 
The trial will be performed at multiple centers located in South Africa, Eastern Europe and Russia.  
A total of 180 XDR-TB and Pre-XDR/MDR intolerant or non-responsive participants who meet all 
of the inclusion criteria and none of the exclusion criteria, aged 18 and over, will be randomized 
to receive one of the 4 active treatment arms. Participants will be randomized to one of the four 
regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will 
utilize a randomization system using stratification with a random element to allocate participants 
evenly across the arms by HIV status and type of TB after they have given written, informed 
consent and met all eligibility criteria.  
Each participant will receive 26 weeks of treatment. If participant’s sputum sample is culture 
positive between the week 16 and week 26 treatment visits and their clinical condition suggests 
they may have an ongoing TB infection, Investigator may consider extending current treatment 
to 39 weeks.   If the culture results between week 16 and week 26 are contaminated, missing or 
considered an isolated positive without clinical significance, available culture results should be 
used to make this decision. All decisions regarding treatment extension should be discussed with 
and approved by the Sponsor Medical Monitor before implementation. Participants will be 
followed for 78 weeks after end of treatment. 
 
4.2 Treatment Plan: Schedule of Assessments 
• 
Screening Period- Screening Visit up to 14 days prior to Treatment 
• 
Treatment Period- Day 1 to Week 26. Additional visits every 3 weeks until last dose when 
dosing extended due to pauses or positive culture at Week 16  
• 
Follow-up Period- 4 Week post end of treatment follow-up Visit to 78 Week post end of 
treatment follow-up Visit 
Refer to: 
• 
Trial Flow Chart (Section 1.2) for the timing of all procedures and laboratory 
samples to done at each visit.   
• 
Trial Procedures (Section 7) for details regarding specific procedures or 
laboratory tests. 
Participants will receive oral daily dosing. They will be randomized to one of the following arms: 
 
Table 8: 
Treatment Groups 
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Treatment Group 
No of Participants 
1 
Linezolid 1200 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
2 
Linezolid 1200 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
3 
Linezolid 600 mg daily for 26 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
4 
Linezolid 600 mg daily for 9 weeks followed by linezolid placebo for 
17 weeks 
• bedaquiline 200 mg once daily for 8 weeks then 100 mg once 
daily for 18 weeks plus;  
• pretomanid 200 mg once daily for 26 weeks. 
• 30 XDR-TB 
• Up to 15 Pre-XDR or 
MDR intolerant/non-
responsive 
 
Figure 4: 
Trial Schematic 
 
26 Weeks of Treatment* 
 
Weeks 1-9 
Weeks 10-26 
1 
1200 mg Linezolid QD 
 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
Primary Endpoint 
follow-up for relapse-
free cure 26 weeks 
after end of treatment 
 
Full follow up 78 
weeks after end of 
treatment 
2 
1200 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100mg QD week 9 
Pretomanid 200 mg QD 
1200 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
3 
600 mg Linezolid QD 
 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
4 
600 mg Linezolid QD 
Bedaquiline 200 mg QD weeks 1-8 
Bedaquiline 100 mg QD week 9 
Pretomanid 200 mg QD 
600 mg Linezolid PLACEBO QD 
Bedaquiline 100 mg QD 
Pretomanid 200 mg QD 
 
 
Participants will be randomized to 1 of the 4 groups listed above.  
N = 45 Participants per group for a total of 180. 30 XDR-TB participants per group    
* Treatment will be extended to 39 weeks for participants who have a positive culture at week 16  
 
5 
Trial Population 
Participants must meet all inclusion and no exclusion criteria within the screening period.  Re-
testing for laboratory or ECG parameters is allowed within the 14-day screening period. Sponsor 
may consider replacement of late screen failure and un-assessable (as detailed in the statistical 
analysis plan) participants. It is the intent of the protocol that the participants are hospitalized 
according to local practices and at the judgment of the treating physician. 
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5.1 Inclusion Criteria 
Participants are required to meet all of the following inclusion criteria during the screening period 
in order to be randomized. 
1. Provide written, informed consent prior to all trial-related procedures (including any 
additional consent required for participants considered as minors per applicable regulatory 
authority or ethics committee). 
2. Willingness and ability to attend scheduled follow-up visits and undergo study 
assessments. 
3. HIV testing (if an HIV test was performed within 1 month prior to screening, it should not 
be repeated as long as a documented  result can be provided [ELISA and/or Western Blot 
and/or Electro-Chemiluminescence].  If HIV status is a confirmed known positive, repeated 
HIV test is not needed if ELISA and/or Western Blot and/or Electro-Chemiluminescence 
documentation of presence of HIV infection is available. 
4. Male or female, aged 18 years or older.  
 
Disease Characteristics: 
 
5. Participants with one of the following pulmonary TB conditions: 
a. 
 XDR-TB with  
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
documented resistance to rifamycins, a fluoroquinolone AND an injectable 
during the current TB diagnosis/disease course any time prior to or during 
screening period (may be sensitive or resistant to isoniazid);  
b. 
Pre-XDR-TB with 
i. 
A documented culture positive or a molecular test positive (for MTB) from a 
sputum specimen collected within 3 months prior to screening or MTB 
confirmed in sputum based molecular test within 3 months prior to or at 
screening and; 
ii. 
documented resistance to rifamycins, and to a fluoroquinolone OR an 
injectable during the current TB diagnosis/disease course any time prior to 
or during screening period (may be sensitive or resistant to isoniazid); 
c. 
MDR-TB with 
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected results within 3 months prior to screening or 
MTB confirmed in sputum based on molecular test within 3 months prior to 
or at screening and; 
ii. 
documented 
resistance to 
rifamycins 
during 
the 
current 
TB 
diagnosis/disease course any time prior to or during screening period (may 
be sensitive or resistant to isoniazid) and; 
iii. 
with documented non-response to treatment with the best available regimen 
for 6 months or more prior to enrolment who in the opinion of the Investigator 
have been adherent to treatment and will be adherent to study regimen.   
d. 
MDR-TB with  
i. 
documented by culture positive or a molecular test positive (for MTB) from 
a sputum specimen collected within 3 months prior to screening or MTB 
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confirmed in sputum based on molecular test within 3 months prior to or at 
screening and: 
ii. 
documented 
resistance to 
rifamycins 
during 
the 
current 
TB 
diagnosis/disease course any time prior to or during screening period (may 
be sensitive or resistant to isoniazid) and; 
iii. 
who are unable to continue second line drug regimen due to a documented 
intolerance to: 
a. PAS, ethionamide, aminoglycosides or fluoroquinolones or ; 
b. Current treatment not listed above that renders participant eligible for 
the study in the Investigator’s opinion.  
6. Chest X-Ray within 6 months prior to or at screening, obtained and read locally by 
investigator or designee with results consistent with pulmonary TB in the opinion of the 
Investigator. 
 
Contraception: 
7. Be of non-childbearing potential or using effective methods of birth control, as defined 
below: 
 
Non-childbearing potential: 
a. Participant - not heterosexually active or practices sexual abstinence; or  
b. Female participant or male participant’s female sexual partner - bilateral 
oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months; 
or  
c. Male participant or female participant’s male sexual partner - vasectomised or 
has had a bilateral orchidectomy at least three months prior to screening. 
 
Effective birth control methods:                                                        
a. Double barrier method which can include a male condom, diaphragm, cervical cap, 
or female condom; or  
b. Female participant: Barrier method combined with hormone-based contraceptives 
or an intra-uterine device for the female participant; 
c. Male participant’s female sexual partner: Double barrier method or hormone based 
contraceptives or an intra-uterine device for the female partner. 
 
And are willing to continue practicing birth control methods throughout treatment and for 6 
months  (female participants) and 12 weeks (male participants) after the last dose of study 
medication. 
 
Note: Hormone based contraception alone may not be reliable when taking IMP; 
therefore, hormone-based contraceptives alone cannot be used by female participants 
to prevent pregnancy. 
 
5.2 Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria during 
the screening period: 
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Medical History and Concurrent Conditions 
1. Any condition in the Investigator’s opinion (i.e., an unstable disease such as 
uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended 
treatment, cancer that could affect survival through the protocol-specified follow up 
period), where participation in the trial would compromise the well-being of participant 
or prevent, limit or confound protocol specified assessments.  
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations.  
3. In the judgment of the Investigator, the participant is not expected to survive for more 
than 6 months. 
4. Karnofsky score < 60 at screening. 
5. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal 
Products or related substances. 
6. Body mass index (BMI) < 17 kg/m2 
7. TB infection with historic DST or MIC results with values suggesting likely resistance 
to pretomanid, delamanid, linezolid or bedaquiline; the Sponsor Medical Monitor must 
be consulted to help interpret any available historic results. 
8. Participants who, upon the evaluation of their pulmonary disease, are expected to 
require a surgical procedure. 
9. Having participated in other clinical studies with dosing of investigational agents within 
8 weeks prior to screening or currently enrolled in an investigational study that includes 
treatment with medicinal agents.  Participants who are participating in observational 
studies or who are in a follow up period of a trial that included drug therapy may be 
considered for inclusion. 
10. Participants with any of the following at Screening: 
• 
QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be 
discussed with and approved by the Sponsor Medical Monitor before enrolment. 
(Per measurements and reading done from screening central ECG.) 
• 
Heart failure 
• 
A personal or family history of congenital QT prolongation 
• 
A history of or known, untreated, ongoing hypothyroidism 
• 
A history of or ongoing bradyarrhythmia 
• 
A history of Torsade de Pointe 
11. Participants with any of the following conditions where the use of linezolid is 
contraindicated:  
• 
A history of thyrotoxicosis 
• 
A history of uncontrolled arterial hypertension 
• 
A history of pheochromocytoma 
• 
A history of carcinoid syndrome 
• 
A history of bipolar disorder 
• 
A history of schizoaffective disorder 
 
12. Females who have a positive pregnancy test at Screening or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the study or within 6 
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months of cessation of treatment.  Males planning to conceive a child during the study 
or within 6 months of cessation of treatment. 
13. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, 
participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the 
course of the study, in the opinion of the Investigator. 
14. Participants with lactose intolerance, lactase deficiency and/or glucose-galactose 
malabsorption. 
 
 
Previous and Concomitant Therapy 
15. Known (during screening) requirement for future Concomitant (during treatment) use 
of any prohibited and/or avoided medications noted in section 5.3. 
16. Prior use of Monoamine Oxidase Inhibitors (MAOIs) within 2 weeks of randomization.  
17. Prior use of serotonergic antidepressants within 3 days of randomization if Investigator 
foresees potential risks for serotonin syndrome when combined with linezolid.  
 
18. Participants who have received more than 2 weeks of bedaquiline, linezolid or 
delamanid prior to first dose of IMP. 
19. Participants with newly diagnosed tuberculosis and HIV that require initiation of 
appropriate HIV therapy before participant has received at least 2 weeks of an anti-
tuberculosis regimen.  
20. HIV infected participants with planned continued use of zidovudine, stavudine or 
didanosine. The antiretroviral therapy (ART) booster cobicistat should not be used. 
Please reference restrictions Section 5.3.3 Antiretroviral Therapy, for guidance on 
ART treatment during the treatment period.  
 
Diagnostic and Laboratory Abnormalities 
 
21. Participants with any of the following toxicities at Screening (labs may be repeated 
during screening period) as defined by the enhanced Division of Microbiology and 
Infectious Disease (DMID) adult toxicity table (November 2007): 
 
a. Viral load >1000 copies/mL (Unless newly diagnosed HIV and not yet on ART who 
otherwise qualify for participation); 
b. CD4+ count < 100 cells/µL (HIV positive participants); 
c. Serum potassium less than the lower limit of normal for the laboratory; 
d. Hemoglobin < 9.0 g/dL or < 90 g/L; 
e. Platelets <100,000/mm3 or < 100 x 10^9/L; 
f. Absolute neutrophil count (ANC) < 1500/ mm3 or < 1.5 x 10^9/L; 
g. Aspartate aminotransferase (AST)  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor Medical Monitor 
h. Alanine aminotransferase  
• 
Grade 3 or greater (> 3.0 x ULN) to be excluded; 
• 
Results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor medical monitor; 
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i. Total bilirubin 
• 
greater than 1.5 x ULN to be excluded; 
• 
1-1.5 x ULN must be discussed with and approved by the Sponsor Medical 
Monitor  
j. Direct bilirubin 
• 
Greater than ULN to be excluded 
k. Serum creatinine level greater than 1.5 times upper limit of normal 
l. Albumin <3.0 g/dl or < 30 g/L  
 
All inclusion and no exclusion criteria must be met.  If no single variable/value is outside of the 
ranges of acceptability, but when multiple values are close to the limits and/or whenever the 
Investigator has reason to suspect that there might be a health problem (other than TB), enrolment 
should only be considered after discussing the case with the Sponsor Medical Monitor. 
No protocol waivers will be granted by the TB Alliance. 
 
5.3 Restrictions 
5.3.1 Prior and Concomitant Medications and Other Treatments 
Concomitant medications should be kept to a minimum during the treatment period of the trial.  
However, if concomitant medications are necessary for the participant’s welfare and are unlikely 
to interfere with the IMP, they may be given at the discretion of the Investigator.  For any 
concomitant medications given as a treatment for a new condition or a worsening of an existing 
condition occurring after signing of the Informed Consent Form, the condition must be 
documented on the Adverse Event pages of the electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be consulted and reviewed 
carefully.  The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected to prevent any potentially serious and/or life-threatening drug 
interactions. 
The following concomitant medications are prohibited during the treatment period and during the 
14 days after treatment completion: 
• 
Medicinal products used to treat pulmonary TB:  including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and metronidazole. 
• 
Concomitant use of Monoamine Oxidase Inhibitors (MAOIs). (e.g., phenelzine, 
isocarboxazid) 
• 
Concomitant use of adrenomimetics (including, but not limited to pseudoephedrine, 
phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics 
(e.g. dopamine). 
• 
Concomitant use of 5-HT1 agonists (triptans), meperidine or buspirone. 
 
The following concomitant medications should be avoided during the treatment period and during 
the 14 days after treatment completion to avoid possible drug interactions with the IMP. Use of 
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any of the following must be discussed and approved by the Sponsor Medical Monitor prior to 
use: 
• 
Concomitant use of any drug known to prolong QTc interval (including but not limited to 
amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, 
clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, 
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, 
pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).  
• 
Treatment with fluoroquinolones (as they are known prolong QTc), are strongly 
discouraged in the trial. They should only be used to treat intercurrent non-TB infections 
and if the benefit of treatment outweighs the risk of prolonged QTc.   
• 
Concomitant use of any drug known to induce significant myelosuppression 
• 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: ketoconazole, 
voriconazole, itraconazole, fluconazole; ketolids such as telithromycin; and macrolide 
antibiotics other than azithromycin) for more than 3 consecutive days; 
• 
The systemic use of CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, 
St. John’s wort, rifamycins and systemic dexamethasone.  
• 
Concomitant use of serotonergic antidepressants should be avoided if possible as 
participants on these agents and linezolid are at risk for serotonin syndrome.  
• 
Caution should be used in treating diabetic patients receiving insulin or oral hypoglycemic 
agents as cases have been reported of hypoglycemic reactions when patients on these 
agents have been treated with linezolid. 
The following concomitant medications which are known to be hepatotoxic should be avoided as 
much as possible during screening and throughout the treatment period.  If there are concerns 
about the co-administration of  hepatoxic drugs, discussion with the Sponsor Medical Monitor is 
encouraged (including but not limited to acetaminophen/paracetamol,  acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, augmentin/co-
amoxiclav, azathioprine, baclofen, bumetanide, captopril, carbamazepine, celecoxib, 
chlorpromazine, chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-trimoxazole, 
darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, fosamprenavir, 
furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, 
loperamide, losartan, methotrexate, metolazone, mirtazepine, nitrofurantoin, omeprazole, other 
non-steroidal anti-inflammatory drugs, paroxetine, phenobarbital, phenothiazines, phenytoin, 
pravastatin, probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, simeprevir, 
simvastatin, sodium valproate, sotalol, sulfasalazine, sumatriptan, tamsulosin, terbinafine, 
tetracycline, theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, topiramate, trazodone, 
tricyclic antidepressants, trimethoprim, verapamil). 
5.3.2 Recommendations for Concomitant use of Anti-Malarials 
The following treatments for malaria are recommended for concomitant use with the IMP, should 
it be necessary: 
• 
Proguanil/atovaquone or  
• 
Artesunate plus sulfadoxine-pyrimethamine  
 
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These recommendations are based on the potential for QT prolongation by bedaquiline and many 
anti-malarials. Due to the extended half-life of bedaquiline commencing anti-malarial treatment 
containing drugs that could prolong the QT interval, shortly after discontinuing bedaquiline, is not 
recommended. 
5.3.3 Antiretroviral Therapy 
For HIV infected participants, to avoid potentiating known key toxicities of linezolid (neuropathy 
and myelosuppression), the following antiretroviral therapies should not be used during the 
treatment period: zidovudine, stavudine, didanosine.  
The ART booster cobicistat should not be used. 
Only the following types of antiretroviral therapy (ART) are permissible during administration of 
regimens: 
• 
Nevirapine based regimen consisting of NVP in combination with any two NRTIs TDF/ABC 
and FTC/3TC.  
• 
Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any 
two NRTIs TDF/ABC and FTC/3TC. 
• 
Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC. 
• 
In patients who have viral load suppressed on efavirenz at the time of screening, their 
ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. If possible, 
the same nucleoside backbone should be used. 
 
The investigator must assess the risks and benefits of these antiretroviral regimens in the 
context of co-infection with TB acknowledging the following caveats: 
• 
Triple NRTI is generally not considered optimal chronic ART; 
• 
Nevirapine based regimens are associated with higher ART failure in participants having 
or known to have previously had a viral load more than or equal to 100,000/ mL. 
5.3.4 Other Restrictions 
Large quantities of foods or beverages with high tyramine content should be avoided while taking 
linezolid.  Quantities of tyramine consumed should be less than 100mg per meal. Foods high in 
tyramine content include those that may have undergone protein changes by aging, fermentation, 
pickling, or smoking to improve flavour, such as aged cheeses (0 to 15 mg tyramine per ounce); 
fermented or air-dried meats (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 
ounces); soy sauce (5mg tyramine per 1 teaspoon). The tyramine content of any protein-rich food 
may be increased if stored for long periods or improperly refrigerated. 
Alcohol should be avoided while on IMP, especially in participants with impaired hepatic function. 
5.4 Trial Discontinuation and Visits 
5.4.1 Treatment Discontinuation and Early Withdrawal 
A participant must be withdrawn from the trial due to the following;  
• 
Pregnancy (unless female post visit for end of treatment/early withdrawal from treatment); 
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• 
Investigator considers it for safety reasons in the best interest of the participant that he/she 
be discontinued, including a concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB treatment.  
• 
At the specific request of the Sponsor or termination of the trial by Sponsor; 
• 
Lost to follow-up 
• 
In the opinion of the investigator, fails to comply with the protocol, including non-
compliance to IMP. 
Participants may be withdrawn from the trial based on the following. The specific situation should 
be discussed with the Medical Monitor before withdrawing the patient. 
o Myco testing results from baseline (Screening through Week 4) indicate sensitivity  
to rifamycins; 
o Myco testing results from baseline (Screening through Week 4) with MICs that 
indicate likely resistance to bedaquiline, pretomanid or linezolid; 
All participants who discontinue trial treatment (but have not withdrawn consent) and received at 
least one dose of IMP will be requested to return for an early withdrawal visit and applicable safety 
Follow Up visits, as per flow chart (Section 1.2). 
A participant may discontinue from the trial at any time at his/her request (withdrawal of 
consent) or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral compliance or administrative issues. When a participant withdraws consent from the 
trial, no additional follow-up visits will be performed.  
5.4.2 Early Withdrawal Follow-up 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made to 
complete the Early Withdrawal assessments.   
Once a participant has been withdrawn early from the trial, they will be requested to attend follow-
up visits as described in Table 9: 
Table 9: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EW visit 
Ophthalmology 
Examination at 
EWa 
Ophthalmology 
Examination  
 
12 week Post 
treatment follow-
up visita 
26 Week  
Post 
Treatment  
Follow-up 
Visit 
78 Week Post 
Treatment 
Follow-up 
Visit 
≤ 14 days 
NA 
NA 
NA 
NA 
15 days to      
≤ 12 weeks 
NA 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if not 
already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 12 weeks after the 
EWD visit date. 
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The 26 and 78 week post treatment follow-up visits will be performed to collect SAE information 
(including verification of survival) and participant reported TB outcome information.  This visit may 
be telephonic, a home or a site visit.  
5.4.3 Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures, should be considered unscheduled regardless of the reason for the visit. The 
assessments which are undertaken as part of an Unscheduled visit should be as clinically 
indicated.  
The following situation/s require an unscheduled visit/s: 
• 
If cultures of both spot sputum samples are contaminated at the following visits, or if 
necessary, in order to help define a participant’s outcome status/assess culture status 
during follow-up, the participant should return for an unscheduled visit(s) to give additional 
samples or to document the participant is not able to produce sputum: 
  
• 
End of treatment visit 
• 
Week 26 post treatment follow-up visit 
• 
Post treatment follow-up visits from week 8 through week 65 (in addition to week 26 
follow-up) 
• 
End of Follow-up Period (week 78 post treatment completion visit) 
• 
Early Withdrawal (if applicable). 
 
• 
At the end of 26 weeks and 78 weeks post treatment completion, to define outcome status, 
and to determine whether the participant has: 
• 
At least two sequential negative sputum culture results; or  
• 
At least two sequential positive sputum culture results; or  
• 
Has been unable to produce sputum after documentation of at least two negative 
sputum cultures with no intervening positive and are clinically asymptomatic. 
 
If they do not fall into one of the above categories, site should continue to collect sputum samples 
x 2 (one early morning and one spot at the research site or 2 spots samples at least 30 minutes 
apart, under the coaching and observation of the trial staff) at a minimum of 7 days or more apart 
until they fall into one of the above categories. 
 
5.4.4 Lost to Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants.  A 
minimum of three contact attempts (telephonic/home visit) will be made for participants who do 
not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant will be 
considered LTFU.  All attempts to contact the participant must be clearly documented in the 
participant’s source documents. 
5.4.5 Early Withdrawal due to TB 
Ultimately it is the investigator’s decision whether a participant should discontinue treatment due 
to a concern that the participant has symptomatic worsening TB and/or bacteriological 
failure/relapse.  
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Discontinuation is usually not indicated by a single positive culture.  Should a participant have a 
single positive culture result after being negative, the investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether it 
is in the participant’s best interest that he/she be discontinued. Prior to discontinuation of a 
participant due to TB, the investigator must discuss the participant with the Sponsor Medical 
Monitor, unless the investigator cannot contact the Sponsor Medical Monitor and considers that 
discontinuation must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the Investigator decides to discontinue trial treatment for a participant due to TB, additional 
sputum samples may need to be collected in order to ensure the participant’s outcome status may 
be determined, details noted in trial flowchart (Section 1.2). 
All Early Withdrawal participants who are confirmed sputum positive (at least two sequential 
sputum positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to specialists who treat XDR-TB, pre-XDR TB or MDR-TB as 
applicable.  
 
 
5.5 Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who is not randomized 
Completed 
Treatment / 
Completed FU* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued FU 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
FU** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* Note that this includes treatment failures who complete all applicable follow-up visits 
** Early Withdrawal 
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5.6 Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific Investigational Site at any time, although this should 
only occur after consultation between involved parties.  Should this occur, the local and central 
Ethics Committee/Institutional review Board (EC/IRB) and Regulatory Authorities will be informed.  
Should the Trial/Investigational Site be closed prematurely, all trial materials (except 
documentation that has to remain stored at the Investigational Site) will be returned to the Sponsor 
or vendor.   The Investigator will retain all other documents until notification given by the Sponsor 
for destruction.  Participants currently on treatment will receive an appropriate regimen and all 
participants will be referred to a unit specializing in the treatment of XDR-TB, Pre-XDR-TB or 
MDR-TB as applicable. 
6 
Treatment 
6.1 IMP Administration  
 Treatment will be administered orally, once daily, with a full glass of water and a meal in the 
dosing schemes (treatment arms) outlined in Table 9. The study drug regimen should be 
initiated as specified below regardless of whether participant has received any of the allowed 
prior exposure of bedaquiline or linezolid (up to 14 days), including a loading dose of 
bedaquiline. The Pharmacy Manual should be referenced for further details. 
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Table 10: 
 Investigational Medicinal Product Details  
Treatment Group 
Active and Placebo 
Linezolid 1200 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 2 linezolid 600 mg active tablets once daily for 26 weeks 
• 1/2 (one half) placebo linezolid tablet once daily for 26 weeks  
Linezolid 1200 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9  
• 2 linezolid 600 mg active tablets once daily for 9 weeks  
• ½ (one half) placebo linezolid  tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolid tablets once daily for 17 weeks 
• ½ (one half) placebo linezolid tablet once daily for 17 weeks 
Linezolid 600 mg 
daily for 26 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
• 1 linezolid 600 mg active tablet once daily for 26 weeks 
• 1 placebo linezolid tablet once daily for 26 weeks  
• ½ (one half) placebo linezolid tablet once daily for 26 weeks 
Linezolid 600 mg 
daily for 9 weeks 
 
• 2 bedaquiline 100 mg active tablets once daily for 8 weeks then 1 
bedaquiline 100 mg active tablet once daily for 18 weeks plus;  
• 1 pretomanid 200 mg active tablet once daily for 26 weeks. 
Weeks 1-9 
• 1 linezolid 600 mg active tablet once daily for 9 weeks 
• 1 placebo linezolid tablet for 9 weeks 
• ½ (one half) placebo linezolid tablet once daily for 9 weeks 
Weeks 10-26 
• 2 placebo linezolidtablets once daily for 17 weeks 
• ½ (one half) placebo linezolid tablet once daily for 17 weeks 
 
6.2 Participant Compliance 
During site clinic visits or hospitalization, the IMP will be administered by the 
Investigator/designated site personnel. During the study, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully trained on how IMP is to be taken. When 
possible, participants will be checked for IMP compliance by the Investigators or trial 
personnel/National TB Treatment Program personnel via the hand-and-mouth procedure (both 
the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP).  Additionally, participant cards/bottles will be checked for unused tablets at 
each visit during the treatment period  
6.3 Treatment Modification(s) 
All treatment modifications should be discussed with the Sponsor Medical Monitor prior to 
implementation, unless a pause or dose reduction is required urgently for a safety concern; the 
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Medical Monitor should be informed within 24 hours of the change if not discussed prior to 
implementation.  
In the event of linezolid specific toxicities, the following should be considered and implemented 
per guidance in the monitoring and safety for specific toxicities section of protocol (8.3): 
• 
Blinded one step reductions (maximum 2 steps) in the dose of linezolid managed by the 
IXRS as per instructions in pharmacy manual and/or IXRS user manual 
o 1200 mg QD to 600 mg QD, 600 mg QD to 300 mg QD or;  
o 600 mg QD to 300 mg QD, 300mg QD to placebo).  
• 
Temporary pause of linezolid  
• 
Permanent discontinuation of linezolid. 
• 
Participants who have a linezolid reduction can go back to a higher dose (1 step or 2 
steps) post discussion with and approval by the Sponsor Medical Monitor. 
Participants experiencing suspected drug related toxicities due to other drugs in the regimen (B-
Pa), the full regimen may be halted for up to 35 consecutive days.  
Interruptions/pauses of the full regimen must not exceed 8 weeks (56 days) cumulatively.   
If participant’s sample is culture positive between the week 16 and week 26 treatment visits and 
their clinical condition suggests they may have an ongoing TB infection, Investigator may consider 
the option to extend  the treatment to which the participant is randomized to 39 weeks. If the 
culture results between week 16 and week 26 are contaminated, missing or considered an 
isolated positive without clinical significance, available culture results should be used to make this 
decision. All decisions regarding treatment extension should be discussed with and approved by 
the Sponsor Medical Monitor before implementation.  
When treatment extended to 39 weeks, pauses of the full regimen must not exceed 13 weeks (91 
days) cumulatively. 
When the total of missed dosing days of the prescribed regimen and/or pauses is greater than 7 
days, the same number of missed doses should be dispensed/treatment extended to make up for 
the total missed doses. 
At no time should the participant be treated with a single agent. 
Every effort should be made for participants to receive a total of at least 9 weeks of linezolid, even 
if pauses are required. 
6.4 IMP Packaging and Labelling 
The complete formulations of the IMP bedaquiline and pretomanid are found in the respective 
Investigator Brochures(5,6). The complete formulations of linezolid are found in the Package 
Inserts(23,24,26).  
The IMP will be packaged as follows: 
• 
Bedaquiline: Bottles containing: 
o 200 mg QD dose- 28 tablets- bedaquiline 100 mg 
o 100mg QD dose- 14 tablets- bedaquiline 100 mg  
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• 
Pretomanid: Blister card containing 14 tablets- pretomanid 200 mg  
• 
Linezolid: Blister Card containing 7 days of dosing as follows: 
o 1200 mg QD Dose  
 
2 blister strips of 7 tablets each (14 tablets) containing active linezolid 600 
mg   
 
1 blister strip of 7 half tablets containing placebo linezolid  
o 600 mg QD Dose:  
 
1 blister strip of 7 tablets containing active linezolid 600 mg   
 
1 blister strip of 7 tablets containing placebo linezolid  
 
1 blister strip of 7 half tablets containing placebo linezolid  
o 300 mg Dose (for reductions):  
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid  
 
1 blister strip of 7 half tablets containing active linezolid 300 mg  
o Placebo Linezolid Dose:  
 
2 blister strips of 7 tablets each (14 tablets) containing placebo linezolid  
 
1 blister strip of 7 half tablets containing placebo linezolid  
 
The packaging of each bottle/blister card will be labelled with, at a minimum, the following 
information: 
• 
Name of Sponsor. 
• 
Name of medication. 
• 
Dosage, quantity and method of administration for bedaquiline and 
pretomanid. 
• 
Potential dosage, quantity and method of administration for linezolid. 
• 
Reference/Lot Number. 
• 
The statement “For Clinical Trial Use Only”. 
• 
Space for completion of Name of Investigator and Site Number. 
• 
MedID: medication identification number  
• 
Storage conditions. 
• 
Period of Use. 
• 
The statement “Keep out of reach of children”. 
• 
Expiry Date. 
• 
Directions for use. 
• 
Space for completion of participant number and visit/date dispensed. 
6.5 Method of Treatment Assignment 
Participants will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive 
web/voice response system (IXRS) which will utilize a randomization system using stratification 
with a random element to allocate participants evenly across the arms by HIV status and type of 
TB.  Information & directions will be provided to each site via the IXRS user manual. 
6.6 Blinding and Procedures for Breaking the Blind 
Bedaquiline and pretomanid treatment will not be blinded.  Linezolid treatment dose and duration 
will be double-blinded.  
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The blind for a participant must not be broken by the site or sponsor except in the case of a 
medical emergency, where treatment of a participant is influenced by the knowledge of what dose 
and duration of linezolid the participant is receiving. The investigator should discuss breaking the 
blind with the Sponsor Medical Monitor (or designee) prior to breaking the blind unless knowledge 
of treatment arm is required urgently for a safety concern. The Sponsor Medical Monitor should 
be informed of the blind break within 24 hours if not discussed prior. IXRS will be programmed 
with blind-breaking instructions, described in the user manual. The Sponsor reserves the right to 
break the blind to fulfil any regulatory requirements regarding reporting of SAEs. If a participant 
is unblinded, they are not required to be withdrawn from the study.  
Individuals who will have access to the linezolid randomization scheme will be restricted to the 
IWRS vendor and IMP supply administrator and the unblinded statisticians providing safety and 
efficacy outputs for the DSMC.  Individuals from pharmacovigilance and regulatory may be 
unblinded following controlled steps in order to fulfil any regulatory requirements regarding 
reporting of expedited reports. All other parties including the Sponsor, CRO, Vendors and site 
staff, will be blinded. 
 There will be three unblinded analyses which will contain results by linezolid treatment group in 
aggregate (see section 9.3). The first analysis will be after all participants have completed 26 
weeks of treatment and here sites, participants, and Sponsor staff will not be unblinded to 
individual linezolid treatment information. A limited number of statisticians will have access to 
individual linezolid treatment assignments.  
The blind for all individual participants will be broken for the primary endpoint analysis (the second 
unblinded analysis) once all clinical data and outcome parameters have been captured, no more 
data queries are pending, and the statistical analysis plan has been finalized. The third analysis 
will occur when all participants have completed 78 weeks of follow-up after end of treatment.   
6.7 Handling, Storage and Accountability  
The investigator or designee must confirm appropriate temperature conditions as per details on 
IMP labelling, have been maintained during transit for all trial treatment received and any 
discrepancies are reported and resolved before use of the trial treatment. 
Only participants enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Upon completion or termination of the trial, all unused 
and/or partially used IMPs must either be returned to Sponsor (or designated vendor) who will 
arrange for destruction or destroyed at site as agreed by Sponsor after final accountability has 
been confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising with 
respect to the trial medication. The Sponsor will take whatever action is required should such a 
situation arise. 
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Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
7 
Trial Variables and Procedures 
The trial flowchart in Section (1.2) should be referenced for timing and sequence of 
assessments. 
7.1 Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written informed consent. 
• 
Visit dates 
• 
Participant disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and treatment history (including past and current TB 
diagnosis, alcohol use and smoking) 
• 
Screening coached spot sputum samples: 
o Smear microscopy for acid-fast bacilli. 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB 
complex and rifamycin resistance. 
• 
Urine pregnancy test: women of child-bearing potential only, whether they are 
sexually active or not. 
• 
Serology: HIV,CD4 count and viral load.  
o If an HIV test was performed within 1 month prior to trial start, it should not be 
repeated as long as documentation of results can be provided (ELISA and/or 
Western Blot and/or Electro-Chemiluminescence). 
o Where required by regulatory authorities or ethics committees: 
 
Separate approval for this to be performed will be obtained from 
participants in the written informed consent process.  
o prior to HIV testing and on receipt of the results, participants will be 
counselled on HIV by trained counsellors if they have indicated as such on 
the HIV consent form. If requested by the participant, HIV counselling 
provided to the participant by the study site should be clearly documented in 
the participant’s medical records/source.  Participants have the right to 
decline to know or receive their HIV test results. This decision should be 
clearly documented in the participant’s medical records/source.   
• 
Karnofsky score (Appendix 4). 
• 
Chest X-Ray: A Chest X-Ray digital image will be obtained and read locally by the 
Investigator or designee.  Digital images will be provided to the Sponsor; this process 
will be documented in the Radiology Manual.  The Investigator is responsible for 
review and analysis for participant inclusion. 
• 
Method of birth control: male and female participants and their partners. 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
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7.2 Efficacy Variables and Procedures 
Two spot sputum samples are collected, one early morning brought from home or collected in the 
hospital ward and one spot collected at the research site under the coaching and observation of 
the trial staff or, if no early morning sample was provided, 2 samples collected on site at least 30 
minutes apart. The Mycobacteriology sampling methodology and requirements will be described 
in a separate document, the Laboratory Manual, which will be provided prior to the trial start.  
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the time to 
positivity (TTP) followed by a speciation test when applicable, to confirm MTB. 
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse; 
• 
Time to Sputum Culture Conversion; 
• 
Number of participants with Sputum Culture Conversion. 
Every effort is to be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favorable) result.  A participant 
who never achieves culture negative status due to inability to produce sputum, but has completed 
26 week /78 week post treatment completion follow-up and is without clinical or biological 
evidence of relapse, will be considered to have a favorable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (found in the Subject Questionnaires Guideline) will record 
participants’ ratings of the severity of common TB symptoms.  
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the trial flow chart. Patient Reported Health Status will be collected using the EQ-5D-5L 
Health Questionnaire (found in the Subject Questionnaires Guideline). This descriptive 
system consists of five health-related quality of life dimensions, each of which will be 
recorded using five levels of severity. Methodology: The Patient Reported Health Status 
methodology and requirements will be described in a separate document/guideline which 
will be provided prior to the trial start. 
 
7.3 Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
trial flow chart and assessed for evaluation of the safety endpoints: 
• 
Laboratory parameters. The Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, which will be provided prior to 
the trial start. The following analyses will be performed: 
o Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential, platelet count),  
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o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), lipase, phosphate, sodium, potassium, 
calcium (corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, 
creatine phosphokinase (CPK).                  
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis.  
• 
12-lead Electrocardiogram (ECG): 
o Investigator assessment: normal, abnormal. 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected 
QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all 
participants and will be described in a separate document which will be 
provided prior to the trial start; 
 
Participants should be lying down (recumbent) for at least 5 minutes prior 
to each 12-lead ECG evaluation; 
 
ECGs are to be recorded for 10 seconds; 
 
All ECGs are to be performed in single. 
 
ECGs should be done before any labs when both included in a visit) 
 
For each participant, the ECGs should, to every extent possible, be 
collected at approximately the same time of day (+/- 1 hours) and in the 
same fed/fast state throughout the trial (e.g. 4 hours after lunch). 
• 
Vital signs: 
o Vital Signs, including weight (should be done before any labs) 
o Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 minutes of 
rest) using an appropriately sized cuff, and using the same type of sphygmomanometer, 
if possible by the same observer, at each relevant visit. 
o Heart rate (bpm). 
o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C). 
• 
Physical examination:  
o Height is measured at screening only. 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and abdominal) 
examinations will be performed and any clinically significant findings will be recorded.   
o Weight (kg) (in light clothing and with no shoes).  
o Using the observed variables weight and height, calculated body mass index (BMI) will be 
derived. 
• 
Ophthalmology slit lamp examination. To be done by an Ophthalmologist trained on AREDS2 
assessment. The ophthalmology slit lamp methodology and requirements will be described in 
a separate document, the Ophthalmology Guideline. The following analyses will be 
performed: AREDS2 opacity typing and grading. 
• 
Ophthalmic examination. The ophthalmic examinations can be performed by any trained study 
staff. The screening exams must be done by the trained site study staff AND an 
Ophthalmologist.  Methodology and requirements will be detailed in the Ophthalmology 
Guideline. 
• 
Ophthalmology History (Screening only); 
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• 
Visual Acuity Test – Corrected. Distance Vision; 
• 
Color Vision Assessment. 
• 
Adverse events. 
• 
Brief peripheral neuropathy screen (found in the Subject Questionnaires Guideline) will record 
ratings. 
• 
Investigator assessment:  
Principal Investigator to review participant status at specified visits in flow chart including any 
time Investigator determines that participant fulfills criteria for primary outcome of treatment 
failure. Investigator to assess whether TB treatment is considered a “success” or “failure”.  If 
considered a failure, should specify if based on bacteriology and/or clinical deterioration 
and/or radiological deterioration. 
7.4 PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Synopsis Flowchart 1.2) will be used to update 
population PK models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this trial population.  PK data from the 
current trial may be combined with prior data (e.g., from the NiX-TB trial) to enhance this 
population PK analysis. The models will be used to estimate individual exposure metrics (e.g., 
Ctrough, Cmax, AUCτ, Cmean, and T >MIC) for subsequent analyses exploring relationships between 
drug exposure and efficacy and safety endpoints.   
 
7.5 Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between Screening through Week 4; 
• 
If consent granted, and when applicable, Pre-screening culture/isolate to be sub cultured 
and shipped and/or tested: 
o At the study lab if/when samples could support inclusion in the trial 
o To the study/central lab for relevant participants/with no baseline (positive cultures 
from screening through Week 4)  
• 
When applicable, 1st positive for MTB at/after week 16 for participant not responding to 
therapy and/or 1st positive during follow-up for potential new infection. 
 
The MTB isolates will be processed at the central lab(s) for: 
• 
MIC against bedaquiline, pretomanid and linezolid;   
• 
Drug Susceptibility Testing in liquid culture for rifampicin, isoniazid, streptomycin, 
ethambutol, pyrazinamide and second line TB drugs including but not limited to 
fluoroquinolones, and injectables; 
• 
Genotyping. 
 
The MTB isolates will be processed at the central lab(s) for: Positive MTB at/after end of 
treatment: Hain MTBDRplus and HainMTBRsl 
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8 
Adverse Events 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; In general, 
hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event. 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalization, 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.   A “suspected 
transmission of infectious agent by a medicinal product” is also considered a serious adverse 
event under the SAE criterion “Other medically important condition”.   
8.1.3 Attribution/Causality 
• 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. 
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• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration will 
be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor/designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
Table 11: 
Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive.  The relationship in time is reasonable; 
therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event, which might be due to the use of the drug.  The 
relationship in time is suggestive, e.g., confirmed by dechallenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).   
 
8.1.4 Severity 
Table 12: 
Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible. 
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Grade 
Severity Rating 
Definition 
GRADE 4 
Potentially Life-
Threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected from the signing of the ICF until the 78-week post treatment follow-up 
visit at the time points specified in the Flowchart (Section 1.2) and recorded in the case report 
from (CRF). The exception is early withdrawal participants who will only have SAEs collected from 
the time of their early withdrawal through the 78-week post treatment visit. 
Medical occurrences that begin after obtaining informed consent will be recorded as adverse 
events. If an adverse event started before signing of the informed consent, but is ongoing at trial 
start, it should be recorded as medical history.  If the pre-existing medical occurrence worsens 
during the trial, and adverse event will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the investigator.  
The Sponsor/investigator/designee will inform Regulatory Authorities and/or IEC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the IEC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in participants who have 
completed the trial. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the trial, and he/she considers the event to be 
reasonably related to the trial treatment or trial participation, the investigator must promptly notify 
the Sponsor, IEC/IRB and regulatory authorities on an expedited basis in accordance with local 
requirements and ICH guidelines for GCP. 
8.2.1 Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
Until the end of the follow-up period; and  
• 
Until all queries on these AEs have been resolved.   
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Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the treating physician.  If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor Medical Monitor. 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  Investigator should contact Sponsor/designee to discuss 
appropriate medical follow-up if consultation required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide Sponsor/representative with a copy of any post-mortem findings including 
histopathology. 
New or updated information on an SAE will be recorded in the originally completed CRF and 
submitted to Sponsor within 24 hours of the information becoming known per SAE reporting 
guidelines. 
8.2.2 Clinical Laboratory Adverse Events 
Changes in the results of the Clinical Laboratory assessment results which the Investigator feels 
are clinically significant will be reported as adverse events.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an adverse event. 
8.2.3 Disease under Study 
Symptoms of the disease under trial (Pulmonary Tuberculosis) experienced by the participant 
while on the trial will be assessed by the Investigator.  If the symptom has: 
• 
worsened while the participant is in the trial; and 
• 
the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event.  
If there is: 
• 
no change; and  
 
• 
the Investigator assesses the symptom as due to the participant’s TB; and  
• 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation.  
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
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8.2.4 Overdose 
Overdose of IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an Adverse Event, including if the taking of 
the suspect medicine led to suicidal intention and subsequent overdose of the suspect medicine, 
or other medication. In this case it will be recorded as an adverse event. If it does not lead to an 
Adverse Event, it will not be recorded as an AE and this will be noted in the participant’s source 
documentation. 
8.2.5 Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
Investigator will report to the Sponsor follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed for 6 months.   
All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following time-
periods: 
• 
During the trial 
• 
Within 6 months after last dose of IMP 
If pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow up will be performed 
unless contraindicated by the pregnancy. 
Pregnancy reporting will follow the same time lines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in preclinical toxicity 
studies Investigator’s Brochures(5,6) and Package Inserts.(23,24,25,26) Please reference section 6.3 
Treatment Modifications, which notes that all treatment modifications should be discussed with 
Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required 
urgently for a safety concern.  The Medical Monitor should be informed within 24 hours of the 
change if not discussed prior to implementation.   
AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization or until the end of the follow-up period and until all queries on these AEs 
have been resolved.  Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization. 
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
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these cases follow-up will be the responsibility of the treating physician. If there is uncertainty, 
Investigator can discuss appropriate follow-up with the Sponsor Medical Monitor.  
 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours where possible. The recommendations for managing participants 
below assumes the laboratory abnormalities of concern have been confirmed. 
8.3.1 Neurological 
Participants with co-administration of a serotonergic agent, including anti-depressants, should be 
monitored closely for signs of serotonin syndrome.  The Investigator should determine whether 
the full regimen or the concomitant agent should be discontinued for those who experience signs 
or symptoms of serotonin syndrome such as cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
Linezolid and/or the full regimen should be paused for participants experiencing a seizure. The 
Sponsor Medical Monitor should be contacted to review details and discuss whether linezolid or 
full regimen should be resumed.  
8.3.2 ALT, AST and Alkaline Phosphatase elevations: 
The Investigator should refer to Appendix 5 – Liver Toxicity Management and to the ZeNix 
Hepatotoxicity Management Guideline to appropriately manage the participant for clinically 
significant elevations of AST, ALT or Alkaline Phosphatase. 
8.3.3 Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
Contact Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 4 elevations 
of lipase, Investigator should consider pausing the full regimen, pending further evaluation. 
8.3.4 Musculoskeletal System and Cardiac Muscle 
Myalgia 
Grade 2 (muscle tenderness at site other than sites of injection and/or venipuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
Participants with Grade 2 signs and symptoms should be followed closely. Participants with Grade 
3 or 4 signs and symptoms should be discussed with the Sponsor Medical Monitor to consider 
pausing trial medication, pending further evaluation. 
CPK 
For participants having elevations in CPK of potential clinical concern, the Investigator should 
check the CK-MB subunit, if high, consider pausing regimen and discuss with Sponsor Medical 
Monitor.  
8.3.5 Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
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Participants should be monitored closely.  The Investigator should discuss with the Sponsor 
Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artifacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen. 
8.3.6 Monitoring Linezolid Toxicities 
The following are guidelines for decisions to pause, reduce and to resume linezolid in response 
to the onset and resolution of known linezolid-specific toxicities.  These are guidelines, and 
decisions must be made in the context of the entire clinical status of the participant.  While the 
investigator may need to urgently interrupt dosing for potentially life threatening symptoms or 
laboratory findings, the Medical Monitor should be contacted and informed of any changes in 
dose within 24 hours.  Questions should be raised to the Sponsor’s Medical Monitor if the 
decision is not clear. 
8.3.6.1 Myelosuppression 
The hematologic parameters of hemoglobin and counts of Neutrophils and platelets are variable 
from measurement to measurement.  While decreases in any of these may be caused by linezolid 
toxicity, decreases of concern should be evaluated in the context of the participant’s full clinical 
status and alternate explanations.  Guidelines below are for situations of concern when it is 
considered likely that linezolid has caused the decrease. 
Anemia 
• 
Consider pausing linezolid if hemoglobin falls below 8 gm/dL or 80g/L (Grade 3) and 
significantly below baseline, or if hemoglobin falls > 25% of baseline. If it is clear that the 
anemia was caused by linezolid, consider resuming linezolid at half the dose when 
hemoglobin improves and linezolid is resumed.  
Leukopenia 
• 
Consider pausing linezolid if the Absolute Neutrophil Count (ANC) falls below 750/mm3  
or 0.75 x 10^9/L (Grade 3) and significantly below baseline.  Ideally confirm with a repeat 
test before making further decisions as ANCs can have diurnal and other variability. If it is 
clear that the leukopenia was caused by linezolid, consider resuming linezolid at half the 
dose when ANC improves and linezolid is resumed.  
Thrombocytopenia 
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• 
Consider pausing linezolid if platelets fall below 50,000/mm3 or 50 x 10^9/L (Grade 3) and 
significantly below baseline. Ideally confirm with a repeat test before making further 
decisions.  If it is clear that the thrombocytopenia was caused by linezolid, consider 
resuming linezolid at half the dose when platelets improves and linezolid is resumed. 
8.3.6.2 Peripheral Neuropathy 
The decision to reduce the dose, or to pause linezolid until symptoms improve is a judgment 
based on changes in signs and symptoms identified by the investigator and informed by 
discussion with the trial participant.  As general guidance, consider pausing and/or reducing 
linezolid when the grade of a neuropathy sign or symptom increases by a grade to grade two or 
greater.  If it is clear that linezolid caused the neuropathy, consider resuming linezolid at half the 
dose, when the neuropathy improves. 
8.3.6.3 Optic Neuropathy 
A participant with visual symptoms of concern or change in visual acuity of 2 lines or more or 
change in color vision of more than one plate should be referred to the site ophthalmologist for 
evaluation with a retinal examination.  Any changes as assessed by the ophthalmologist that raise 
concern that an optic neuropathy may be developing should be discussed with the medical 
monitor and linezolid should be paused.  If a likely or definite optic neuropathy is confirmed, 
linezolid should be permanently discontinued. 
8.3.6.4 Lactic Acidosis 
Lactic acidosis as a toxicity of linezolid should be considered if participants have gastrointestinal 
symptoms that are not explained by other more common causes of their symptoms.  Such 
participants should have lactate measured and, as indicated, a full evaluation of pH and 
bicarbonate. Note that lactate should not be measured in participants who have no symptoms of 
concern, as elevated asymptomatic lactate may be common and it is difficult to interpret the 
clinical relevance of this. Also evaluate whether any concomitant medications, such as anti-
retroviral therapies, may be associated with lactic acidosis and consider pausing them until the 
acidosis resolves. Consider pausing linezolid if a patient has GI symptoms and acidosis likely to 
be secondary to linezolid toxicity that is not otherwise explained. 
8.4 Safety Monitoring by Data Monitoring Committee 
A DSMC will be appointed for the trial. The primary responsibility of the DSMC will be to act in an 
advisory capacity to the Sponsor to safeguard the interests of trial participants by monitoring 
participant safety, assess participant risk versus benefit, and assess data quality and general 
evaluation of the trial progress. Its activities will be delineated in a DSMC charter that will define 
the membership, responsibilities and the scope and frequency of data reviews. The DSMC will 
operate on a conflict-free basis independently of the Sponsor and the trial team. It will comprise 
at least 3 voting members that include at least 2 clinicians and one statistician.  The DSMC may 
have an organizational meeting prior to commencement of the trial. The DSMC will have meetings 
where it will review unblinded data during a closed session. These meetings will be planned at 
regular intervals. The Sponsor or the DSMC may convene ad hoc meetings based on rates of 
SAEs and/or to review results of the futility analysis or if safety concerns arise during the trial.  
After its assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
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9 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 Analysis Population 
The primary analysis population will include both XDR and non-XDR (pre-XDR and MDR 
intolerant and non-responsive TB) participants (up to 45 per arm).  A secondary analysis will be 
restricted to the XDR participants only (30 per arm).    
A modified intent-to-treat (mITT) and a per-protocol (PP) analysis for each arm and analysis 
population will be conducted.    The mITT will be considered the primary analysis and will include 
all those in the ITT analysis with additional specific exclusions detailed in the statistical analysis 
plan (SAP). 
Other analyses will be performed (for sensitivity) including a full intent-to-treat (ITT) analysis with 
no exclusions, and an analysis excluding only those who were later found to be ineligible at 
baseline (based on data collected prior to randomization).    
The Safety analysis population will include data from all randomized participants who received at 
least one dose of IMP.  
Full details of all the analysis populations will be defined in the SAP. 
9.2 Sample Size 
The objective of this trial is to evaluate the efficacy, safety and tolerability of various doses and 
durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants 
with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB. 
In order to fulfil this objective, it is planned to randomize 30 XDR-TB participants per treatment 
group and up to 15 pre-XDR and/or MDR intolerant/non-responsive -TB participants per group. A 
sample size of 30-45 per arm will provide more than 90% power to demonstrate that the lower 
bound of the 95% confidence interval of this estimate is greater than 50%, using a 2-sided 5% 
significance level. This assumes that the true cure rate is 80 percent.   
There will not be a standard-of-care control group. A 50% treatment success rate was chosen as 
the target, because it is above the entire range of the historical control for cure of XDR-TB and 
because a cure rate of 50% in XDR, pre-XDR or MDR-TB treatment intolerant/failures with a 
shortened, simplified, all oral, inexpensive and safer regimen would clearly represent an important 
therapeutic advancement. A standard-of-care control group cannot reasonably be included in the 
trial for several reasons.  1) Given that the regimens being tested contain B and L, these drugs 
would need to be excluded from the control group.  However, they are beginning to be used 
increasingly in XDR-TB, despite lack of firm evidence, but with positive anecdotal reports.  Asking 
patients in the control group to avoid these medications could present an ethical issue.  2) The 
success rate of standard-of-care treatment for XDR-TB, particularly without B and L (see below), 
and the risk and difficulty of its administration contrast markedly with the early findings of B-L-Pa 
in the Nix-TB trial.  It is unlikely that patients would sign informed consent to receive standard-of-
care treatment if there is an alternative, but even if they do there remains an ethical issue of 
comparing such a disadvantaged treatment with such an advantaged treatment.  3) The scientific 
validity of comparing a 12-month endpoint (B-L-Pa) with a 30- or 36-month endpoint (standard of 
care) would represent a significant challenge.   
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9.3 Interim Analyses 
No formal interim analyses are planned.  However, there will be three planned unblinded 
analyses which will contain results by linezolid treatment group in aggregate as described 
below. The first analysis will be done after all participants have completed 26 weeks of 
treatment. The analysis will be on treatment safety events (mainly the specific toxicities 
described in section 8.3) and time to culture conversion (on treatment). The sites, participants, 
and Sponsor staff will not be unblinded to individual linezolid treatment information. A limited 
number of statisticians will have access to individual linezolid treatment assignments.  
The blind for all individual participants will be broken for the primary endpoint analysis (the 
second unblinded analysis) once all clinical data and outcome parameters for the primary 
endpoint have been captured, no more data queries are pending, and the statistical analysis 
plan has been updated accordingly.   
 
There will be three database locks, for the three planned unblinded data analyses for this trial:  
1. 
When all participants have completed 26 weeks of treatment   
2.  
When all participants have completed 26 weeks of follow-up after end of treatment.  
2. 
When all participants have completed 78 weeks of follow-up from after end of treatment.  
9.4 Primary and Secondary Endpoint Analysis 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT). 
A secondary analysis will be restricted to the XDR participants only (30 per arm). We will 
evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that 
the incidence of bacteriologic failure or relapse or clinical failure (including mortality) at 6 months 
(26 weeks) after the end of therapy is less than 50%.   
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and 
safety and to control the overall type I error rate the following analysis strategy will be adopted 
for both the primary and secondary analysis populations: 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 
weeks) with the L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a 
success.  Similarly, L600 9 weeks will only be tested if L600 26 weeks is a success.   A 
Bonferroni adjustment will be made for comparing the L1200 9 weeks and L600 26 weeks arms 
simultaneously, using p<0.025.  For these comparisons the lower bound of the 97.5% 
confidence interval will need to exceed 50% for success.   
No formal statistical pairwise comparisons between the arms will be performed. 
9.5 Safety and Tolerability Analysis 
• 
The incidence of all-cause mortality will be summarized. 
• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
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• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake.  Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
• 
Cardiovascular Safety:  QT intervals will be adjusted using Fridericia’s correction and Bazett’s 
correction. QT/QTc values and changes from pre-dose (average of Screening and Day 1 
values) at each time point will be summarized using descriptive statistics by group and time 
of collection.  These will be presented as descriptive analyses, and no inferential tests will be 
carried out. 
o Post-baseline QT/QTc intervals will be classified into the following categories:   
 
QT/QTc < 450 msec 
 
450 msec < QT/QTc < 480 msec 
 
480 msec < QT/QTc < 500 msec 
 
QT/QTc > 500 msec   
o QTc changes from baseline will be classified into the following categories: 
 
increase < 30 msec,  
 
30 msec and < 60 msec, and  
 
increase > 60 msec.  
o Frequency counts will be used to summarize the number of participants at each 
time point according to the above categories. 
o ECG results will be classified as normal or abnormal (investigator assessment) 
and summarized using frequency counts by dose group and time of collection. 
• 
Ophthalmology: Descriptive statistics, including changes from baseline, will be summarized 
and listed by participant for ophthalmology slit lamp examination (age related eye disease 
study 2 [AREDS2] lens opacity classification and grading). Categorical data for lens opacity 
will be summarized in a frequency table for the right and left eye, respectively.  
• 
Visual acuity and color vision:   Descriptive statistics, including changes from baseline, will be 
summarized and listed by participant for both Visual Acuity and Color Assessments. 
Categorical data for changes in visual acuity and color vision from baseline will be summarized 
in a frequency table for the right and left eye, respectively.  
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• 
Descriptive statistics of neuropathy data derived from Brief Peripheral Neuropathy Screen. 
Categorical data for observed signs and symptoms of neuropathy will be summarized in 
frequency tables, including changes in signs and symptoms from baseline.  
• 
Other safety variables: Laboratory Parameters, Physical Examination, Vital signs (see 
Appendix 3), Concomitant medication, ophthalmic examination and peripheral neuropathy.  
Descriptive summary statistics will be presented. The incidence of liver related laboratory 
abnormalities will be explored. 
9.6 Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update population pharmacokinetic 
(PopPK) models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further 
evaluate the effects of covariates on model parameters in this study trial population, and to derive 
individual exposure metrics for use in exposure-response analyses. PK data from the current trial 
may be combined with prior data (e.g., from the NiX-TB trial) to enhance this population PK 
analysis. Detailed plans for the PopPK analysis will be outlined in a separate modeling plan, and 
results will be reported in separate modeling report. 
9.7 Pharmacokinetics/Pharmacodynamics 
For each analyte, the PopPK model will be used to derive individual exposure metrics such as 
steady-state Ctrough, Cmax, AUCτ, and time-above-minimum-inhibitory-concentration (T>MIC), 
or alternative individual summaries of these metrics over the treatment period to account for dose 
adjustments and interruptions as appropriate. Relationships between such exposure metrics and 
efficacy and safety endpoints will be explored graphically and by model-based analyses as 
appropriate. Planning details and results will be included in the separate modeling plan and report. 
10 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants specific eCRF pages will be 
completed as described in the eCRF Completion Guidelines.  For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-Patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
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All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator has 
to 
permit 
trial 
related 
monitoring, audits, 
Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-Patient records while participants is on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial center files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection subsequent to trial completion.  The essential documents should be retained for 
not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify Sponsor/designees 
prior to destroying any records pertaining to the trial. 
11 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, ICH GCP, and the ethical principles that have their origin in the Declaration of 
Helsinki.  
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures, where available will be adhered to for all clinical and 
bioanalytical activities relevant to the quality of the trial.  Participant compliance will be monitored 
throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-investigators. Written 
IEC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
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with the protocol, ICH GCP, the ethical principles that have their origin in the Declaration of 
Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for the purpose of monitoring various aspects of the trial, and to assure appropriate conduct of 
the trial in accordance with ICH GCP.  Visits will take place usually within a predetermined interval, 
but this may vary during the course of the trial.  The Investigator and site staff will allow the trial 
monitor and authorized representatives of the Sponsor to (1) inspect all CRFs, written informed 
consent documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs (where applicable), training records, facilities and 
other trial related systems/processes, and (2) access clinical supplies, dispensing and storage 
areas.  The Investigator and site staff should also (1) agree to assist with monitoring activities if 
requested and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Monitoring 
Plan requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB and Health Authority, per their guidelines. The 
site PI/all study staff is responsible for knowing and adhering to their IRB and Health Authority (as 
required) requirements. 
11.4 Auditing 
For the purpose of compliance with ICH GCP and regulatory agency guidelines, it may be 
necessary for Sponsor-authorized Quality Assurance personnel and/or authorized personnel from 
an external regulatory agency to conduct an audit or inspection of the investigational site.  The 
purpose of an audit is to assess the quality of data with regard to accuracy, adequacy and 
consistency, and to assure that studies are in accordance with the guidelines.  Having the highest 
quality data from studies is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by ICH GCP to be 
maintained by each site; drug storage, dispensing and return; all trial-related supplies; and source 
documents against the CRFs to assure the adequacy and accuracy of the information which has 
been recorded, including the verification of any AEs which have occurred. The auditors or 
inspectors may also review site SOPs (where applicable), training records, site facilities and other 
trial related systems/processes. 
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In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
12 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with ICH GCP, the ethical principles that have 
their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
Review 
The protocol and required trial related documents will be reviewed by the sites respective 
IEC/IRB.  The trial will not start until the IEC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, plus 
any other trial related documents required for review.  The IEC/IRB shall be constituted and shall 
operate in accordance with International ICH GCP, the ethical principles that have their origin in 
the Declaration of Helsinki. The Investigator will maintain an accurate and complete record of all 
submissions made to, and responses from the IRB/IEC.  The records should be filed in the 
Investigator’s Trial File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for the purpose of determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
considered to be part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary. The investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same IEC/IRB responsible for approval of this protocol.  Each 
informed consent form shall include the elements required by the ICH GCP and must adhere to 
the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
ICF. 
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Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the IEC/IRB approved written informed consent form 
will be signed and dated by both the participant and the person obtaining consent (Investigators 
or designees), and by any other parties required by the IEC/IRB. Ongoing participants must be 
re-consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative.  Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s 
medical record. 
The monitor will inspect the original completed consent form(s) for all participants 
12.5 Confidentiality  
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with ICH GCP, applicable local 
legislation/regulations.  Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the Sponsor or designees. 
13 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible IEC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors. (30)  
Because the Study is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Study must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Study must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
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14 Protocol Amendment Policy 
Any change to the protocol will be effected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the IEC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, IEC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant Authorities 
and/or IEC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the IEC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
15 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the Global Alliance for TB Drug Development (TB Alliance).  The TB Alliance 
is a not for profit, product development partnership accelerating the discovery and development 
of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, 
be compatible with antiretroviral therapies for those HIV-TB participants currently on such 
therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The Sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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16 References  
1. “A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis”. ClinicalTrials.gov, 25 
January 2017. https://www.clinicaltrials.gov/ct2/show/NCT02333799 
2. Bonilla CA, Crossa A, Jave HO, Mitnick CD, Jamanca RB, Herrera C, Ascencios L, 
Mendoza A, Bayona J, Zignol M and Jaramillo E (2008).  “Management of Extensively 
Drug-Resistant Tuberculosis in Peru: Cure Is Possible”. PLoS One 3(8): e2957. 
3. Cox H, Ford, N. “Linezolid for the treatment of complicated drug-resistant tuberculosis: a 
systematic review and meta-analysis” INT J TUBERC LUNG DIS 16(4):447–454, 2012.  
4. Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, van Niekerk C, 
Erondu N, Ginsberg AM, Becker P and Spigelman MK (2012). “Phase II Dose-Ranging 
Trial of the Early Bactericidal Activity of PA-824”. Antimicrobial Agents and Chemotherapy; 
56(6): 3027-3031.  
5. Bedaquiline (TMC207) Investigator’s Brochure, Janssen Research and Development., 
Edition 9, 09 October 2015.  
6. Investigator’s Brochure Pretomanid (PA-824), Global Alliance for TB Drug Development., 
Version 17, 22 December 2016.  
7. Keshavjee S, Gelmanova IY, Shin SS, Mishushtin SP, Andreev YG, Atwood S, Furin JJ 
and Miller A (2012). “Hepatotoxicity during treatment for multidrug-resistant tuberculosis: 
occurrence, management and outcome”. Int J Tuberc Lung Dis 16(5):596-603.   
8. Leach KL, Brickner SJ, Noe MC, Miller PF. "Linezolid, the first oxazolidinone antibacterial 
agent" Ann NY Acad Sci. 2011 Mar; 1222:49-54. 2011.  
9. Lee, et al. "Linezolid for treatment of chronic extensively drug-resistant tuberculosis" N 
Engl J Med. 2012 Oct 18; 367(16):1508-18. 
10. Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, 
Reynolds RC, and Orme IM. “Preclinical Testing of the Nitroimidazopyran PA-824 for 
Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models” 
Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301. 
11. Lytvynenko N, Cherenko S, Feschenko Y, Pogrebna M, Senko Y, Barbova A, Manzi M, 
Denisiuk O, Ramsay A and Zachariah R (2014). “Management of multi and extensively 
drug resistant tuberculosis in Ukraine: how well are we doing?” IUALTD Public Health 
Action 4(3): S67-S72. 
12. Manjunatha U, Boshoff HI, Berry CE. The mechanism of action of PA-824: novel insights 
from transcriptional profiling. Commun Integr Biol. 2009; 2(3):215-218. 
13. Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton, JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci USA. 2006; 103(2):431-436. 
14. McLeay SC, Vis P, van Heeswijk RPG and Green B (2014). “Population Pharmacokinetics 
of Bedaquiline (TMC207), a Novel Antituberculosis Drug”. Antimicrobial Agents and 
Chemotherapy 58(9): 5315-5324. 
15. Mdluli K, Nuermberger, E. “Pre-Clinical Drug Combination Studies to Identify Novel 
Regimens for TB”. In: Recent Advances in TB Drug Development symposium, 40th Union 
World Conference, International Union Against TB and Lung Disease, Cancun, Mexico, 
2009. 
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16. Mdluli K, Nuermberger E, Taylor K, Williams N, Koen A, Khisimuzi E, Rokeya T, Si-Yang 
L, Peloquin C, Dinesh C. “Sterilizing activity of novel TMC207- and PA-824-containing 
regimens in a murine model of tuberculosis” Antimicrobial Agents and Chemotherapy 
2011; 55: 5485-5492. 
17. Migliori GB, Sotgiu G, Gandhi NR, Falzon D, DeRiemer K, Centis R, Hollm-Delgado MG, 
Palmero D, Perez-Guzman C, Vargas MH, D’Ambrosio L, Spanevello A, Bauer M, Chan 
ED, Schaaf HS, Keshavjee S, Holtz TH, Menzies D and “The Collaborative Group for 
Meta-Analysis of Individual Patient Data in MDR-TB” (2013). “Drug resistance beyond 
XDR-TB: results from a large individual patient data meta-analysis”. Eur Respir J. 42(1): 
169-179.  
18. Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006; 50(8):2621-2625. 
19. Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal, I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 2008; 
52(4):1522-1524. 
20. Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005; 172(11):1452-1456. 
21. O’Donnell MR, Padayatchi N, Master I, Osburn G and Horsbaugh CR. “Improved Early 
Results for Patients with Extensively Drug Resistant Tuberculosis and HIV in South 
Africa”. Int J Tuberc Lung Dis. 13(7): 855-861. 
22. Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
23. Package Insert for South Africa, ZYVOXID® (linezolid), Pfizer Pharmaceuticals, May 
2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=1045. Date last accessed: 15 April 
15 2016.  
24. Package Insert, Lizomac™ 600 (linezolid), MacLeods Pharmaceutical, 2014. 
25. Package 
Insert, 
SIRTURO®, 
Janssen 
Therapeutics, 
December 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204384s006lbl.pdf. Date last 
accessed: 15 April 2016. 
26. Package 
Insert, 
ZYVOX®, 
Pfizer 
Pharmaceuticals, 
June 
2015. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021130s030,021131s029,02
1132s034lbl.pdf. Date last accessed: 15 April 2016.  
27. Park IN, et al. “Efficacy and tolerability of daily-half dose linezolid in patients with 
intractable multidrug-resistant tuberculosis.” B Antimicrobial Chemotherapy 2006; 58:701-
704. 
28. Pietersen E, et al. "Long-term outcomes of patients with extensively drug-resistant 
tuberculosis in South Africa: a cohort study" Lancet, 2014 Jan 16. pii: S0140-
6736(13)62675-6.  
29. Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, Vasilyeca I, 
Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, Van 
Baelen B, van Heeswijk RPG and Dannemann B (2016). “Bedaquiline safety data in a 
broad patient population treated for drug-resistant TB including XDR-TB (C209 study)”. 
Tuberculosis 47: 394-402.  
30. “Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work in 
Medical Journals”, December 2016 update.  http://www.icmje.org/icmje-recommendations.pdf,  
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31. Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578.  
32. Schecter GF, et al.  “Linezolid Treatment for MDR-TB”. Clinical Infectious Diseases 2010; 
50:49-55. 
33. Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008; 
322(5906):1392-1395. 
34. Singla R. "Linezolid: an Effective, Safe and Cheap Drug for Patients Failing Multidrug-
resistant Tuberculosis Treatment in India" Eur Respir J. 2012 Apr; 39(4):956-62. doi: 
10.1183/09031936.00076811. Epub 2011 Sep 29. 
35. Stover, C. K., P. Warrener, D. R. VanDevanter, et al. 2000. “A small-molecule 
nitroimidazopyran drug candidate for the treatment of tuberculosis”. Nature 405:962–966. 
36. Tasneen R, Betoudji F, Tyagi S, et al.  Contributions of oxazolidinones to the efficacy of 
novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis.  
Antimicrob. Agents Chemother Posted Online 26 October 2015.  Dol:10.1128/AAC.01691-
15. 
37. Tasneen R, Tyagi S, Williams K, Grosset J, Nuermberger E. “Enhanced bactericidal 
activity of rifampin and/or pyrazinamide when combined with PA-824 in a murine model of 
tuberculosis”. Antimicrob Agents Chemother. 2008; 52(10):3664-3668. 
38. Tato M, et al. "In vitro activity of linezolid against Mycobacterium tuberculosis complex, 
including multidrug-resistant Mycobacterium bovis isolates". Int. J. Antimicrob Agents 
2006 Jul; 28(1)75-8.  
39. Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”.  
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
40. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. Bactericidal 
activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2005; 49(6): 2289-2293. 
41. WHO Treatment of Tuberculosis Guidelines, 4th Edition. 2010.  
42. World Health Organization. Global Tuberculosis Report 2014, 19th ed. 2014. 
43. World Health Organization. Global Tuberculosis Report 2015, 20th ed. 2015. 
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Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
exact figure/100/scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at 
least 20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life-
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization 
or hospice care probable. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common Toxicity 
Criteria (CTC), and World Health Organization (WHO)) have been adapted for use by the 
Division of Microbiology and Infectious Diseases (DMID) and modified to better meet the 
needs of Patients in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low : 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low : 
<100 mg/dL 
High: 
>600 mg/dL 
Low : 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated w ith 
gross bleeding or 
w ith disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life-
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
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Hypocalcemia 
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life-
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life-
threatening arrhythmia 
Hyperbilirubinemia 
(w hen accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(w hen other liver 
function are in the  
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase  
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
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Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, w ith or 
w ithout clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment required 
acute treatment 
required; 
outpatienttreatm
ent or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension w ith 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable w ith oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock;   
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled w ith 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV 1 of peak 
flow  
requires treatment; 
normalizes w ith 
bronchodilator; FEV 1 
50% - 70% (of peak 
flow ) 
no normalization w ith 
bronchodilator;FEV 1 
25% - 50% of peak 
flow ; or  retractions 
present 
cyanosis: FEV 1 < 
25% of peak flow  
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea w ith normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
 
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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3-
4 loose stools/day 
or mild diarrhea 
last < 1 w eek 
moderate or 
persistent; 5-7 loose 
stools/day or 
diarrhea lasting >1 
w eek 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization   
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
sw allow ing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
sw allow  solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
 
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NEUROLOGICAL 
 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
w eakness no 
objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function 
objective 
w eakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment  required 
moderate 
discomfort; non-
narcotic analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
w ith symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment (mod 
decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or w rists) or 
loss of sensation of 
at least mod 
degree in multiple 
different body 
areas (i.e., upper 
and low er 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis;  or 
seizures 
 
 
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MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering w ith 
function 
moderate pain, 
analgesics and/or 
pain interfering w ith 
function but not w ith 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering w ith 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain w ith 
inflammation, 
erythema or joint 
sw elling – but not 
interfering w ith 
function 
moderate pain w ith 
inflammation, 
erythema or joint 
sw elling – interfering 
w ith function, but 
not w ith activities of 
daily living 
severe pain w ith 
inflammation, 
erythema or joint 
sw elling –and 
interfering w ith 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia w ith no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or w ith 
moderate 
impairment of 
activity 
severe muscle 
tenderness w ith 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected Stevens-
Johnson or  
necrosis requiring 
surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection 
Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 
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Protocol Version V3.0 RUS / 18 MARCH 2020  
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CONFIDENTIAL 
Page 94 of 98 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus w ithout rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial narcotic 
therapy 
intractable; requires 
repeated narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 50% 
> 48 hours 
normal activity 
decreased > 50% 
can’t w ork 
unable to care for 
self 
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Protocol Version V3.0 RUS / 18 MARCH 2020  
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Page 95 of 98 
Appendix 3:  Cardiovascular Safety 
 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 90 mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or 
Grade 4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
 
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Page 96 of 98 
Appendix 4:  Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms of 
disease.  
80 
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of 
assistance needed. 
Cares for self; unable to carry on normal activity or to 
do active work. 
70 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
60 
Requires considerable assistance and frequent medical 
care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109(22). 
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Protocol Version V3.0 RUS / 18 MARCH 2020  
Protocol Name: ZeNix 
 
 
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Page 97 of 98 
 
Appendix 5: Liver Toxicity Management  
Standard anti-TB chemotherapy is known to cause derangement of liver function tests in a 
substantial number of patients. In many cases this will be asymptomatic and self-limiting. In some 
cases, severe hepatitis and even fulminant liver failure and death can occur.  
In pre-marketing clinical trials of new drugs and regimens it is especially important to identify and 
carefully manage any trial participants who are at risk of progression to serious liver injury.  The 
observation of altered liver function to a degree that has a high risk of progressing to liver failure 
has been referred to informally as Hy’s Law;(31,39); this reflects that pure hepatocellular injury 
sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, Hy’s Law cases have the following three components:  
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo.  
2. Among trial participants showing such aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show elevation of serum total bilirubin (TBL) 
to >2x ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase 
(ALP)).  
3. No other reason can be found to explain the combination of increased AT and total bilirubin 
level (TBL), such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury.  
During the trial, liver function will be monitored regularly with clinical assessment and blood tests 
in study participants and this will assist in follow up laboratory measurements that can document 
either resolution of abnormalities or signal the potential for drug-induced liver injury (DILI).  In a 
clinical trial of new drugs and combinations it is especially important for investigators to follow 
closely any participants who have evidence of hepatic inflammation or potential toxicity. The 
following procedure describes the management of deranged liver function tests in study 
participants. 
Procedure 
Blood tests for liver function will be taken routinely at screening (Day -14 to -1) and at the specific 
time points designated in the protocol, and at Early Withdrawal.  If at any other visit the clinician 
suspects derangement of liver function, e.g. the participant describes nausea and vomiting, right 
upper abdominal pain or is jaundiced, blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of hepatitis or hepatic impairment and any 
potentially contributing causes.  
Suspected liver toxicity (or elevated liver enzymes detected in the absence of symptoms) must 
be taken seriously and detailed guidance will be provided in a separate document “ZeNix 
Hepatotoxicity Management Guideline”. Investigators should refer to this document as a guide to 
management in cases of suspected or proven liver toxicity.  Importantly, the trial Medical Monitor 
is available to provide further assistance if there is any uncertainty or additional questions. 
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The laboratory source (print-out of any results) should be stored alongside or transcribed into the 
clinical source document. Each abnormal value should be marked as clinically significant (CS) or 
non-clinically significant (NCS); the assessment of significance is at the discretion of the 
investigator. All clinically significant abnormal results must be recorded as Adverse Events in the 
eCRF and graded clinically as per the DMID adult toxicity table grading, (Appendix 2).  
Assessments and decision making for elevations in aminotransferase values or bilirubin of various 
levels of concern are detailed below: 
Elevated liver enzymes considered of clinical significance, but not accompanied by other signs 
and symptoms, should be reported as an adverse event and should usually be recorded as 
elevated liver enzymes. If the term "hepatitis" is used, the Safety Data Manager will question the 
site for additional evidence to support the diagnosis, such as clinical signs and serological or 
biopsy data. While a liver biopsy is not required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for cases where there is supportive evidence 
beyond a liver enzyme abnormality. However, if the investigator will confirm the diagnosis of 
hepatitis just on the basis of clinical signs and laboratory values the diagnosis will be accepted. 
Should other symptoms or signs be present, these should also be recorded as adverse events. 
Restarting Medication 
Liver function tests that are improving should be repeated regularly, such as every 3 days for the 
first week then once a week until they return to near baseline values for the participant. Manage 
the participant symptomatically as required using medications that are not potentially hepatotoxic. 
Infection control issues must be carefully managed whilst TB medications are being withheld, 
especially if the participant is still culture positive for acid fast bacilli. 
If medication has been temporarily stopped, once the liver function values have decreased 
substantially a decision must be made about further TB management.  This will be dependent on 
the clinical context and a decision must be made in discussion with the Sponsor Medical Monitor. 
Treatment can only be restarted if the trial Medical Monitor is in agreement with the plan. In all 
cases treatment should be recommenced under close supervision for any evidence of recurrent 
liver function abnormalities.  
If there is a further significant elevation of hepatic enzymes or bilirubin or symptoms of clinical 
concern after resumption of study medication, the study medication should be withdrawn 
permanently. Participants who permanently discontinue study medication should be managed as 
clinically indicated according to local National TB Programme guidelines. The Sponsor Medical 
Monitor can be contacted for further advice when referring to the National Treatment Program. 
The trial Medical Monitor is available to assist the Investigators in both the management of liver 
toxicity and decisions regarding the holding or re-introduction of trial medication. Investigators 
must involve the Medical Monitor in any decisions regarding medication hold or re-start, and there 
should always be a low threshold for contacting the Medical Monitor in cases of elevated liver 
enzymes. 
Refer to ZeNix Hepatotoxicity Management Guideline for further details. 
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SAP_001.pdf: 
Global Alliance for TB Drug Development 
Clinical Trial Report 
NC-007-(B-Pa-L) 
ZeNix 
CONFIDENTIAL 
 
16.1.9 
Documentation of Statistical Methods 
ZeNix SAP Safety, Version 1.0, 27Oct2017 
ZeNix SAP Efficacy, Version 1.0, 15Sep2017 
ZeNix SAP, Version 2.0, 11Aug2020 
ZeNix SAP, Version 3.0, Jan2021 
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A Phase 3 partially-blinded, randomized trial assessing the safety and 
efficacy of various doses and treatment durations of linezolid plus bedaquiline 
and pretomanid in participants with pulmonary infection of either extensively 
drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or 
non-responsive multi-drug resistant tuberculosis (MDR-TB). 
27 October 2017 
Final Safety Statistical Analysis Plan 
Version 1.0 
Prepared by: 
PPD 
3900 N Paramount Parkway 
Morrisville, NC 27560 
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NC-007-(B-Pa-L) 
 
Date Issued: 27Oct2017 
 
  
 
 
 
II
DOCUMENT REVISION HISTORY 
 
Version 
Date 
Remarks 
0.1 
17AUG2017 
Initial version 
0.2 
08SEP2017 
Updates based on client review of initial 
version 
0.3 
26OCT2017 
Updates based on client comments on Version 
0.2 
1.0 
27OCT2017 
Final version 
 
 
 
 
 
 
 
 
 
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III
TABLE OF CONTENTS 
DOCUMENT REVISION HISTORY ....................................................................................... II 
TABLE OF CONTENTS ........................................................................................................... III 
LIST OF ABBREVIATIONS ...................................................................................................... V 
1.
INTRODUCTION ............................................................................................................ 7 
2.
OBJECTIVES ................................................................................................................... 8 
3.
INVESTIGATIONAL PLAN .......................................................................................... 8 
OVERALL STUDY DESIGN AND PLAN .................................................................................. 8 
STUDY ENDPOINTS ............................................................................................................. 8 
3.2.1. 
Primary Endpoint........................................................................................................ 8 
3.2.2 
Secondary Endpoints .................................................................................................. 8 
3.2.3 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) .......... 8 
3.2.4 
Safety and Tolerability ................................................................................................ 8 
3.3 
TREATMENTS ...................................................................................................................... 9 
4 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 9 
4.1 
DEFINITION OF STUDY DAYS AND BASELINE .................................................................... 10 
4.2 
SAMPLE SIZE .................................................................................................................... 10 
4.3 
RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................................ 11 
4.4 
ANALYSIS SET .................................................................................................................. 11 
4.4.1 
INTENT-TO-TREAT (ITT) ............................................................................................... 11 
4.4.2 
Safety ......................................................................................................................... 11 
4.4.3 
Modified Intent-to-Treat (mITT) and Per-Protocol (PP) ......................................... 11 
5 
PATIENT DISPOSITION ............................................................................................. 11 
5.1 
DISPOSITION ..................................................................................................................... 11 
5.2 
PROTOCOL DEVIATIONS ................................................................................................... 11 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 12 
6.1 
DEMOGRAPHICS ................................................................................................................ 12 
6.2 
BASELINE CHARACTERISTICS ........................................................................................... 12 
6.3 
MEDICAL HISTORY ........................................................................................................... 13 
6.4 
INCLUSION AND EXCLUSION CRITERIA ............................................................................. 13 
7 
TREATMENTS AND MEDICATIONS ....................................................................... 13 
7.1 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 13 
7.1.1 
Prior Medications ..................................................................................................... 13 
7.1.2 
Concomitant Medications ......................................................................................... 13 
7.1.3 
Concomitant Procedures .......................................................................................... 14 
7.2 
STUDY TREATMENTS ........................................................................................................ 14 
8 
EFFICACY ANALYSIS................................................................................................. 15 
9 
SAFETY ANALYSIS ..................................................................................................... 15 
9.1 
ADVERSE EVENTS ............................................................................................................. 15 
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9.1.1 
Incidence of TEAEs ................................................................................................... 15 
9.1.2 
Severity (DMID Toxicity Grade) of TEAEs .............................................................. 16 
9.1.3 
Drug-related TEAEs ................................................................................................. 16 
9.1.4 
Serious TEAEs .......................................................................................................... 16 
9.1.5 
TEAEs Leading to Treatment Discontinuation, Interruption, and Reduction .......... 16 
9.1.6 
TEAEs Leading to Study Discontinuation................................................................. 17 
9.1.7 
Death ......................................................................................................................... 17 
9.2 
CLINICAL LABORATORY EVALUATION ............................................................................. 17 
9.3 
VITAL SIGN MEASUREMENTS ........................................................................................... 19 
9.4 
PHYSICAL EXAMINATION ................................................................................................. 20 
9.5 
ELECTROCARDIOGRAM ..................................................................................................... 20 
9.6 
OPHTHALMOLOGIC ASSESSMENT ..................................................................................... 21 
9.7 
PERIPHERAL NEUROPATHY ASSESSMENT ......................................................................... 21 
10 
DATA SAFETY MONITORING COMMITTEE ....................................................... 21 
11 
PHARMACOKINETICS/PHARMACODYNAMICS ................................................ 22 
12 
INTERIM ANALYSIS ................................................................................................... 22 
13 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 22 
14 
REFERENCES ................................................................................................................ 22 
15 
APPENDICES ................................................................................................................. 23 
15.1 
LIST OF PLANNED SUMMARY TABLES ........................................................................... 23 
15.2 
LIST OF PLANNED DATA LISTINGS ................................................................................ 25 
15.3 
LISTING OF PLANNED FIGURES ...................................................................................... 26 
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List of Abbreviations 
AE  
Adverse Event  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AREDS2 
Age Related Eye Disease Scale 2 
AST 
Aspartate Aminotransferase 
AT 
Aminotransferase 
AUC
Area Under Curve Over a Dosing interval 
B 
Bedaquiline 
BMI 
Body Mass Index 
bpm 
Beats per Minute 
BPNS 
Brief Peripheral Neuropathy Scale 
CK(-MB) 
Creatine Kinase(-MB isoenzyme) 
C(max), (min) 
Plasma Concentration (maximum), (minimum) 
CO2 
Carbon Dioxide 
CPK 
Creatine Phosphokinase 
Ctrough 
Trough Plasma Concentration 
DMID 
Division of Microbiology and Infection Disease 
DSMC 
Data Safety Monitoring Committee 
DST 
Drug Sensitivity Testing 
ECG 
Electrocardiogram 
(e)CRF
(electronic) Case Report Form 
GGT
Gamma-glutamyl Test 
HIV
Human Immunodeficiency Virus 
HGB
Hemoglobin 
ITT
Intent to Treat 
IXRS
Interactive Voice and Web Response System 
kg
Kilogram 
L
Linezolid 
LDH
Lactate dehydrogenase 
MIC
Minimum Inhibitory Concentration 
MTB
Mycobacterium tuberculosis 
MDR-TB
Multi Drug Resistant Tuberculosis 
mg/dl
Milligrams per Deciliter 
MGIT™
Mycobacterial Growth Indicator Tube 
mITT
Modified Intent to Treat 
Pa
Pretomanid 
PD
Pharmacodynamic 
PP
Per Protocol 
PK
Pharmacokinetic 
PR
PR Interval 
RBC
Red Blood Cell 
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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TB 
Tuberculosis 
TEAE 
Treatment Emergent Adverse Events 
T>MIC
Time Above Minimum Inhibitory Concentration 
(BA) TTP
(Bacteriocidal Activity) Time to Positivity  
ULN
Upper Limit of Normal 
WHO
World Health Organization 
WBC
White Blood Cell 
XDR-TB
Extensively Drug Resistant Tuberculosis 
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1. 
Introduction
This study is being conducted under the sponsorship of TB Alliance. The clinical monitoring, 
data management, and statistical analysis are being performed under contract with PPD, in 
collaboration with TB Alliance. A separate analysis plan for evaluation of efficacy will be 
developed and will not be included in this statistical analysis plan (SAP). 
The Clinical, Data Management, and Biostatistics departments at PPD will work diligently and 
collaboratively, internally and with the Sponsor, to ensure that the data collected and analyzed 
for this study are of the highest quality possible.  This will be accomplished in part by having 
thorough edit checks written, programmed, and updated as needed to guarantee high quality data. 
Edit checks will be reviewed by the statistician on an ongoing basis to evaluate whether any need 
to be added. 
This SAP is based on the protocol versions 1.0 dated 23Feb2017 and 1.0 RUS/BEL dated 
28Feb2017. 
Tuberculosis (TB) is the world’s leading infectious disease killer and is responsible for more 
deaths than Human Immunodeficiency (HIV). It is the leading cause of death among HIV-
infected individuals, and there is more TB in the world today than at any other time in history. 
As a result of poor treatment adherence, in addition to primary transmission, drug resistance is 
becoming more common and fears of an epidemic with strains of extensively drug resistant TB 
(XDR-TB) that is very difficult to treat are growing. Novel drugs and regimens for TB are 
needed for the growing number of patients with XDR-TB. 
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with XDR-TB might be improved when added to background regimens. Linezolid was 
identified in a small study as a potentially efficacious drug in patients with XDR-TB when added 
to a failing regimen and this drug has increasingly been added to complex regimens to treat 
patients with multi-drug resistant tuberculosis (MDR-TB). With the current availability of three 
drugs for which there is little, if any, pre-existing resistance among strains of Mycobacterium 
tuberculosis (MTB) (pretomanid [Pa], bedaquiline [B], and linezolid [L]), there is the 
opportunity to evaluate a new regimen that may be administered orally once daily to treat 
patients with XDR-TB. A key advantage of this regimen over standard of care for MDR-TB, as 
well as XDR-TB, is that this is an all-oral daily regimen for 6 months of treatment, in 
comparison to standard regimens of 6-8 drugs over 9-30 months of treatment that include daily 
injections for a minimum of 6 months.  
This trial will provide a regimen containing 3 drugs against which there is no expected MTB 
resistance in the community for patients with limited treatment options, while simultaneously 
gathering important efficacy and safety data on a regimen that could potentially treat all strains 
of MTB. Data from previous trials shows that the combination of B-Pa is well tolerated and has 
the potential to shorten treatment in patients who are susceptible to the drugs. The ongoing Nix-
TB trial has shown that the B-Pa-L regimen has manageable toxicity and encouraging efficacy as 
an all oral 6 month regimen administered to patients with XDR-TB. This current trial will 
provide important information on the toxicity and efficacy of the regimen under alternate doses 
and durations of linezolid to optimize the dosing scheme for the best benefit to risk balance. 
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2. Objectives
The objective of this study is to evaluate the efficacy, safety and tolerability of various doses and 
durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in 
participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-
responsive MDR-TB. 
3.
Investigational Plan
Overall Study Design and Plan
This is a Phase 3, multi-center, partially-blinded, randomized clinical trial conducted in 4 
treatment groups (Section 3.3). Patients, trial investigators and staff, including laboratory staff, 
will be blinded to dose and scheduled duration of linezolid. Bedaquiline and pretomanid dosing 
will not be blinded. 
The trial will be performed at multiple centers located in South Africa, Eastern Europe and 
Russia. A total of 120 XDR-TB and up to 60 Pre-XDR/MDR treatment intolerant or non-
responsive patients who meet all of the inclusion criteria and none of the exclusion criteria, aged 
14 and over (aged 18 and over in Russia and Belarus), will be randomized to receive 1 of the 4 
active treatment arms. Enrolment will stop when 120 XDR-TB patients are randomized. Patients 
will be randomized after they have given written informed consent and met all eligibility criteria. 
Each patient will receive 26 weeks of treatment. If a patient’s week 16 sample remains culture 
positive, the Investigator may consider an option to extend current treatment to 39 weeks, in 
consultation with the Sponsor Medical Monitor. Patients will be followed for 78 weeks after end 
of treatment. The schedule of events at Section 1.2 of the protocol provides more details. 
Study Endpoints 
3.2.1. Primary Endpoint 
Details of the primary endpoint can be found in the Efficacy SAP. 
3.2.2 Secondary Endpoints 
Details of the secondary endpoints can be found in the Efficacy SAP. 
3.2.3 Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) 
This SAP will only handle descriptive summaries of plasma drug concentrations and PK 
parameters. Details on further analysis of PK and PK/PD endpoints can be found in the PK/PD 
modelling SAP. 
3.2.4 Safety and Tolerability 
•
All-cause mortality.
•
Incidence of treatment emergent adverse events (TEAEs) by drug relatedness and
seriousness, leading to early withdrawal from treatment, leading to pauses of linezolid,
leading to linezolid reductions and leading to death.
•
Quantitative and qualitative clinical laboratory result measurements, including observed
and change from baseline.
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• 
Quantitative and qualitative measurement of electrocardiogram (ECG) results read by a 
central cardiology service, including observed and change from baseline. 
• 
Ophthalmology slit lamp examination results (age related eye disease study 2 [AREDS2]) 
lens opacity classification and grading) for the right and left eye, including observed and 
change from baseline. 
• 
Changes in ophthalmic exam for visual acuity and color vision, including observed and 
change from baseline. 
• 
Changes noted in peripheral neuropathy signs and symptoms, including observed and 
change from baseline. 
3.3 
Treatments   
The test product will be supplied as: 
• 
bedaquiline 100 mg tablets 
• 
pretomanid 200 mg tablets 
• 
linezolid (scored) 600 mg tablets 
• 
placebo linezolid (scored) 600 mg tablets 
• 
linezolid half tablet (pre-cut) 300 mg (needed for blinded dose reductions) 
• 
placebo linezolid half tablet (pre-cut) 300 mg (needed for blinded dose reductions) 
 
Linezolid treatment will be supplied as 2 rows of full tablets and one row of half-tablets to allow 
for all possible dosing options while maintaining the blind. Treatment will be administered 
orally, once daily, with a full glass of water and a meal in the following dosing schemes 
(treatment groups): 
 
 
4 
General Statistical Considerations 
All summary tables will be presented by treatment group and total, unless otherwise specified. 
The treatment grouping will be: 
 
Linezolid 1200mg 
Linezolid 600mg 
Total 
26 weeks 
(N=XXX) 
9 weeks 
(N=XXX) 
26 week 
(N=XXX) 
9 weeks 
(N=XXX) 
 
(N=XXX) 
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The following conventions will be used for all data presentations and analyses unless otherwise 
specified.  
Variables will be summarized by scheduled study visit where appropriate. If there are multiple 
assessments in a visit, the latest non-missing value within a visit will be used in the summaries. 
For the categorical variables, the counts and percentages of each possible value will be tabulated 
by treatment group and total. For continuous variables, summaries will include the number of 
patients with non-missing values (n), mean, median, SD, minimum, and maximum values. 
Change from baseline values will be summarized where applicable. Means and medians will be 
presented to 1 more decimal place than the recorded data. Standard deviations (SDs) will be 
presented to 2 more decimal places than the recorded data. Minimum and maximum values will 
be reported with the same precision as the raw data.  
All data from all sites will be pooled. No inferential tests will be carried out. 
There will be no specific strategy to deal with missing data. In categorical summaries, a missing 
category will be included if and only if any data for the given endpoint are missing. 
Percentages will be computed based on the number of non-missing data points for patients in the 
applicable analysis set. Percentages will be reported to one decimal place, and 0% will not be 
presented.  
For the individual patient listings, all data will be listed by treatment group, center, patient 
identifier (ID), HIV status, and XDR status. Study day will be presented where appropriate. Any 
repeat assessments or additional assessments, along with any unscheduled visits, will be 
presented in the listings. Sort order of data listings will be treatment group, ID, and visit date. 
All statistical safety analyses tables, listings and figures will be produced using SAS® Version 
9.2, or higher. 
A separate document, as an appendix to this SAP, will contain the mockup tables, listings, and 
figures (TLF shells). 
4.1 
Definition of Study Days and Baseline 
Study Day 1 is defined as the date on which a patient is administered the first dose of the study 
medication. Other study days are defined relative to the Study Day 1 with Day 2 being the day 
after Study Day 1 and Day -1 being the day prior to Study Day 1. 
For all the endpoints, baseline is defined as the last non-missing measurement prior to first dose 
of study treatment unless otherwise stated. 
4.2 
Sample Size 
In order to fulfil the objective of the study, it is planned to randomize 30 XDR-TB patients per 
treatment group and up to 15 pre-XDR and/or MDR treatment intolerant/non-responsive -TB 
patients per group. A sample size of 30-45 per arm will provide more than 90% power to 
demonstrate that the lower bound of the 95% confidence interval of this estimate is greater than 
50%, using a 2-sided 5% significance level. This assumes that the true cure rate is 80 percent. 
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4.3 
Randomization, Stratification, and Blinding 
Patients will be randomized to 1 of the 4 regimens in a 1:1:1:1 ratio, using an interactive 
voice/web response system (IXRS), stratified by HIV status and type of TB. A total of up to 180 
patients will be enrolled: 120 (30 per treatment arm) XDR-TB patients, and up to 60 (15 per arm) 
pre-XDR or treatment intolerant/non-responsive MDR pulmonary tuberculosis patients, male and 
female, aged 14 and over. Replacement of late screen failure and un-assessable patients may be 
considered by the Sponsor. 
The blind must not be broken except in the case of a medical emergency, where treatment of the 
patient is influenced by the knowledge of what dose and duration of linezolid the patient is 
receiving. It is requested that the Investigator make every effort to contact the Sponsor Medical 
Monitor (or designee) prior to breaking the blind. IWRS will be programmed with blind-
breaking instructions, described in the user manual. The Sponsor reserves the right to break the 
blind in order to fulfil any regulatory requirements regarding reporting of serious adverse events 
(SAEs). 
In the absence of any medical emergencies requiring a blind break, the blind for all patients will 
be broken once all clinical data and outcome parameters have been captured, no more data 
queries are pending and the statistical analysis plan has been finalized. 
4.4 
Analysis Set 
4.4.1 Intent-to-Treat (ITT) 
The ITT analysis set is defined in the efficacy SAP. 
4.4.2 Safety 
The safety analysis set will include all randomized patients who received at least one dose of 
study treatment. Patients will be analyzed as to the treatment they actually received. 
4.4.3 Modified Intent-to-Treat (mITT) and Per-Protocol (PP) 
The mITT and PP analysis sets are defined in the efficacy SAP. 
5 
Patient Disposition 
5.1 
Disposition 
See the efficacy SAP for the details on how the patient disposition are to be presented. However, 
for this SAP, a listing containing all patient disposition data will be included. 
5.2 
Protocol Deviations 
All major and minor deviations will be summarized by deviation type for all ITT patients. A 
listing of all protocol deviations will be provided as well. A blinded review of the deviation log 
collected by the clinical group, as well as a programmatic listing of study deviations to determine 
major and minor protocol deviations, will be conducted between soft and hard database lock. The 
protocol deviations will be approved by TB Alliance, and the deviation log with the 
classification of deviation will be provided to PPD. For the details on how the major and minor 
deviations determine patient exclusion and inclusion into ITT, MITT and PP analysis sets, please 
refer to the efficacy SAP. 
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6 
Demographics and Baseline Characteristics 
6.1 
Demographics 
Age (years), height (cm), weight (kg), and body mass index (BMI) (kg/m2) will be summarized 
as continuous variables. BMI is defined as the patient’s weight (kg) divided by the square of 
their height (m). The number and percentage of patients will be presented for categorical 
variables including race (Asian, Black or African American, White, Mixed Race, Native 
Hawaiian or Other Pacific Islander, Other), and sex (male, female). 
Demographics will be summarized for the ITT and safety sets. A patient listing of demographics 
will also be provided. 
6.2 
Baseline Characteristics 
The following baseline characteristics will be summarized using the ITT set. Number and 
percentage will be reported, unless otherwise noted. 
• 
History of TB (type) (drug sensitive, MDR TB, XDR TB) 
• 
Current TB type (MDT-TB (NR), MDR-TB (TI), pre-XDR-TB, XDR-TB) 
• 
Smoking status (never, current, former)  
o 
Type (cigarettes, cigars, smokeless tobacco) 
o 
Amount consumed (per day, per week, per month, per year) 
o 
Duration of use (summary statistics) 
• 
Alcohol use (never, current, former)  
o 
Type (beer, wine, spirits) 
o 
Amount consumed (per day, per week, per month, per year) 
o 
Duration of use (summary statistics) 
• 
Screening Coached Spot Sputum result 
o 
Smear microscopy for acid-fast bacilli (no AFB seen, scanty positive, 1+, 2+, 3+) 
o 
Hain assay MTBDRplus or equivalent result (sensitive, resistant, indeterminate, 
not done) 
o 
Gene Xpert Rifampicin resistance result (sensitive, resistant, indeterminate) 
• 
HIV status (as collected in CRF) 
o 
Viral load (IU/mL) (summary statistics) 
o 
CD4 count (cells/µL) (summary statistics) 
• 
Karnofsky performance status 
• 
Chest x-ray (normal, abnormal) 
o 
Cavities (none, unilateral, bilateral) 
• 
Ophthalmologic history  
o 
History of vision and/or eye disorders (yes, no) 
o 
Immediate family history of cataracts (yes, no) 
o 
History of prior eye surgery (yes, no) 
o 
History of trauma to their right eye (yes, no) 
o 
History of trauma to their left eye (yes, no) 
All baseline characteristics will be presented in a listing. 
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6.3 
Medical History 
Medical history will be coded using the latest version of Medical Dictionary for Drug Regulatory 
Activities (MedDRA). The number and percentage of patients with clinically significant 
medical/treatment history will be summarized by system organ class (SOC) and preferred term 
(PT). Percentages will be calculated based on number of patients in the ITT set. 
A patient medical history data will be presented in a listing. 
6.4 
Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria can be referenced in the protocol, Sections 5.1 and 5.2, 
respectively. Any patient who violates the inclusion and/or exclusion criteria (screen failures as 
well as late screen failures) will be presented in a listing.  
7 
Treatments and Medications 
7.1 
Prior and Concomitant Medications 
For the purpose of inclusion in prior and/or concomitant medication summary tables, incomplete 
medication start and stop dates will be imputed as follows: 
Missing start dates will be handled as follows (where UK, UKN and UNKN indicate unknown or 
missing day, month and year respectively):  
•
UK-MMM-YYYY: impute to 01-MMM-YYYY;
•
UK-UKN-YYYY: impute to 01-JAN-YYYY;
•
UK-UKN-UNKN: impute to date of initial screening.
Missing stop dates will be handled as follows (where UK, UKN and UNKN indicate unknown or 
missing day, month and year respectively):  
•
UK-MMM-YYYY: Assume the last day of the month;
•
UK-UKN-YYYY: Assume 31-DEC-YYYY;
•
UK-UKN-UNKN: Assume last day of study visit.
All medications will be coded according to the latest version of World Health Organization drug 
dictionary. Summaries on prior and concomitant medication will be performed using the ITT set. 
Data on prior and concomitant medications will be presented in a listing. 
7.1.1 Prior Medications 
A prior medication is defined as any medication that has a stop date that was used before the start 
of the trial (prior to Day 1). Prior medications collected in the CRF will be classified as TB 
medications and non-TB medications. The number and percentages of patients with at least one 
prior medication will be summarized separately for TB medications and non-TB medications. 
Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) classification 
1 and 3 and preferred drug term. 
7.1.2 Concomitant Medications 
A concomitant medication is defined as any medication that has a stop date that is on or after the 
date of first dose of study treatment. The number and percentages of patients with at least one 
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concomitant medication will be summarized. Concomitant medication will be summarized by 
ATC 1 and 3 and preferred drug term.  
7.1.3 Concomitant Procedures 
The number and percentages of patients with at least one concomitant procedure will be 
summarized. In addition, concomitant procedures will be summarized by SOC and PT and raw 
data will be presented in a listing. 
 
7.2 
Study Treatments 
A patient’s drug exposure in days will be defined as (date of last dose - date of first dose+1). 
Drug exposure in weeks will be calculated by dividing the exposure in days by 7. The date of last 
dose is the last available date in the study medication page. 
The duration of exposure to study treatment by treatment will be summarized for all patients in 
the safety set and will be presented in a table by summary statistics. The duration of exposure 
will then be classified into categories “<26 weeks”, “26 to ≤39 weeks”, or “>39 weeks” and will 
be presented by number and percentage of patient in each duration category. Percentages will be 
computed from the number of patients in the safety set. 
Drug compliance (%) for bedaquiline and pretomanid will be collected from the eCRF and 
summarized using descriptive statistics. Number and percentage of patients in each compliance 
category (<80%, 80 to <90%, ≥90%) will be presented. Percentages will be calculated out of the 
number of patients who were dosed at that dosing period in the safety set. Linezolid exposure 
data will not be included in the compliance determination since patients are allowed to stop/re-
start administration.  
The following exposure parameters will be summarized according to the general methods: 
• Treatment extension (number of subjects with treatment extended to 39 weeks). The 
treatment extension information will be retrieved from the CRF Treatment Extension 
page. 
• Linezolid pause (number and percentage of patients with at least one dose pause, number 
of dose pauses, reason for dose pause). The Linezolid pause information will be retrieved 
from the CRF IMP Dosing pages indicated by a pause of Linezolid and scheduled 
dispense of Bedaquiline and Pretomanid. 
• Linezolid dose reduction (number of patients with at least one dose reduction, number of 
patients with at least one 1-step dose reduction, number of patients with at least one 2-
step dose reduction,  number of dose reductions including the number of 1-step decrease 
in dose and 2-step decrease in dose, reason for dose reduction).  
• Patients experiencing suspected drug related toxicities due to B-Pa treatments can have 
the full study medication paused for up to 35 consecutive days. Full regimen pauses will 
be summarized by number and percentage of patients with at least one full regimen 
pause, number of full regimen pauses and reason for regimen pause. Information related 
to these are found on the CRF IMP Dosing pages as pause selected on each dosing page, 
Linezolid, Bedaquiline and Pretomanid. 
A summary of each patient’s exposure will be presented in a listing. 
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8 
Efficacy Analysis 
The efficacy analysis is detailed in the efficacy SAP. 
9 
Safety Analysis 
All safety summaries will be presented for all patients in the safety analysis set, unless otherwise 
stated. 
9.1 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as adverse events (AEs) which started 
at or after the first administration of study treatment and includes those events started prior to the 
first administration of study treatment but which worsened after the first intake. Adverse events 
starting after the last administration of study treatment until the last scheduled 
visit/assessment/measurement will be regarded as treatment-emergent. 
Adverse event verbatim reported terms will be coded by SOC and PT using the latest version of 
MedDRA. 
AE duration will be calculated as (Stop Date – Start Date) + 1. Partial dates for AEs will not be 
imputed. In the case where it is not possible to define an AE as treatment-emergent or not, the 
AE will be classified as treatment-emergent. 
An overview summary of the number and percentage of patients with any TEAEs, severe 
TEAEs, drug-related TEAEs, TEAEs related to linezolid, TEAEs related to bedaquiline, TEAEs 
related to pretomanid, serious TEAEs, TEAEs leading to discontinuation of linezolid, TEAEs 
leading to discontinuation of full regimen, TEAEs leading to reduction of linezolid, TEAEs 
leading to interruption of linezolid, TEAEs leading to interruption of full regimen, TEAE leading 
to study discontinuation, and TEAE leading to death will be provided. In addition, the number 
and percentage of patients with the following specific TEAEs will be presented: serotonin 
syndrome, grade 2, 3, or 4 myalgia, grade 3 or 4 cardiac rhythm disturbances, peripheral 
neuropathy, optic neuropathy, myelosuppression and lactic acidosis.  
9.1.1 Incidence of TEAEs 
Summaries of the total number of TEAEs and the number and percentage of patients with at least 
one TEAE will be provided. The number and percentage of patients and the number of events 
will also be presented by SOC and PT. At each level of patient summarization, a patient is 
counted once within each PT and then each SOC if the patient reports one or more events. 
Percentages will be based on the number of patients in the safety set. The number of events will 
also be summarized.  
A summary of TEAEs will also be presented in descending order based on the total for SOCs. If 
the total incidence for any 2 or more SOCs is equal, the SOCs will be presented in alphabetical 
order. Within each SOC, the PTs will be presented in alphabetical order. 
All AEs will be presented in a listing. 
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9.1.2 Severity (DMID Toxicity Grade) of TEAEs 
A summary of TEAEs by severity will be presented in a table. The severity that will be presented 
represents the most extreme severity captured on the Adverse Event CRF page. The possible 
severities are ‘Grade 1: Mild,’ ‘Grade 2: Moderate,’ ‘Grade 3: Severe’, and ‘Grade 4: Potentially 
life-threatening.’ In the TEAE severity table, if a patient reported multiple occurrences of the 
same TEAE, only the most severe TEAE is presented. TEAEs that are missing severity will be 
presented in tables as ‘Severe’ but will be presented in the data listing with a missing severity.  
A separate table will be presented for ‘Grade 3: Severe’ or ‘Grade 4: Potentially life-threatening’ 
TEAEs. 
9.1.3 Drug-related TEAEs 
A summary of TEAEs by relationship to study treatment will be presented in a table by incidence 
of occurrence. The investigator will provide an assessment of the relationship of the event to the 
study treatment and specifically for linezolid, bedaquiline, and pretomanid. The possible 
relationships are ‘Not related’, ‘Unlikely’, ‘Possibly’, ‘Probably’, and ‘Certainly’. In the TEAE 
relationship table, if a patient reports multiple occurrences of the same TEAE, only the most 
closely related occurrence will be presented. All TEAEs that have a missing relationship will be 
presented in the summary table as “Certainly” but will be presented in the data listing with a 
missing relationship. 
9.1.4 Serious TEAEs 
An SAE is defined as any untoward medical occurrence that at any dose results in death, is life-
threatening, is a congenital anomaly/birth defect, requires in-patient hospitalization or 
prolongation, results in significant disability/incapacity, or a medically important event. 
Treatment-emergent SAEs will be categorized and presented by SOC and PT in the same manner 
to that described in Section 9.1.1. 
9.1.5 TEAEs Leading to Treatment Discontinuation, Interruption, and Reduction 
A summary of TEAEs with ‘Action Taken with study treatment’ as ‘Permanently Discontinued’ 
for overall, linezolid only  and full regimen will be presented in a table. At each level of patient 
summarization, a patient is counted once if the patient reported one or more events.   
The same presentation will be provided for interruption of linezolid (‘Action Taken with Study 
Treatment Linezolid’ is ‘Interrupted’ and action taken for Bedaquiline/Pretomanid is 
‘Unchanged’) and Full Regimen (‘Action Taken with study treatment Linezolid and  
Bedaquiline/Pretomanid’ is ‘Interrupted’) and reduction of linezolid (‘Action Taken with study 
treatment Linezolid’ is ‘Reduced’). 
Data will be categorized and presented by SOC and PT in the same manner to that described in 
Section 9.1.1. 
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9.1.6 TEAEs Leading to Study Discontinuation 
A summary of TEAEs where the answer to ‘Action Taken’ is ‘Withdrawn from Study’ will be 
presented in a table. At each level of patient summarization, a patient is counted once if the 
patient reported one or more events. 
Data will be categorized and presented by SOC and PT in the same manner to that described in 
Section 9.1.1. 
9.1.7 Death 
A summary of TEAEs where the answer to ‘Outcome’ in the AE form is ‘Fatal’ will be 
presented in a table. Data will be categorized and presented by SOC and PT in the same manner 
to that described in Section 9.1.1. 
A separate table will be presented that contains the cause of death as well as the following details 
about death (Yes/No): 
•
Death was related to TB
o
Death due to treatment failure
•
Death was violent or accidental (excluding suicide)
•
Death was due to suicide
A detailed data listing with relevant information will be provided. 
9.2 
Clinical Laboratory Evaluation 
A list of laboratory tests (hematology, clinical chemistry, and urinalysis) to be included in the 
analysis is presented in Section 7.3 of the protocol. Laboratory assessments will be done by a 
central laboratory. All summaries will be based on the units provided by the central laboratory, 
no conversion will be done.  The laboratory evaluations will be summarized for baseline, post-
baseline, and change from baseline at each visit. Only the scheduled measurements from central 
laboratory will be included in the summaries. In any case where a local laboratory needs to 
perform the assessment, results from this will only be presented in a listing. 
Severity for laboratory parameters described in the DMID toxicity grades will be performed. 
Laboratory values outside normal ranges will be identified, and the number and percentage of 
patients with at least one post-baseline abnormality will be summarized in shift tables comparing 
the baseline results to each post-baseline timepoint for those patients with results at both 
timepoints. All post-baseline clinical laboratory results, including scheduled and unscheduled 
measurements, will be included in the abnormality summaries. 
Incidence of grade 3 or 4 severity for laboratory parameters according to DMID grading will be 
summarized by visit. 
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Results indicating liver-related abnormalities (i.e., ALT, AST and/or Alkaline Phosphatase) will 
also be summarized separately. A newly notable laboratory abnormality is defined as an 
abnormality observed post baseline that meets the notable criteria in Table 1 and that did not 
exist at baseline. Patients can still meet the criteria for a newly notable laboratory abnormality if 
the baseline value is missing. The table below displays the general variables and thresholds of 
interest. Patients are considered to have notable laboratory abnormalities if his/her response falls 
within the specified definitions at least once during the treatment period. In addition, total 
bilirubin versus ALT on the logarithmic scale will be presented in an eDISH plot. Here, 2 x ULN 
for total bilirubin, and 3 x ULN for ALT will be provided accordingly (using horizontal and 
vertical lines). The most extreme measurement up to last study drug administration for the 
aforementioned laboratory tests will be presented. 
 
Table 1: 
Notable Criteria for Laboratory Data –Liver Function Tests 
Laboratory 
Variable 
SI 
Units 
AST 
>3 x ULN 
>5 x ULN 
>8 x ULN 
>10 x ULN 
ALT 
>3 x ULN 
>5 x ULN 
>8 x ULN 
>10 x ULN 
Total Bilirubin  
>1.5 x ULN 
>2 x ULN 
Alkaline 
Phosphatase (ALP) 
>2 x ULN 
>3 x ULN 
Lipase 
>2 x ULN 
>5 x ULN 
Other: 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN  
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN 
ALP > 3 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN and ALP < 2 x ULN 
(potential Hy’s law case) 
 
Number and percentage of patients with myelosuppression as well as the number of occurrences 
of myelosuppression will be summarized. Patients are considered to have myelosuppression if 
his/her response falls within the specified criteria in Table 2 at least once during the treatment 
period. 
 
 
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Table 2: 
  Notable Criteria for Laboratory Data –Myelosuppression 
Laboratory 
Variable 
Criteria 
HGB 
< 8gm/dL (Grade 3) and 
significantly below 
baseline or 
Hgb falls> 25% beneath 
baseline 
ANC 
< 750/mm3 (Grade 3) and 
significantly below 
baseline 
 
Platelets 
< 50,000/mm3 (Grade 3) 
and significantly below 
baseline 
For each laboratory test, abnormal values will be identified as those (above/high or below/low) 
the reference range, and will be flagged in the data listing. 
All clinical laboratory data including those assessments done by a local laboratory will be 
presented in data listings. Separate listings for patients with toxicity grade 3 or higher will be 
provided for hematology (WBC, HGB, RBC, platelets, absolute neutrophils, absolute 
lymphocytes, absolute monocytes, absolute eosinophils, absolute basophils, and absolute bands), 
chemistry (a listing displaying liver function parameters total bilirubin, direct bilirubin, indirect 
bilirubin, ALT, AST, GGT and ALP; and another listing for sodium, potassium, bicarbonate, 
urea, creatinine, glucose, calcium, total protein, albumin, LDH, CPK, uric acid, lipase, and CK-
MB (if applicable)) and urinalysis (lipase, bilirubin, blood, protein, and microalbumin/creatinine 
ratio). A separate listing will also be provided for Hy’s Law cases. 
9.3 
Vital Sign Measurements 
Vital sign measurements include height (cm), weight (kg), body temperature (◦C), respiratory 
rate (breaths/min), blood pressures (mmHg) (resting more than 5 minutes), and heart rate (bpm).  
These measurements will be summarized for baseline, post-baseline, and change from baseline at 
each visit. Only the vital signs collected at the scheduled visits or time points will be included in 
the summary.  
Abnormal vital sign assessment results will be identified, and the number and percentage of 
patients with at least one post-baseline abnormality will be summarized. All post-baseline vital 
sign assessment results, including scheduled and unscheduled measurements, will be included in 
the abnormality summaries. A newly notable vital sign abnormality is defined as an abnormality 
observed post baseline that meets the notable criteria in Table 3 and that did not exist at baseline. 
Patients can still meet the criteria for a newly notable vital sign abnormality if the baseline value 
is missing. Table 3 displays the general variables and thresholds of interest.  
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Patients are considered to have notable vital sign abnormalities if his/her response falls within 
the specified definitions at least once during the treatment period.  
 
Table 3. Clinically notable criteria for vital sign data 
Abnormality 
Code 
Vital Sign 
Heart Rate 
(bpm) 
DBP (mmHg) 
SBP (mmHg) 
RR 
(breaths/min) 
Abnormally low 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mmHg 
< 12 breaths/min 
Grade 1 or mild 
 
> 90 mmHg to  
< 100 mmHg 
> 140 mmHg to 
< 160 mmHg 
17 – 20 
breaths/min 
Grade 2 or 
moderate 
 
≥ 100 mmHg to 
< 110 mmHg 
≥ 160 mmHg to 
< 180 mmHg 
21 – 25 
breaths/min 
Grade 3 or severe 
 
≥ 110 mmHg 
≥ 180 mmHg 
> 25 breaths/min 
Abnormally high 
≥ 120 bpm 
 
 
Intubation 
bpm: beats per minute, DBP: diastolic blood pressure, SBP: systolic blood pressure. 
Patients with abnormal vital signs will be presented in a listing. 
9.4 
Physical Examination 
Only physical examination date/time and a question of ‘Were there any significant findings?’ 
were collected on the CRF. Any abnormal findings should be captured directly on the medical 
history or AE pages directly as appropriate. Physical examination date/time and observed 
significant findings (yes/no) for all patients will be presented in a listing. 
9.5 
Electrocardiogram 
All patients will have a standard 12-lead (ECG) assessment (heart rate, PR interval, RR interval, 
QT, corrected QT Interval (QTc) (QTcB and QTcF), QRS) performed by a central cardiologist. 
All summaries will be based on a central cardiologist assessment. Any assessment done by a 
local laboratory will only be presented in a listing. 
 
QT intervals will be adjusted using Fridericia’s correction and Bazett’s correction. QT/QTc 
values and changes from pre-dose (average of Screening and Day 1) values at each time point 
will be summarized using descriptive statistics by group and time of collection. 
Post-baseline QT/QTc intervals will be classified into the following categories: 
• 
QT/QTc < 450 msec 
• 
450 msec ≤ QT/QTc < 480 msec 
• 
480 msec ≤ QT/QTc < 500 msec 
• 
QT/QTc ≥ 500 msec 
QTc changes from baseline will be classified into the following categories: 
• 
increase < 30 msec, 
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• 
increase ≥ 30 msec and < 60 msec, and 
• 
increase ≥ 60 msec. 
Frequency counts will be used to summarize the number of patients at each time point according 
to the above categories. 
Interpreted ECG results based on investigator assessment will be classified as “normal”, 
“abnormal, not clinically significant”, or “abnormal, clinically significant”. The number and 
percentages of patients with normal, abnormal not clinically significant, and abnormal clinically 
significant will be presented. In addition, shift tables will be provided to summarize the status 
changes from baseline to each scheduled post-baseline assessment.  
ECG data for all patients including those assessments done by a local laboratory will be 
presented in a listing. A separate listing for patients with abnormal results will be provided. 
9.6 
Ophthalmologic Assessment 
Results from the assessments of Ophthalmology slit lamp examinations (AREDS2 lens opacity 
classification and grading), along with visual acuity and color vision will be summarized using 
descriptive statistics for baseline, post-baseline, and change from baseline at each visit. Only the 
assessments collected at the scheduled visits or time points will be included in the summary. All 
ophthalmology-related results will be presented in a listing. 
9.7 
Peripheral Neuropathy Assessment 
Descriptive summary statistics will be presented for the results of Peripheral Neuropathy 
Assessment for baseline, post-baseline, and change from baseline at each visit. Shift tables will 
be provided to summarize the status changes from baseline in signs and symptoms to each 
scheduled post-baseline assessment. All neuropathy-related results will be presented in a listing. 
10 
Data Safety Monitoring Committee 
A DSMC will be appointed for the study. The primary responsibility of the DSMC will be to act 
in an advisory capacity to the Sponsor to safeguard the interests of trial patients by monitoring 
patient safety, assess patient risk versus benefit, and assess data quality and general evaluation of 
the trial progress. Its activities will be delineated in a DSMC charter that will define the 
membership, responsibilities and the scope and frequency of data reviews. The DSMC will 
operate on a conflict-free basis independently of the Sponsor and the study team. It will comprise 
at least 3 voting members that include at least 2 clinicians and one statistician. The DSMC may 
have an organizational meeting prior to commencement of the trial. The DSMC will have 
meetings where it will review unblinded data during a closed session. These meetings will be 
planned at regular intervals. The Sponsor or the DSMC may convene ad hoc meetings based on 
rates of SAEs and/or to review results of the futility analysis or if safety concerns arise during 
the trial. After its assessment, the DSMC will recommend to the Sponsor continuation, 
modification or termination of the clinical trial. 
The blinded team will prepare the safety tables, listings and/or figures using the surrogate 
randomization and materials/kits schedule, and the unblinded team will prepare the unblinded 
analysis for the DSMC using the actual randomization schedule which will be provided to PPD. 
Only the unblinded team at PPD will receive the actual randomization schedule. 
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11 
Pharmacokinetics/Pharmacodynamics 
Derivation of PK/PD parameters described in the protocol Section 9.6 and 9.7 will be covered in 
a separate modeling plan, to be completed post trial start. Results will be reported in separate 
modeling report and provided to PPD. 
Descriptive statistics (n, arithmetic mean, SD, coefficient of variation (CV%), median, minimum 
and maximum, geometric mean and geometric CV (%)) will be used to summarize the plasma 
concentration at each scheduled sampling time/window per analyte. In addition, the derived PK 
parameters will be summarized descriptively and reported in a listing. 
12 
Interim Analysis 
No formal interim analyses are planned. Primary analysis will be performed on the 26 week 
follow-up data (after end of treatment when the last randomized patient has completed the 26 
week follow-up period after end of treatment). See the efficacy SAP for details on the follow-up 
timing for the primary analysis. There will be 2 database locks, data analyses and trial reports 
generated for this trial: 
1. When all patients have completed 26 weeks of follow-up after end of treatment. This will
contain all data from randomization up to 26 weeks of follow-up after end of treatment.
2. When all patients have completed 78 weeks of follow-up from after 26 weeks of follow-up.
This will contain all data after 26 weeks of follow-up to 78 weeks of follow-up after end of
treatment.
13 
Changes in the Planned Analysis 
The analyses described in the statistical analysis plan do not differ from those specified in the 
protocol. 
14 
References 
Lee, et al. "Linezolid for treatment of chronic extensively drug-resistant tuberculosis" N 
Engl J Med. 2012 Oct 18; 367(16):1508-18. 
Lytvynenko N, Cherenko S, Feschenko Y, Pogrebna M, Senko Y, Barbova A, Manzi M, 
Denisiuk O, Ramsay A and Zachariah R (2014). “Management of multi and extensively 
drug resistant tuberculosis in Ukraine: how well are we doing?” IUALTD Public Health 
Action 4(3): S67-S72. 
World Health Organization. Global Tuberculosis Report 2015, 20th ed. 2015. 
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15 
Appendices 
15.1 
List of Planned Summary Tables 
Table 
Number 
Title 
Analysis Set 
14.1.1 
Protocol Deviations 
ITT Analysis Set 
14.1.2.1 
Demographics and Baseline Characteristics 
ITT Analysis Set 
14.1.2.2 
Demographics and Baseline Characteristics 
Safety Analysis Set 
14.1.3.1 
Medical History 
ITT Analysis Set 
14.1.3.2 
Prior TB Medications 
ITT Analysis Set 
14.1.3.3 
Prior Medications (Non-TB) 
ITT Analysis Set 
14.1.3.4 
Concomitant Medications 
ITT Analysis Set 
14.1.3.5 
Concomitant Procedures 
ITT Analysis Set 
14.1.4.1 
Drug Compliance 
Safety Analysis Set 
14.1.4.2 
Study Drug Exposure to Linezolid, Bedaquiline, and 
Pretomanid 
Safety Analysis Set 
14.1.4.3 
Study Drug Modifications 
Safety Analysis Set 
14.2.1 
Summary of Plasma Concentrations by Scheduled 
Time and Analyte 
PK Analysis Set 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse 
Events 
Safety Analysis Set 
14.3.1.2 
Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term  
Safety Analysis Set 
14.3.1.2.1 
Treatment-Emergent Adverse Events Related to 
Linezolid by System Organ Class and Preferred 
Term 
Safety Analysis Set 
14.3.1.2.2 
Treatment-Emergent Adverse Events Related to 
Bedaquiline by System Organ Class and Preferred 
Term 
Safety Analysis Set 
14.3.1.2.3 
Treatment-Emergent Adverse Events Related to 
Pretomanid by System Organ Class and Preferred 
Term 
Safety Analysis Set 
14.3.1.3 
Treatment-Emergent Adverse Events by Severity 
Safety Analysis Set 
14.3.1.4 
Grade 3 or 4 Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term 
Safety Analysis Set 
14.3.1.5 
Treatment-Emergent Adverse Events Leading to 
Linezolid Reduction by System Organ Class and 
Preferred Term 
Safety Analysis Set 
14.3.1.6.1 
Treatment-Emergent Adverse Events Leading to 
Safety Analysis Set 
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Linezolid Interruption by System Organ Class and 
Preferred Term 
14.3.1.6.2 
Treatment-Emergent Adverse Events Leading to 
Full Regimen Interruption by System Organ Class 
and Preferred Term 
Safety Analysis Set 
14.3.1.7.1 
Treatment-Emergent Adverse Events Leading to 
Linezolid Discontinuation by System Organ Class 
and Preferred Term 
Safety Analysis Set 
14.3.1.7.2 
Treatment-Emergent Adverse Events Leading to 
Full Regimen Discontinuation by System Organ 
Class and Preferred Term 
Safety Analysis Set 
14.3.1.8 
Treatment-Emergent Adverse Events Leading to 
Study Discontinuation by System Organ Class and 
Preferred Term 
Safety Analysis Set 
14.3.2.1 
Treatment-Emergent Serious Adverse Events by 
System Organ Class and Preferred Term  
Safety Analysis Set 
14.3.2.2.1 
Treatment-Emergent Serious Adverse Events 
Related to Linezolid by System Organ Class and 
Preferred Term 
Safety Analysis Set 
14.3.2.2.2 
Treatment-Emergent Serious Adverse Events 
Related to Bedaquiline by System Organ Class and 
Preferred Term 
Safety Analysis Set 
14.3.2.2.3 
Treatment-Emergent Serious Adverse Events 
Related to Pretomanid by System Organ Class and 
Preferred Term 
Safety Analysis Set 
14.3.2.3.1 
Treatment-Emergent Adverse Events Leading to 
Death by System Organ Class and Preferred Term 
Safety Analysis Set 
14.3.2.3.2 
Death Summary  
Safety Analysis Set 
14.3.4.1.1 
Hematology by Visit 
Safety Analysis Set 
14.3.4.1.2 
Change from Baseline by Laboratory Test and Visit 
- Hematology
Safety Analysis Set 
14.3.4.1.3 
Shift from Baseline by Laboratory Test and Visit - 
Hematology 
Safety Analysis Set 
14.2.4.1.4 
Incidence of Myelosuppression 
Safety Analysis Set 
14.3.4.2.1 
Chemistry by Visit 
Safety Analysis Set 
14.3.4.2.2 
Change from Baseline by Laboratory Test and Visit 
- Chemistry
Safety Analysis Set 
14.3.4.2.3 
Shift from Baseline by Laboratory Test and Visit – 
Chemistry 
Safety Analysis Set 
14.3.4.2.4 
Summary of Clinically Notable Laboratory Results 
Safety Analysis Set 
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15.2 
List of Planned Data Listings 
Listing 
Number 
Title 
Analysis Set 
16.2.1 
Disposition 
ITT Analysis Set 
16.2.2 
Major Protocol Deviations 
ITT Analysis Set 
16.2.3 
Analysis Set 
16.2.4.1 
Demographics 
ITT Analysis Set 
16.2.4.2 
Baseline Characteristics 
ITT Analysis Set 
16.2.4.3 
Medical History 
ITT Analysis Set 
16.2.4.4 
Prior and Concomitant Medications 
ITT Analysis Set 
16.2.4.5 
Concomitant Procedures 
ITT Analysis Set 
16.2.5.1 
Study Drug Administration 
Safety Analysis Set 
16.2.5.2 
Study Drug Compliance 
Safety Analysis Set 
by Visit - Chemistry (Liver) 
14.2.4.3 
Incidence of DMID Severity Grades 3 or 4 
Hematology and Chemistry Parameters 
Safety Analysis Set 
14.3.4.4.1 
Urinalysis by Visit 
Safety Analysis Set 
14.3.4.4.2 
Change from Baseline by Laboratory Test and Visit 
- Urinalysis
Safety Analysis Set 
14.3.5.1.1 
Vital Signs by Visit 
Safety Analysis Set 
14.3.5.1.2 
Change from Baseline in Vital Signs by Visit 
Safety Analysis Set 
14.3.5.1.3 
Abnormal Vital Signs 
Safety Analysis Set 
14.3.5.2.1 
ECG Results by Visit 
Safety Analysis Set 
14.3.5.2.2 
Change from Baseline in Electrocardiogram Result 
Safety Analysis Set 
14.3.5.2.3 
Shift from Baseline in Electrocardiogram 
Interpretation 
Safety Analysis Set 
14.3.5.3.1 
AREDS Lens Opacity and Grading by Visit 
Safety Analysis Set 
14.3.5.3.2 
Change from Baseline in AREDS2 Opacity Grade 
by Opacity Type, Eye, and Visit 
Safety Analysis Set 
14.3.5.4.1 
Visual Acuity by Visit 
Safety Analysis Set 
14.3.5.4.2 
Change from Baseline in Visual Acuity by Eye and 
Visit 
Safety Analysis Set 
14.3.5.5.1 
Color Vision by Visit 
Safety Analysis Set 
14.3.5.5.2 
Change from Baseline in Color Vision by Eye and 
Visit 
Safety Analysis Set 
14.3.5.6.1 
Peripheral Neuropathy by Visit 
Safety Analysis Set 
14.3.5.6.2 
Shift from Baseline in Peripheral Neuropathy by 
Eye and Visit 
Safety Analysis Set 
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16.2.5.3 
Individual Plasma Concentration 
PK Analysis Set 
16.2.7.1.1 
Adverse Events 
Safety Analysis Set 
16.2.7.1.2 
Serious Adverse Events 
Safety Analysis Set 
16.2.7.1.3 
Adverse Events that Lead to Discontinuation of 
Study Drug 
Safety Analysis Set 
16.2.7.1.4 
DMID Grade 3 or 4 Adverse Events 
Safety Analysis Set 
16.2.7.1.5 
Adverse Events Leading to Death 
Safety Analysis Set 
16.2.7.1.6 
Deaths 
Safety Analysis Set 
16.2.8.1.1 
Laboratory Results – Hematology 
Safety Analysis Set 
16.2.8.1.2 
Laboratory Results for Patients with Toxicity 
Grade 3 or Higher – Hematology 
Safety Analsyis Set 
16.2.8.2.1 
Laboratory Results – Chemistry 
Safety Analysis Set 
16.2.8.2.2 
Laboratory Results for Patients with Toxicity 
Grade 3 or Higher – Chemistry 
Safety Analysis Set 
16.2.8.3.1 
Laboratory Results – Chemistry (Liver) 
Safety Analysis Set 
16.2.8.3.2 
Laboratory Results for Patients with Toxicity 
Grade 3 or Higher – Chemistry (Liver) 
Safety Analysis Set 
16.2.8.4.1 
Laboratory Results – Urinalysis 
Safety Analysis Set 
16.2.8.4.2 
Laboratory Results for Patients with Toxicity 
Grade 3 or Higher – Urinalysis  
Safety Analysis Set 
16.2.8.5 
Hy’s Law Cases 
Safety Analysis Set 
16.2.8.6.1 
Vital Sign Results 
Safety Analysis Set 
16.2.8.6.2 
Vital Sign for Patients with Abnormal Results 
Safety Analysis Set 
16.2.8.7.1 
Electrocardiogram Result 
Safety Analysis Set 
16.2.8.7.2 
Electrocardiogram Results for Patients with 
Abnormal Findings 
Safety Analysis Set 
16.2.8.8 
AREDS2 Opacity Type and Grade 
Safety Analysis Set 
16.2.8.9 
Visual Acuity 
Safety Analysis Set 
16.2.8.10 
Color Vision 
Safety Analysis Set 
16.2.8.11 
Peripheral Neuropathy Assessment 
Safety Analysis Set 
15.3 
Listing of Planned Figures 
Figure Number Title 
Analysis Set 
16.2.1.1 
Kaplan-Meier Curve of Time (Days) to First 
Dose Interruption and/or Dose Reduction of 
Linezolid due to Adverse Event 
ITT Analysis Set 
16.2.5.1 
Patients with Dosing Changes and Interruptions 
and Adverse Events Associated with the Dosing 
Changes 
Safety Analysis Set 
16.2.8.1.1 
Laboratory Profile Plot for Patients with Grade 3 
Safety Analysis Set 
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or Higher Toxicity Grade for HGB, WBC, 
Neutrophils and/or Platelets 
16.2.8.3.1 
ALT versus Total Bilirubin, expressed as 
multiple of ULN 
Safety Analysis Set 
16.2.8.3.2 
AST versus Total Bilirubin, expressed as 
multiple of ULN 
Safety Analysis Set 
16.2.8.3.3 
ALT versus Total Bilirubin, eDish plot 
Safety Analysis Set 
16.2.8.3.4 
Liver Enzyme Profile Plot for Patients with 
Treatment-emergent Grade 3 or Higher Toxicity 
Grade for AST, ALT, ALP and/or Total 
Bilirubin 
Safety Analysis Set 
16.2.8.7.1 
Mean QTcF (msec) +/- SD by Visit 
Safety Analysis Set 
16.2.8.7.2 
Electrocardiogram Profile Plot for Patients with 
Any QT, QTcB and/or QTcF Value >= 500 msec 
or Any Increase from Baseline > 60 msec 
Safety Analysis Set 
16.2.8.11 
Total Neuropathy Score and Linezolid Dosing 
per Subject  
Safety Analysis Set 
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Efficacy Statistical Analysis Plan 
 
 
 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various 
doses and treatment durations of linezolid plus bedaquiline and pretomanid in participants with 
pulmonary infection of either extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB).   
 
Protocol Number: NC-007-(B-Pa-L). 
 
Version: 1.0 
 
Author name: 
Angela Crook 
Author position:
Trial Statistician
 
 
 
 
Author signature: 
 
 
Date:
Approval name: 
Daniel Everitt 
Approval position: 
Vice President and Senior Medical 
Officer 
 
 
 
 
Approval signature: 
 
 
Date:
 
 
 
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Table of Contents 
 
1. 
Introduction ................................................................................................................................... 4 
2. 
Primary Efficacy Endpoint ............................................................................................................... 5 
3. 
Definitions and data handling issues ............................................................................................... 6 
3.1. 
Definitions ......................................................................................................................................... 6 
3.2. 
Inability to produce sputum .............................................................................................................. 7 
3.3. 
Isolated positive cultures ................................................................................................................... 7 
3.4. 
Timing of events ................................................................................................................................ 7 
4. 
Analysis populations ....................................................................................................................... 8 
4.1. 
Exclusions from ITT analysis (late screening failures) ....................................................................... 8 
4.2. 
Additional exclusions from MITT analysis ......................................................................................... 8 
4.3. 
Additional exclusions from PP analysis ............................................................................................. 9 
4.4. 
Lost to Follow-up or Early Withdrawal .............................................................................................. 9 
4.5. 
Definition of adequate treatment ................................................................................................... 10 
4.6. 
Determining cause of death ............................................................................................................ 10 
5. 
Baseline comparisons of key characteristics .................................................................................. 10 
6. 
Classification of primary endpoint status ....................................................................................... 11 
6.1.1. 
Favourable status (all analyses) ............................................................................................... 11 
6.1.2. 
Unfavourable status in ITT population .................................................................................... 11 
6.1.3. 
Unfavourable status in MITT population ................................................................................. 11 
6.1.4. 
Unfavourable status in PP population ..................................................................................... 11 
7. 
Primary endpoint analysis ............................................................................................................. 11 
8. 
Sensitivity analyses of primary endpoint analysis .......................................................................... 12 
9. 
Secondary efficacy analyses of primary endpoint ........................................................................... 12 
9.1. 
Time to event unfavorable outcome analysis ................................................................................. 12 
10. 
Secondary efficacy endpoints .................................................................................................... 13 
10.1. 
Incidence of bacteriologic failure or relapse at 24 months after the end of treatment ............. 13 
10.2 
Time to sputum culture conversion to negative status ................................................................... 13 
10.3 
Culture conversion status at 4, 6, 8, 12 and 16 weeks .................................................................... 13 
10.4 
TB symptoms ................................................................................................................................... 13 
10.5 
Patient reported health status ........................................................................................................ 13 
10.6 
Weight ............................................................................................................................................. 13 
11 
Sub-group analyses ................................................................................................................... 14 
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12 
Reasons for treatment failure as determined by the local PI ....................................................... 14 
13 
APPENDICES .............................................................................................................................. 15 
14.1 
Appendix 1: Algorithm for Interpretation of Positive MGIT Results ............................................... 15 
14.2 
Appendix 2: Interpretation of Relapse/Re-infection using Whole Genome Sequence (WGS) ....... 17 
 
 
 
 
Version History: 
Version Number/Date
Change
0.1 07 August 2017
First version drafted
0.2 21 August 2017
Circulated to wider team after incorporating comments from DE
0.3 01 Sep 2017
Circulated to team after incorporating comments from CM and PPD
0.4 06 Sep 2017
Circulated new draft following call 06 Sept 2017 
 
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1. Introduction 
This document outlines the efficacy statistical analysis plan (SAP) for the protocol ZeNix, a phase 3 partially-
blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of 
linezolid plus bedaquiline and pretomanid in participants with pulmonary infection of either extensively 
drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug 
resistant tuberculosis (MDR-TB).   Bedaquiline and pretomanid treatment will not be blinded.  Linezolid 
treatment dose and duration will be double-blinded. 
 
Participants will have a screening period of up to 9 days and will be randomized to receive one of the 
following 4 active treatment arms: 
 
1. Linezolid 1200 mg daily for 26 weeks 
 
2 linezolid 600 mg active tablets once daily for 26 weeks 
 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
2. Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
 
2 linezolid 600 mg active tablets once daily for 9 weeks  
 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
3. Linezolid 600 mg daily for 26 weeks 
 
1 linezolid 600 mg active tablet once daily for 26 weeks 
 
1 placebo linezolid 600 mg tablet once daily for 26 weeks  
 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
4. Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
 
1 linezolid 600 mg active tablet once daily for 9 weeks 
 
1 placebo linezolid 600 mg tablet for 9 weeks 
 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
  
 
Participants will be randomised to one of the four regimens in a 1:1:1:1 ratio, using an interactive web 
response system (IWRS), stratified by HIV status and type of TB.  A total of up to 180 participants will be 
enrolled: 120 (30 per treatment arm) XDR-TB participants, and up to 60 (15 per arm) pre-XDR or treatment 
intolerant/non-responsive MDR pulmonary tuberculosis Participants, male and female, aged 14 and over.  . 
Sponsor may consider replacement of late screen failure and unassessable patients. 
 
positive, the investigator may consider extending current treatment to 39 weeks, in consultation with the 
Sponsor Medical Monitor.   Participants will be followed for 78 weeks after end of treatment. 
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The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT).  No formal 
statistical comparisons between the randomised groups will be made. 
 
 
2. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the incidence of bacteriologic failure or relapse or clinical failure at 6 
months after the end of therapy.  See section 6 for the detailed definition 
.   
 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) analysis; a 
modified intent to treat (MITT) analysis and a per protocol (PP) analysis.   
 
The 
ITT  population will likely be increased by factors other than 
bacteriologic or clinical treatment failure and relapse. The MITT analysis will therefore be considered 
primary for publication purposes.  However, we recognize that FDA and other regulatory agencies will 
consider the ITT analysis primary. 
 
NB: In the event that more than 10% of patients within any randomised group are culture positive at 4 
months and have their treatment extended for a further 3 months, the primary endpoint analysis will be 
defined as 15 months from start of therapy for all patients.  For each patient the assessment closest to this 
time point will be taken as this 15 month (from start of therapy) endpoint. 
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3. Definitions and data handling issues 
3.1. Definitions 
Positive culture refers to the culture being positive for M.tb.  False positive or contaminated sputum 
cultures, without speciation data confirming presence of M.tb, will be treated as missing.  Specimens 
classified as non-tuberculous mycobacteria (NTM) and negative for M.tb will be treated as contaminated.  
Full details of the bacteriology algorithm for reporting MGIT results can be found in Appendix 1.  Two 
sputum samples per visit are collected at each visit throughout treatment and follow-up.  The culture result 
for a given visit is established using all samples obtained for that visit. A positive culture takes precedence 
over a negative culture at the same visit. (Appendix 1) 
 
Culture negative status is achieved when a patient produces at least 2 negative culture results at different 
visits (at least 7 days apart) without an intervening positive culture result for M.tb.  The date of the first 
negative culture of these two is the date at which culture negative status was obtained.  Once obtained, 
culture negative status continues until there are two positive cultures at different visits (at least 7 days 
apart), without an intervening negative culture, or until there is a single positive culture not followed by 
two negative cultures.  Culture negative status can be achieved at any time during treatment or follow-up 
but before any re-treatment. Culture negative status can be re-established.  
 
Patients with two contaminated or missing samples at a given visit will be asked to return to produce two 
more sputum samples.   
 
Treatment failure is defined as being declared an unfavourable status (as defined in section 6) at or before 
the end of treatment or failing to attain culture negative status and being declared an unfavourable 
outcome or patient is withdrawn at or before the end of treatment for clinical (TB) reasons including being 
re-treated (or changing from protocol treatment) for TB. 
 
Relapse is defined as failing to maintain culture negative status or being declared an unfavourable outcome 
after the end of treatment in those patients who attained culture negative status by the end of treatment, 
and had culture conversion to positive status with the same Mycobacterium tuberculosis (M.tb) strain or 
after the end of treatment in those patients who attained culture negative status by the end of treatment 
and were withdrawn for clinical (TB) reasons including being re-treated (or changing from protocol 
treatment) for TB.  Details are given in Appendix 2. 
 
Reinfection is defined as failing to maintain culture negative status or being declared an unfavourable 
outcome (including being withdrawn for clinical (TB) reasons including being re-treated or changing from 
protocol treatment for TB) after the end of treatment in those patients who attained culture negative 
status by the end of treatment and had culture conversion to positive status with a Mycobacterium 
tuberculosis (M.tb) strain that is different from the infecting strain at baseline. If reinfection cannot be 
distinguished from relapse, the patient will be assumed to have relapsed. A single positive sample will be 
sufficient for strain typing to compare to baseline. Full details are in Appendix 2.  
 
The treatment period is defined as 6 months (total of 26 weeks) of the B-Pa therapy (linezolid may be 
stopped early) plus any days made up for interrupted  doses of B-Pa therapy (or 9 months in those 
remaining culture positive at month 4 and who are not withdrawn). 
 
The follow-up period is defined as the period after the last treatment dose to the end of follow-up. 
  
 
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3.2. Inability to produce sputum 
In general, inability to produce sputum is treated as being equivalent to having a negative (favourable) 
culture result.  This includes the rare situation where a patient never achieves culture negative status due 
to inability to produce sputum, but completes follow-up without clinical or microbiological evidence of 
relapse.  Such a patient will be considered to have a favourable outcome.   
 
    
3.3. Isolated positive cultures 
It is known that occasionally patients produce sputum samples that are isolated positives , that is a 
positive culture preceded by a series of negative cultures and followed thereafter by at least 2 negative 
cultures without an intervening positive result.  This phenomenon may be the result of a sealed cavity 
breaking down or laboratory contamination and does not in itself signify that the patient is relapsing. In the 
event of a single positive culture result occurring in a patient who has previously been classified as having 
culture negative status (in the absence of any retreatment), the patient will not be classified as 
a recurrence unless a second positive culture result is obtained at a separate visit (at least 7 days apart) 
without an intervening negative culture or unless the patient is lost to follow up or completes the study 
(and is unable to be brought back) before two negative cultures are obtained.  As there is a higher 
incidence of positives with liquid culture and sometimes 
he clinical 
condition of the patient will also be considered in deciding whether the patient has an unfavourable 
outcome and re-treatment is indicated. 
 
To expand a bit, most of the experience with isolated positives has been with solid culture.  Because liquid 
culture is more sensitive, it is possible that more than one isolated positive may occasionally occur.  
Therefore, the clinical condition of the patient will also be considered when deciding whether re-treatment 
is indicated and in determining the outcome.  For example, if a patient after being culture negative has two 
positive cultures in a row, but is deemed to be doing well clinically, the investigator may choose to leave 
the patient untreated on clinical grounds.  In such a case, so long as two consecutive negative cultures are 
eventually obtained in the absence of treatment, the patient will not be classified as an unfavourable 
outcome. 
 
3.4. Timing of events 
In all analyses, visit date rather than day or week number will be used to define the timing of events.   For 
all participants, the 6-month regimen will be taken as a total of 26 weeks, i.e. 182 dosing days (for B-Pa), 
from the start of therapy, after accounting for any treatment interruptions.  For those who extend 
treatment to 9 months this will be 39 weeks (273 days) (for B-Pa) from start of therapy, again after 
accounting for any treatment interruptions.    
 
For the end of treatment visit (months 6/9), a ±1-week window will be applied (as per the protocol).   For 
the 3-monthly visits after the end of therapy, a window of ±2 weeks will be applied (as per the protocol). 
Additional programming will be required for cases where end of treatment date is not clearly recorded.    
 
In the event that more than 10% of patients within any randomised group are culture positive at 4 months 
and have their treatment extended for a further 3 months, the primary endpoint analysis will be defined as 
15 months from start of therapy for all patients.  In this case the visit date for the endpoint analysis will be 
chosen as the one closest to 65 weeks (26+39) from start of therapy (unless patient is declared 
unfavourable before this date).  
 
 
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4. Analysis populations  
Patients who are never culture positive during the baseline period, (screening through week 4) but are 
eligible based on documented M.tb by culture or molecular test within 3 months prior to screening will be 
included in all analysis populations. 
 
The analysis populations for efficacy analyses are: 
 
o The Intent to treat (ITT) population is defined as all randomised patients excluding late screening 
failures (see 4.1) 
o The Modified intent to treat (MITT) population is defined as the ITT population with extra 
exclusions (See 4.2) 
o The Per-protocol (PP) population is defined as the MITT population with extra exclusions (see 4.3) 
Exclusions from these populations 
  
4.1. Exclusions from ITT analysis (late screening failures) 
1. Patients withdrawn from treatment because they were found to be ineligible (late exclusions from the 
study), based on data collected prior to randomisation, including patients who do not have documented 
evidence of M.tb within 3 months of screening. Note, reinfections will not be excluded from the ITT 
population and will be considered unfavourable.  All patients without a proven favourable outcome will be 
considered unfavourable. 
 
4.2. Additional exclusions from MITT analysis  
1. Patients who, having completed treatment, are lost to follow-up or withdrawn from the study, their last 
at least two negative culture results at different visits (at least 7 days apart, without an intervening positive 
culture) 
 
2.  Women who become pregnant during treatment and stop their allocated treatment  
 
3.  Patients who die during treatment from violent or accidental cause (e.g. road traffic accident). N.B.: This 
does not include death from suicide, which will be considered an unfavourable outcome.  
 
4. Patients who die during follow-up (after the end of treatment) with no evidence of failure or relapse of 
their TB, their last status being culture negative 
 at different visits (at least 7 days apart), and who 
have not already been classified as unfavourable.  
 
5. Patients who, after being classified as having culture negative status, are re-infected with a new strain 
different from that with which they were originally infected.  Reinfection will be defined specifically as a 
patient infected with a strain that is genetically different from the initial strain (see Appendix 2).  
 
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6. Patients who are able to produce sputum at their primary endpoint visit, whose sputum samples are all 
contaminated or missing, who cannot be brought back for repeat cultures, provided they have not already 
been classified as unfavourable and provided their last positive culture was followed by at least two 
negative cultures.  N.B.:  This does not apply to patients who are unable to produce sputum at 6 months 
after end of treatment, or to patients who are able to be brought back subsequently and produce negative 
cultures. 
 
Patients in categories 1-6 above who had already been classified as having an unfavourable outcome will 
not be excluded. 
 
4.3. Additional exclusions from PP analysis  
1. Patients lost to follow-up or withdrawn before the end of treatment due to reasons other than 
treatment failure, unless they have already been classified as having an unfavourable outcome. 
 
2. Patients whose treatment was modified or extended (beyond what is permitted in the protocol) for 
reasons (e.g. an adverse drug reaction) other than an unfavourable therapeutic response to treatment, 
unless they have already been classified as having an unfavourable outcome. 
 
3. Patients not meeting the definition of having received an adequate amount of their allocated study 
regimen (see section 4.5 for definition), provided this is not due to unfavourable outcome. 
 
4. 
major protocol deviations for analysis
already been classified as having an unfavourable outcome on the basis of data obtained prior to the 
protocol deviation. 
 
A list of all protocol deviations will be compiled throughout the course of the study.  
 
A Major Protocol Deviation for Analysis is defined as a serious protocol deviation which is likely to affect to 
a significant degree the scientific value of the trial.  These patients will be included in the ITT and MITT 
analyses, but not in the Per Protocol analysis.  A list of all major protocol deviations for analysis will be 
approved by the study Coordinating Investigator before database lock.   
 
4.4. Lost to Follow-up or Early Withdrawal 
Lost to Follow-up or Early Withdrawals before the end of the treatment (month 6 or 9) are considered as 
unfavourable outcomes for ITT and MITT.  However, these patients will be excluded from the Per Protocol 
analysis.  The MITT and Per Protocol analyses will consider Lost to Follow-up after end of treatment  as 
unassessable unless at the time of default from follow-up the patient a) was already classified as having an 
results at different visits (at least 7 days 
apart), in which cases the patient will be classified as having an unfavourable outcome.  We believe this is 
the most appropriate approach for the primary analysis because together with the non-tuberculosis deaths, 
this group is likely to considerably out-number the bacteriological failures and relapses.  These patients will 
be considered as having an unfavourable outcome in the ITT analysis. 
 
There is a clear precedent for this analytic approach in other TB trials, and these trials also provide 
examples of why the inclusion of the losses to follow-up as unfavourable greatly affects the results. 
 
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Data from the Priftin trial which led to accelerated approval of rifapentine and a trial conducted by the 
International Union Against TB & Lung Disease (IUATLD) in African and Asian sites illustrate the problems 
associated with classifying all losses to follow-up and deaths as having an unfavourable outcome.  
 In the Priftin trial bacteriological relapses occurred in 5% of patients on the rifampicin based regimen 
compared to 11% on the rifapentine based regimen.  Approximately one third of patients were lost to 
follow-up and when this group combined with patients unassessable for other reasons were added to the 
bacteriological failures, the rates increased to 53% and 57% respectively.  The true bacteriological relapses 
were greatly outnumbered by these other groups. At the time of the licensing submission to the FDA it was 
recognised that because there were a substantial number of patients likely to be unassessable the main 
focus should be on the relapse rates.  In the final statistical report the results were first reported excluding 
those unassessable and then assuming all losses had an unfavourable outcome and finally assuming all 
losses had a favourable outcome. 
  
In the study conducted by the IUATLD the published failure/relapse rates 12 months after stopping 
treatment based on 1044 assessable patients were 4% for the control regimen and 10% and 14% in each of 
the experimental arms.  If the 311 unassessable patients were considered to have an unfavourable 
outcome these rates would increase to 24%, 32% and 35% respectively. The 311 unassessable patients 
were not evenly distributed across the three trial arms. There were 42 deaths, of which 20 occurred in one 
of the experimental arms (the more efficacious of the two) and 11 in each of the other, a difference which 
was not considered to be due to the treatment, but due to chance.  There were also imbalances among 
those without a bacteriological assessment (7 in one arm versus 19 and 22 in the other two arms) and in 
the distribution of losses to follow-up. 
 
4.5. Definition of adequate treatment  
The definition of adequate treatment sets a limit for the amount of treatment missed.  Patients not taking 
the adequate amount of treatment by this definition will be excluded from the PP analysis. 
 
Patients treated for 6 months with no treatment extension, to meet the definition of adequate treatment 
they must have taken at least 146 doses (80%) of their allocated 182 day (26 weeks) treatment regimen 
within 242 days of starting therapy (i.e. 26 weeks plus an allowable 56 day halt (including a maximum of 35 
consecutive days) as per the protocol).  
 
For patients who have their treatment extended to 9 months (39 weeks), to meet the definition of 
adequate treatment, they must have taken at least 219 doses (80%) within 333 days. 
 
A dose is defined as taking the required daily dose of both pretomanid and bedaquiline. 
 
4.6. Determining cause of death 
A list of all TB-related and non-TB-related deaths will be generated and approved by a review committee of 
physicians not associated with the trial before database lock.    Similarly, a list of violent or accidental 
deaths will be generated.  
 
 
5. Baseline comparisons of key characteristics 
The following baseline characteristics of patients will be summarised:  age, gender, race, site, weight, 
height, BMI, smoking status, TB type (XDR /non-XDR), HIV status/CD4 count/on ARV, cavitation, initial 
bacterial load in sputum as indicated by baseline Time to Positivity (TTP) result from MGIT, drug resistance. 
 
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6. 
Classification of primary endpoint status 
Patients will be classified as having a favourable, unfavourable or unassessable status at 6 months after the 
end of therapy. Patients excluded from analysis are considered unassessable. 
 
6.1.1. Favourable status (all analyses) 
Patients with a negative culture status at 6 months from end of therapy who had not already been 
    
 
6.1.2. Unfavourable status in ITT population 
Patients in the ITT analysis population who do not have a favourable outcome at 6 months from end of 
therapy will be considered to have an unfavourable response in the ITT analysis.   
 
6.1.3. Unfavourable status in MITT population 
1. Patients not classified as having achieved or maintained culture negative status when last seen, or 
2. Patients previously classified as having culture negative status who, following the end of treatment, 
have two positive cultures without an intervening negative culture, (however, see Section 3.3 for an 
exception), or 
3. Patients who had a positive culture not followed by at least two negative cultures when last seen, or  
4. Patients dying from any cause during treatment, except from violent or accidental cause (e.g. road 
traffic accident) not including suicide (i.e., suicide will be considered an unfavourable outcome) or 
5. Patients definitely or possibly dying from TB related cause during the follow-up phase or 
6. Patients requiring an extension of their treatment beyond that permitted by the protocol, a restart or a    
change of treatment for any reason except reinfection or pregnancy, or 
7. Patients lost to follow up or withdrawn from the study before the end of treatment 
8. If patient has surgery and the resected tissue is cultured and is positive for MTB 
 
 
6.1.4. Unfavourable status in PP population 
1. Patients not classified as having achieved or maintained culture negative status when last seen, or 
2. Patients previously classified as having culture negative status who, following the end of treatment, 
have two positive cultures without an intervening negative culture, (however, see Section 3.3 for an 
exception), or 
3. Patients who had a positive culture not followed by at least two negative cultures when last seen, or  
4. Patients dying from any cause during the treatment phase, except from violent or accidental cause (e.g. 
road traffic accident) not including suicide (i.e., suicide will be considered an unfavourable outcome), or 
5. Patients definitely or possibly dying from TB related cause during the follow-up phase, or 
6. Patients requiring a restart or a change of treatment because of an unfavourable outcome with or 
without bacteriological confirmation, i.e. on bacteriological, radiographic or clinical grounds, unless due to 
reinfection with a new organism 
7. If patient has surgery and the resected tissue is cultured and is positive for MTB 
 
 
 
7. 
Primary endpoint analysis 
The MITT analyses will be considered primary.   
 
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The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT) including all 
TB types.  A key secondary analysis will be restricted to the XDR participants only (30 per arm).  
 
We will evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that the 
incidence of bacteriologic failure or relapse or clinical failure (including mortality) -unfavorable outcome - 
at 6 months (26 weeks) after the end of therapy is less than 50%.   
 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 weeks) with the 
L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a success.  Similarly, L600 9 weeks 
will only be tested if L600 26 weeks is a success.   A Bonferroni adjustment will be made for comparing the 
L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025.  For these comparisons the lower 
bound of the 97.5% confidence interval will need to exceed 50% for success.   
 
No formal statistical pairwise comparisons between the arms will be performed. 
 
The proportion of assessable patients with a favourable and unfavourable outcome, with 95% and 97.5% 
confidence intervals, will be presented.  For success, the lower bound of the 95% confidence interval (or 
97.5% as applicable) for a favourable outcome should be above 50%.   
 
This MITT analysis is consistent with the TB literature over the past 50 years.  However, we recognise that 
FDA and other regulatory agencies will consider the ITT analysis primary, where all patients who are not 
proven to have a favourable outcome will be classified as having an unfavourable outcome. 
 
   
8. 
Sensitivity analyses of primary endpoint analysis 
In addition to analysing the primary endpoint data by ITT, MITT and PP and separately for XDR-TB patients 
(key secondary efficacy analyses), it is planned to conduct the following sensitivity analyses: 
 
1. An analysis of patients in the MITT and PP populations where reinfections are classified as unfavourable 
outcomes 
 
2. An analysis of the MITT and PP populations treating all deaths as unfavourable  
 
3.  An analysis of the ITT, MITT and PP populations excluding patients who were never culture positive 
during the baseline period (screening through week 4), but were eligible based on documented M.tb by 
culture or molecular test within 3 months prior to screening 
 
 
9. 
Secondary efficacy analyses of primary endpoint 
The following analyses will be performed on MITT and PP populations only unless otherwise stated. 
 
9.1. Time to event unfavorable outcome analysis 
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-hazards 
regressions analysis.  These analyses will be performed according to ITT, MITT and PP endpoint 
classifications.  Time to event will be calculated in days from the date of enrolment up to the first date 
associated with the reason for unfavourable status or (if favourable) the date of the 6 month after end of 
therapy visit. 
 
10. Secondary efficacy endpoints 
10.1. Incidence of bacteriologic failure or relapse at 24 months after the end of treatment  
Efficacy analyses as described for the primary endpoint will be repeated for the 24 month after the end of 
treatment endpoint as a confirmatory analysis. 
 
10.2 
Time to sputum culture conversion to negative status 
For patients with positive baseline culture results, time to culture negative status (first of two negative 
cultures without an intervening positive culture) will be analysed using survival analysis techniques, Kaplan 
Meier plots and Cox proportional hazard regression. 
 
10.3 
Culture conversion status at 4, 6, 8, 12 and 16 weeks  
Patients will be classified as being culture positive, culture negative, dead or unassessable at 4, 6, 8, 12 and 
16 weeks.  Every effort will be made to obtain a sputum sample from all patients, but it is recognised that 
some patients may not have produced any sputum in the preceding week and may be unable to do so 
when requested.  Patients who cannot produce sputum will be classified as being culture negative at that 
time point.  The proportion culture negative will be those classified as being culture negative divided by the 
total considered culture negative, culture positive or have died. This proportion will be estimated from the 
Kaplan Meier estimates from the time to culture conversion to negative status analysis. 
 
10.4 
TB symptoms 
Each TB symptom will be summarised by n (%): none (0), mild (1), moderate (2), severe (3) at each visit 
collected as per the protocol: baseline, week 8, end of treatment, 6 and 24 months from end of treatment.  
 
In addition baseline and change from baseline score at each time point listed above for each symptom and 
for total symptom score will be summarised by mean, median, IQR and range.   
 
10.5 
Patient reported health status 
Patient reported health status is measured by the 5 domains of EQ5D.   These will be summarised at 
baseline, week 8, end of treatment, 6 and 24 months from end of treatment by randomised group and 
change from baseline at each follow-up assessment by mean, median, IQR and range by randomised group.  
 
10.6 
Weight 
Baseline weight and change from baseline weight throughout treatment and at 6 and 24 months after the 
end of therapy will be summarised by mean, median, IQR and range 
 
 
11 Pharmacokinetics-Pharmacodynamics (PK-PD)analyses 
Details of the PK parameter estimation and analysis are detailed in a separate PK SAP. PK-PD analyses will 
be described in a separate PK-PD SAP.   
 
 
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12 Sub-group analyses 
To assess consistency of results, exploratory sub-group analyses of the primary endpoint on the MITT 
analysis population will be considered. For example, depending on numbers consideration will be given to 
subgroup analyses by: age; gender; race; smoking status; HIV status/CD4 count; cavitation, initial bacterial 
load in sputum as indicated by baseline TTP result from MGIT; ARV taken or not during the treatment 
period. 
 
 
13 Reasons for treatment failure as determined by the local PI 
Reason(s) that led the site investigator to conclude that an individual patient failed treatment or relapsed 
will be classified as a) bacteriology alone, b) clinical deterioration alone, c) radiological deterioration alone, 
d) bacteriology plus clinical deterioration, e) bacteriology plus radiological deterioration, f) clinical 
deterioration plus radiological deterioration, or g) bacteriology plus clinical deterioration plus radiological 
deterioration.  These classifications will be tabulated and compared to outcomes derived from the 
algorithm described in section 6.     
 
 
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14 APPENDICES 
14.1 
Appendix 1: Algorithm for Interpretation of Positive MGIT Results  
Figure A1. Algorithm for reporting MGIT final results  
Note: MGIT cultures with no ID/speciation will be treated as a missing result. 
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Table A1. Derived MGIT results per visit  
Derived sample Culture 1 
(Visit X ) 
Derived Sample Culture 2    
(Visit X) 
Final Derived Result             
for Visit X 
Positive 
Missing/Negative/Contaminated 
Positive 
Negative 
Missing/Contaminated 
Negative 
Contaminated 
Missing/Contaminated 
Contaminated 
 
 
 
 
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14.2 
Appendix 2: Interpretation of Relapse/Re-infection using Whole Genome Sequence (WGS)  
 
The purpose of the WGS analysis is to determine if the two M. tuberculosis strains from a given patient (positive culture at baseline and at or after the 
end of treatment) can be considered the same (treatment failure/bacteriologic failure or relapse/bacteriological relapse), or different (re-
infection/bacteriological re-infection).   To do this, WGS of the two M. tuberculosis strains are compared, the number of   SNPs/variants determined, 
and the criteria outlined below followed.  These cut offs have been determined from previously published reports (REMoxTB and RIFAQUIN trials) that 
show a clear genetic distinction between relapse and re-infection cases of M.tb infection. 
 
 
 
 
 
 
 
 
>12 and <100 SNPs different = Indeterminate.  These results will be reviewed on case by case basis and are likely to be rare.  Additional 
sequence analysis may be performed and/or additional samples may need to be tested.  Any additional investigations will be documented on 
-
will be considered a relapse unless there is sufficient evidence to support a classification of re-infection.   
 
 
 
 
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Efficacy Statistical Analysis Plan 
 
 
 
Protocol Title: A Phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various 
doses and treatment durations of linezolid plus bedaquiline and pretomanid in participants with 
pulmonary infection of either extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB).   
 
 
Protocol Number: NC-007-(B-Pa-L). 
 
Version: 2.0 
 
 
Author name: 
Angela Crook 
Author position:
Trial Statistician
 
Author signature: 
 
 
Date:
Approval name: 
Daniel Everitt 
Approval position: 
Vice President and Chief Medical Officer 
 
 
Approval signature: 
 
 
Date: 
 
 
 
 
 
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Efficacy Statistical Analysis Plan 
 
 
Pg. 2 of 16 
 
Table of Contents 
 
1. 
Introduction ................................................................................................................................... 4 
2. 
Primary Efficacy Endpoint ............................................................................................................... 5 
3. 
Definitions and data handling issues ............................................................................................... 6 
3.1. 
Definitions ......................................................................................................................................... 6 
3.2. 
Inability to produce sputum .............................................................................................................. 7 
3.3. 
Isolated positive cultures ................................................................................................................... 7 
3.4. 
Timing of events ................................................................................................................................ 7 
4. 
Analysis populations ....................................................................................................................... 8 
4.1. 
Exclusions from ITT analysis (late screening failures) ....................................................................... 8 
4.2. 
Additional exclusions from MITT analysis ......................................................................................... 8 
4.3. 
Additional exclusions from PP analysis ............................................................................................. 9 
4.4. 
Lost to Follow-up or Early Withdrawal .............................................................................................. 9 
4.5. 
Definition of adequate treatment ................................................................................................... 10 
4.6. 
Determining cause of death ............................................................................................................ 10 
5. 
Baseline comparisons of key characteristics .................................................................................. 10 
6. 
Classification of primary endpoint status ....................................................................................... 11 
6.1.1. 
Favourable status (all analyses) ............................................................................................... 11 
6.1.2. 
Unfavourable status in ITT population .................................................................................... 11 
6.1.3. 
Unfavourable status in MITT population ................................................................................. 11 
6.1.4. 
Unfavourable status in PP population ..................................................................................... 11 
7. 
Primary endpoint analysis ............................................................................................................. 12 
8. 
Sensitivity analyses of primary endpoint analysis .......................................................................... 12 
9. 
Secondary efficacy analyses of primary endpoint ........................................................................... 12 
9.1. 
Time to event unfavorable outcome analysis ................................................................................. 13 
10. 
Secondary efficacy endpoints .................................................................................................... 13 
10.1. 
Incidence of bacteriologic failure or relapse at 18 months after the end of treatment ............. 13 
10.2 
Time to sputum culture conversion to negative status ................................................................... 13 
10.3 
Culture conversion status at 4, 6, 8, 12, 16 and 26 weeks .............................................................. 13 
10.4 
TB symptoms ................................................................................................................................... 13 
10.5 
Patient reported health status ........................................................................................................ 13 
10.6 
Weight ............................................................................................................................................. 13 
11 
Week 26 analysis ...................................................................................................................... 13 
12 
Pharmacokinetics-Pharmacodynamics (PK-PD) analyses ............................................................. 14 
13 
Sub-group analyses ................................................................................................................... 14 
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Pg. 3 of 16 
14 
Reasons for treatment failure as determined by the local PI ....................................................... 14 
15 
APPENDICES .............................................................................................................................. 15 
15.1 
Appendix 1: Interpretation of Relapse/Re-infection using Whole Genome Sequence (WGS) ....... 16 
Version History: 
Version Number/Date
Change
0.1 07 August 2017 
First version drafted
0.2 21 August 2017
Circulated to wider team after incorporating comments from DE
0.3 01 Sep 2017
Circulated to team after incorporating comments from CM and PPD
0.4 06 Sep 2017
Circulated new draft following call 06 Sept 2017 
1.1 2019 
new draft with updates, removal of original appendix 1, and addition of week 
26 analysis 
1.2 March 2020
General corrections
1.3 April 2020
Added surgery clause
1.4 26 May 2020
Added COVID clause
1.5 June 2020
Minor amendments after review meeting
2.0 August 2020 
Up versioned v1.5 to v2.0 
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Efficacy Statistical Analysis Plan 
 
 
Pg. 4 of 16 
 
1. Introduction 
This document outlines the efficacy statistical analysis plan (SAP) for the protocol ZeNix, a phase 3 partially-
blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of 
linezolid plus bedaquiline and pretomanid in participants with pulmonary infection of either extensively 
drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-responsive multi-drug 
resistant tuberculosis (MDR-TB).   Bedaquiline and pretomanid treatment will not be blinded.  Linezolid 
treatment dose and duration will be double-blinded. 
 
Participants will have a screening period of up to 9 days and will be randomized to receive one of the 
following 4 active treatment arms: 
 
1. Linezolid 1200 mg daily for 26 weeks 
 
2 linezolid 600 mg active tablets once daily for 26 weeks 
 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
2. Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
 
2 linezolid 600 mg active tablets once daily for 9 weeks  
 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
3. Linezolid 600 mg daily for 26 weeks 
 
1 linezolid 600 mg active tablet once daily for 26 weeks 
 
1 placebo linezolid 600 mg tablet once daily for 26 weeks  
 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
4. Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
 
1 linezolid 600 mg active tablet once daily for 9 weeks 
 
1 placebo linezolid 600 mg tablet for 9 weeks 
 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
  
 
Participants will be randomised to one of the four regimens in a 1:1:1:1 ratio, using an interactive web 
response system (IWRS), stratified by HIV status and type of TB.  A total of up to 180 participants, male and 
female, aged 14 and over, will be enrolled.  
 
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Pg. 5 of 16 
 
sputum sample is culture positive 
between week 16 and week 26 treatment visits and their clinical condition suggests they may have an 
ongoing TB infection, Investigator may consider extending current treatment to 39 weeks.  If the culture 
results between week 16 and week 26 are contaminated, missing or considered an isolated positive 
without clinical significance, available culture results should be used to make this decision. All decisions 
regarding treatment extension should be discussed and approved by the Sponsor Medical Monitor before 
implementation.   Participants will be followed for 78 weeks after end of treatment. 
 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT).  No formal 
statistical comparisons between the randomised groups will be made. 
 
 
2. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the incidence of bacteriologic failure or relapse or clinical failure at 6 
months after the end of therapy.  See section 6 for the detailed definition 
.   
 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) analysis; a 
modified intent to treat (MITT) analysis and a per protocol (PP) analysis.   
 
The 
ITT  population will likely be increased by factors other than 
bacteriologic or clinical treatment failure and relapse. The MITT analysis will therefore be considered 
primary for publication purposes.  However, we recognize that FDA and other regulatory agencies will 
consider the ITT analysis primary. 
 
NB: In the event that more than 10% of patients within any randomised group are culture positive at 4 
months and have their treatment extended for a further 3 months, the primary endpoint analysis will be 
defined as 15 months from start of therapy for all patients.  For each patient the assessment closest to this 
time point will be taken as this 15 month (from start of therapy) endpoint. 
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Efficacy Statistical Analysis Plan 
 
 
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3. Definitions and data handling issues 
3.1. Definitions 
Positive culture refers to the culture being positive for M.tb.  False positive or contaminated sputum 
cultures, without speciation data confirming presence of M.tb, will be treated as missing.  Specimens 
classified as non-tuberculous mycobacteria (NTM) and negative for M.tb will be treated as contaminated.    
Two sputum samples per visit are collected at each visit, excluding at Week 5,7,14 & 18, throughout 
treatment and follow-up.  The culture result for a given visit is established using all samples obtained for 
that visit. A positive culture takes precedence over a negative culture at the same visit. Refer to Appendix 1 
for further details. 
 
Culture negative status is achieved when a patient produces at least 2 negative culture results at different 
visits (at least 7 days apart) without an intervening positive culture result for M.tb.  The date of the first 
negative culture of these two is the date at which culture negative status was obtained.  Once obtained, 
culture negative status continues until there are two positive cultures at different visits (at least 7 days 
apart), without an intervening negative culture, or until there is a single positive culture not followed by 
two negative cultures.  Culture negative status can be achieved at any time during treatment or follow-up 
but before any re-treatment. Culture negative status can be re-established.  
 
Patients with two contaminated or missing samples at a given visit will be asked to return to produce two 
more sputum samples.   
 
Treatment failure is defined as being declared an unfavourable status (as defined in section 6) at or before 
the end of treatment or failing to attain culture negative status and being declared an unfavourable 
outcome or patient is withdrawn at or before the end of treatment for clinical (TB) reasons including being 
re-treated (or changing from protocol treatment) for TB. 
 
Relapse is defined as failing to maintain culture negative status or being declared an unfavourable outcome 
after the end of treatment in those patients who attained culture negative status by the end of treatment, 
and had culture conversion to positive status with the same Mycobacterium tuberculosis (M.tb) strain or 
after the end of treatment in those patients who attained culture negative status by the end of treatment 
and were withdrawn for clinical (TB) reasons including being re-treated (or changing from protocol 
treatment) for TB.  Details are given in Appendix 2. 
 
Reinfection is defined as failing to maintain culture negative status or being declared an unfavourable 
outcome (including being withdrawn for clinical (TB) reasons including being re-treated or changing from 
protocol treatment for TB) after the end of treatment in those patients who attained culture negative 
status by the end of treatment and had culture conversion to positive status with a Mycobacterium 
tuberculosis (M.tb) strain that is different from the infecting strain at baseline. If reinfection cannot be 
distinguished from relapse, the patient will be assumed to have relapsed. A single positive sample will be 
sufficient for strain typing to compare to baseline. Full details are in Appendix 2.  
 
The treatment period is defined as 6 months (total of 26 weeks) of the B-Pa therapy (linezolid may be 
stopped early) plus any days made up for interrupted doses of B-Pa therapy (or 9 months in those who are 
extended). 
 
The follow-up period is defined as the period after the last treatment dose to the end of follow-up. 
  
 
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Efficacy Statistical Analysis Plan 
 
 
Pg. 7 of 16 
 
3.2. Inability to produce sputum 
In general, inability to produce sputum is treated as being equivalent to having a negative (favourable) 
culture result.  This includes:  
- 
the rare situation where a patient never achieves culture negative status due to inability to produce 
sputum, but completes follow-up without clinical or microbiological evidence of relapse.   
- 
during the COVID-19 lockdown situation where this data is collected remotely/telephonically 
Such patients will be considered to have a negative (favourable) outcome.  
 
    
3.3. Isolated positive cultures 
It is known that occasionally patients produce sputum samples that are isolated positives , that is a 
positive culture preceded by a series of negative cultures and followed thereafter by at least 2 negative 
cultures without an intervening positive result.  This phenomenon may be the result of a sealed cavity 
breaking down or laboratory contamination and does not in itself signify that the patient is relapsing. In the 
event of a single positive culture result occurring in a patient who has previously been classified as having 
culture negative status (in the absence of any retreatment), the patient will not be classified as 
a recurrence unless a second positive culture result is obtained at a separate visit (at least 7 days apart) 
without an intervening negative culture or unless the patient is lost to follow up or completes the study 
(and is unable to be brought back) before two negative cultures are obtained.  As there is a higher 
incidence of positives with liquid culture and sometimes ev
he clinical 
condition of the patient will also be considered in deciding whether the patient has an unfavourable 
outcome and re-treatment is indicated. 
 
To expand a bit, most of the experience with isolated positives has been with solid culture.  Because liquid 
culture is more sensitive, it is possible that more than one isolated positive may occasionally occur.  
Therefore, the clinical condition of the patient will also be considered when deciding whether re-treatment 
is indicated and in determining the outcome.  For example, if a patient after being culture negative has two 
positive cultures in a row, but is deemed to be doing well clinically, the investigator may choose to leave 
the patient untreated on clinical grounds.  In such a case, so long as two consecutive negative cultures are 
eventually obtained in the absence of treatment, the patient will not be classified as an unfavourable 
outcome. 
 
3.4. Timing of events 
In all analyses, visit date rather than day or week number will be used to define the timing of events.   For 
all participants, the 6-month regimen will be taken as a total of 26 weeks, i.e. 182 dosing days (for B-Pa), 
from the start of therapy, after accounting for any treatment interruptions.  For those who extend 
treatment to 9 months this will be 39 weeks (273 days) (for B-Pa) from start of therapy, again after 
accounting for any treatment interruptions.    
 
For the end of treatment visit (months 6/9), a ±1-week window will be applied (as per the protocol).   For 
the 3-monthly visits after the end of therapy, a window of ±2 weeks will be applied (as per the protocol). 
Additional programming will be required for cases where end of treatment date is not clearly recorded.    
 
In the event that more than 10% of patients within any randomised group have their treatment extended 
for a further 3 months, the primary endpoint analysis will be defined as 15 months from start of therapy for 
all patients.  In this case the visit date for the endpoint analysis will be chosen as the one closest to 65 
weeks (26+39) from start of therapy (unless patient is declared unfavourable before this date).  
 
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Efficacy Statistical Analysis Plan 
 
 
Pg. 8 of 16 
 
 
4. Analysis populations  
Patients who are never culture positive during the baseline period, (screening through week 4) but are 
eligible based on documented M.tb by culture or molecular test within 3 months prior to screening will be 
included in all analysis populations. 
 
The analysis populations for efficacy analyses are: 
 
o The Intent to treat (ITT) population is defined as all randomised patients excluding late screening 
failures (see 4.1) 
o The Modified intent to treat (MITT) population is defined as the ITT population with extra 
exclusions (See 4.2) 
o The Per-protocol (PP) population is defined as the MITT population with extra exclusions (see 4.3) 
Exclusions from these populations 
  
4.1. Exclusions from ITT analysis (late screening failures) 
1. Patients found to be ineligible (late exclusions from the study), based on data collected prior to 
randomisation, including patients who do not have documented evidence of M.tb within 3 months of 
screening.  
 
4.2. Additional exclusions from MITT analysis  
1. Patients who, having completed treatment, are lost to follow-up or withdrawn from the study, their last 
at least two negative culture results at different visits (at least 7 days apart, without an intervening positive 
culture) 
 
2.  Women who become pregnant during treatment and stop their allocated treatment  
 
3. Patients with suspected/confirmed COVID19 during treatment and stop their allocated treatment 
 
4.  Patients who die during treatment from violent or accidental cause (e.g. road traffic accident). N.B.: This 
does not include death from suicide, which will be considered an unfavourable outcome.  
 
5. Patients who die during follow-up (after the end of treatment) with no evidence of failure or relapse of 
 at different visits (at least 7 days apart), and who 
have not already been classified as unfavourable.  
 
6. Patients who, after being classified as having culture negative status, are re-infected with a new strain 
different from that with which they were originally infected.  Reinfection will be defined specifically as a 
patient infected with a strain that is genetically different from the initial strain (see Appendix 2).  
 
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Efficacy Statistical Analysis Plan 
 
 
Pg. 9 of 16 
 
7. Patients who are able to produce sputum at their primary endpoint visit, whose sputum samples are all 
contaminated or missing, who cannot be brought back for repeat cultures, provided they have not already 
been classified as unfavourable and provided their last positive culture was followed by at least two 
negative cultures.  N.B.:  This does not apply to patients who are unable to produce sputum, or to patients 
who are able to be brought back subsequently and produce negative cultures. 
 
Patients in categories 1-7 above who had already been classified as having an unfavourable outcome will 
not be excluded. 
 
4.3. Additional exclusions from PP analysis  
1. Patients lost to follow-up or withdrawn before the end of treatment due to reasons other than 
treatment failure, unless they have already been classified as having an unfavourable outcome. 
 
2. Patients whose treatment was modified or extended (beyond what is permitted in the protocol) for 
reasons (e.g. an adverse drug reaction) other than an unfavourable therapeutic response to treatment, 
unless they have already been classified as having an unfavourable outcome. 
 
3. Patients not meeting the definition of having received an adequate amount of their allocated study 
regimen (see section 4.5 for definition), provided this is not due to unfavourable outcome. 
 
4. 
major protocol deviations for analysis
already been classified as having an unfavourable outcome on the basis of data obtained prior to the 
protocol deviation. 
 
A list of all protocol deviations will be compiled throughout the course of the study.  
 
A Major Protocol Deviation for Analysis is defined as a serious protocol deviation which is likely to affect to 
a significant degree the scientific value of the trial.  These patients will be included in the ITT and MITT 
analyses, but not in the Per Protocol analysis.  A list of all major protocol deviations for analysis will be 
approved by a review committee before all planned analyses.   
 
4.4. Lost to Follow-up or Early Withdrawal 
Lost to Follow-up or Early Withdrawals before the end of the treatment (month 6 or 9) are considered as 
unfavourable outcomes for ITT and MITT.  However, these patients will be excluded from the Per Protocol 
analysis.  The MITT and Per Protocol analyses will consider Lost to Follow-up after end of treatment  as 
unassessable unless at the time of default from follow-up the patient a) was already classified as having an 
followed by at least two negative culture results at different visits (at least 7 days 
apart), in which cases the patient will be classified as having an unfavourable outcome.  We believe this is 
the most appropriate approach for the primary analysis because together with the non-tuberculosis deaths, 
this group is likely to considerably out-number the bacteriological failures and relapses.  These patients will 
be considered as having an unfavourable outcome in the ITT analysis. 
 
There is a clear precedent for this analytic approach in other TB trials, and these trials also provide 
examples of why the inclusion of the losses to follow-up as unfavourable greatly affects the results. 
 
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Efficacy Statistical Analysis Plan 
 
 
Pg. 10 of 16 
 
Data from the Priftin trial which led to accelerated approval of rifapentine and a trial conducted by the 
International Union Against TB & Lung Disease (IUATLD) in African and Asian sites illustrate the problems 
associated with classifying all losses to follow-up and deaths as having an unfavourable outcome.  
 In the Priftin trial bacteriological relapses occurred in 5% of patients on the rifampicin based regimen 
compared to 11% on the rifapentine based regimen.  Approximately one third of patients were lost to 
follow-up and when this group combined with patients unassessable for other reasons were added to the 
bacteriological failures, the rates increased to 53% and 57% respectively.  The true bacteriological relapses 
were greatly outnumbered by these other groups. At the time of the licensing submission to the FDA it was 
recognised that because there were a substantial number of patients likely to be unassessable the main 
focus should be on the relapse rates.  In the final statistical report the results were first reported excluding 
those unassessable and then assuming all losses had an unfavourable outcome and finally assuming all 
losses had a favourable outcome. 
  
In the study conducted by the IUATLD the published failure/relapse rates 12 months after stopping 
treatment based on 1044 assessable patients were 4% for the control regimen and 10% and 14% in each of 
the experimental arms.  If the 311 unassessable patients were considered to have an unfavourable 
outcome these rates would increase to 24%, 32% and 35% respectively. The 311 unassessable patients 
were not evenly distributed across the three trial arms. There were 42 deaths, of which 20 occurred in one 
of the experimental arms (the more efficacious of the two) and 11 in each of the other, a difference which 
was not considered to be due to the treatment, but due to chance.  There were also imbalances among 
those without a bacteriological assessment (7 in one arm versus 19 and 22 in the other two arms) and in 
the distribution of losses to follow-up. 
 
4.5. Definition of adequate treatment  
The definition of adequate treatment sets a limit for the amount of treatment missed.  Patients not taking 
the adequate amount of treatment by this definition will be excluded from the PP analysis. 
 
For patients treated for 6 months with no treatment extension, to meet the definition of adequate 
treatment they must have taken at least 146 doses (80%) of their allocated 182 day (26 weeks) treatment 
regimen within 238 days of starting therapy (i.e. 26 weeks plus an allowable 56 day halt (including a 
maximum of 35 consecutive days) as per the protocol).  
 
For patients who have their treatment extended to 9 months (39 weeks), to meet the definition of 
adequate treatment, they must have taken at least 219 doses (80%) of their allocated 273 day (39 weeks) 
treatment within 364 days (i.e. 39 weeks plus an allowable 91 day halt (including a maximum of 35 
consecutive days) as per the protocol). 
 
A dose is defined as taking the required daily dose of both pretomanid and bedaquiline. 
 
4.6. Determining cause of death 
A list of all TB-related and non-TB-related deaths will be generated and approved by a review committee of 
physicians not associated with the trial before database lock.    Similarly, a list of violent or accidental 
deaths will be generated.  
 
 
5. Baseline comparisons of key characteristics 
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Efficacy Statistical Analysis Plan 
 
 
Pg. 11 of 16 
 
The following baseline characteristics of patients will be summarised:  age, gender, race, site, weight, 
height, BMI, smoking status, TB type (XDR /non-XDR), HIV status/CD4 count/on ARV, cavitation, initial 
bacterial load in sputum as indicated by baseline Time to Positivity (TTP) result from MGIT, baseline drug 
resistance. 
 
 
6. 
Classification of primary endpoint status 
Patients will be classified as having a favourable, unfavourable or unassessable status at 6 months after the 
end of therapy. Patients excluded from analysis are considered unassessable. 
 
6.1.1. Favourable status (all analyses) 
Patients with a negative culture status at 6 months from end of therapy who had not already been 
classified as having 
    
 
6.1.2. Unfavourable status in ITT population 
Patients in the ITT analysis population who do not have a favourable outcome at 6 months from end of 
therapy will be considered to have an unfavourable response in the ITT analysis.   
 
6.1.3. Unfavourable status in MITT population 
1. Patients not classified as having achieved or maintained culture negative status when last seen, or 
2. Patients previously classified as having culture negative status who, following the end of treatment, 
have two positive cultures without an intervening negative culture, (however, see Section 3.3 for an 
exception), or 
3. Patients who had a positive culture not followed by at least two negative cultures when last seen, or  
4. Patients dying from any cause during treatment, except from violent or accidental cause (e.g. road 
traffic accident) not including suicide (i.e., suicide will be considered an unfavourable outcome) or 
5. Patients definitely or possibly dying from TB related cause during the follow-up phase or 
6. Patients requiring an extension of their treatment beyond that permitted by the protocol, a restart or a    
change of treatment for any reason except reinfection or pregnancy, or 
7. Patients lost to follow up or withdrawn from the study before the end of treatment 
8. Patients who have had surgery and the resected tissue is cultured and is positive for MTB.  
 
 
6.1.4. Unfavourable status in PP population 
1. Patients not classified as having achieved or maintained culture negative status when last seen, or 
2. Patients previously classified as having culture negative status who, following the end of treatment, 
have two positive cultures without an intervening negative culture, (however, see Section 3.3 for an 
exception), or 
3. Patients who had a positive culture not followed by at least two negative cultures when last seen, or  
4. Patients dying from any cause during the treatment phase, except from violent or accidental cause (e.g. 
road traffic accident) not including suicide (i.e., suicide will be considered an unfavourable outcome), or 
5. Patients definitely or possibly dying from TB related cause during the follow-up phase, or 
6. Patients requiring a restart or a change of treatment because of an unfavourable outcome with or 
without bacteriological confirmation, i.e. on bacteriological, radiographic or clinical grounds, unless due to 
reinfection with a new organism 
7. Patients who have had surgery and the resected tissue is cultured and is positive for MTB. 
 
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Efficacy Statistical Analysis Plan 
 
 
Pg. 12 of 16 
 
 
 
7. 
Primary endpoint analysis 
The MITT analyses will be considered primary.   
 
The primary efficacy analysis will be conducted using culture results including all TB types.   
 
We will evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that the 
incidence of bacteriologic failure or relapse or clinical failure (including mortality) -unfavorable outcome - 
at 6 months (26 weeks) after the end of therapy is less than 50%.   
 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 weeks) with the 
L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a success.  Similarly, L600 9 weeks 
will only be tested if L600 26 weeks is a success.   A Bonferroni adjustment will be made for comparing the 
L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025.  For these comparisons the lower 
bound of the 97.5% confidence interval will need to exceed 50% for success.   
 
No formal statistical pairwise comparisons between the arms will be performed. 
 
The proportion of assessable patients with a favourable and unfavourable outcome, with 95% and 97.5% 
confidence intervals, will be presented.  For success, the lower bound of the 95% confidence interval (or 
97.5% as applicable) for a favourable outcome should be above 50%.   
 
This MITT analysis is consistent with the TB literature over the past 50 years.  However, we recognise that 
FDA and other regulatory agencies will consider the ITT analysis primary, where all patients who are not 
proven to have a favourable outcome will be classified as having an unfavourable outcome. 
 
   
8. 
Sensitivity analyses of primary endpoint analysis 
In addition to analysing the primary endpoint data by ITT, MITT and PP and separately for XDR-TB patients 
(key secondary efficacy analyses), it is planned to conduct the following sensitivity analyses: 
 
1. An analysis of patients in the MITT and PP populations where reinfections are classified as unfavourable 
outcomes 
 
2. An analysis of the MITT and PP populations treating all deaths as unfavourable  
 
3.  An analysis of the ITT, MITT and PP populations excluding patients who were never culture positive 
during the baseline period (screening through week 4), but were eligible based on documented M.tb by 
culture or molecular test within 3 months prior to screening 
 
 
9. 
Secondary efficacy analyses of primary endpoint 
The following analyses will be performed on ITT, MITT and PP populations only unless otherwise stated. 
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Efficacy Statistical Analysis Plan 
 
 
Pg. 13 of 16 
 
 
9.1. Time to event unfavorable outcome analysis 
Time to an unfavourable outcome will be analysed with Kaplan Meier plots.  These analyses will be 
performed according to ITT, MITT and PP endpoint classifications.  Time to event will be calculated in days 
from the date of enrolment up to the first date associated with the reason for unfavourable status or (if 
favourable) the date of the 6 month after end of therapy visit. 
 
10. Secondary efficacy endpoints 
10.1. Incidence of bacteriologic failure or relapse at 18 months after the end of treatment  
Efficacy analyses as described for the primary endpoint will be repeated at the 18 month after the end of 
treatment endpoint as a confirmatory analysis. 
 
10.2 
Time to sputum culture conversion to negative status 
For patients with positive culture results from day 1 to week 4 (baseline excluding screening), time to 
culture negative status (first of two negative cultures without an intervening positive culture) will be 
analysed using survival analysis techniques and Kaplan Meier plots. 
 
10.3 
Culture conversion status at 4, 6, 8, 12, 16 and 26 weeks 
Patients will be classified as being culture positive, culture negative, dead or unassessable (including those 
without positive culture results from day 1 to week 4) at 4, 6, 8, 12, 16 and 26 weeks.  Every effort will be 
made to obtain a sputum sample from all patients, but it is recognised that some patients may not have 
produced any sputum in the preceding week and may be unable to do so when requested.  Patients who 
are unable to produce sputum will be classified as being culture negative at that time point.  The proportion 
of culture negative will be those classified as being culture negative divided by the total considered culture 
negative, culture positive or have died. This proportion will be estimated from the Kaplan Meier estimates 
from the time to culture conversion to negative status analysis. 
 
10.4 
TB symptoms 
Each TB symptom will be summarised by n (%): none (0), mild (1), moderate (2), severe (3) at each visit 
collected as per the protocol: baseline, week 8, week 16, end of treatment, 6 and 18 months from end of 
treatment.  
 
In addition, baseline and change from baseline score at each time point listed above for each symptom and 
for total symptom score will be summarised by mean, median, IQR and range.   
 
10.5 
Patient reported health status 
Patient reported health status is measured by the 5 domains of EQ5D.   These will be summarised at 
baseline, week 8, week 16, end of treatment, 6 and 18 months from end of treatment by randomised group 
and change from baseline at each follow-up assessment by mean, median, IQR and range by randomised 
group.  
 
10.6 
Weight 
Baseline weight and change from baseline weight throughout treatment and at 6 and 24 months after the 
end of therapy will be summarised by mean, median, IQR and range 
 
11 Week 26 analysis 
 
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Efficacy Statistical Analysis Plan 
Pg. 14 of 16 
This analysis is culture conversion status at week 26 with details outlined in section 10.3 above, with the 
inclusion of culture conversion status at weeks 20 and 23.  
This week 26 analysis will only be performed once all patients have reached the week 26 timepoint. 
12 Pharmacokinetics-Pharmacodynamics (PK-PD) analyses 
Details of the PK parameter estimation and analysis are detailed in a separate PK SAP. PK-PD analyses will 
be described in a separate PK-PD SAP.   
13 Sub-group analyses 
To assess consistency of results, exploratory sub-group analyses of the primary endpoint on the MITT analysis 
population will be considered. For example, depending on numbers consideration will be given to subgroup 
analyses by: age; gender; race; smoking status; HIV status; cavitation, initial bacterial load in sputum as 
indicated by baseline TTP result from MGIT; ARV taken or not during the treatment period, geographical 
location. 
14 Reasons for treatment failure as determined by the local PI 
Reason(s) that led the site investigator to conclude that an individual patient failed treatment or relapsed 
will be classified as a) bacteriology alone, b) clinical deterioration alone, c) radiological deterioration alone, 
d) bacteriology plus clinical deterioration, e) bacteriology plus radiological deterioration, f) clinical
deterioration plus radiological deterioration, or g) bacteriology plus clinical deterioration plus radiological
deterioration.  These classifications will be tabulated and compared to outcomes derived from the
algorithm described in section 6.
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15 APPENDICES 
Appendix  1. Derived MGIT results per visit 
Derived sample Culture 1 
(Visit X ) 
Derived Sample Culture 2 
(Visit X) 
Final Derived Result 
for Visit X 
Positive 
Missing/Negative/Contaminated 
Positive 
Negative 
Missing/Contaminated 
Negative 
Contaminated 
Missing/Contaminated 
Contaminated 
Pg. 15 of 16 
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Efficacy Statistical Analysis Plan 
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Appendix 2: Interpretation of Relapse/Re-infection using Whole Genome Sequence (WGS) 
The purpose of the WGS analysis is to determine if the two M. tuberculosis strains from a given patient (positive culture at baseline and at or after the 
end of treatment) can be considered the same (treatment failure/bacteriologic failure or relapse/bacteriological relapse), or different (re-
infection/bacteriological re-infection).   To do this, WGS of the two M. tuberculosis strains are compared, the number of   SNPs/variants determined, 
and the criteria outlined below followed.  These cut offs have been determined from previously published reports (REMoxTB and RIFAQUIN trials) that 
show a clear genetic distinction between relapse and re-infection cases of M.tb infection. 
>12 and <100 SNPs different = Indeterminate.  These results will be reviewed on case by case basis and are likely to be rare.  Additional
sequence analysis may be performed and/or additional samples may need to be tested.  Any additional investigations will be documented on
-
will be considered a relapse unless there is sufficient evidence to support a classification of re-infection. 
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Statistical Analysis Plan 
 
Protocol Title: A Phase 3 partially-blinded, randomised trial assessing the safety and efficacy of various 
doses and treatment durations of linezolid plus bedaquiline and pretomanid in participants with 
pulmonary infection of either extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment 
intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB).   
 
Protocol Number: NC-007-(B-Pa-L). 
Version: 3.0 
 
Author name: 
Stella Maris Fabiane 
Author position: 
Statistician, UCL 
Author signature: 
 
Date: 
 
 
 
Approval name: 
Daniel Everitt 
Approval position: 
Vice President and Chief Medical Officer,  
TB Alliance 
Approval signature: 
 
Date: 
 
 
 
 
 
 
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ZeNix Statistical Analysis Plan v3.0.docx  
 
Pg. 2 of 35 
 
Version History: 
Version Number/Date 
Change 
0.1 07 August 2017 
First version drafted 
0.2 21 August 2017 
Circulated to wider team after incorporating comments from DE 
0.3 01 Sep 2017 
Circulated to team after incorporating comments from CM and PPD 
0.4 06 Sep 2017 
Circulated new draft following call 06 Sept 2017 
1.1 2019 
new draft with updates, removal of original appendix 1, and addition of week 
26 analysis 
1.2 March 2020 
General corrections 
1.3 April 2020 
Added surgery clause 
1.4 26 May 2020 
Added COVID clause 
1.5 June 2020 
Minor amendments after review meeting 
2.0 August 2020 
Up versioned v1.5 to v2.0 
2.1 November 2020 
Combining efficacy and safety SAP 
2.2 November 2020 
Incorporation of comments after review meeting 
2.3 December 2020 
New round of comments 
2.4 January 2021 
New round of comments 
2.5 January 2021 
New round of comments 
3.0 January 2021 
Last comments (about ECG) incorporated, upversioned to 3.0 
 
 
 
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List of Abbreviations 
AE  
Adverse Event  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
B 
Bedaquiline 
BLQ 
Below the Limit of Quantitation 
BMI 
Body Mass Index 
BPaL 
Combination of Bedaquiline plus Pretomanid plus Linezolid 
DMID 
Division of Microbiology and Infectious Disease 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
(e)CRF 
(electronic) Case Report Form 
GGT 
Gamma-glutamyl Transferase 
HeR 
Heart Rate 
HIV  
Human Immunodeficiency Virus 
HGB 
Hemoglobin 
ITT 
Intent to Treat 
IMP 
Investigational Medication Product 
IWRS 
MeDRA 
Interactive Web Response System 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
MDR-TB Multi Drug Resistant Tuberculosis 
MGIT™ 
Mycobacterial Growth Indicator Tube 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per Protocol 
PK 
PT 
Pharmacokinetic 
Preferred term 
PR 
PR interval – time from start of P wave to start of QRS complex on ECG 
QT 
QT interval – time from start of Q wave to end of T wave on ECG 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QRS 
QRS complex (ventricular depolarization) on ECG 
RBC 
Red Blood Cell 
RR 
RR interval – time between two QRS complexes on ECG 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TB 
Tuberculosis 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
XDR-TB 
Extensively Drug Resistant Tuberculosis 
 
 
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CONTENTS 
1 
Introduction ........................................................................................................................... 7 
1.1 
Trial Intervention .............................................................................................................. 8 
1.2 
Randomisation, Stratification and Blinding ........................................................................... 8 
2 
Outcome measures ................................................................................................................. 9 
2.1 
Primary Efficacy Endpoint .................................................................................................. 9 
2.2 
Secondary Efficacy Endpoints ........................................................................................... 10 
2.3 
Secondary Safety and Tolerability Outcomes ...................................................................... 10 
2.3.1 
All-cause mortality ................................................................................................... 10 
2.3.2 
Treatment emergent adverse events (TEAEs) ............................................................... 10 
2.3.2.1 
Incidence ............................................................................................................ 11 
2.3.2.2 
Severity............................................................................................................... 11 
2.3.2.3 
Drug relatedness .................................................................................................. 11 
2.3.2.4 
Seriousness ......................................................................................................... 11 
2.3.2.5 
Leading to treatment discontinuation...................................................................... 11 
2.3.2.6 
Leading to study discontinuation ............................................................................ 11 
2.3.2.7 
Leading to pauses of linezolid ................................................................................. 11 
2.3.2.8 
Leading to linezolid reductions ............................................................................... 11 
2.3.2.9 
Leading to death .................................................................................................. 12 
2.3.2.10 
Liver-related, liver and drug related and serious liver-related TEAEs ......................... 12 
2.3.3 
Clinical safety laboratory measurements ..................................................................... 12 
2.3.4 
Electrocardiogram ................................................................................................... 12 
2.3.5 
Peripheral neuropathy.............................................................................................. 12 
2.3.6 
Changes in ophthalmology ........................................................................................ 12 
2.3.7 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) ...................... 12 
2.4 
Exploratory Objectives..................................................................................................... 13 
2.4.1 
Subgroup analyses ................................................................................................... 13 
3 
Definitions and data handling issues ....................................................................................... 13 
3.1 
Definitions ..................................................................................................................... 13 
3.1.1 
Positive culture........................................................................................................ 13 
3.1.2 
Culture negative status ............................................................................................. 13 
3.2 
Bacteriological failure, Relapse or Reinfection ..................................................................... 14 
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3.2.1 
Treatment failure..................................................................................................... 14 
3.2.2 
Relapse .................................................................................................................. 14 
3.2.3 
Reinfection ............................................................................................................. 14 
3.2.4 
Inability to produce sputum ...................................................................................... 14 
3.2.5 
Isolated positive cultures .......................................................................................... 15 
3.3 
Major Protocol Deviations for Analysis............................................................................... 15 
3.4 
Trial Timings .................................................................................................................. 15 
3.5 
Definition of adequate treatment...................................................................................... 16 
3.6 
Determining cause of death ............................................................................................. 16 
3.7 
General Statistical Considerations for Safety Analysis ........................................................... 17 
3.8 
Newly notable abnormalities ............................................................................................ 17 
4 
Sample Size .......................................................................................................................... 17 
5 
Analysis populations ............................................................................................................. 18 
6 
Endpoint definitions .............................................................................................................. 18 
6.1 
ITT Population ................................................................................................................ 18 
6.1.1 
Unassessable status (late exclusions) .......................................................................... 18 
6.1.2 
Favourable status (all analysis populations) ................................................................. 19 
6.1.3 
Unfavourable status ................................................................................................. 19 
6.2 
MITT Population ............................................................................................................. 19 
6.2.1 
Unassessable status (additional exclusions from MITT analysis) ...................................... 19 
6.2.2 
Unfavourable status ................................................................................................. 20 
6.3 
PP Population................................................................................................................. 20 
6.3.1 
Unassessable status (additional exclusions from PP) ..................................................... 20 
6.3.2 
Unfavourable status ................................................................................................. 20 
6.4 
Lost to Follow-up or Early Withdrawal ............................................................................... 21 
6.5 
Baseline comparisons of key characteristics ........................................................................ 22 
7 
Efficacy Statistical Analyses .................................................................................................... 22 
7.1 
Primary endpoint analysis ................................................................................................ 22 
7.1.1 
Sensitivity analyses of primary endpoint ..................................................................... 23 
7.1.2 
Secondary efficacy analyses of primary endpoint.......................................................... 23 
7.1.2.1 
Time to event unfavorable outcome analysis ............................................................ 23 
7.2 
Secondary efficacy endpoints ........................................................................................... 23 
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7.2.1 
Incidence of bacteriologic failure or relapse at 18 months after the end of treatment........ 24 
7.2.2 
Time to sputum culture conversion to negative status................................................... 24 
7.2.3 
Culture conversion status at 4, 6, 8, 12, 16 and 26 weeks............................................... 24 
7.2.4 
TB symptoms .......................................................................................................... 24 
7.2.5 
Participant reported health status .............................................................................. 24 
7.2.6 
Weight and BMI....................................................................................................... 24 
7.3 
Week 26 analysis ............................................................................................................ 25 
7.4 
Sub-group analyses ......................................................................................................... 25 
7.5 
Reasons for treatment failure as determined by the local PI.................................................. 25 
7.6 
Minimum Inhibitory Concentrations .................................................................................. 25 
8 
Safety Statistical Analysis....................................................................................................... 26 
8.1.1 
Serious TEAEs.......................................................................................................... 26 
8.1.2 
TEAEs Leading to Early Withdrawal............................................................................. 26 
8.1.3 
TEAEs leading to death ............................................................................................. 26 
8.1.4 
Liver-related TEAEs .................................................................................................. 27 
8.1.4.1 
Liver and drug-related TEAEs.................................................................................. 27 
8.1.4.2 
Serious liver-related TEAEs..................................................................................... 27 
8.1.4.3 
Incidence of hepatotoxicity .................................................................................... 27 
8.1.5 
Additional TEAE summary ......................................................................................... 27 
8.1.6 
Additional AE summary after 14 days post end of treatment .......................................... 27 
8.2 
Clinical Evaluation ........................................................................................................... 27 
8.2.1 
Clinical Laboratory Evaluation.................................................................................... 27 
8.2.2 
Myelosuppression.................................................................................................... 28 
8.2.3 
Vital Sign Measurements .......................................................................................... 29 
8.3 
Electrocardiogram .......................................................................................................... 29 
8.4 
Ophthalmology Tests....................................................................................................... 30 
8.5 
Peripheral Neuropathy .................................................................................................... 30 
8.6 
Pharmacokinetics/Pharmacodynamics ............................................................................... 30 
9 
Participant Disposition ............................................................................................................ 31 
9.1 
Participant Disposition..................................................................................................... 31 
9.2 
Study protocol deviations ................................................................................................ 31 
10 
Demographics and baseline characteristics ........................................................................... 31 
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10.1 
Demographics ................................................................................................................ 31 
10.2 
Baseline characteristics.................................................................................................... 31 
10.3 
Medical History .............................................................................................................. 32 
10.4 
Inclusion and Exclusion Criteria ......................................................................................... 32 
11 
Treatment and Medications ................................................................................................ 32 
11.1 
Prior and Concomitant Medications................................................................................... 32 
11.1.1 
Prior Medications .................................................................................................... 33 
11.1.2 
Concomitant Medications ......................................................................................... 33 
11.1.3 
Concomitant Procedures........................................................................................... 33 
11.1.4 
Study Treatment Exposure ........................................................................................ 33 
12 
Appendices ....................................................................................................................... 34 
12.1 
Derived MGIT results per visit ........................................................................................... 34 
12.2 
Interpretation of Relapse/Re-infection using Whole Genome Sequence (WGS) ........................ 35 
 
 
 
 
 
 
1 INTRODUCTION 
 
This document outlines the statistical analysis for both efficacy and safety. This includes, but is not limited 
to, the efficacy primary endpoint, secondary efficacy and safety endpoints, populations, TB symptoms, 
EQ5D, adherence and weight. Summaries of plasma drug concentrations and PK parameters will also be 
described. 
 
ZeNix is a phase 3 partially-blinded, randomised trial assessing the safety and efficacy of various doses and 
treatment durations of linezolid plus bedaquiline and pretomanid in participants with pulmonary infection 
of either extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB or treatment intolerant or non-
responsive multi-drug resistant tuberculosis (MDR-TB).    
 
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1.1 TRIAL INTERVENTION 
 
Participants will have a screening period of up to 9 days and will be randomised to receive one of the 
following 4 active treatment arms: 
 
1. Linezolid 1200 mg daily for 26 weeks 
• 
2 linezolid 600 mg active tablets once daily for 26 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
2. Linezolid 1200 mg daily for 9 weeks 
Weeks 1-9  
• 
2 linezolid 600 mg active tablets once daily for 9 weeks  
• 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
3. Linezolid 600 mg daily for 26 weeks 
• 
1 linezolid 600 mg active tablet once daily for 26 weeks 
• 
1 placebo linezolid 600 mg tablet once daily for 26 weeks  
• 
1 placebo linezolid 300 mg half tablet once daily for 26 weeks 
 
4. Linezolid 600 mg daily for 9 weeks 
Weeks 1-9 
• 
1 linezolid 600 mg active tablet once daily for 9 weeks 
• 
1 placebo linezolid 600 mg tablet for 9 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 9 weeks 
Weeks 10-26 
• 
2 placebo linezolid 600 mg tablets once daily for 17 weeks 
• 
1 placebo linezolid 300 mg half tablet once daily for 17 weeks 
 
1.2 RANDOMISATION, STRATIFICATION AND BLINDING 
 
Participants will be randomised to one of the four regimens in a 1:1:1:1 ratio, using an interactive web 
response system (IWRS), stratified by HIV status (positive vs. negative) and type of TB (XDR-TB vs. MDR-TB).  
A total of up to 180 participants, male and female, aged 14 and over, will be enrolled. Bedaquiline and 
pretomanid treatment will not be blinded.  Linezolid treatment dose and duration will be double-blinded. 
After all participantscomplete their treatment phase, the statisticians will no longer be blinded to 
treatment allocation (see blinding plan for more detail). 
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Each participant will receive 26 weeks of treatment.  If participant’s sputum sample is culture positive 
between week 16 and week 26 treatment visits and their clinical condition suggests they may have an 
ongoing TB infection, Investigator may consider extending current treatment to 39 weeks.  If the culture 
results between week 16 and week 26 are contaminated, missing or considered an isolated positive 
without clinical significance, available culture results should be used to make this decision. All decisions 
regarding treatment extension should be discussed and approved by the Sponsor Medical Monitor before 
implementation.   Participants will be followed for 18 months after end of treatment. 
 
The primary efficacy analysis will be conducted using culture results from liquid culture (MGIT).  No formal 
statistical comparisons between the randomised groups will be made. 
 
 
 
 
2 OUTCOME MEASURES 
 
2.1 PRIMARY EFFICACY ENDPOINT 
 
The primary efficacy endpoint will be the incidence of bacteriologic failure or relapse or clinical failure at 6 
months after the end of therapy.  See section 6 for the detailed definition of an “unfavourable response”.   
 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) analysis; a 
modified intent to treat (MITT) analysis and a per protocol (PP) analysis.   
 
The “unfavourable” rates in any defined ‘ITT’ population will likely be increased by factors other than 
bacteriologic or clinical treatment failure and relapse. The MITT analysis will therefore be considered 
primary for publication purposes.  However, we recognize that FDA and other regulatory agencies will 
consider the ITT analysis primary. 
 
NB: In the event that more than 10% of participants within any randomised group are culture positive at 4 
months and have their treatment extended for a further 3 months, the primary endpoint analysis will be 
defined as 15 months from start of therapy for all.  For each participant the assessment closest to this time 
point will be taken as this 15 month (from start of therapy) endpoint. 
 
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2.2 SECONDARY EFFICACY ENDPOINTS 
 
Secondary endpoints which will be analysed according to the MITT population (unless otherwise stated) 
include: 
• 
Proportion of favourable at 18 months after the end of treatment (ITT, MITT and PP populations)  
• 
Incidence of bacteriologic failure or relapse, or clinical failure through follow up until 18 months 
after the end of treatment. 
• 
Time to unfavourable status (ITT, MITT and PP populations)  
• 
Time to sputum culture conversion to negative status through the treatment period  
• 
Culture conversion status at 4, 6, 8, 12, 16 and 26 weeks (ITT population) 
• 
Change in weight and BMI from baseline 
• 
Change in TB symptoms from baseline 
• 
Change in participant reported health status from baseline 
 
2.3 SECONDARY SAFETY AND TOLERABILITY OUTCOMES 
 
All safety summaries in this section will be presented for all participants in the Safety analysis set, as 
defined in §5, unless otherwise stated.  
 
Adverse event verbatim reported terms will be coded by system organ class (SOC) and preferred term (PT) 
using the latest version of MedDRA.  
 
Adverse events are defined as either:  
• 
Treatment emergent adverse events (TEAEs) which are adverse events (AEs) which started or 
worsened on or after the first administration of IMP up to and including 14 days after the last study 
drug administration, or  
• 
Post-treatment AEs which are AEs that start or worsen more than 14 days after the last 
administration of IMP. 
 
Secondary safety and tolerability are outlined below in §2.3.1-2.3.6. These data will be presented as 
descriptive analyses, and no inferential tests will be carried out. 
 
2.3.1 All-cause mortality  
The proportion of participants who died from any cause during the study 
 
2.3.2 Treatment emergent adverse events (TEAEs)  
 
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2.3.2.1 Incidence 
The proportion of participants who experienced at least one treatment-emergent adverse event (TEAE). 
 
2.3.2.2 Severity 
Of those experiencing at least one TEAE, the highest grade experienced. The highest grade experienced is 
defined as the most extreme severity captured on the Adverse Event CRF page. The possible severities are 
‘Grade 1: Mild,’ ‘Grade 2: Moderate,’ ‘Grade 3: Severe’, and ‘Grade 4: Potentially life-threatening.’   
 
2.3.2.3 Drug relatedness 
The proportion of participants experiencing at least one TEAE related to any study medication. A related AE 
is defined as ‘Possibly’, ‘Probably’, or ‘Certainly’ related to study medication by the investigator. 
 
2.3.2.4 Seriousness 
The proportion of participants experiencing at least one serious TEAE. A serious AE (SAE) is defined as any 
untoward medical occurrence that at any dose results in death, is life-threatening, is a congenital 
anomaly/birth defect, requires in-participant hospitalisation or prolongation, results in significant 
disability/incapacity, or is a medically important event. 
 
2.3.2.5 Leading to treatment discontinuation 
The proportion of participants experiencing a TEAE that led to discontinuation of the whole treatment and 
the proportion of participants experiencing a TEAE that led to the discontinuation of linezolid only. This will 
be AEs where action taken with study treatment is ‘Permanently Discontinued’ for BPaL, or for linezolid 
alone. 
 
2.3.2.6 Leading to study discontinuation 
The proportion of participants experiencing a TEAE that led to study discontinuation. This will be AEs where 
action taken with study treatment is ‘Withdrawn from Study’ or ‘Other Action’. 
 
2.3.2.7 Leading to pauses of linezolid 
The proportion of participants experiencing a TEAE that led to a pause in linezolid. 
 
2.3.2.8 Leading to linezolid reductions  
The proportion of participants experiencing a TEAE that led to a reduction in linezolid dose. 
 
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2.3.2.9 Leading to death 
The proportion of participants experiencing a TEAE that led to death. This will be AEs where the answer to 
‘Outcome’ on the AE form is ‘Fatal’. 
2.3.2.10  Liver-related, liver and drug related and serious liver-related TEAEs 
The proportion of participants experiencing liver related, drug and liver related and serious liver related 
TEAEs. Liver related AEs are those where the preferred term specifies ‘Hepatic’. Drug and liver related are 
those AEs that are liver related and related to a drug (‘Possibly’, ‘Probably’, and ‘Certainly’) and serious liver 
related TEAEs are those that are liver related and the AE is considered serious (as described in §2.3.2.4). 
2.3.3 Clinical safety laboratory measurements 
The incidence of newly notable (an abnormality observed post baseline that meets the notable criteria) 
grade 3 or 4 severity for laboratory parameters according to DMID grading. Participants are considered to 
have notable laboratory abnormalities if his/her response falls within the specified definitions (see Tables 1 
and 2 in §8.2.1) at least once during the treatment period.  
2.3.4 Electrocardiogram  
ECG results (heart rate, RR interval, PR interval, QRS interval, QT interval and QTcF interval), which are read 
by a central cardiology service, observed measurements and change from baseline. QT/QTcF intervals and 
their change from baseline will be categorised according to §8.4 below. The EGC results will be considered 
at baseline, week 8, week 16, end of treatment (week 26 or 39), and early withdrawal in all participants. 
2.3.5 Peripheral neuropathy 
The observed and change from baseline in peripheral neuropathy (from the peripheral neuropathy 
assessment form) at week 8, week 16, end of treatment (week 26 or 39), month 6 follow-up and early 
withdrawal. 
2.3.6 Changes in ophthalmology 
The change (increase or decrease) in visual acuity and colour vision, and lens opacity from baseline at end 
of treatment (week 26 or 39), follow-up (week 4 and 12, respectively) and early withdrawal. 
2.3.7 Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) 
This SAP provides descriptive summaries of plasma drug concentrations and PK parameters only. Full 
details on the full analysis of PK and PK/PD data can be found in the PK/PD modelling SAP. 
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2.4 EXPLORATORY OBJECTIVES 
2.4.1 Subgroup analyses 
Subgroup analyses will be carried out and analysed for the primary efficacy endpoint (as described in 
§2.1 for the MITT population). These subgroups are described in §7.4.
3 DEFINITIONS AND DATA HANDLING ISSUES 
3.1 DEFINITIONS 
3.1.1 Positive culture  
Positive culture refers to the culture being positive for MTB.  
The MGIT culture results that are positive with contamination, contaminated, or with no result will be 
treated as missing.  
Two sputum samples are collected at each scheduled visit, excluding at weeks 5,7,14 and 18, throughout 
treatment and follow-up.  The culture result for a given visit is established using all samples obtained for 
that visit. A positive culture takes precedence over a negative culture at the same visit. Refer to Appendix 
12.1 for further details. 
3.1.2 Culture negative status  
Culture negative status is achieved when a participant produces at least 2 negative culture results at 
different visits (at least 7 days apart) without an intervening positive culture result for MTB.  The date of 
the first negative culture of these two is the date at which culture negative status was obtained.  Once 
obtained, culture negative status continues until there are two positive cultures at different visits (at least 7 
days apart), without an intervening negative culture, or until there is a single positive culture not followed 
by two negative cultures.  Culture negative status can be achieved at any time during treatment or follow-
up but before any re-treatment. Culture negative status can be re-established.  
Participants with two contaminated or missing samples at a given visit will be asked to return to produce 
two more sputum samples.   
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3.2 BACTERIOLOGICAL FAILURE, RELAPSE OR REINFECTION 
 
3.2.1 Treatment failure  
Treatment failure is defined as being declared an unfavourable status (as defined in §6) at or before the 
end of treatment or failing to attain culture negative status and being declared an unfavourable outcome or 
participant is withdrawn at or before the end of treatment for clinical (TB) reasons including being re-
treated (or changing from protocol treatment) for TB. 
 
3.2.2 Relapse  
Relapse is defined as  
• 
failing to maintain culture negative status or  
• 
being declared an unfavourable outcome after the end of treatment in those participants who 
attained culture negative status by the end of treatment, and had culture conversion to positive 
status with an MTB strain that is genetically identical to the infecting strain at baseline or  
• 
being declared an unfavourable outcome after the end of treatment in those participants who 
attained culture negative status by the end of treatment and were withdrawn for clinical (TB) 
reasons including being re-treated (or changing from protocol treatment) for TB.   
Details are given in Appendix 12.2. 
 
3.2.3 Reinfection  
Reinfection is defined as failing to maintain culture negative status or being declared an unfavourable 
outcome (including being withdrawn for clinical (TB) reasons including being re-treated or changing from 
protocol treatment for TB) after the end of treatment in those participants who attained culture negative 
status by the end of treatment and had culture conversion to positive status with a MTB strain that is 
genetically different from the infecting strain at baseline. If reinfection cannot be distinguished from 
relapse, the participant will be assumed to have relapsed. A single positive sample will be sufficient for 
strain typing to compare to baseline. Full details are in Appendix 12.2.  
 
3.2.4 Inability to produce sputum 
In general, inability to produce sputum is treated as being equivalent to having a negative culture result (if 
and only if no other culture result is produced at that visit) 
.  This includes:  
- 
the rare situation where a participant never achieves culture negative status due to inability to 
produce sputum, but completes follow-up without clinical or microbiological evidence of relapse.   
- 
during the COVID-19 lockdown situation where this data is collected remotely/telephonically 
 
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3.2.5 Isolated positive cultures 
It is known that occasionally participants produce sputum samples that are “isolated positives”, that is a 
positive culture preceded by a series of negative cultures and followed thereafter by at least 2 negative 
cultures without an intervening positive result. This phenomenon may be the result of a sealed cavity 
breaking down or laboratory contamination and does not in itself signify that the participant is relapsing. In 
the event of a single positive culture result occurring in a participant who has previously been classified as 
having culture negative status (in the absence of any retreatment), the participant will not be classified as 
a recurrence unless a second positive culture result is obtained at a separate visit (at least 7 days apart) 
without an intervening negative culture or unless the participant is lost to follow up or completes the study 
(and is unable to be brought back) before two negative cultures are obtained. As there is a higher incidence 
of positives with liquid culture and sometimes even serial “isolated positives” the clinical condition of the 
participant will also be considered in deciding whether the participant has an unfavourable outcome and 
re-treatment is indicated. 
To expand a bit, most of the experience with isolated positives has been with solid culture. Because liquid 
culture is more sensitive, it is possible that more than one isolated positive may occasionally occur. 
Therefore, the clinical condition of the participant will also be considered when deciding whether re-
treatment is indicated and in determining the outcome. For example, if a participant after being culture 
negative has two positive cultures in a row, but is deemed to be doing well clinically, the investigator may 
choose to leave the participant untreated on clinical grounds. In such a case, so long as two consecutive 
negative cultures are eventually obtained in the absence of treatment, the participant will not be classified 
as an unfavourable outcome. 
 
3.3 MAJOR PROTOCOL DEVIATIONS FOR ANALYSIS  
 
A major protocol deviation for analysis is defined as a serious protocol deviation which is likely to affect to a 
significant degree the scientific value of the trial.  These participants will be included in the ITT and MITT 
analyses, but not in the Per Protocol analysis.  A list of all major protocol deviations for analysis will be 
approved by a review committee before all planned analyses.   
 
3.4 TRIAL TIMINGS 
 
In all analyses, visit date rather than day or week number will be used to define the timing of events.   For 
all participants, the 6-month regimen will be taken as a total of 26 weeks, i.e. 182 dosing days (for B-Pa), 
from the start of therapy, after accounting for any treatment interruptions.  For those who extend 
treatment to 9 months this will be 39 weeks (273 days) (for B-Pa) from start of therapy, again after 
accounting for any treatment interruptions.    
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Unscheduled visits and visits outside of these windows will be slotted into windows as appropriate. Visits 
falling outside of the defined protocol visit windows will be put into separate visits so that all data, both 
collected at scheduled and unscheduled time points, are used. 
For the end of treatment visit (months 6/9), a ±1-week window will be applied (as per the protocol).   For 
the 3-monthly visits after the end of therapy, a window of ±2 weeks will be applied (as per the protocol). 
Additional programming will be required for cases where end of treatment date is not clearly recorded.    
In the event that more than 10% of participants within any randomised group have their treatment 
extended for a further 3 months, the primary endpoint analysis will be defined as 15 months from start of 
therapy for all participants.  In this case the visit date for the endpoint analysis will be chosen as the one 
closest to 65 weeks (26+39) from start of therapy (unless participant is declared unfavourable before this 
date).  
The treatment period is defined as 6 months (total of 26 weeks) of the B-Pa therapy (linezolid may be 
stopped early) plus any days made up for interrupted doses of B-Pa therapy (or 9 months in those who are 
extended). 
The follow-up period is defined as the period after the last treatment dose to the end of follow-up. 
 
3.5 DEFINITION OF ADEQUATE TREATMENT  
 
The definition of adequate treatment sets a limit for the amount of treatment missed.  Participants not 
taking the adequate amount of treatment by this definition will be excluded from the PP analysis. 
For participants treated for 6 months with no treatment extension, to meet the definition of adequate 
treatment they must have taken at least 146 doses (80%) of their allocated 182 day (26 weeks) treatment 
regimen within 238 days of starting therapy (i.e. 26 weeks plus an allowable 56 day halt (including a 
maximum of 35 consecutive days) as per the protocol).  
For participants who have their treatment extended to 9 months (39 weeks), to meet the definition of 
adequate treatment, they must have taken at least 219 doses (80%) of their allocated 273 day (39 weeks) 
treatment within 364 days (i.e. 39 weeks plus an allowable 91 day halt (including a maximum of 35 
consecutive days) as per the protocol). 
A dose is defined as taking the required daily dose of both pretomanid and bedaquiline. 
 
3.6 DETERMINING CAUSE OF DEATH 
 
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A list of all TB-related and non-TB-related deaths will be generated and approved by a review committee of 
physicians not associated with the trial before database lock. Similarly, a list of violent or accidental deaths 
will be generated.  
 
3.7 GENERAL STATISTICAL CONSIDERATIONS FOR SAFETY ANALYSIS 
 
If there are multiple assessments in a visit, the highest grade non-missing value within a visit will be used in 
the summaries, however all will be shown in the listings. If numeric data is beyond range of lab detectability 
and result is showed as “<XX” or “>XX” then the numeric XX value will be used for summary statistics. 
There will be no specific strategy to deal with missing data. A complete case analysis will be performed. 
All statistical analyses tables, listings and figures will be produced using STATA Version 16.0 or higher. 
 
3.8 NEWLY NOTABLE ABNORMALITIES  
 
Newly notable laboratory abnormality is defined as an abnormality observed post baseline that meets the 
notable criteria in Table 1 and that did not exist at baseline. Participants can still meet the criteria for a 
newly notable laboratory abnormality if the baseline value is missing.  
 
 
4 SAMPLE SIZE  
 
In order to fulfil the objective of the study, it is planned to randomise 45 XDR-TB, pre-XDR and/or MDR 
treatment intolerant/non-responsive -TB participants per group. A sample size of 45 per arm will provide 
more than 90% power to demonstrate that the lower bound of the 95% confidence interval of this estimate 
is greater than 50%, using a 2-sided 5% significance level. This assumes that the true cure rate is 80 percent. 
 
 
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5 ANALYSIS POPULATIONS  
Participants who are never culture positive during the baseline period, (day 1 through week 4) but are 
eligible based on documented MTB by culture or molecular test within 3 months prior to screening will be 
included in all analysis populations. 
 
The analysis populations for efficacy analyses are: 
 
• 
The Intent to treat (ITT) population is defined as all randomised participants excluding late 
screening failures (see §6.1) 
• 
The Modified intent to treat (MITT) population is defined as the ITT population with extra 
exclusions (See §6.2) 
• 
The Per-protocol (PP) population is defined as the MITT population with extra exclusions (see §6.3) 
• 
The Safety population, defined as all randomised participants who received at least one dose of 
study treatment. Participants will be analysed as to the treatment they actually received regardless 
of randomised allocation. 
 
Exclusions from these populations will be reported as “unassessable” status and are described below.  
 
6 ENDPOINT DEFINITIONS 
Participants will be classified as having a favourable, unfavourable or unassessable status at 6 months after 
the end of therapy. Participants excluded from analysis are considered unassessable. 
 
6.1 ITT POPULATION 
The ITT population is defined as all randomised participants excluding late screening failures. 
 
6.1.1 Unassessable status (late exclusions) 
Participants found to be ineligible (late exclusions from the study), based on data collected prior to 
randomisation, including participants who do not have documented evidence of MTB within 3 months of 
screening. 
 
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6.1.2 Favourable status (all analysis populations) 
Participants with a negative culture status at 6 months from end of therapy who had not already been 
classified as having an unfavourable outcome, and whose last positive culture result (“isolated positive 
culture”) was followed by at least two negative culture results. 
 
6.1.3 Unfavourable status  
Participants in the ITT analysis population who do not have a favourable outcome at 6 months from end of 
therapy will be considered to have an unfavourable response in the ITT analysis.   
 
6.2 MITT POPULATION 
 
6.2.1 Unassessable status (additional exclusions from MITT analysis) 
In addition to those excluded from the ITT analysis (see §6.1.1), the following participants will be excluded: 
1. Participants who, having completed treatment, are lost to follow-up or withdrawn from the study, 
their last status being culture negative and their last positive culture result (“isolated positive 
culture”) followed by at least two negative culture results at different visits (at least 7 days apart, 
without an intervening positive culture) 
2. Women who become pregnant during treatment and stop their allocated treatment  
3. Participants with suspected/confirmed COVID19 during treatment and stop their allocated 
treatment 
4. Participants who died during treatment from violent or accidental cause (e.g. road traffic accident). 
N.B.: This does not include death from suicide, which will be considered an unfavourable outcome.  
5. Participants who die during follow-up (after the end of treatment) with no evidence of failure or 
relapse of their TB, their last status being culture negative and their last positive culture result 
(“isolated positive culture”) followed by at least two negative culture results at different visits (at 
least 7 days apart), and who have not already been classified as unfavourable.  
6. Participants who, after being classified as having culture negative status, are re-infected with a 
strain that is genetically different from the initial strain (see Appendix 12.2).  
7. Participants who are able to produce sputum at their primary endpoint visit, whose sputum 
samples are all contaminated or missing, who cannot be brought back for repeat cultures, provided 
they have not already been classified as unfavourable and provided their last positive culture was 
followed by at least two negative cultures.  N.B.:  This does not apply to participants who are 
unable to produce sputum, or to participants who are able to be brought back subsequently and 
produce negative cultures. 
 
Participants in categories 1-7 above who had already been classified as having an unfavourable outcome 
will not be excluded. 
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6.2.2 Unfavourable status 
1.
Participants not classified as having achieved or maintained culture negative status when last seen,
or
2.
Participants previously classified as having culture negative status who, following the end of
treatment, have two positive cultures without an intervening negative culture (however, see §3.1.2
for an exception), or
3.
Participants who had a positive culture not followed by at least two negative cultures when last
seen, or
4.
Participants dying from any cause during treatment, except from violent or accidental cause (e.g.
road traffic accident), not including suicide (e.g., suicide will be considered an unfavourable 
outcome), or
5.
Participants definitely or possibly dying from TB related cause during the follow-up phase, or
6.
Participants requiring an extension of their treatment beyond that permitted by the protocol a
restart or a change of treatment for any reason except reinfection or pregnancy, or
7.
Participants who have had surgery and the resected tissue is cultured and is positive for MTB.
8.
Participants lost to follow up or withdrawn from the study before the end of treatment.
6.3 PP POPULATION 
6.3.1 Unassessable status (additional exclusions from PP) 
In addition to the exclusions from the MITT population, the following will apply to the PP population: 
1.
Participants lost to follow-up or withdrawn before the end of treatment due to reasons other than 
treatment failure, unless they have already been classified as having an unfavourable outcome.
2.
Participants whose treatment was modified or extended (beyond what is permitted in the protocol) for 
reasons (e.g. an adverse drug reaction) other than an unfavourable therapeutic response to treatment, 
unless they have already been classified as having an unfavourable outcome.
3.
Participants not meeting the definition of having received an adequate amount of their allocated study 
regimen (see §3.7 for definition), provided this is not due to unfavourable outcome.
4.
Participants who are classified as “major protocol deviations for analysis” (see §3.3), unless they have 
already been classified as having an unfavourable outcome on the basis of data obtained prior to the 
protocol deviation. 
A list of all protocol deviations will be compiled throughout the course of the study. 
6.3.2 Unfavourable status  
Points 1-7 in §6.2.2 Unfavourable status in the MITT Population section above. 
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6.4 LOST TO FOLLOW-UP OR EARLY WITHDRAWAL 
Lost to Follow-up or Early Withdrawals before the end of the treatment (month 6 or 9) are considered as 
unfavourable outcomes for ITT and MITT.  However, these participants will be excluded from the Per 
Protocol analysis.  The MITT and Per Protocol analyses will consider Lost to Follow-up after end of 
treatment  as unassessable unless at the time of default from follow-up the participant a) was already 
classified as having an unfavourable outcome, b) did not have culture negative status, or c) had a positive 
culture result (“isolated positive culture”) not followed by at least two negative culture results at different 
visits (at least 7 days apart), in which cases the participant will be classified as having an unfavourable 
outcome.  We believe this is the most appropriate approach for the primary analysis because together with 
the non-tuberculosis deaths, this group is likely to considerably out-number the bacteriological failures and 
relapses.  These participants will be considered as having an unfavourable outcome in the ITT analysis. 
 
There is a clear precedent for this analytic approach in other TB trials, and these trials also provide 
examples of why the inclusion of the losses to follow-up as unfavourable greatly affects the results. 
Data from the Priftin trial which led to accelerated approval of rifapentine and a trial conducted by the 
International Union Against TB & Lung Disease (IUATLD) in African and Asian sites illustrate the problems 
associated with classifying all losses to follow-up and deaths as having an unfavourable outcome.  
In the Priftin trial bacteriological relapses occurred in 5% of participants on the rifampicin based regimen 
compared to 11% on the rifapentine based regimen. Approximately one third of participants were lost to 
follow-up and when this group combined with participants unassessable for other reasons were added to 
the bacteriological failures, the rates increased to 53% and 57% respectively. The true bacteriological 
relapses were greatly outnumbered by these other groups. At the time of the licensing submission to the 
FDA it was recognised that because there were a substantial number of participants likely to be 
unassessable the main focus should be on the relapse rates. In the final statistical report the results were 
first reported excluding those unassessable and then assuming all losses had an unfavourable outcome and 
finally assuming all losses had a favourable outcome. 
In the study conducted by the IUATLD the published failure/relapse rates 12 months after stopping 
treatment based on 1044 assessable participants were 4% for the control regimen and 10% and 14% in 
each of the experimental arms. If the 311 unassessable participants were considered to have an 
unfavourable outcome these rates would increase to 24%, 32% and 35% respectively. The 311 unassessable 
participants were not evenly distributed across the three trial arms. There were 42 deaths, of which 20 
occurred in one of the experimental arms (the more efficacious of the two) and 11 in each of the other, a 
difference which was not considered to be due to the treatment, but due to chance. There were also 
imbalances among those without a bacteriological assessment (7 in one arm versus 19 and 22 in the other 
two arms) and in the distribution of losses to follow-up. 
 
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6.5 BASELINE COMPARISONS OF KEY CHARACTERISTICS 
The following baseline characteristics of participants will be summarised:  age, sex, race, geography, 
weight, height, BMI, smoking status, alcohol use, TB type (XDR /non-XDR), HIV status/CD4 count/on ARV, 
cavitation, initial bacterial load in sputum as indicated by baseline Time to Positivity (TTP) result from MGIT, 
baseline drug resistance. 
 
 
7 EFFICACY STATISTICAL ANALYSES 
 
7.1 PRIMARY ENDPOINT ANALYSIS 
The MITT analyses will be considered primary.   
 
The primary efficacy analysis will be conducted using culture results including all TB types.   
 
We will evaluate the hypothesis, separately for each of the experimental B-L-Pa treatment arms, that the 
incidence of bacteriologic failure or relapse or clinical failure (including mortality) -unfavorable outcome - 
at 6 months (26 weeks) after the end of therapy is less than 50%.   
 
Given the uncertainty about the dosing and duration of linezolid and effect on efficacy and safety and to 
control the overall type I error rate the following analysis strategy will be adopted for both the primary and 
secondary analysis populations: 
 
The primary comparison will be for the linezolid 1200mg taken for 26 weeks arm (L1200 26 weeks) with the 
L1200 9 weeks and L600 26 weeks only being tested if L1200 26 weeks is a success.  Similarly, L600 9 weeks 
will only be tested if L600 26 weeks is a success. A Bonferroni adjustment will be made for comparing the 
L1200 9 weeks and L600 26 weeks arms simultaneously, using p<0.025. For these comparisons the lower 
bound of the 97.5% confidence interval will need to exceed 50% for success.   
 
No formal statistical pairwise comparisons between the arms will be performed. 
 
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The proportion of assessable participants with a favourable and unfavourable outcome, with 95% and 
97.5% confidence intervals, will be presented.  For success, the lower bound of the 95% confidence interval 
(or 97.5% as applicable) for a favourable outcome should be above 50%.   
 
This MITT analysis is consistent with the TB literature over the past 50 years.  However, we recognise that 
FDA and other regulatory agencies will consider the ITT analysis primary, where all participants who are 
not proven to have a favourable outcome will be classified as having an unfavourable outcome. 
 
7.1.1 Sensitivity analyses of primary endpoint  
In addition to analysing the primary endpoint data by ITT, MITT and PP and separately for XDR-TB 
participants (key secondary efficacy analyses), it is planned to conduct the following sensitivity analyses: 
 
1. An analysis of participants in the MITT and PP populations where reinfections are classified as 
unfavourable outcomes 
 
2. An analysis of the MITT and PP populations treating all deaths as unfavourable  
 
3.  An analysis of the ITT, MITT and PP populations excluding participants who were never culture 
positive during the baseline period (day1 through week 4), but were eligible based on documented 
MTB by culture or molecular test within 3 months prior to screening 
 
7.1.2 Secondary efficacy analyses of primary endpoint 
7.1.2.1 Time to event unfavourable outcome analysis 
Time to an unfavourable outcome will be analysed with Kaplan Meier plots.  These analyses will be 
performed according to ITT, MITT and PP endpoint classifications.  Time to event will be calculated in days 
from the date of enrolment up to the first date associated with the reason for unfavourable status or (if 
favourable) the date of the 6 month after end of therapy visit. 
 
7.2 SECONDARY EFFICACY ENDPOINTS 
The following analyses will be performed on ITT only unless otherwise stated. 
 
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7.2.1 Incidence of bacteriologic failure or relapse at 18 months after the end of treatment  
Efficacy analyses as described for the primary endpoint will be repeated at the 18 month after the end of 
treatment endpoint as a confirmatory analysis, for ITT, MITT and PP populations 
 
7.2.2 Time to sputum culture conversion to negative status 
For participants with positive culture results from day 1 to week 4 (baseline excluding screening), time to 
culture negative status (first of two negative cultures without an intervening positive culture) will be 
analysed using survival analysis techniques and Kaplan Meier plots. This analysis will be done for the MITT 
population. 
 
7.2.3 Culture conversion status at 4, 6, 8, 12, 16 and 26 weeks 
Participants will be classified as being culture positive, culture negative, dead or unassessable (including 
those without positive culture results from day 1 to week 4) at 4, 6, 8, 12, 16 and 26 weeks.  Every effort 
will be made to obtain a sputum sample from all participants, but it is recognised that some participants 
may not have produced any sputum in the preceding week and may be unable to do so when requested.  
Participants who are unable to produce sputum will be classified as being culture negative at that time 
point.  The proportion of culture negative will be those classified as being culture negative divided by the 
total considered culture negative, culture positive or have died.  
 
7.2.4 TB symptoms 
Each TB symptom will be summarised by n (%): none (0), mild (1), moderate (2), severe (3) at each visit 
collected as per the protocol: baseline, week 8, week 16, end of treatment, 6, 12 and 18 months from end 
of treatment.  
In addition, baseline and change from baseline score at each time point listed above for each symptom and 
for total symptom score will be summarised by mean, median, IQR and range.   
 
7.2.5 Participant reported health status 
Participant reported health status is measured by the 5 domains of EQ5D.   These will be summarised at 
baseline, week 8, week 16, end of treatment, 6, 12 and 18 months from end of treatment by randomised 
group and change from baseline at each follow-up assessment by mean, median, IQR and range by 
randomised group.  
 
7.2.6 Weight and BMI 
Baseline weight and BMI and their change from baseline at weeks 8 and 16, end of treatment, and at 6 and 
18 months after the end of therapy will be summarised by mean, median, IQR and range 
 
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7.3 WEEK 26 ANALYSIS 
This analysis is culture conversion status at week 26 with details outlined in §7.2.3 above, with the inclusion 
of culture conversion status at weeks 20 and 23.  
This week 26 analysis will only be performed once all participants have reached the week 26 time point.  
 
7.4 SUB-GROUP ANALYSES 
To assess consistency of results, exploratory sub-group analyses of the primary endpoint on the MITT 
analysis population will be considered. For example, depending on numbers consideration will be given to 
subgroup analyses by:  
• 
age  
• 
sex 
• 
race  
• 
smoking status  
• 
alcohol use 
• 
HIV status  
• 
cavitation  
• 
initial bacterial load in sputum as indicated by baseline TTP result from MGIT  
• 
ARV taken or not during the treatment period  
• 
geographical location 
• 
Baseline resistance to Bedaquiline (pending numbers) 
 
7.5 REASONS FOR TREATMENT FAILURE AS DETERMINED BY THE LOCAL PI 
Reason(s) that led the site investigator to conclude that an individual participant failed treatment or 
relapsed will be classified as a) bacteriology alone, b) clinical deterioration alone, c) radiological 
deterioration alone, d) bacteriology plus clinical deterioration, e) bacteriology plus radiological 
deterioration, f) clinical deterioration plus radiological deterioration, or g) bacteriology plus clinical 
deterioration plus radiological deterioration.  These classifications will be tabulated and compared to 
outcomes described in§7.1.     
 
7.6 MINIMUM INHIBITORY CONCENTRATIONS 
Minimum Inhibitory Concentrations (MICs) for all three drugs will be tabulated separately. Baseline and 
week 16 values will be tabulated for all participants that have them measured. If multiple visits have the 
measures, week 16 will be used. For descriptive purposes only. A listing will be provided for the participants 
who have MICs for both time points. 
 
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8 SAFETY STATISTICAL ANALYSIS 
All safety endpoints will be presented descriptively, and no inferential tests will be carried out. 
AE duration will be calculated as (Stop Date – Start Date) + 1. Partial dates for AEs will not be imputed. In 
the case where it is not possible to define an AE as treatment-emergent or not, the AE will be classified as 
treatment-emergent. 
At each level of participant summarisation, a participant is counted once within each PT and then each SOC 
if the participant reports one or more events. 
 
 
8.1.1 Serious TEAEs 
Treatment-emergent SAEs will be categorised and presented by SOC and PT in the same manner to that 
described in §8.2.1. Serious SAEs will be presented in the data listing. 
 
8.1.2 TEAEs Leading to Early Withdrawal 
A summary of TEAEs with ‘Action Taken with study treatment’ as ‘Permanently Discontinued’ will be 
presented. At each level of participant summarisation, a participant is counted once if the participant 
reported one or more events. 
The same presentation will be provided for interruption of linezolid (‘Action Taken with Study Treatment 
Linezolid’ is ‘Interrupted’ and action taken for Bedaquiline/Pretomanid is ‘Unchanged’) and Full Regimen 
(‘Action Taken with study treatment Linezolid and Bedaquiline/Pretomanid’ is ‘Interrupted’) and reduction 
of linezolid (‘Action Taken with study treatment Linezolid’ is ‘Reduced’). 
 
8.1.3 TEAEs leading to death 
A summary of TEAEs where the answer to ‘Outcome’ in the AE form is ‘Fatal’ will be presented in a table. 
Data will be categorised and presented by SOC and PT in the same manner to that described in §8.2.1. 
A separate table will be presented that contains the cause of death as well as the following details about 
death (Yes/No): 
• 
Death was related to TB 
• 
Death was violent or accidental (excluding suicide) 
• 
Death was due to suicide 
 
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8.1.4 Liver-related TEAEs 
A summary of TEAEs that has preferred terms under “Hepatic” according to MedDRA dictionary will be 
presented by SOC and PT in the same manner to that described in §8.2.1. 
8.1.4.1 Liver and drug-related TEAEs 
A summary of liver-related TEAEs that are drug related (i.e. ‘Possibly’, ‘Probably’, and ‘Certainly’) will be 
presented by SOC and PT for treatment arm and each treatment drug (Bedaquiline, Pretomanid, and 
Linezolid) in the same manner to that described in §8.2.1. 
8.1.4.2 Serious liver-related TEAEs 
A summary of TEAEs that are liver related and serious (as described in §2.3.2.4) will be presented by SOC and 
PT for treatment arm in the same manner to that described in §8.2.1. 
Liver enzyme profile plots will be provided for participants with treatment emergent serious adverse events 
that have toxicity grade 3 or higher for either AST, ALT, ALP or total bilirubin.  
8.1.4.3 Incidence of hepatotoxicity 
Proportion of participants experiencing at least one liver function test (AST or ALT) that is >3 x ULN or at least 
one hepatic SAE (as described in §8.2.1).  
8.1.5 Additional TEAE summary 
The number and percentage of participants with the following specific TEAEs will be presented separately: 
grade 2, 3 or 4 myalgia, grade 3 or 4 cardiac rhythm disturbances, grade 3 or 4 lipase, pancreatitis, 
peripheral neuropathy and myelosuppression. 
8.1.6 Additional AE summary after 14 days post end of treatment 
The number and percentage of participants that had an AE graded 3 or 4 after 14 days post end of 
treatment. 
8.2 CLINICAL EVALUATION 
8.2.1 Clinical Laboratory Evaluation 
A list of laboratory tests (haematology, clinical chemistry, and urinalysis) to be included in the analysis is 
presented in §7.3 of the protocol. Laboratory assessments done by a central laboratory will be summarised 
in tables. All summaries will be based on the units provided by the central laboratory, no conversion will be 
done.  The laboratory evaluations will be summarised for baseline, post-baseline, and change from baseline 
at day 1, week8, end of treatment, month 6 follow-up and month 18 follow-up. 
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Laboratory values outside normal ranges will be identified, and the number and percentage of participants 
with at least one post-baseline abnormality will be summarised in shift tables comparing the baseline 
results to each post-baseline timepoint for those participants with results at both timepoints.  
 
The table below displays the general variables and thresholds of interest. Participants are considered to 
have notable laboratory abnormalities if his/her response falls within the specified definitions at least once 
during the treatment period.  
 
 
 
Table 1: Notable Criteria for Laboratory Data  
Lab Test Type 
Laboratory 
Variable 
SI 
Units 
Liver 
AST 
>3 x ULN and ≤5 x ULN 
>5 x ULN and ≤8 x ULN 
>8 x ULN 
ALT 
>3 x ULN and ≤5 x ULN 
>5 x ULN and ≤8 x ULN 
>8 x ULN 
Total Bilirubin  
>2 x ULN 
Alkaline Phosphatase (ALP) 
>2 x ULN 
Chemistry Labs 
Other: 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN  
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN and ALP < 2 x ULN (potential Hy’s law case) 
Lipase 
>2xULN and ≤5 x ULN 
>5xULN 
 
 
8.2.2 Myelosuppression 
Number and percentage of participants with myelosuppression as well as the number of occurrences of 
myelosuppression will be summarised. Participants are considered to have myelosuppression if his/her 
response falls within the specified criteria in Table 2 at least once during the treatment period. 
 
Table 2: Notable Criteria for Laboratory Data – Myelosuppression 
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Laboratory 
Variable 
Criteria 
HGB 
<8g/dL (Grade 3) and significantly below baseline or HGB falls >25% beneath baseline 
 
ANC 
< 750/mm3 (Grade 3) and significantly below baseline  
 
Platelets  
< 50,000/mm3 (Grade 3) and significantly below baseline  
 
8.2.3 Vital Sign Measurements 
Vital sign measurements include body temperature (◦C), respiratory rate (breaths/min), blood pressures 
(mmHg) (resting more than 5 minutes), and heart rate (bpm).  
These measurements will be summarised for baseline and change from baseline at week8, end of 
treatment, month 6 follow-up and month 18 follow-up. Only the vital signs collected at the scheduled visits 
or time points will be included in the summary.  
Abnormal vital sign assessment results will be identified, and the number and percentage of participants 
with at least one post-baseline abnormality will be summarised.  General variables and thresholds of 
interest are outlined in appendix 3 of the protocol.  
 
 
8.3 ELECTROCARDIOGRAM 
All participants will have a standard 12-lead (ECG) assessment (heart rate (HeR), PR interval, RR interval, 
corrected QTcF intervals (adjusted using Fridericia’s correction) performed by a central cardiologist. All 
summaries will be based on the central cardiologist assessment.  
For all ECG parameters (HeR, PR, RR, QTcF), actual values and changes from measurement closest to prior 
to dosing at each time point will be summarised using descriptive. 
 
Post-baseline QTcF intervals will be classified into the following categories: 
• 
QTcF < 450 msec 
• 
450 msec ≤ QTcF < 480 msec 
• 
480 msec ≤ QTcF < 500 msec 
• 
QTcF ≥ 500 msec 
 
QTcF changes from baseline will be classified into the following categories: 
• 
increase ≤ 30 msec, 
• 
increase > 30 msec and ≤ 60 msec, and 
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• 
increase > 60 msec. 
 
Frequency counts will be used to summarize the number of participants at each time point according to the 
above categories.  
Interpreted ECG results based on CRF investigator assessment will be classified as “normal”, “abnormal, not 
clinically significant”, or “abnormal, clinically significant”. The number and percentages of participants with 
normal, abnormal not clinically significant, and abnormal clinically significant will be presented. In addition, 
shift tables will be provided to summarise the status changes from baseline to post-baseline assessments.  
Participants with any QTcF values ≥ 500 will be presented in a figure. 
 
8.4 OPHTHALMOLOGY TESTS 
Results from the assessments of Ophthalmology slit lamp examinations (lens opacity classification and 
grading), visual acuity and colour vision will be summarised for baseline, end of treatment, and follow-up.  
 
8.5 PERIPHERAL NEUROPATHY  
Peripheral neuropathy assessments as reported by the participants (from the peripheral neuropathy 
assessment form) will be summarised at baseline, week 8, end of treatment, and month 6 follow-up.  
 
8.6 PHARMACOKINETICS/PHARMACODYNAMICS 
Descriptive statistics (n, arithmetic mean, standard deviation (SD), coefficient of variation (CV%), median, 
minimum and maximum, geometric mean and geometric CV (%)) will be used to summarise the plasma 
concentration at each scheduled sampling time/window per analyte. The geometric mean is obtained by 
computing the arithmetic mean of the logarithm-transformed values of concentration and then using the 
exponentiation to return the computation to the original scale. Geometric CV(%) is calculated as follows: CV 
(%)=Square root of [exp(𝜎𝜎ො2) – 1] * 100, where 𝜎𝜎ො2 denotes the variance of the log-transformed values.  
For a concentration value below the limit of quantitation (BLQ), a concentration value of zero is included 
for the computation of arithmetic mean and a concentration value of 50% the lower limit of quantitation 
(plasma LLOQ = x.xx units) is included for the computation of geometric mean. If 50% or more of the values 
are BLQ at one timepoint, the arithmetic mean and geometric mean is reported as BLQ. If the calculated 
arithmetic mean and/or geometric mean are less than LLOQ, the arithmetic mean and/or geometric mean 
are reported as BLQ.  
Derivation of PK/PD parameters described in the protocol Section 9.6 and 9.7 will be covered in a separate 
modelling SAP.  
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9 PARTICIPANT DISPOSITION 
9.1 PARTICIPANT DISPOSITION 
Participant disposition for all participants who signed informed consent will be presented as follows: 
No. of participants screened, screen failed, randomised, and received at least one dose of treatment.  
Of those receiving at least one dose, the number and proportion who completed the IMP, who 
discontinued IMP, who completed the study, who discontinued from the study. The reasons for 
discontinuation of IMP and study participation will also be summarised.  
9.2 STUDY PROTOCOL DEVIATIONS 
All major and minor deviations will be summarised by deviation type for all ITT participants. 
10 DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The following demographics and baseline characteristics will be summarised using the ITT population. 
Number and percentage will be reported, unless otherwise noted. 
10.1 DEMOGRAPHICS 
Age (years), height (cm), weight (kg), and body mass index (BMI) (kg/m2) will be summarised as continuous 
variables. BMI is defined as the participant’s weight (kg) divided by the square of their height (m). The 
number and percentage of participants will be presented for categorical variables including race (Black or 
African American, White), country, and sex (male, female). 
10.2 BASELINE CHARACTERISTICS 
•
History of TB (type) (DS-TB, Mono-Resistant TB, MDR TB, PRE-XDR TB, XDR TB)
•
Current TB type (MDR-TB (NR), MDR-TB (TI), pre-XDR-TB, XDR-TB)
•
Smoking status (never, current, former) 
•
Alcohol status (never, current, former) 
•
Screening Coached Spot Sputum result
o
Smear microscopy for acid-fast bacilli (no AFB seen, scanty positive, 1+, 2+, 3+)
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o Hain assay MTBDRplus or equivalent result (sensitive, resistant, indeterminate, not done)  
o Gene Xpert Rifampicin resistance result (sensitive, resistant, indeterminate)  
• 
Serology  
o HIV status (positive, negative as collected in CRF) 
o CD4 count (summary statistics) 
o Viral load (summary statistics) 
• 
Karnofsky performance status 
• 
Chest X-ray (normal, abnormal) 
o Cavities (none, unilateral, bilateral) 
• 
Ophthalmologic history  
o History of vision and/or eye disorders (yes, no) 
o Immediate family history of cataracts (yes, no) 
o History of prior eye surgery and/or trauma (yes, no) 
 
10.3 MEDICAL HISTORY 
Medical history will be coded using the latest version of Medical Dictionary for Drug Regulatory Activities 
(MedDRA). The number and percentage of participants with clinically significant medical/treatment history 
will be summarised by system organ class (SOC) and preferred term (PT). Percentages will be calculated 
based on number of participants in the ITT analysis set. 
 
10.4 INCLUSION AND EXCLUSION CRITERIA 
Participants who violate the inclusion and/or exclusion criteria (screen failures as well as late screen 
failures) will be presented in a listing.  
 
 
11 TREATMENT AND MEDICATIONS 
 
11.1 PRIOR AND CONCOMITANT MEDICATIONS 
For the purpose of inclusion in prior and/or concomitant medication summary tables, incomplete 
medication start and stop dates will be imputed as follows: 
Missing start dates will be handled as follows (where UK, UKN and UNKN indicate unknown or missing day, 
month and year respectively):  
• 
UK-MMM-YYYY: impute to 01-MMM-YYYY;  
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• 
UK-UKN-YYYY: impute to 01-JAN-YYYY; 
• 
UK-UKN-UNKN: impute to date of initial screening. 
Missing stop dates will be handled as follows (where UK, UKN and UNKN indicate unknown or missing day, 
month and year respectively):  
• 
UK-MMM-YYYY: Assume the last day of the month; 
• 
UK-UKN-YYYY: Assume 31-DEC-YYYY; 
• 
UK-UKN-UNKN: Assume last day of study visit. 
All medications will be coded according to the latest version of World Health Organization drug dictionary. 
Summaries on prior and concomitant medication will be performed using the ITT set.  
 
11.1.1 Prior Medications 
A prior medication is defined as any medication that has a stop date before the start of the study drug 
(prior to Day 1). Prior medications collected in the CRF will be classified as TB medications and non-TB 
medications. The number and percentages of participants with at least one prior medication will be 
summarised for TB medications and non-TB medications.  
 
11.1.2 Concomitant Medications 
A concomitant medication is defined as any medication that has a stop date that is on or after the date of 
first dose of study treatment (Day 1). The number and percentages of participants with at least one 
concomitant medication will be summarised.  
 
11.1.3 Concomitant Procedures 
The number and percentages of participants with at least one concomitant procedure (defined similarly as  
concomitant medications above) will be summarised.  
 
11.1.4 Study Treatment Exposure 
A participant’s drug exposure in days will be defined as (date of last dose - date of first dose +1). Drug 
exposure in weeks will be calculated by dividing the exposure in days by 7. The date of last dose is the last 
available date in the study medication page, if missing then the date of last dose in the disposition 
treatment page will be used. 
The duration of exposure to IMP and its category will be summarised for all participants in the safety set 
and will be presented in a table by summary statistics. The groupings are  
1. <9 or <26 weeks (less than allocated)  
2. 9 or 26 weeks (as expected)  
3. 9 or 26 weeks to 38 weeks (missed dose extension)  
4. 39 weeks (official treatment extension) 
 
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Drug compliance (%) for bedaquiline and pretomanid will be collected from the eCRF and summarised using 
descriptive statistics. Number and percentage of participants in each compliance category (<80%, 80 to 
<90%, ≥90%) will be presented. Percentages will be calculated out of the number of participants who were 
dosed at that dosing period in the safety set. Linezolid exposure data will not be included in the compliance 
determination since participants are allowed to stop/re-start administration.  
The following exposure parameters will be summarised according to the general methods:  
• 
Treatment extension (number of participants with an official treatment extension to 39 weeks). 
• 
Linezolid pause (number and percentage of participants with at least one dose pause, number of 
dose pauses, reason for dose pause). The Linezolid pause information will be retrieved from the 
CRF IMP Dosing pages indicated by a pause of Linezolid and scheduled dispense of Bedaquiline and 
Pretomanid.  
• 
Linezolid dose reduction (number of participants with at least one dose reduction, number of 
participants with at least one 1-step dose reduction, number of participants with at least one 2-
step dose reduction, number of dose reductions including the number of 1-step decrease in dose 
and 2-step decrease in dose, reason for dose reduction).  
• 
Participants experiencing suspected drug related toxicities due to B-Pa treatments can have the full 
study medication paused for up to 35 consecutive days. Full regimen pauses will be summarised by 
number and percentage of participants with at least one full regimen pause, number of full 
regimen pauses and reason for regimen pause. Information related to these are found on the CRF 
IMP Dosing pages as pause selected on each dosing page, Linezolid, Bedaquiline and Pretomanid.  
 
12 APPENDICES 
 
12.1 DERIVED MGIT RESULTS PER VISIT  
 
Derived sample Culture 1 
(Visit X ) 
Derived Sample Culture 2    
(Visit X) 
Final Derived Result             
for Visit X 
Positive 
Missing/Negative/Contaminated 
Positive 
Negative 
Missing/Contaminated 
Negative 
Contaminated 
Missing/Contaminated 
Contaminated 
 
 
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12.2 INTERPRETATION OF RELAPSE/RE-INFECTION USING WHOLE GENOME SEQUENCE 
(WGS)  
 
The purpose of the WGS analysis is to determine if the two MTB strains from a given participant (positive 
culture at baseline and at or after the end of treatment) can be considered the same (treatment 
failure/bacteriologic failure or relapse/bacteriological relapse), or different (re-infection/bacteriological re-
infection).   To do this, WGS of the two MTB strains are compared, the number of SNPs/variants 
determined, and the criteria outlined below followed.  These cut offs have been determined from 
previously published reports (REMoxTB and RIFAQUIN trials) that show a clear genetic distinction between 
relapse and re-infection cases of MTB infection. 
 
• 
≤12 SNPs different = Relapse 
• 
≥100 SNPs different = Reinfection 
• 
>12 and <100 SNPs different = Indeterminate.   
 
These results will be reviewed on case by case basis and are likely to be rare.  Additional sequence analysis 
may be performed and/or additional samples may need to be tested.  Any additional investigations will be 
documented on the ‘WGS Indeterminate Proforma’ which also includes the final conclusion of ‘relapse’ or 
re-infection’ based on this further review. A participant will be considered a relapse unless there is 
sufficient evidence to support a classification of re-infection 
 
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