Clinical trial NCT04550832
Conditions: Infections and Infestations Pulmonary Tuberculosis
Keywords: drug-sensitive TB
Sponsor: LigaChem Biosciences, Inc.
Start date: 2021-10-28; Completion date: 2023-09-11
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is to describe the safety, tolerability and exposure-toxicity relationship of Depazolid given over 16 weeks, in combination with standard-dose Bedaquiline, Delamanid and Moxifloxacin, compared to standard-dose Bedaquiline, Delamanid and Moxifloxacin alone

Detailed description:
This will be an open label Phase IIb dose-finding, randomized, controlled study with a duration of 16 weeks of experimental therapy of Delpazolid(DZD) - Bedaquiline/Delamanid/ Moxifloxacin (BDM) in adult patients with newly diagnosed, smear positive, uncomplicated, drug sensitive pulmonary tuberculosis (TB) to evaluate the safety, efficacy, tolerability, pharmacokinetics and exposure/response-relationship of different doses of delpazolid in combination with bedaquiline, delamanid and moxifloxacin.

Participants will be randomized to one of five arms containing BDM standard dose with different doses of DZD.

Arms: arm 1: Participants receive the following medication for the duration of 16weeks together with food.

* Delpazolid : Will not administered
* Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
* Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
* Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily arm 2: Participants receive the following medication for the duration of 16weeks together with food.

* Delpazolid : Will be dosed 400 mg orally once daily
* Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
* Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
* Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily arm 3: Participants receive the following medication for the duration of 16weeks together with food.

* Delpazolid : Will be dosed 800 mg orally once daily
* Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
* Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
* Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily arm 4: Participants receive the following medication for the duration of 16weeks together with food.

* Delpazolid : Will be dosed 1200 mg orally once daily
* Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
* Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
* Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily arm 5: Participants receive the following medication for the duration of 16weeks together with food.

* Delpazolid : Will be dosed 800 mg orally twice daily
* Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 days, then 200 mg three times a week.
* Delamanid: will be dosed as per the licensed dose: 200 mg orally twice daily doses of 100 mg.
* Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily
Interventions: intervention 1: Delpazolid intervention 2: Bedaquiline, Delamanid, Moxifloxacin
Intervention descriptions: intervention 1: Delpazolid is not licensed yet. Current experience in humans upto Phase IIA. Dose according to randomization to dosing arms 2-5. intervention 2: These three licensed drugs form the backbone of a new regimen to which delpazolid is added in arms 2-5.

Protocol documents:
Prot_000.pdf: 
 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
1 
 
 
 
Study Protocol 
 
 
Study Title: 
A Phase IIb, Open-Label, Randomized Controlled Dose Ranging Multi-Center Trial to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Exposure-Response 
Relationship of different doses of Delpazolid in combination with Bedaquiline 
Delamanid Moxifloxacin in Adult Subjects with Newly Diagnosed, Uncomplicated, 
Smear-Positive, Drug-sensitive Pulmonary Tuberculosis 
 
Short title: 
PanACEA DElpazolid dose-finding and COmbination DEvelopment (DECODE) 
 
Protocol Number: 
PanACEA - DECODE – 01/LCB01-0371-20-2-02 
 
Protocol Version No: 
2.1  
Protocol Date: 
08 September 2021 
Confidential document 
 
 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
2 
 
 
Sponsor: 
LegoChem Biosciences, Inc. 
8-26 Munpyeongseo-ro 
Daedeok-gu 
Daejeon 
Republic of Korea 
Sponsor Delegated Person: 
InSook Cho 
LegoChem Biosciences, Inc. 
Clinical Development Center 
25, Yeonmujang 5ga-gil,  
Seongdong-gu, Seoul 
Republic of Korea 
Phone: +82 2 461 0716 
Email: isc2018@legochembio.com 
Sponsor Medical Experts/ 
Immediately Reportable Events: 
Dr. Norbert Heinrich 
 
University Hospital, LMU Munich  
Division for Infectious Diseases and Tropical Medicine 
Leopoldstrasse 5  
80802 Munich  
Germany 
Phone: +49 89 4400 598 05 
Email: norbert.heinrich@med.uni-muenchen.de    
 
Dr. Alexa Dierig  
University Hospital, LMU Munich  
Division for Infectious Diseases and Tropical Medicine 
Leopoldstrasse 5  
80802 Munich  
Germany 
Phone: +49 89 4400 598 05 
Email: alexa.dierig@med.uni-muenchen.de    
 
Dr. Anna Jarchow-MacDonald  
University Hospital, LMU Munich  
Division for Infectious Diseases and Tropical Medicine 
Leopoldstrasse 5  
80802 Munich  
Germany 
Phone: +49 89 4400 598 05 
Email: anna.jarchowmacdonald@med.uni-muenchen.de    


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
3 
 
 
Trial Statistician: 
 
 
 
 
Dr. Patrick Phillips 
University of California, San Francisco 
Department of Medicine, Division of Pulmonary & Critical Care 
Medicine 
1001 Potrero Avenue 
San Francisco, CA 94110 
United States 
Phone: +1 415.206.3960 
Email: Patrick.Phillips@ucsf.edu 
Pharmaceutical Expert: 
Dr. Rob Aarnoutse 
Radboud University Nijmegen Medical Centre 
Department of Pharmacy 
Geert Grooteplein 10, P.O. Box 9101 
6500 HB Nijmegen  
The Netherlands 
Phone: + 31 24 361 6405 
Email: Rob.Aarnoutse@radboudumc.nl 
Sponsor Monitor: 
Alison Scott 
Design House, 121 Amkor Road,  
Centurion, 0157,  
South Africa 
Alison.scott@tcd-global.com 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
4 
 
African Study Centres 
South Africa 
South Africa National PI: Prof. Dr. Robert S. Wallis 
 
The Aurum Institute 
Tembisa Clinical Research Centre, cnr Rev RTJ Namane and 
Flint Mazibuko Drive, Hospital View, Tembisa, Gauteng, South 
Africa, 1632 
South Africa 
Phone: +2710 590 1300 
Email: msebe@auruminstitute.org 
 
University of Cape Town Lung Institute (UCTLI) 
George Street 
Mowbray 
7700 Cape Town 
South Africa 
Phone: +27 21 406 6850 / +27 21 650 1910 
Email: rodney.dawson@uct.ac.za 
 
TASK Eden 
4 Victoria Street 
George Central 6529  
George, South Africa 
Phone: +27 44 873 3395  
Email: kirsten@taskeden.org.za 
 
Clinical HIV Research Unit (CHRU) 
University of the Witwatersrand 
Helen Joseph Hospital  
Perth Road, Westdene 
2092 Johannesburg 
South Africa 
Phone: +27 11 276 8800 
Email: mrassool@witshealth.co.za  
 
Tanzania 
Tanzania National PI: Dr. Lilian Tina Minja  
Phone: +255 25250 3364 
Email: tminja@nimr-mmrc.org 
 
National Institute for Medical Research (NIMR-MMRC) 
PO Box 2410 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
5 
 
Hospital Hill Road 
Mbeya 
Tanzania 
Phone: +255 25250 3364 
Email: tminja@nimr-mmrc.org 
 
Ifakara Health Institute 
Bagamoyo Research and Training Centre 
Bagamoyo District Hospital  
P.O. Box 74 
Bagamoyo  
Tanzania 
Phone:+255 232 440 065 
Email: bagamoyo@ihi.or.tz    
 
Ki’bongoto Infectious Disease Hospital (KIDH) 
Kilimanjaro Clinical Research Institute (KCRI) 
Sokoine Road Box 2236 
Moshi 
Tanzania 
Phone: +255 272 754 201 
Email: sempagama@yahoo.com 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
6 
 
Sponsor Signature Page 
 
 
Protocol title: A Phase IIb, Open-Label, Randomized Controlled Dose Ranging Multi-Center Trial to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Exposure-Response Relationship of different doses of 
Delpazolid in combination with Bedaquiline, Delamanid and Moxifloxacin in Adult Subjects with Newly 
Diagnosed, Uncomplicated, Smear-Positive, Drug-sensitive Pulmonary Tuberculosis : PanACEA Delpazolid 
dose-finding and COmbination DEvelopment (DECODE) 
 
 
Protocol Number: PanACEA--DECODE-01/ LCB01-0371-20-2-02 
Protocol Version: 2.1, dated 08 September 2021 
 
I hereby approve the protocol PanACEA-DECODE-01, Version 2.1, dated 08.09.2021, and confirm that it 
contains all necessary information to conduct the study according to the ethical principles laid down in the 
declaration of Helsinki, Good Clinical Practice and all applicable local regulations.  
 
 
 
 
 
 
________________________________ 
___________________ 
(Sponsor Delegated Person)  
Date 
 
 
 
 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
7 
 
Principal Investigator Signature Page 
 
 
Protocol title: A Phase IIb, Open-Label,  Randomized Controlled Dose Ranging Multi-Center Trial to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Exposure-Response Relationship of different doses 
of Delpazolid in combination with Bedaquiline, Delamanid and Moxifloxacin in Adult Subjects with Newly 
Diagnosed, Uncomplicated, Smear-Positive, Drug-sensitive Pulmonary Tuberculosis 
 
Protocol Number: PanACEA-DECODE-01/ LCB01-0371-20-2-02 
Protocol Version: 2.1, dated 08. September 2021 
 
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. 
 
 
 
 
 
 
  
 
 
                                                     
 
Principal Investigator Signature  
 
Principal Investigator Printed Name and Qualification 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
8 
 
1 PROTOCOL SYNOPSIS 
 
Short protocol Title 
PanACEA DElpazolid dose-finding and COmbination DEvelopment (DECODE) 
Full protocol title  
A Phase IIb, Open-Label, Randomized Controlled Dose Ranging Multi-Center Trial to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Exposure-Response Relationship of 
different doses of Delpazolid in combination with Bedaquiline, Delamanid and 
Moxifloxacin in Adult Subjects with Newly Diagnosed, Uncomplicated, Smear-Positive, 
Drug-sensitive Pulmonary Tuberculosis 
Name of IMP 
Delpazolid (DZD) 400 mg tablets 
Non-IMP study drugs 
Bedaquiline (BDQ), Delamanid (DLM), Moxifloxacin (MXF) 
Indication 
Pulmonary Tuberculosis (TB) 
Objectives 
Safety and Tolerability Objective: 
To describe the safety, tolerability and exposure-toxicity relationship of DZD given over 16 
weeks, in combination with standard-dose BDQ, DLM and MXF, compared to standard-
dose BDQ, DLM and MXF alone  
Efficacy Objectives:  
Primary Efficacy Objective: 
 
To establish an exposure-response model for DZD, given over 16 weeks in 
combination with standard-dose BDQ, DLM and MXF, on the change in liquid 
culture MGIT time to positivity (TTP)  
Secondary Efficacy Objective: 
 
To assess dose and exposure-response relationships for DZD, based on secondary 
efficacy endpoints, including month-2 culture status in liquid media and on solid 
media, and time to culture conversion in liquid and on solid media 
 
To assess the relative efficacy of increasing DZD doses compared to the 
background regimen without DZD, based on primary and secondary efficacy 
endpoints. 
 
To assess the proportion of patients who suffer relapse within 12 months post 
randomization, out of those patients completing 16 weeks of therapy and 
achieving sustained sputum culture conversion, defined as two successive 
negative liquid media cultures at or before WK08, with no positives to follow until 
the week 16 visit.  
Pharmacokinetics Objectives: 
Primary Pharmacokinetics Objective: 
 
To describe the pharmacokinetics (PK) of DZD through development of a 
population PK model 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
9 
 
Secondary Pharmacokinetics Objective: 
 
To describe the PK of BDQ, DLM and MXF including their main metabolites  
Mycobacteriology Identification and Characterization Objectives: 
 
To assess the minimum inhibitory concentrations (MIC) of BDQ, DLM, MXF, 
DZD of the infecting strain, at baseline and on representative isolate(s) grown 
at or after WK08. 
 
To investigate the frequency of acquired mutations in the infecting strain 
over treatment 
 
In patients with recurrent disease: comparison of initial and recurrence isolate by 
whole genome sequencing to discriminate relapse from reinfection 
Study Design 
This will be an open label Phase IIb dose-finding, randomized, controlled study with a 
duration of 16 weeks of experimental therapy of DZD – Bedaquiline/Delamanid/ 
Moxifloxacin (BDM) in adult patients with newly diagnosed, smear positive, uncomplicated, 
drug sensitive pulmonary tuberculosis (TB) to evaluate the safety, efficacy, tolerability, 
pharmacokinetics and exposure/response-relationship of different doses of delpazolid in 
combination with bedaquiline, delamanid and moxifloxacin. 
Participants will be randomized to one of five arms containing BDM with different doses of 
DZD: 
 
Arm 1 (D0): 15 patients will receive 0 mg of DZD 
 
Arm 2 (D400): 15 patients will receive 400 mg DZD orally once daily 
 
Arm 3 (D800-OD): 15 patients will receive 800 mg DZD orally once daily 
 
Arm 4 (D1200): 15 patients will receive 1200 mg DZD orally once daily 
 
Arm 5 (D800-BD): 15 patients will receive 800 mg DZD orally twice daily 
Decision rule for 
managing post week 16 
treatment or follow - up 
Patients will stop therapy after the week 16 visit, if they achieve early sputum culture 
conversion (SCC) to negative. This is defined as two successive negative liquid media 
cultures, the first of which is at or before week 08, with no positive cultures to follow.  
Results for the negative cultures need to be available by the week 16 (day 112) visit, with a 
time window of +6 days to accommodate for late availability of culture results, in order for 
patients to stop therapy.    
Post treatment follow-up visits at weeks 18, 26, 38 and 52 will serve to determine whether 
they have achieved lasting cure.  Patients with a positive culture or other indication as 
described under 11.4  during the follow up period will undergo a standardized assessment 
for potential poor treatment outcome. If this procedure results in a diagnosis of recurrent 
disease, they will be referred to the national TB program. 
Patients who do not achieve SCC as defined above will be referred to the national TB 
program for standard of care TB treatment according to national guidelines, to complete at 
least 6 months of treatment in total.  
In addition to the rule above, additional positive sputum LAM testing results late in 
treatment may be used to enhance detection of patients at risk for unfavourable outcome, 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
10 
 
who would NOT qualify for treatment stop after 16 weeks. The sponsor will produce a 
centralized decision rule when kits for this assessment become available. 
Time Schedule  
Per Subject: 52 weeks in total, including a 36-week follow-up Study duration: Anticipated 
Recruitment Period: Q3 2021 – Q1 2022. 
Study duration: Planned End Date (LPLV): Q2 - Q3 2022 
Population 
A total of 75 male or female subjects, aged between 18 and 65 years with newly 
diagnosed, drug sensitive, uncomplicated, smear-positive, pulmonary TB will be included 
Sample size 
To be analysed: N = 15 patients per arm with a total of N = 75 patients, and a wide range 
of DZD doses (from 0mg to 800mg BID) has been determined as an adequate sample size 
for population PK modelling, and for exposure-response modelling to detect a clinically 
meaningful dose-dependent relationship.  
Dosage and 
Administration 
Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 14 
days, then 200 mg orally three times a week.  
Delamanid:  will be dosed as per the licensed dose: 100 mg orally twice daily (totalling 
200mg daily) 
Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily 
Delpazolid: not licensed: Current experience in humans up to Phase 2a. Dose according to 
randomization to dosing arm: 
 
Arm 1 (D0): 15 patients will receive 0 mg of DZD 
 
Arm 2 (D400): 15 patients will receive 400 mg DZD orally once daily 
 
Arm 3 (D800-OD): 15 patients will receive 800 mg DZD orally once daily 
 
Arm 4 (D1200): 15 patients will receive 1200 mg DZD orally once daily 
 
Arm 5 (D800-BD): 15 patients will receive 800 mg DZD orally twice daily 
All above drugs will be given for 16 weeks. 
Evaluation Criteria 
Primary Endpoints 
The safety of DZD will be assessed by evaluation of AEs during treatment and follow-up 
phase, including assessments of vital signs, physical examinations, weight, detailed 
neurological examinations, colour vision and visual acuity tests, 12-lead ECG, and routine 
clinical laboratory tests (including chemistry, haematology and urinalysis data). 
Primary Safety Endpoint  
 
Proportion of patients experiencing expected oxazolidinone class toxicities, 
including peripheral or optical neuropathy, incident leukopenia, anemia or 
thrombocytopenia, or adverse events in line with tyramine pressor response, of 
Grade 2 or higher, possibly, probably or definitely related to DZD 
Primary Efficacy Endpoint 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
11 
 
The efficacy of DZD will be evaluated by measuring the change in mycobacterial load over 
time on treatment as quantified by time to positivity in BD MGIT 960® liquid culture 
described by non-linear mixed-effects methodology 
Secondary Endpoints 
Secondary safety endpoints  
 
All adverse events 
 
Adverse events of Grade 3 severity or higher 
 
Adverse events possibly, probably or definitely related to study drugs 
 
Treatment discontinuations or interruptions related to adverse events/serious 
adverse events 
 
Frequency, severity and type of ECG alterations 
 
Changes in ECG intervals of PR, RR, QRS, QT, Fridericia-corrected QT [QTcF] 
 
Proportion of participants with QTcF > 500ms in ECGs on treatment 
 
Proportion of participants with a prolongation of QTcF of grade 3 and above as 
defined under 14.6. 
Secondary Efficacy Endpoints:  
 
Proportion of patients who suffer relapse, defined as recurrent disease caused by 
a strain identical to the baseline isolate, within 12 months post randomisation, out 
of patients completing 16 weeks of therapy and achieving stable culture 
conversion to negative (SCC) as defined below by week 08, with no positives to 
follow by the week 16 visit. 
 
Time to recurrent TB, and to relapse, within 12 months post randomisation 
 
Time to stable sputum culture conversion (SCC) to negative on liquid media 
(defined as two negative cultures without an intervening positive culture). Time 
will be measured as time on treatment until the first negative culture. 
 
Proportion of participants who achieved SCC at each time point during treatment 
 
Proportion of participants with negative sputum culture on solid media at WK 08 
and other timepoints 
 
Proportion of participants developing drug resistance among those not converting 
to negative culture  
Pharmacokinetic Endpoints 
A population PK model will be developed for DZD. The following secondary parameters will 
be derived for DZD, for BDQ, DLM and their main metabolites, and for MXF: 
 
Area under the plasma concentration curve from morning dosing to 24 hours (AUC 
0-24) on day 14 (WK2) 
 
The observed maximum concentration (Cmax) on day 14 
 
Time to reach Cmax (Tmax) on day 14 
 
The minimum observed plasma concentration (Cmin) at day 14 (24 hours following 
the last dose for intake once daily (QD) and 12 hours following the last dose for 
twice daily intake (BID)) 
 
Apparent oral clearance (Cl/F) 


 
 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
12 
 
 
Apparent volume of distribution (Vd/F) 
 
Terminal half-life (t1/2)  
Mycobacteriology Identification and Characterization Endpoints 
Sputum cultures grown from various timepoints will be assessed as follows: 
 
Minimum inhibitory concentrations (MIC) of BDQ, DLM, MXF, DZD, from a baseline 
isolate, and a representative isolate obtained at or after WK08, if any. 
 
Frequency of acquired mutations in the infecting strain over treatment assessed 
by whole genome sequencing 
 
Comparison between bacterial strain causing recurrent disease, and the strain at 
baseline by whole genome sequencing, to discriminate relapse from re-infection 
Exploratory endpoints 
Exploratory endpoints will be analysed depending on laboratory capacity, availability of test 
kits and budget, and may not be tested in all trial sites equally. 
 
Rate of change in molecular bacterial load assay (MBLA) during treatment 
 
Time to stable culture conversion to negative in MBLA (defined as two negative 
MBLAs without an intervening positive)  
 
Rate of change in bacterial load measured by quantification of sputum 
lipoarabinomannan (LAM) during treatment 
Analysis timepoints 
Analysis for the primary endpoints, and secondary endpoints unrelated to disease 
recurrence or relapse, will be performed after data are available (allowing for time for 
culture growth) after the last patient completed their WK16 (or otherwise last treatment) 
visit. A partial database lock will be performed for this purpose, with a final database lock 
at the end of study after all long-term outcome data are available. 
Safety data review 
trigger rules 
An independent data safety monitoring board (DSMB) will be convened for the trial. The 
DSMB will review safety data at regular intervals, but will also perform expedited review if 
the following conditions are met: 
 
Four or more patients experience a grade 3 or higher AE (CTCAE version 5.0) 
in the same organ system that are at least possibly related to one of the study 
drugs, and qualify as “unexpected” by being more severe than in previous 
experience with the drug in question. 
 
Two or more patients experience a grade 4 or higher AE (CTCAE 5.0) in the 
same organ system that are at least possibly related to one of the study 
drugs, and qualify as “unexpected” by being more severe than in previous 
experience with the drug in question 
 
One patient experiences a grade 5 AE (death) that is at least possibly related 
to one of the study drugs 


 
 
Protocol No: PanACEA - DECODE – 01/ LCB01-0371-20-2-02 
Protocol Version No: V2.1, dated 08 September 2021 
 
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2  SCHEDULE OF EVENTS 
Key: WK: week of treatment; MGIT: liquid media (BD mycobacterium growth indicator tube; LJ: Loewenstein - Jensen solid media; MBLA: molecular bacterial load assay; PK: pharmacokinetics, X: refers to all visits 
mentioned above, ZN: Ziehl-Neelsen stain, PG: pharmacogenomics 
Time points 
Screening 
Treatment 
Follow-up 
 
 
Treatment visit days each ± 2 days (except for WK2 visit, which may occur with a window of -2 days only 
Follow-up visit 1  
± 4 days 
Follow-up visit 2 – 4 A 
each ± 7 days 
Day 
-8 to 0 
Day 
01 
Day 
07 
Day 
14 
Day 
21 
Day 
28 
Day 
35 
Day 
42 
Day 
49 
Day 
56 
Day 
63 
Day 
70 
Day 
77 
Day 
84 
Day 
91 
Day 
98 
Day 
105 
Day 
112 
Day 
126  
Day 
182 
Day 
266 
Day 
364 
Visit  
SCR 
WK 
00 
WK 
01 
WK 
02 
WK 
03 
WK 
04 
WK 
05 
WK 
06 
WK 
07 
WK 
08 
WK 
09 
WK 
10 
WK 
11 
WK 
12 
WK 
13 
WK 
14 
WK 
15 
WK 
16 
FU 1  
WK 18 
FU 2 A 
WK 26 
FU 3 A 
WK 38 
FU 4     
WK 52 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check in-/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testB 
x 
 
 
 
 
 
 
 
 
 
xB 
 
 
 
 
 
 
 
xB 
 
 
 
HIV test (+ CD4 count + viral 
load)C 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screeningD 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment & Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization 
 
 
 
xK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SputumE 
1 x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
3x 
2x 
2x 
2x 
2x 
2x per visit:  MGIT, MBLA, (LJ 
culture, ZN smear), rest: storageE 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination, vital signsF 
x 
xG 
x 
xG 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(xG) 
(xG) 
(xG) 
Neurological examination/vision 
testingG 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
(x) 
(x) 
ECG (12-lead; pre-dose)H 
1x 
3x 
1x F 
1x F 
1x F 
1x F 
1x F 
1x F 
1x F 
1x F 
1x F 
  
1x F 
  
1x F 
  
 
1x F 
  
  
  
  
Drug Susceptibility TestingI 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
(x) 
 
 
 
 
 
 
Screening/Safety LabJ 
xJ 
 
x 
xJ 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
x 
x 
 
 
 
Study treatmentA 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Intensive PK sampling K 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker/PG blood sampleL 
x 
 
 
x 
 
x 
 
 
x 
 
 
 
x 
 
x 
 
 
x 
 
 
 
 
Concomitant Medication 
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 


 
 
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A)  
Continuation Treatment and follow-up visits: Participants of all 5 arms will complete their experimental treatment on Day 112. Omission of anti-TB treatment after this and conduct of     
 follow-up visits 2-3 will be conditional on culture conversion with first negative at or before WK08 (see decision rule). Participants who do not convert to negative culture will receive 
standard TB treatment according to their national TB program through governmental clinics, and will not have visits FU 2 and FU3. FU 4 will be conducted for all participants. 
B)  
Serum pregnancy test: blood samples of 7.5mL; for women of childbearing potential only. 
C)  
HIV Testing: blood samples of 7.5mL will be taken; CD4 count if HIV positive. If the patient is on ARVs at the time of screening, perform viral load count. Genotypic resistance testing 
mandatory if viral load is insufficiently controlled (>1,000 copies/µl) and patient would need to be switched back to a non-dolutegravir regimen after the study, recommended otherwise. 
D)  
Urine drug screening: for opiates, amphetamines, cannabinoids, cocaine, benzodiazepines and barbiturates. Results on other drugs generated by a combination test may be used as well. 
E)  
Sputum sampling: 3 sputa will be collected per time point during treatment phase, 1 spot sputum at SCR and 2 at FU 1-4 each. Two spot sputum samples during treatment and follow-up 
phase will be processed for mycobacterial culture MGIT liquid culture at all time-points. LJ will be performed at WK00, WK08, WK12, WK16,  and FU1-FU4 from two samples each. An 
isolate from baseline, and all isolates from all cultures positive after WK08 will be stored. The third sputum sample may be a spot or an early morning sputum, and will be stored for 
future biomarkers work. A Ziehl-Neelsen stained sputum smear will be performed at SCR and WK16 from concentrated sputum and at additional visits as required by the national TB 
programs.  
F)  
Physical examination and vital signs: Additional Blood pressure and heart rate recordings WK00 at 1h, 2h and 3h (± 10 mins) after intake of IMP and WK02 during hospitalization at 1h, 
2h, 3h, 4h, 6h (± 10 mins) after intake of IMP with a meal. During follow up visits FU 2-4 symptom orientated physical examination only or to follow up on (S)AEs. 
G)  
Detailed neurological examination: to include central and peripheral system testing (i.e. cranial nerves testing, vibration sensitivity, position, pin prick, light touch) and vision testing  
      
(Snellen, Ishihara). During follow up visits FU 2-4 symptom orientated neurological examination only or to follow up on (S)AEs. 
H)  
ECG: to be recorded after 10 minutes supine rest, before intake of study treatment. Triplicate ECG at WK00, single ECGs at SCR, WK01 – 09, WK11, WK13 and WK16. If a QTcF of >480ms,  
 
or a QTc-prolongation over baseline of >50ms is seen in a single ECG during experimental treatment, two more ECGs should be registered, to obtain a more precise, average QTcF     
measurement. 
I)  
Microbiology/Susceptibility Testing: rapid test for RIF and INH susceptibility at SCR. Minimum inhibitory concentration (MIC) for study drugs at baseline, and from a representative isolate 
if any growth at or after WK08. 
J)  
Screening/Safety lab:   full blood count (blood samples of 2mL), ALT, AST, gamma-glutamyl transferase (yGT), Alkaline Phosphatase (AP), Lipase, direct and total bilirubin, albumin, serum 
creatinine, electrolytes (Na+, K+, Serum Calcium, Magnesium, Cl-, PO43-), random glucose (blood samples of 7.5mL for blood chemistry). Urinalysis including dipstick for pH, protein, 
glucose, ketones, urobilinogen, blood and leukocytes. Urine microscopy on abnormal dipstick results as per the investigator’s decision.    
 
At SCR and WK02 (and at additional visits, if clinically indicated): Coagulation aPTT, PT, INR (blood samples of 3mL) 
K)  
Intensive PK sampling (WK02): In all participants, blood samples of 8ml will be taken for measurements of DZD and other study drugs’ concentrations over time. Study drugs will be dosed 
with food. Time of intake of food, drugs and of blood sampling will be recorded. Participants will be hospitalized and receive standard meals at days of intensive PK sampling. Intensive PK 
time points (7 samples in total) at WK02: 0 (within 1h before dosing), 1, 2, 4, 8, 12, (± 10 mins) and 24 hours (± 30 mins) after dosing 
L)  
Host biomarker sample storage: Conditional on patient consent to sub-studies. One 5ml blood sample will be taken for plasma/ storage, one 2.5ml blood sample will be collected in PAXgene 
bottles for transcriptomic analysis, one 10ml sample will be collected for immunological analyses (not all sites) with safety blood draw. Plasma and PAXgene whole blood samples should 
be stored at -70oC. At screening, one sample for pharmacogenomics sub-studies will be stored (5ml).  
 


 
 
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Table of contents  
 
1 
Protocol Synopsis 
8 
2 
SCHEDULE OF EVENTS 
13 
3 
ABBREVIATIONS 
18 
4 
BACKGROUND INFORMATION 
21 
4.1 
The need for new TB drugs 
21 
4.2 
Delpazolid previous experience 
22 
4.3 
The TB Burden in Tanzania and South Africa 
22 
5 
RATIONALE FOR THE STUDY 
23 
6 
INVESTIGATIONAL PRODUCT 
24 
6.1 
Delpazolid 
24 
7 
NON-IMP DRUGS USED IN THE STUDY 
30 
7.1 
Bedaquiline 
30 
7.2 
Delamanid 
32 
7.3 
Moxifloxacin 
34 
7.4 
Combination of drugs used in the study 
35 
8 
STUDY OBJECTIVES 
37 
8.1 
Safety and Tolerability Objective: 
37 
9 
TRIAL ENDPOINTS 
38 
9.1 
Primary Endpoints 
38 
9.2 
Secondary Endpoints 
38 
10 
TRIAL DESIGN 
40 
10.1 
Summary 
40 
10.2 
Trial population 
40 
10.3 
Inclusion Criteria 
41 
10.4 
Exclusion Criteria 
42 
10.5 
Schedule of events 
44 
11 
Trial Assessments 
49 
11.1 
Demographic and background assessments 
49 
11.2 
Efficacy assessments 
49 
11.3 
Safety assessments 
50 
11.4 
Assessments when Recurrence is Suspected 
53 
11.5 
Pharmacokinetic assessments 
53 
11.6 
Additional biomarker assessments 
54 
12 
STUDY TREATMENT 
55 


 
 
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12.1 
Study drug regimens 
55 
12.2 
Study drug dosage and administration 
55 
12.3 
Study drug management 
57 
12.4 
Treatment after End of Study Therapy (Post-study Access to Treatment) 
58 
12.5 
Measurement of Adherence to Study Treatment 
59 
12.6 
Concomitant and Prohibited Medication 
59 
13 
PARTICIPANT ENROLMENT 
64 
13.1 
Recruitment procedures 
64 
13.2 
Informed consent 
65 
13.3 
Exclusion of particular groups 
66 
13.4 
Vulnerable participants 
66 
13.5 
Procedures to assign participants to treatment groups 
66 
13.6 
Methods of avoiding bias 
66 
13.7 
Participant withdrawal 
67 
13.8 
Adjustment of sample size during the study 
68 
13.9 
Safety: expedited safety data review 
68 
13.10 
Additional safety considerations: individual patient stopping criteria for safety 
68 
14 
REPORTING ADVERSE EVENTS 
71 
14.1 
Definitions 
71 
14.2 
Clarifications and exceptions 
73 
14.3 
Additional immediately reportable events 
73 
14.4 
Eliciting adverse event information 
73 
14.5 
Assessment of Causality 
74 
14.6 
Assessment of Severity 
75 
14.7 
Other AE definitions 
76 
14.8 
Adverse event reporting 
77 
14.9 
Serious adverse event reporting 
77 
14.10 
Clinical Laboratory adverse events 
78 
14.11 
Pregnancy as adverse event 
78 
14.12 
Disease under study 
79 
14.13 
Follow-up of adverse events 
79 
15 
STATISTICAL CONSIDERATIONS 
80 
15.1 
Sample size determination 
80 
15.2 
Populations to be analysed 
80 
15.3 
Analysis of safety endpoints 
81 
15.4 
Analysis of primary efficacy endpoint 
82 


 
 
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15.5 
Procedure for accounting for missing, unused and spurious data 
82 
15.6 
Procedure for reporting any deviations from the original statistical plan 
82 
15.7 
Timing of analyses 
82 
16 
DATA HANDLING AND QUALITY ASSURANCE 
82 
16.1 
Data collection 
83 
16.2 
Source documents 
83 
16.3 
Study monitoring 
83 
16.4 
Inspection of records 
84 
16.5 
Records retention 
84 
16.6 
Confidentiality of personal data 
85 
17 
ETHICAL CONSIDERATIONS 
85 
17.1 
Basic principles 
85 
17.2 
Involvement of ethical committees 
85 
17.3 
Regulatory authorities 
85 
17.4 
Investigators view of the ethical issues and considerations 
86 
17.5 
Falsification of data 
86 
18 
ADMINISTRATIVE CONSIDERATIONS 
86 
18.1 
Trial committees 
86 
18.2 
Trial registration 
86 
18.3 
Financing 
87 
18.4 
Patient insurance 
87 
18.5 
Patient compensation for trial-related expenditures 
87 
18.6 
Publication Policy 
87 
18.7 
Protocol amendment policy 
88 
19 
REFERENCES 
89 
20 
APPENDIX 
93 
20.1 
Management and classification of liver toxicity 
93 
20.2 
MAO inhibitor food restriction list 
95 
20.3 
Sub-studies 
96 
21 
Possible Drug Interactions 
98 
21.1 
Anti-TB drugs in PanACEA-DECODE and anti-nausea / anti-emetic drugs 
98 
21.2 
Anti-TB drugs in PanACEA-DECODE and antacids / H2-antagonists / proton pump inhibitors 
101 
 
 
 


 
 
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3 ABBREVIATIONS 
ACTG 
Acquired Immunodeficiency Syndrome Clinical Trials Group 
ADL 
Activities of Daily Life 
ADR 
Adverse Drug Reactions 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
aPTT 
Activated prolonged Thrombin Time  
ARV 
Antiretroviral 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration Curve 
AUC(0-t) 
Area under the Plasma Concentration Curve from zero to t 
BDM 
Bedaquiline, Delamanid, Moxifloxacin 
BDMD 
Bedaquiline, Delamanid, Moxifloxacin, Delpazolid 
BDQ 
Bedaquiline 
BID 
Bis in die (twice daily) 
BMI 
Body Mass Index 
BP 
Blood Pressure 
Cmax 
Maximum Observed Plasma Concentration  
CD4 
Cluster of Differentiation 4 (T Helper Cell) 
CIOMS 
Council for International Organizations of Medical Sciences 
CoA 
Certificates of Analyses 
CRF 
Case Report Form  
CRO 
Contract Research Organisation 
Ct 
Cycle threshold in GeneXpert MTB/RIF® test 
CTCAE 4.0 
Common Terminology Criteria for Adverse Events 4.0  
DLM 
Delamanid 
DMP 
Drug Management Plan 
DOTS 
Directly Observed Treatment Short course 
DSMB 
Data Safety Monitoring Board 
DS 
Drug sensitive  
DZD 
Delpazolid 
eCrCl 
estimated creatinine clearance 
EDTA  
Ethylene Diamine Tetraacetic Acid 
EBA  
Early Bactericidal Activity 
eCRF 
electronic Case Report Form 
 
EMB  
Ethambutol 
FDA 
Food and Drug Administration (USA) 
GCP  
Good Clinical Practice 
HED 
Human Equivalent Dose 
hERG  
Human Ether- à -go-go-Related Gene 
HIV 
Human Immunodeficiency Virus 


 
 
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HRZE 
Isoniazid, rifampicin, pyrazinamide, ethambutol 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization  
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
INH 
Isoniazid 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Randomisation System 
kg 
kilogram 
LAM 
Lipoarabinomannan 
LCB 
LegoChem Biosciences, Inc. 
LZD 
Linezolid 
m 
meter 
MBLA 
Molecular Bacterial Load Assay 
MDR 
Multidrug-Resistant 
MGIT 
Mycobacterium Growth Indicator Tube 
MIC 
Minimum Inhibitory Concentration 
MOP 
Manual of Procedures 
MXF 
Moxifloxacin 
MTB 
Mycobacterium tuberculosis 
NIMR-MMRC 
National Institute for Medical Research Mbeya- Medical Research Centre 
NOAEL 
No Observed Adverse Events Level 
OVX 
Ovariectomy 
PCR 
Polymerase Chain Reaction 
PK 
Pharmacokinetics 
PT 
Prothrombin Time 
PTM  
Pretomanid 
PZA 
Pyrazinamide 
QD 
quaque die (once per day) 
QRS 
Electrocardiographic QRS Interval 
QTcB 
QT-Interval corrected by Bazett’s formula 
QTcF 
QT-Interval corrected by Fridericia’s formula 
RIF 
Rifampicin 
SA 
South Africa 
SAE 
Serious Adverse Event 
SA GCP 
South African Good Clinical Practice 
SAR 
Serious Adverse Reaction 
SAP 
Statistical Analyses Plan 
SSCC 
Serial Sputum Colony Count 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
STEP 
Selection Trial with extended Post-treatment follow up 
STZ 
Sutezolid 


 
 
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TEAE 
Treatment-Emergent Adverse Event 
TB 
Tuberculosis 
Tmax 
Time to Reach Cmax 
TSC 
Trial Steering Committee 
TTP 
Time to Positivity in Liquid Media 
UGT  
Uridine Diphosphate (UDP)-Glucuronosyltransferase 
ULN 
Upper limit of normal 
VZ/F 
Apparent Volume of Distribution 
WHO 
World Health Organization 
XDR 
Extensively drug-resistant 
 
 


 
 
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4 BACKGROUND INFORMATION 
4.1 The need for new TB drugs  
While progress has been made in recent years in controlling tuberculosis (TB) globally, TB has 
remained a persistent problem in the developing countries of Africa, Asia and Eastern Europe. TB 
is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, 
ranking above HIV/AIDS [1]. The current first-line anti-tubercular agents have been in use for over 
20 years and are relatively ineffective in controlling TB as a public health problem. The long 
treatment duration and treatment-related toxicity result in poor compliance. As a result of poor 
treatment compliance, drug resistance is becoming more common. Multidrug-resistant TB (MDR-
TB) is a public health emergency, especially in sub-Saharan Africa where human immunodeficiency 
virus (HIV) infection is endemic. Prevailing challenges such as lack of universal MDR-TB diagnosis, 
lengthy and toxic treatments that cure only 52% of patients, complicated with development of 
extensively drug-resistant (XDR) TB, are major impediments in MDR-TB control. Models predict 
that if the current status is kept up, MDR-TB incidence and associated death trend will increase 
dramatically and will overturn and become the dominant form of TB by 2050 [2]. Novel 
approaches to counter-attack the threat are highly needed. 
A step in the right direction is a new TB regimen composed of bedaquiline (BDQ), pretomanid 
(PTM) and linezolid (LZD), which was superior to the current first-line regimen of isoniazid, 
pyrazinamide, rifampicin and ethambutol (HRZE) in mouse studies. In the TB Alliance’s NiX-TB trial, 
the regimen was given to patients with extensively drug-resistant TB (XDR-TB) for six months, and 
has achieved lasting cure in 19 out of 20 patients that have completed the follow-up period to 
date [3, 4]. However, safety of this regimen is an important concern. Toxicity attributed to LZD, 
specifically, led to treatment interruptions in 71% of patients, which can be considered acceptable 
only in the XDR patient population with an otherwise dire prognosis. 
PanACEA has taken the opportunity to build on knowledge derived from NiX-TB, and aims to take 
steps to test a similar regimen to be used in a larger population of TB patients. We have access to 
drugs of similar class and effectiveness (e.g. delamanid (DLM), a nitroimidazole and delpazolid 
(DPZ), an oxazolidinone), and safety data available up to now suggests that these drugs may have 
a more favourable safety profile compared to their counterparts (LZD and PTM). DLM is approved 
for use in Europe, Japan, and several other countries. DZD is a new, investigational oxazolidinone 
that will most likely have similar or better efficacy as LZD, however is much less toxic as indicated 
by in vitro and early human data [5].  
PanACEA proposes to investigate the combination of BDM - DZD: BDQ, DLM, moxifloxacin (MXF) 
and DZD. A more in-depth discussion of the advantages and potential of DZD will be continued in 
the section below.  


 
 
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4.2 Delpazolid previous experience 
DZD (LCB01-0371), discovered in 2010, is an oxazolidinone antibiotic that binds to the V region of 
the bacterial 23S rRNA, interfering with the early compound formation of 30S and 50S rRNA, thus 
inhibiting protein biosynthesis being developed by LegoChem Biosciences Inc.   
DZD demonstrated good safety in Phase I studies up to 21 days, and good activity in a Phase 2a 
14-day EBA study in drug-sensitive TB patients [6] with a total of 239 patients exposed. The early 
bactericidal activity (EBA) study tested daily doses of 400 mg BID, 800 mg QD, 1200 mg QD and 
800 mg BID. Good antibacterial activity was seen, but the study results did not permit to choose 
the best dose for further clinical trials. 
Preclinical studies suggest that DZD has low potential for metabolic interactions with other 
medications. Mainly, inhibition of Monoaminooxidase (MAO) was seen in secondary 
pharmacology testing in vitro, of similar (MAO-A) or lower inhibitory magnitude (MAO-B) than in 
the licensed oxazolidinone, linezolid. 
Unlike other oxazolidinone drugs, DZD is eliminated mainly by the renal route. The ensuing 
relatively short half-life leads to the hope that the main, severe oxazolidinone class toxicities in 
chronic dosing, suppression of hematopoiesis and occurrence of peripheral neuropathy, will not 
be seen with DZD as these are mostly associated with high drug concentrations at the end of the 
dosing interval [7]. This hope seems to be confirmed so far in human studies, which have dosed 
for up to 21 days. 
LCB has animal toxicity data available for 6 months of DZD dosing in rats, and 9 months of dosing 
in dogs, which according to regulatory guidance will permit long-term dosing.   
A further detailed description of all study drugs is provided in section 6. 
4.3 The TB Burden in Tanzania and South Africa  
Tanzania, an East African country with a population of 56 million inhabitants and a 2016 per capita 
GDP of $879 US, is a country with a high burden of drug sensitive (DS) TB. In 2016 the incidence 
for all forms of TB was 287 per 100,000. Thirty-four percent of tested TB patients are HIV positive. 
The incidence of TB in Tanzania is slowly declining. The rate of MDR-TB among new cases of TB is 
still low (1.3%, 95% CI 0.47-2.1), but higher for retreatment cases (6.2%, 95% CI 5.1-7.4). Overall, 
treatment success is high, with 90% success-rate amongst new and relapsed cases in 2015, and 
80% treatment success for previously treated cases. The MDR/RR-TB cases that started on second-
line treatment in 2014 have had treatment-success in 76% of all cases (143 total) [8]. 
South Africa has a population of 56 million persons and a per capita GDP of $5,273 (US) in 2016. 
The country has one of the highest TB burdens globally, with a 2016 incidence of 781 per 100,000. 
59% of tested patients are HIV positive, which is, as a major risk factor for TB one of the biggest 
contributors to the TB epidemic in SA. MDR-TB is more frequent than in Tanzania, at 3.4% (95% CI 
2.5-4.3) of all newly diagnosed cases, and 7.1% (95% CI 4.8-9.5) of retreatment cases. 
Unfortunately, MDR-TB and XDR-TB have been on the rise in SA in recent years. In 2016 there 


 
 
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were 967 cases of XDR-TB, with 628 cases starting on treatment. So far, the treatment-success in 
XDR-TB has been approximately 27% [9]. 
5 RATIONALE FOR THE STUDY 
New TB treatment regimens are vital to combat the TB epidemic, and most importantly, the drug-
resistant TB epidemic. 
In MDR-TB, only 52% of MDR cases achieve cure [1]. A model of MDR-TB in Vietnam showed that 
under current diagnostic and treatment practices, MDR-TB incidence will increase by 17%, and 
deaths by 22%, within ten years [10]. In a similar model in China, MDR-TB will become the 
dominant form of TB by 2050 [2].  
To effectively combat this epidemic, more potent drug combinations with regards to sterilizing 
capacity are necessary. These can be created through introduction of novel drugs with a low pre-
existing resistance.  
As evidenced by the success of the Nix-TB regimen composed of BDQ, a nitroimidazole, and LZD in 
patients with high levels of drug resistance, this drug combination is effective in curing TB within 
6 months of treatment.  
DZD in combination with BDM, is key in advancing a TB regimen with low pre-existing resistance 
and improved tolerability compared to LZD containing regimens. 
DZD has a good safety profile, as has been assessed both pre-clinically and clinically for up to 21 
days in healthy volunteers. 
Previously DZD has been studied in patients in an EBA monotherapy study. DZD showed good 
activity in this study [11], but the question of selecting the best possible dose is not answered yet, 
since a reliable dose-response was not observed then. 
A 14-day EBA is not long enough to assess the safety of different doses of DZD, since oxazolidinone 
class toxicity usually becomes apparent at a later stage in treatment. 
Based on this, we believe it is more valuable to evaluate DZD over a dosing period which will 
generate enough accurate data on efficacy and safety to link exposure to safety observations. A 
time-period of dosing for 4 months is minimal to get a reliable estimate of toxicity, given that 
oxazolidinone class toxicity occurs not immediately during therapy [7]. 
A U.S. FDA guidance recently described an incompletely understood dose-toxicity and dose-
response relationship as the cause for failure of many drug development programmes. It 
suggested testing several doses in phase IIb, and then continuing one or two selected doses [12]. 
PanACEA developed the concept this of this DZD dose selection study to establish an exposure-
response model and an exposure–toxicity model if specific toxicity is observed. Based on data 
from this study, a DZD dose will be selected for further assessment in following studies. 


 
 
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6 INVESTIGATIONAL PRODUCT 
6.1 Delpazolid 
Delpazolid (LCB01-0371) belongs to the oxazolidinone class of antibiotics and is currently under 
development for the indication treatment of TB, especially to improve upon the limitations of 
existing oxazolidinone compounds.  
Oxazolidinones are a class of antimicrobial drugs that act by blocking protein translation, 
preventing the formation of the protein initiation complex. DZD binds to the V region of bacterial 
23SrRNA and is interfering with the early compound formation of 30S and 50S rRNA. Therefore, it 
inhibits the protein biosynthesis at a very early stage leading to inhibition of bacterial proliferation 
and survival. Nonclinical studies demonstrated antibacterial activity towards various clinical 
pathogens, including methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci 
(VRE), and Mycobacterium tuberculosis (M. tuberculosis).  
Currently, DZD is available in two formulations: a tablet, containing 400 mg of DZD, to be used in 
this trial, and a parenteral injection. 
 
6.1.1 Delpazolid: Efficacy in animal models 
The efficacy of DZD in comparison to Linezolid, PNU-10480 and isoniazid was evaluated in a M. 
tuberculosis mouse model (figure 1). Mice were treated with DZD (150 mg/kg), Linezolid (150 
mg/kg), PNU-10480 (150 mg/kg) or isoniazid (25 mg/kg) for 4 weeks. DZD decreased the CFU of 
M. tuberculosis by 3.08 log in the lung compared to a 1.11 log reduction (Linezolid), 4.21 log 
reduction (PNU-10480) and 2.23 log reduction (isoniazid). 
Figure 1. In Vivo Bactericidal Activity of LCB01-0371 in C57BL/6 Mice Infected with M. Tuberculosis 
 


 
 
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6.1.2 Delpazolid: Pharmacokinetics and product metabolism in animals 
Several in vitro studies were conducted in mice, rats and dogs to assess the pharmacokinetics of 
DZD.  
DZD is mainly eliminated via urinary excretion, followed by fecal excretion. Plasma protein binding 
is low.  
No inhibition of the hepatic enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, CYP2E1, and CYP3A4 over the concentration range tested was observed. Treatment with 
DZD (at 2 to 200 μM for 48 hours) did not increase mRNA expression of drug metabolizing enzymes 
(CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, UGT1A1, UGT1A4, UGT1A9, and UGT2B7) 
and transporters (MDR1, BCRP, MRP2, NTCP, OATP1B1, OCT1) using human hepatocytes. 
Furthermore, there was no evidence that DZD inhibited the transport activities of MDR1, BCRP, 
MRP1, MRP2, OCT1, OCT2, NTCP, OAT1, OAT3, OATP1B1, OATP1B3, and OATP2B1 transporters. 
Significant inhibition was only observed against monoamine oxidase (MAO)-A enzyme.  
The potential of DZD and linezolid to bind to MAO-A and MAO-B receptors was tested in vitro 
using human recombinant enzymes. DZD showed inhibition of MAO-A and MAO-B with IC50 values 
of 12.6 μM and 27.0 μM, respectively. Linezolid showed inhibition of MAO-A and MAO-B with IC50 
values of 26.3 μM and 1.51 μM, respectively. 
Further details about DZD absorption, bioavailability, distribution and metabolism can be found in 
the Investigator’s Brochure. 
6.1.3 Delpazolid: preclinical animal toxicity studies  
Overall, preclinical toxicology studies were performed as single and repeat-dose studies up to 4 
weeks in rats and dogs and further repeat-dose studies up to a duration of 26 weeks in rats, and 
up to 39 weeks in dogs. No accumulation after treatment with multiple doses of DZD occurred. 
Repeat-dose studies in rats 
In the 4-week oral toxicity study in rats, groups of rats received drug levels of 0, 30, 60 and 140 
mg/kg/d. All main study animals survived to their scheduled terminal or recovery necropsies with 
the exception of 2 males. One control male was euthanized on day 26 due to a possible handling 
injury and a male at 140 mg/kg/d was euthanized on day 30 due to test article related 
gastrointestinal ulceration. No test article related effects for clinical findings, body weight, food 
consumption measurement, ophthalmoscopic examinations, 
haematology, coagulation 
evaluations, macroscopic examinations and organ weight measurement were noticed at dose 
levels of 30 and 60 mg/kg/d. At 140 mg/kg/d, test article related decreases in mean body weight 
and food consumption occurred. Furthermore, test article-related clinical findings and effects in 
hematology, coagulation and urinalysis parameters were observed as were adverse clinical 
chemistry findings. Therefore, 60 mg/kg/d was the no-observed adverse effect level (NOAEL) in 
this group. 


 
 
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In the 26-week repeat oral dose toxicity study in rats dose levels of 10, 25, 50,100 → 75 (from 
week 11 of dosing) mg/kg/d and a control group (0.5% Methylcellulose and 0.1% Tween 80 in 
water for injection) were selected. A recovery period of 4 weeks was added, to evaluate the 
reversibility of potential toxicity. For observation of systemic exposure, a toxicokinetic study was 
also conducted and the vehicle or test substance was administered to all groups twice a day with 
a total daily dose of 20 mL/kg/d. As observed in the 4-week study, no accumulation or saturation 
of DZD was evident. Tmax of DZD ranged from 0.50 to 1.00 hours. Systemic exposure was similar in 
both sexes and increased in proportion to dose between 10 and 75 mg/kg/d. No death or 
toxicologically significant test substance-related clinical findings were observed in the test 
substance dosing groups. No test substance-related toxic effects in food consumption, 
ophthalmology, urinalysis, clinical chemistry and bone marrow examinations were observed. Test 
substance-related adverse observations: decrease in mean body weight in males in the 100 → 75 
mg/kg/d group and decrease in red blood cell, haematocrit and mean corpuscular haemoglobin in 
males in the 50 and 100 → 75 mg/kg/d groups were observed. Furthermore, there was a decrease 
in absolute testis weight at 50 and 100 → 75 mg/kg/d and decrease in epididymis weight at 25, 50 
and 100 → 75 mg/kg/d noted, as well as signs of atrophy in the testis and epididymis at 25, 50 and 
100 → 75 mg/kg/d in the histopathological examinations and also cell debris in lumen and 
oligospermia at these dose levels. Therefore, a NOAEL of 10 mg/kg/d for male rats and 100 → 75 
mg/kg/d for female rats was considered. 
In the 28-day intravenous rat study a dose of 60, 120 and 240 mg/kg/d were administered. Three 
deaths at 240 mg/kg/d occurred and were treatment related. Microscopic changes (decreased 
hematopoietic cellularity in the bone marrow) were noted in males at 120 and 240 mg/kg/d and 
in females at 240 mg/kg/d. Decreased food consumption at 240 mg/kg/d was observed (120 
mg/kg/d in females during the first week only) and atrophy and/or secretory depletion in a wide 
variety of other tissues were considered secondary to the decreased food consumption. All 
changes in the male sex organs were fully reversible. Therefore, the NOAEL was considered to be 
120 mg/kg/d.       
Repeat-dose studies in dogs 
In the 4-week oral toxicity study in beagle dogs, the test article was administered twice daily at 
dose levels of 5, 10 and 20 mg/kg/d, as was the vehicle in the control group. The toxicokinetic 
parameters calculated for males and female were similar. The combined mean AUC0-24 values on 
day 27 were 13.8, 29.8 and 65.4 hr ug/mL at 5, 10 and 20 mg/kg/d, respectively. Combined mean 
Cmax values on day 27 were 2.21, 5.5 and 11.6 ug/mL/d, respectively. No deaths occurred during 
the study.  
The NOAEL was 20 mg/kg/d for male dogs and 10 mg/kg/d for female dogs due to adverse effects 
on clinical signs, body weight, food consumption, hematology/clinical chemistry and pathology. 
In the 39-week repeated oral dose toxicity study with a recovery period of 4 weeks to assess the 
reversibility of adverse events, 0, 2, 5 and 10 mg/kg/d were administered to male and female dogs. 
20 mg/kg/d was given until week 5, followed by a 2-week withdrawal period and continued at 15 
mg/kg/d. The decrease was necessary due to gastrointestinal symptoms in females. The systemic 


 
 
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exposure of the test substance was determined through a toxicokinetic study. The AUC0-24 and Cmax 
were increased in proportion to the dose level and similar between both sexes. The mean Tmax was 
similar across dose levels and varied between 0.50 and 0.88 hours. No differences between sexes 
was noted and accumulation did not occur. There were no deaths during the experimental period. 
No test-related adverse effects were observed in any test substance dosing group for 
ophthalmologic examination, electrocardiogram, urinalysis, organ weights, necropsy or 
histopathology. Gastrointestinal symptoms (females only), decrease in body weight and food 
consumption (males and females) were noticed at 20 mg/kg/d and all subjects recovered after a 
change from 20 to 15 mg/kg/d. 
In the 28-day intravenous infusion toxicity and toxicokinetic study in Beagle dogs, doses of 5, 15 
and 30 mg/kg/d were administered. One female was killed at 30 mg/kg/d. Bone marrow and 
lymphoid tissue depletion was observed, as were gastrointestinal tract and other tissue changes 
due to inappetence. Eosinophilic round inclusions within centrilobular hepatocytes were observed 
at all doses (at lowest dose only in males). In summary, the NOAEL was 15 mg/kg/d. 
Genotoxicity  
No evidence of genotoxicity was observed in a bacterial reverse mutation assay, in a L5178Y/TK+/- 
mouse lymphoma mutagenesis assay and in a rat micronucleus assay. 
Reproductive toxicity 
Reproductive toxicity studies at dose levels of 0, 15, 30 and 60 mg/kg/d were performed in rats 
following oral administration and the reproductive performance, in utero development, dams and 
embryo-fetal development were examined. The NOAEL (reproductive performance and in utero 
development) was 15 mg/kg/d in males due to decreased sperm motility and abnormal sperm. In 
females, the NOAEL was 60 mg/kg/d.  
The NOAEL for maternal animals was considered to be 30 mg/kg/d based on body weight, and the 
NOAEL for embryo-fetal development in rats was 15 mg/kg/d based on decreased fetal body 
weight at higher doses tested. 
In rabbits, embryo-fetal development was observed at dose levels of 1, 3 and 10 mg/kg/d, with 
test substance related effects evident at 10 mg/kg, and the high- and low-dose levels were 
determined to be 3 and 0.3 mg/kg/d. 
 
 
6.1.4 Delpazolid: Efficacy and safety in clinical studies  
DZD has been clinically tested up to Phase 2A with the oral tablet formulation (7 Phase 1 studies-
1 study withdrawn and 1 Phase 2a study) and up to phase 1 (1 study) with the intravenous 
formulation. A total of 239 subjects received DZD, for a maximum administration period of 21 
days. 


 
 
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In the single ascending dose study LCB01-0371-11-1-01, the multiple ascending 7-day dose study 
LCB01-0371-12-1-02 and the multiple ascending 21-day dose study LCB01-0371-14-1-01 the 
safety, tolerability, and pharmacokinetics of DZD were examined.  
Altogether, there were no signs of significant myelosuppression or neuropathy. All ECG results 
were normal or assessed as not clinically significant. No deaths or SAEs occurred.  
In the single-dose phase 1 study DZD was dosed up to 3200 mg. 20 adverse events occurred in 15 
subjects. Most AEs were mild; moderate AEs only occurred at 3200 mg. 
In the 7-day repeat-dose study, DZD was dosed up to 1600 mg BID. Most AEs were mild. Moderate 
AEs occurred in the 1600 mg BID group and this group was terminated after the first dose. The 
maximum tolerated dose in this study was 1200 mg BID. 
In the 21-day repeat-dose study, DZD was dosed at a maximum of 1200 mg BID. Most AEs were 
mild, except for AEs of decreased neutrophil count, abnormal haematology test and abnormal 
liver function. 1 subject in the 1200 mg BID group showed a low haematocrit 17 days after drug 
administration and the study drug was discontinued at the discretion of the investigator. A non-
compartmental PK analysis was also performed in 28 out of 40 subjects. Accumulation was almost 
non-existent with multiple dosing. 
A food-effect study LCB01-0371-13-1-03 demonstrated a delayed absorption, a decrease in the 
maximum blood concentration and a decrease of the AUClast by 10%. It was concluded that diet 
does not have a meaningful influence on treatment. 
In another dose escalating phase 1 study LCB01-0371-16-1-01, DZD was administered 
intravenously to 36 healthy male participants to investigate the pharmacokinetics, safety and 
tolerability. A maximum dose of 1200 mg i.v. was administered. No severe or life-threatening AEs 
occurred. However, dose escalation was stopped at 1200 mg i.v. due to probably drug related AEs. 
Furthermore, 2 subjects from the 1200 mg i.v. group experienced moderate nausea and were 
withdrawn from the study. Therefore, 800 mg i.v. is the maximum defined dose for i.v. 
administration. Infusion site-related AEs were the most frequent AEs and appeared to be 
increased with the administered dose.  
In the phase 2a early bactericidal activity study, all DZD doses administered showed killing of 
sputum bacilli.  
The average daily change in log-CFU in DZD treatment groups were -0.044 ± 0.016 for 800 mg QD 
group, -0.053±0.017 for 400 mg BID group, -0.043±0.016 for 800 mg BID group and -0.019±0.017 
for 1200 mg QD group. The average daily CFU change in the control groups was -0.192±0.028 for 
the HRZE (isoniazid 75 mg, pyrazinamide 400 mg, RIF 150 mg, ethambutol hydrochloride 275 mg 
contained per tablet) group and -0.154±0.023 for Linezolid 600 mg BD group.   
Using a model based approach, the DZD patients achieved a daily decline in log-colony-forming 
units (CFU) over the 14 days of 23%, 27%, 22% and 10% of the results obtained from the patients 
receiving the HRZE combination in the 800 mg BID, 400 mg BID, 800 mg BID, and 1,200 mg BID 
groups respectively.  The results are similar to previously reported EBA results for oxazolidinones 


 
 
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[13].  The ADR occurrence rate in study groups were 18.75% (3/16 subjects, 8 cases) in 400 mg BID 
group, 18.75% (3/16 subjects, 6 cases) in 800 mg BID group, and 37.50% (6/16 subjects, 13 cases) 
in 1200 mg QD group, while there was no ADR in 800 mg QD group. That of control groups were 
50.00% (4/8 subjects, 9 cases) in HRZE and 50.00% (4/8 subjects, 7 cases) in LZD 600mg group.  
The most frequently reported ADR was gastrointestinal disorder, especially nausea and diarrhoea. 
 
Figure 2. Phase 2a EBA study: daily decline in log-CFU with different treatments 
 
6.1.5 Delpazolid: interpretation of preclinical animal and clinical human findings 
Comparing effects of DZD in rats and dogs and humans at the longest application period, DZD had 
an effect of the gastrointestinal system, presenting with decreased body weight in rats and in 
dogs, decreased food consumption in dogs, and gastrointestinal symptoms in dogs and humans. 
In humans, these symptoms occurred during fasting conditions and most likely will be improved 
under fed conditions, which we are planning to use in this study. 
6.1.6 Delpazolid: Discussion of risk for tyramine pressor syndrome in this study 
Oxazolidinones, like LZD, are known to have a weak reversible monoaminooxidase (MAO) 
inhibitory effect in vitro due to their structural similarity to the reversible MAO inhibitor 
toloxatone [14]. Therefore, oxazolidinones can block the metabolization of dietary tyramine and 


 
 
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thus may act as pressor enhancers, as documented for LZD in rats [15] and in rare cases in humans 
[16].  
Tyramine is a naturally occurring trace amine, which acts as catecholamine releasing agent. When 
intestinal MAO-A is inhibited, higher levels of tyramine can be absorbed in the intestines, leading 
to indirect increase of norepinephrine signalling at nerve endings, which might cause arterial 
hypertension and hypertensive crisis.  
The potential interaction of foods with a high tyramine content and irreversible MAO-inhibitors is 
well documented. The interaction with drugs, having reversible MAO-inhibitory effects, like 
Linezolid, and DZD in studies to date, and oral tyramine doses within the range of normal dietary 
intake (up to 100mg per meal) showed no significant changes in blood pressure [17, 18]. Reversible 
MAO-A inhibitors, e.g. moclobemide have been extensively studied and their PK, clinical PK and 
toxicological profiles have been thoroughly defined. Here, just minimal interaction with 
exogenous amines, like tyramine have been found [19, 20].  
A specific tyramine pressor test study was conducted for linezolid in humans, to examine the 
quantity of oral tyramine intake required to produce a blood pressure increase by 30mmHg. It was 
found that very high doses of tyramine, of above 100 mg, were required to produce such a blood 
pressure increase, similar to the specific MAO-A inhibitor, moclobemide which was used as a 
control [16]. Based on these findings, the actual recommendations for tyramine quantities for 
patients receiving LZD are <100mg per meal [21, 22] and moclobemide is prescribed without 
dietary tyramine restrictions in the UK, but with a general precaution in the product label to avoid 
excessive amounts of tyramine-rich foods [23]. 
No studies with DZD were so far conducted to address this issue.  
In this study, we have decided to approach the issue with some caution and restrict the use of 
certain foods with the highest tyramine content: certain cheeses, certain meats, beers and wine, 
and soy sauce (see Appendix 20.2 for restricted foods). 
In addition, we have added scheduled post-IMP blood pressure measurements at the visit Day 01 
and Week 02 to detect eventual increases in blood pressure. 
7 NON-IMP DRUGS USED IN THE STUDY 
For clarity, all licenced drugs in this study (all drugs other than DZD), are referred to as ´non-IMP 
study drugs´. BDQ, DLM and MXF are meant by this term. When reference is made to ´study drugs´ 
all drugs including DZD are meant.   
7.1 Bedaquiline 
BDQ, developed by Janssen Therapeutics, is a diarylquinoline compound with a novel mechanism 
of action against MTB. The inhibition of mycobacterial adenosine triphosphate synthase. The Food 
and Drug Administration (FDA), on 28 December 2012, granted accelerated approval to SIRTURO® 
(BDQ) tablets as a part of combination therapy in adults with MDR-TB. It is the first new anti-TB 


 
 
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drug to be approved after 40 years. It is also the first to be introduced specifically for the treatment 
of MDR-TB in combination with other drugs. Since 2018, SIRTURO® is approved and part of the 
national standard recommended treatment regimen for Rifampicin-resistant and MDR-TB in South 
Africa [24], and is approved in Tanzania. 
Very recently, WHO has recommended BDQ to be part of therapy of MDR-TB [25]. 
7.1.1 Bedaquiline: Efficacy in clinical studies 
In vitro, BDQ has potent activity against drug-susceptible and drug-resistant MTB isolates and is 
also bactericidal against dormant (non-replicating) MTB in a murine TB model, BDQ is as active as 
the triple combinations of INH, RIF, and pyrazinamide (PZA), with BDQ accelerating clearance of 
bacilli and displaying synergy with PZA. Drug regimens that include BDQ are considered the most 
effective experimental combinations for treatment of DS-TB in the presence of PZA, or in regimens 
without PZA that include a nitroimidazole where there is a higher likelihood of PZA resistance [26, 
27].  
In vivo, BDQ has been evaluated in DS-TB patients in a Phase 2a study and in MDR-TB patients in 
Phase IIb studies, and there is now a large post-registration database containing data mostly from 
use of the drug in South Africa. A Phase 3 study is currently recruiting (STREAM stage 2), but results 
are not expected until 2022. 
7.1.2 Bedaquiline: Pharmacokinetics 
BDQ is well absorbed with a Tmax of 4-6 hours irrespective of the dose [28]. Dose-proportionality 
of Cmax and AUC is seen up to 700 mg with single doses and 400 mg with multiple doses. The 
average t1/2 of BDQ is 132 days and is 112 days for its M2 metabolite. Administration with food 
increases the bioavailability by 95%. In individuals of black race, concentrations of BDQ are 
appreciably lower (52%) compared to individuals of non-black race [29]. BDQ is metabolized by 
oxidative metabolism via the CYP3A4 isoenzyme to its N-desmethyl metabolite, M2. BDQ has an 
extensive t1/2, therefore it accumulates over time. In adults, drug accumulation is mitigated by 
using the current loading dose of 400 mg once daily for two weeks followed by a reduction in dose 
and dosing frequency to 200 mg three times weekly for six additional weeks. 
7.1.3 Bedaquiline: Safety and tolerability  
The primary safety concerns about BDQ included an increase in late mortality in the phase 2b trial, 
which also identified QT interval prolongation. At 24 weeks, the mean change in QTcF in the BDQ 
arm was a 15.4 ms increase, with 3.3 ms increase in the placebo arm [30]. Despite of the fact that 
most of the phase 2b deaths were attributed to TB by the investigators, the phase 2b deaths led 
to a black box warning on the package insert. More recently, however, results using BDQ in 2,093 
patients in France, Georgia, Armenia, and South Africa were presented in a review by the WHO 
BDQ guideline development group, published in 2017 [31]. MDR-TB patients who received BDQ 
for a mean of 6.37 months were significantly more likely to survive (adjusted odds ratio for death 
(OR) 0.39; 95% CI 0.31-0.59; p<0.001; adjusted hazard ratio (HR) 0.48; 95% CI 0.39-0.59) compared 
to those who did not. This effect was present across resistance profile categories and history of 


 
 
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previous TB disease and may alleviate some concerns stemming from the unclear safety situation 
after the phase 2b study. 
7.2 Delamanid 
DLM is a nitroimidazole that inhibits the synthesis of mycolic acids, a crucial component of the cell 
wall of MTB. It represents a promising new weapon in the arsenal for treatment of MDR-TB and 
was developed by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). DLM has received regulatory 
approvals in several countries, and is currently recommended by WHO for the treatment of MDR-
TB in specific cases [32-34]. 
7.2.1 Delamanid: Efficacy in clinical studies 
Delamanid was licensed by the European Medicines Agency (EMA) based on results from a phase 
2b study, with a primary endpoint of 2 months culture conversion [35]. DLM was added to an 
optimized background regimen for the patients’ MDR-TB, compared with placebo.  
In liquid media, 45.4% of 141 patients had negative sputum samples at month 2, compared with 
29.6% of 125 patients who received placebo. 
In the phase 3 study, DLM shortened the time to culture conversion by 6 days (median: OBR + 
DLM: 51 days; OBR + placebo: 57 days). The standard of care arm performed much better than in 
past studies, with 53.5% of patients achieving two-month culture conversion; vs 58.4 % when DLM 
was added. In the DLM arm, 81.4% of patients achieved cure or treatment completion compared 
to 81.2% in the placebo arm. Additional drug resistance was acquired during treatment by 6.5% 
of patients on the placebo arm, and by 1.9% of patients on the DLM arm. The conclusion was that 
DLM showed modest improvement of treatment outcomes, but due to the unexpected high 
efficacy of the standard treatment did not show similar improved activity as in the earlier phase 
2b study. 
7.2.2 Delamanid: Safety in clinical studies 
Twelve phase I trials of DLM in healthy adults have shown a favourable side effect profile, with the 
most commonly reported side effects emerging while on treatment being dizziness, nausea and 
headache. The total number of adult individuals exposed to DLM in these safety trials has been 
949, and overall, the side effects were similar in the groups receiving DLM plus optimized 
background regimen and the groups receiving placebo plus optimized background regimen.  
DLM has been studied in a Phase 2a study in DS-TB patients and placebo-controlled phase 2b and 
phase 3 trials in MDR-TB. Both in the phase 2b and in the phase 3 studies, the safety profile of 
DLM in MDR-TB patients was favourable [36]. Serious treatment emergent AEs were similar in 
patients treated with DLM or placebo on a background regimen in the phase 3 trial that was 
recently reported. Eight (2.3%) patients in that trial discontinued due to AEs on DLM, compared 
to three (1.8%) on placebo. The proportion of patients experiencing hepatotoxicity was 6.5% in 
the DLM arm and 7.1% in the placebo arm, suggesting that DLM did not add to hepatotoxicity of 


 
 
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the background regimen. In the DLM arm, 18 (5.3%) patients experienced a prolongation of their 
QT interval, as opposed to 5 (2.9%) on placebo.  
The QTc prolongation seen in patients treated with DLM is characterized by a slow increase over 
the first 6-10 weeks of treatment followed by stability, thereafter, appearing to correlate with 
plasma concentrations of the major metabolite, DM-6705. Both hypoalbuminemia (<2.8 g/dl) and 
hypokalaemia have been found to be risk factors for DLM associated QTc prolongation. 
In the phase 3 study, the mean placebo-corrected QTcF change was 5.3 ms (90% CI: 2.8 - 7.9) at 
week 8, and 2.5 ms (-0.3 - 5.3) at week 26. Low albumin concentration (DLM is metabolized by 
albumin) was not associated with higher QTcF prolongation in that study.  
7.2.3 Delamanid: Pharmacokinetics 
In adults, DLM reaches a peak concentration (Tmax) four hours post-dose, and the apparent 
terminal elimination half-life (t1/2) is 30-38 hours. DLMs bioavailability is increased 2- to 4-fold 
when it is taken with food. The t1/2 of its main metabolites is approximately 150-600 hours. The PK 
profile of DLM is similar for healthy volunteers and for patients with TB. Among adult patients with 
MDR-TB, a dose of 100 mg twice daily achieves an AUC0-24h of 7234 h*ng/mL (CV% 32) at two 
weeks and an AUC0-24h of 7925 h*ng/mL (CV% 38) at two months [35]. Once daily dosing of 200 
mg of DLM (four 50-mg tablets), previously resulted in a mean ± SD AUCτ of 5,950 ± 1,440 ng·h/mL 
and a Cmax of 476 ± 119 ng/mL (Day 15) in healthy subjects [37]. 
 
DLM is metabolized to M1, a unique metabolite formed by cleavage of the 6-nitro-2,3-
dihydroimidazo[2,1-b] oxazole moiety, in plasma albumin in vitro. The metabolic activities in dogs 
and humans are higher than those in rodents. In animals and humans eight metabolites (M1-M8) 
produced by cleavage of the imidazooxazole moiety of DLM were identified in the plasma after 
repeated oral administration [38]. DLM was initially catalyzed to M1 and subsequently 
metabolized by three separate pathways, which suggested that M1 is a crucial starting point. The 
major pathway in humans was hydroxylation of the oxazole moiety of M1 to form M2 and then 
successive oxidation to the ketone form (M3) mainly by CYP3A4. M1 had the highest exposure 
among the eight metabolites after repeated oral dosing in humans, which indicated that M1 was 
the major metabolite. Non-hepatic formation of M1 and multiple separate pathways for 
metabolism of M1 suggest that clinically significant drug-drug interactions with DLM and M1 are 
limited [38]. 
 
Albumin in serum primarily regulates the metabolism of DLM, with the cytochrome P450 3A4 
enzyme also contributing modestly, so concurrent administration with medications known to 
inhibit or induce this enzyme may modestly alter drug levels [38, 39]. In addition, administration 
of DLM to patients with albumin levels <2.8 g/dL is not recommended. DLM and its major 
metabolites do not show meaningful inhibition of CYP isoenzyme activity, including CYP1A1/2, 
CYP2A6, CYP2B6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. DLM is not an inducer of 
CYP1A2, CYP2C9 nor CYP3A4/5. In DDI studies of DLM used in healthy volunteers in combination 
with tenofovir, efavirenz and/or lopinavir-ritonavir, no significant DDIs were seen; when given 


 
 
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with lopinavir/ritonavir, a modest increase in DLM area under the concentration-time curve of 
25% was observed [37]. Co-administration of DLM with first-line TB drugs resulted in lower DLM 
exposures (47 and 42% for the AUC and Cmax values, respectively) as well as decreased exposure 
of the three primary metabolites. DLM did not affect RIF, pyrazinamide nor INH exposure while 
the ethambutol (EMB) AUC0-τ and Cmax values were about 25% higher with DLM co-
administration. Although there was a decrease in the DLM concentrations when co-administered 
with TB drugs, this was posed to be likely related to decreased DLM absorption (because of 
ingestion of many tablets in a short time frame) and not to CYP induction. Overall, the drug-drug 
interactions between DLM and selected antiretroviral agents (including the strong CYP inhibitor 
ritonavir) and a combination of anti-TB drugs was judged as not clinically significant [37]. 
 
7.3  Moxifloxacin  
MXF belongs to the group of fluoroquinolones (FQ). FQs are a mainstay of MDR-TB treatment, and 
MXF is considered one of the most potent drugs in second line MDR-TB therapy, recently reviewed 
by WHO [40] with only moderate pre-existing resistance in the community.  MXF is a potent QTc 
prolongation agent and is frequently used as a positive control in QTc studies of new drugs. 
7.3.1 Moxifloxacin: Efficacy in clinical studies 
Efficacy studies looking at the added value of MXF included the Rifaquin study by Jindani et al, 
which showed that a 6-month regimen including rifapentine and MXF (in which INH was replaced 
by daily MXF for 2 months followed by one weekly dose of both MXF and 1200 mg of rifapentine 
for 4 months) was as effective as standard of care [41]. In the REMox study, a 4-month regimen 
containing MXF was further investigated. Although the 4-month regimen (replacing either INH or 
EMB with MXF in two different arms) did not show non-inferiority in comparison to standard of 
care, the potential of MXF itself was shown, with more rapid decline in bacterial load compared 
to standard of care in both MXF-containing arms [42].  
7.3.2 Moxifloxacin: Pharmacokinetics 
MXF is easily and rapidly absorbed after oral administration. The bioavailability of MXF following 
oral dosing exceeds 90% (52). MXF is widely distributed, with some tissue concentrations reported 
in excess of plasma levels. MXF is metabolized in the liver via glucuronide and sulfate conjugation 
by cytosolic enzymes glucuronosyltransferase and sulfotransferase [43]. The major human uridine 
diphosphate (UDP)-glucuronosyltransferases (UGTs) responsible for formation of the glucuronide 
metabolite are UGT1A1, UGT1A3, and UGT1A9 (UGT1A1 being the main isoform). MXF is a 
substrate of p-glycoprotein, and the drug transporter protein plays an important role in its 
absorption, distribution and elimination [44]. The cytochrome P450 (CYP450) enzyme system is 
not involved in the metabolism of MXF nor is it affected by the drug (58). Neither MXF nor its 
metabolites inhibit the CYP450 enzymes. Similarly, MXF was shown not to be an inhibitor of any 
of the major human UDP-glucuronosyltransferases. The sulphate conjugate accounts for 38% of 
the oral dose and is excreted in faeces; about 14% of an oral dose is converted to the glucuronide 
conjugate and is excreted in urine [45]. Peak plasma levels of the sulphate and glucuronide 


 
 
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metabolites are <10% and about 40% those of the parent drug, respectively. Overall, about 45% 
of an oral dose is excreted unchanged as parent drug, and about 51% as known sulphate and 
glucuronide metabolites, which are biologically inactive. Co-administration with food may slightly 
prolong time to maximum concentration and may reduce the maximum serum concentration (C 
max) by 16%; these effects are thought to be insignificant, and MXF may therefore be 
administered with or without food [46].  
7.3.3 Moxifloxacin: Safety and tolerability  
Data on the long-term use of MXF show that it has an excellent safety profile [47]. Comprehensive 
safety data is available from Phase II to Phase IV studies performed by Bayer Healthcare, 
comparing MXF to a comparator group of patients receiving various other antibiotics. 23.9% of 
patients suffered adverse drug reactions (ADRs) due to oral application of MXF, while 22.0 % of 
patients in the comparator group suffered such reactions [48]. Nausea (7.5%) and diarrhoea (5.8%) 
are the most frequent individual AEs reported for MXF, but also for the comparator group. Nausea 
is more common in the MXF group. All other AEs differ by less than 1% between the treatment 
groups. Headache (4.4%) and dizziness (3.6%) were third and fourth most frequently encountered 
AEs in patients with oral MXF. Among 13.368 patients who received the drug via oral route, 3 fatal 
ADRs were registered. Among 1.144 patients who received the drug via intravenous route, no fatal 
ADRs were registered. In PO active-controlled studies, 38 of the 10,613 MXF-treated patients 
(0.4%) and 51 of the 10,685 comparator recipients (0.5%) had at least 1 AE with fatal outcome. 
Myocardial infarction and septic shock (reported in 5 patients each) are the most frequent AEs 
leading to death. Serious adverse drug reactions (SADRs) were reported in 59 (0.6%) and 53 (0.5%) 
of MXF and comparator-treated patients, respectively. The most common SADRs are abdominal 
pain and vomiting, reported with an incidence <0.1%. 
7.4 Combination of drugs used in the study  
Three of the drugs used in this study have the potential to increase cardiac QT intervals, which has 
in the past discouraged large-scale use of these drugs together in a regimen. We provide recent 
data below to suggest that these drugs have been combined safely:  
Best evidence on this question is available from the prospectively randomized ACTG 5343 
(DELIBERATE) trial. This trial compared MDR-TB treatments containing either BDQ or DLM alone, 
or both drugs in combination, over a treatment period of 24 weeks.  
The study found a mean change in QTcF from baseline of 11.9 ms (95% CI: 7.4 - 16.5) in the BDQ 
arm, 8.6 ms (4.0 - 13.2) in the DLM arm, and 20.7 ms (16.1 - 25.4) in the BDQ+DLM arm [49]. 
The combined effect on the QTcF interval of co-administration of bedaquiline and delamanid was 
clinically modest and no more than additive. This study demonstrated the cardiac safety of the 
combined use of these drugs in patients with MDR-TB taking MBT with normal baseline QTcF 
values. 
These data from a randomized study are corroborated by a meta-analysis by the group of Migliori 
et al. analysed combined treatment of drug-resistant TB with BDQ and DLM in Armenia, France, 


 
 
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India, Latvia, Russian Federation, South Africa, South Korea, and The Netherlands. This review is 
the largest up to date, and included 87 cases of 7 different studies, of which 54.5% of patients 
suffered from XDR-TB and 27.3% were HIV co-infected. The study concluded the following: Most 
M/XDR patients were concomitantly treated with BDQ and DLM, and in most cases for a duration 
> 6 months. The sputum culture conversion rate after 6 months of treatment was considerably 
higher (81.4%) than historical M/XDR-TB patient cohorts. Out of 87 patients, 23 (26.4%) showed 
>1 episode of QT prolongation >450 ms in men or 470 ms in women, or a QT increase >60 ms from 
baseline values, however only 2.3% of treatments were interrupted for the occurrence of life-
threatening cardiac adverse events [50].  
Médecins Sans Frontières published data on 28 patients receiving BDQ and DLM in combination 
from South Africa, India and Armenia [51]: 25 of 28 patients received at least one additional QT-
prolonging agent, clofazimine or MFX, and 2 patients received both. The key finding from this 
cohort was that no patient exceeded a QTcF interval of 500 ms, which is the cut-off point best 
supported as a safety issue by clinical data. Only 4 patients had a change of QTcF >60 ms over their 
baseline QT interval, and all of them had received clofazimine as QT prolonging agent. In no 
patient, study drug was permanently discontinued. Of 16 SAEs in 7 patients, 6 were considered 
possibly related to DLM, BDQ or to both drugs. Eleven SAEs were considered possibly related to 
other TB drugs. The only fatal event in this cohort was associated with immune reconstitution 
inflammatory syndrome (IRIS), characterized by acute renal failure and hypoglycaemia. The most 
common SAE in the cohort was gastrointestinal (4/16, 25%), a common side effect of a number of 
MDR-TB drugs that may have been part of the regimen (thioamides or para-aminosalicylic acid, 
PAS). Nervous system disorders accounted for 4/16 SAEs (25%) and psychiatric disorders 2/16, 
(12%). Both SAEs are commonly associated with cycloserine, another drug commonly used in 
MDR-TB regimens. Of note, 23 (82%) patients in this report received LZD as part of their regimen. 
Further published case reports include 7 patients: 2 single XDR patients were summarized in a 
review of case series [52] and 5 more XDR patients’ outcomes were published as a separate case 
series, with patients living in Russia (2), India (2), or the Netherlands (1) [53]. One of 2 in the first 
case review and 2 of 5 patients in the second case review experienced QTcF >500 ms; in one case 
prolongation reverted on repeat examination; the second patient was started on concomitant 
verapamil and had an unspecified dose adjustment. All 3 of the patients exceeding an absolute 
QTcF prolongation of 500ms had received CFZ as additional QT-prolonging agent in their regimen.  
Recent safety data summarized below shows that MXF can also be safely combined with a BDQ-
nitroimidazole combination without exacerbating QT prolongation: 
The TB Alliance NC005 study assessed regimens containing BDQ, PTM and PZA, with and without 
MXF [54]. Published data of QT prolonging effects of PTM 200mg given alone in a 14-day EBA study 
[55] and DLM in its Phase III study [36] suggests that DLM would not cause more QT prolongation 
than PTM.  
In the regimen containing BDQ+PTM+PZA, the mean QTcF change from baseline was 21.9 ms (95% 
confidence interval 18.2-25.7), very much in line with that seen for BDQ + DLM in the ACTG 5343 
DELIBERATE study mentioned above. In patients receiving MXF in addition to BDQ+PTM+PZA, 


 
 
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QTcF prolongation was unchanged at 21.9 (95% CI 18.7-25.0); so, in this study, there was no 
difference in QTcF due to the addition of MXF. In the control arm (INH + RIF + PZA + EMB) the 
mean increase from baseline was 10.2 ms (95% CI 7.0-13.4)[56].  
Serious treatment-emergent AEs were equally distributed in the BDQ+PTM+MXF+ PZA group (60 
patients) and the BDQ+PTM+PZA group without MXF (59 patients), with 4 events occurring in each 
arm. The INH+RIF+PZA+EMB arm also had 4 events in 61 patients. In all arms, most patients 
experienced at least one treatment-emergent AE: 57 of 60 in the MXF-containing arm, 50 of 59 in 
the arm without MXF, and 44 of 61 in the control arm. 
8 STUDY OBJECTIVES 
8.1 Safety and Tolerability Objective: 
Overall, the primary objective is to describe the safety, tolerability and exposure-toxicity 
relationship of DZD given over 16 weeks in combination with standard-dose BDQ, DLM and MXF 
compared to standard-dose BDQ, DLM and MXF alone.  
The aim is to identify the optimal dose of DZD to be used in subsequent studies that provides the 
best efficacy at acceptable safety of the drug when given daily over 4 months in patients with 
newly diagnosed, uncomplicated, smear-positive, drug-sensitive, pulmonary tuberculosis. 
8.1.1 Efficacy Objectives 
Primary Efficacy Objective: 
 
To establish an exposure-response model for DZD, given over 16 weeks in combination with 
standard-dose BDM, on the change in liquid culture MGIT time to positivity (TTP)  
 
Secondary Efficacy Objective: 
 
To assess dose and exposure-response relationships for DZD, based on secondary efficacy 
endpoints, including month-2 culture status in liquid media and on solid media, and time to 
culture conversion in liquid and on solid media 
 
To assess the relative efficacy of increasing DZD doses compared to the background regimen 
without DZD, based on primary and secondary efficacy endpoints. 
 
To assess the proportion of patients who suffer relapse within 12 months post randomisation, 
out of those patients completing 16 weeks of therapy and achieving sustained sputum culture 
conversion, defined as two successive negative liquid media cultures at or before WK08, with 
no positives to follow by the week 16 visit.  
8.1.2 Pharmacokinetics Objectives  
Primary Pharmacokinetics Objective: 
 
To describe the pharmacokinetics (PK) of DZD through development of a population PK 
model 
Secondary Pharmacokinetics Objective: 


 
 
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 
To describe the PK of BDQ, DLM and MXF including their main metabolites  
8.1.3 
Mycobacteriology Identification and Characterization Objectives 
 
To assess the minimum inhibitory concentrations (MIC) of BDQ, DLM, MXF, DZD of the 
infecting strain. 
 
To investigate the frequency of acquired mutations in the infecting strain over treatment 
 
In patients with recurrent disease: comparison of initial and recurrence isolate by whole 
genome sequencing, to differentiate between relapse and reinfection 
9 TRIAL ENDPOINTS 
9.1 Primary Endpoints 
9.1.1 Primary Safety endpoint 
Participants will be regularly assessed for AEs during treatment and follow-up phase, including 
assessments of vital signs, physical examination, weight, detailed neurological examination, 
colour vision and visual acuity tests, 12-lead ECGs and routine clinical laboratory tests (including 
chemistry, haematology and urinalysis data).  
The safety of DZD will be investigated by evaluation of:  
 
Proportion of patients experiencing expected oxazolidinone class toxicities, defined as 
peripheral or optical neuropathy, or incident leukopenia, anemia or thrombocytopenia, 
or adverse events in line with tyramine pressor response, all of Grade 2 or higher, possibly, 
probably or definitely related to  DZD 
9.1.2 Primary Efficacy Endpoint 
The efficacy of DZD will be evaluated by measuring the change in mycobacterial load over time on 
treatment as quantified by time to positivity in BD MGIT 960® liquid culture described by non-
linear mixed-effects methodology 
9.2 Secondary Endpoints 
9.2.1 Secondary safety endpoints 
• 
All adverse events 
 
Adverse events of Grade 3 severity or higher 
 
Adverse events possibly, probably or definitely related to study drugs 
 
Treatment discontinuations or interruptions related to adverse events/serious adverse events 
 
Frequency, severity and type of ECG alterations 
 
Changes in ECG intervals of PR, RR, QRS, QT, Fridericia-corrected QT [QTcF] 


 
 
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 
Proportion of participants with QTcF > 500ms in ECGs on treatment 
 
Proportion of participants with a prolongation of QTcF > 60ms in ECGs of grade 3 and above as defined 
under 14.6 Table 2 
9.2.2 Secondary Efficacy Endpoints 
Further efficacy of DZD will be evaluated by assessment of: 
 
Proportion of patients who suffer relapse, defined as recurrent disease caused by a strain 
identical to the baseline isolate, within 12 months post randomisation, out of patients 
completing 16 weeks of therapy and achieving stable culture conversion to negative (SCC) as 
defined below by week 08, with no positives to follow by the week 16 visit. 
 
Time to recurrent TB, and to relapse, within 12 months post randomisation 
 
Time to stable sputum culture conversion (SCC) to negative on liquid media (defined as two 
negative cultures without an intervening positive culture). Time will be measured as time on 
treatment until the first negative culture. 
 
Proportion of participants who achieved SCC at each time point during treatment 
 
Proportion of participants with negative sputum culture on solid media at WK 08 and other 
timepoints 
 
Proportion of participants developing drug resistance among those not converting to negative 
culture  
9.2.3 Pharmacokinetic Endpoints  
A population PK model will be developed for DZD. The following secondary parameters will be 
derived for DZD, for BDQ, DLM and their main metabolites, and for MXF:  
 
Area under the plasma concentration curve from morning dosing to 24 hours (AUC 0-24) 
on day 14 (WK02) 
 
The observed maximum concentration (Cmax)  on day 14  
 
Time to reach Cmax (Tmax) on day 14   
 
The minimum observed plasma concentration (Cmin) at day 14 (24 hours following the last 
dose for QD and 12 hours following the last dose for BID) 
 
Apparent oral clearance (Cl/F) 
 
Apparent volume of distribution (Vd/F) 
 
Terminal half-life (t1/2)  
Analyses may be limited by available budget, which may lead to parameters for certain drugs 
not being reported.    


 
 
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9.2.4 Mycobacteriology Identification and Characterization Endpoint 
Sputum cultures from various timepoints during the study will be assessed as follows: 
 
Minimum inhibitory concentrations (MIC) of BDQ, DLM, MXF, DZD of the infecting strain, 
at baseline and on representative isolate(s) grown at or after WK08, if any. 
 
Frequency of acquired mutations in the infecting strain over treatment by whole genome 
sequencing 
 
Comparison between bacterial strain causing recurrent disease, and the strain at baseline 
by whole genome sequencing, to discriminate relapse from re-infection. 
These assessments will be performed dependent on availability of lab capacity and budget, 
so may not be completed for all possible timepoints. 
9.2.5 Exploratory Endpoints 
The following exploratory endpoints will be analysed depending on laboratory capacity, 
availability of test kits and budgets permit and may not be tested in all trial sites:  
 
Rate of change of bacterial load measured by molecular bacterial assay (MBLA) during 
treatment 
 
Time to stable conversion to negative in MBLA (defined as two negative MBLAs without 
an intervening positive) 
 
Rate of change in bacterial load measured by quantification of sputum 
lipoarabinomannan (LAM) during treatment 
These assessments will be performed dependent on availability of lab capacity and budget. 
 
10 TRIAL DESIGN 
10.1 Summary 
This will be an open label Phase IIb, randomized, controlled, dose-finding, multi-centre study in 
participants with newly diagnosed, smear positive, uncomplicated, DS pulmonary TB.  
10.2 Trial population 
Participants will be randomized to one of five arms containing a BDM backbone with different 
doses of DZD, ranging from 0mg DZD (no DZD present in the regimen) up to 1,600mg (800mg BD). 
75 participants will be randomized into this study, with 15 participants per arm. 
In the case of unforeseen delays or a rate of dropouts or non-evaluable participants that is higher 
than anticipated, it may be necessary to recruit more participants than planned into the entire 
study (see sample size considerations, Chap. 15.1). 


 
 
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Participants will be randomised by centralized allocation, using a probabilistic minimisation 
algorithm, which will stratify participants by bacterial load in sputum as measured by GeneXpert 
cycle threshold, site and HIV status. 
Participants will visit the study clinic on a weekly basis for sputum collection, safety monitoring 
and receipt of study medication.  
After the completion of 16 weeks of experimental treatment, participants in the experimental 
arms, who did not achieve two successive negative liquid media cultures with the first at or before 
WK08, with no positives to follow by the week 16 visit, will be referred to their local health care 
facility  to complete their course of anti-TB treatment according to the national TB program. 
10.3 Inclusion Criteria 
Participants are required to meet all the following criteria in order to be randomized: 
1. Provide written, informed consent prior to all trial-related procedures including HIV testing. 
2. Male or female, aged between 18 and 65 years, inclusive. 
3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive. 
4. Newly diagnosed, previously untreated, drug susceptible pulmonary TB: presence of MTB 
complex and rapid molecular tests result confirming susceptibility to RIF and INH such as 
GeneXpert and/or HAIN MTBDR plus.  
5. A chest X-ray (no older than 2 weeks) which, in the opinion of the Investigator, is consistent 
with TB. 
6. Sputum positive on microscopy from concentrated sputum for acid-fast bacilli on at least 
one sputum sample (at least 1+ on the IUATLD/WHO scale). 
7. The participant is willing to forgo consumption of foods high in tyramine for the period of 
taking study medication (See Appendix, section 20.2, page 95). 
8. The participant is either unable to conceive/father children AND/OR his/her partner is 
unable to conceive/father children AND/OR they will consent to be using effective methods 
of contraception when engaging in heterosexual intercourse, as defined below: 
a. Non-childbearing potential: 
i. Female participant/sexual partner of male participant: Bilateral 
oophorectomy, and/or hysterectomy or bilateral tubal ligation more than 12 
months ago and/or has been postmenopausal with a history of no menses 
for at least 12 consecutive months 
ii. Male participant/sexual partner of female participant: Vasectomised or has 
had a bilateral orchidectomy minimally three months prior to screening 
iii. Male participants having a pregnant female partner or a male sexual 
partner: At least one barrier method has to be used in this case. 
b. Effective contraception methods: 


 
 
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i. Female participants: Two methods, including methods that the patient’s 
sexual partner(s) use. At least one must be a barrier method. Contraception 
must be practised for at least until 12 weeks after the last dose of DZD.  
ii. Male participants: Two methods, including methods that the patient’s 
female sexual partner(s) use. At least one must be a barrier method. 
Effective contraception must be ensured for at least 16 weeks after the last 
dose of DZD. 
Note: hormone-based contraception alone may not be reliable when taking RIF 
during continuation phase; therefore, hormone-based contraceptives alone cannot 
be used by female participants/female partners of male participants to prevent 
pregnancy. 
 
10.4 Exclusion Criteria  
Participants for whom one of the following criteria is met will be excluded from trial: 
1. Circumstances that raise doubt about free, unconstrained consent to study participation 
(e.g. prisoner or mentally handicapped person) 
2. Poor general condition where delay in treatment cannot be tolerated or death within four 
months is likely. 
3. Poor social condition which would make it unlikely that the patient would be able to 
complete follow-up 
4. The patient is pregnant or breast-feeding. 
5. The patient is infected with HIV with a CD4 count <220 cells/mm3. If >220 cells/mm3, 
patients will be included only if any of the following is applicable:  
 
The patient is antiretroviral (ARV) naïve and able to postpone commencing HIV 
treatment for 2 months after the trial has started and then restrict regimens to 
those containing dolutegravir (see section 12.6.2 on ARVs) 
or 
The patient is ARV experienced (has been on ARV´s a minimum of 5 months) and 
able to switch to a dolutegravir-based regimen.  
 
The patient is treated with nucleosidic reverse transcriptase inhibitors (are 
permitted as concomitant medication).  
 
The patient is treated with protease inhibitors as part of antiretroviral treatment 
regimens, which will be stopped at least 3 days before the start of study 
treatment (WK01, day1) for a patient to be eligible.  


 
 
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 
The patient is treated with Efavirenz as part of antiretroviral treatment regimens 
which would have to be stopped 14 days before the start of study treatment 
(WK00, Day 01) for a patient to be eligible.  
6. The patient has a known intolerance to any of the study drugs or concomitant disorders or 
conditions for which study drugs or standard TB treatment are contraindicated. 
7. The patient has a history of, or current evidence of clinically relevant cardiovascular 
metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or 
any other condition that will influence treatment response, study adherence or survival in 
the judgement of the investigator, especially:  
a. Neuropathy, or significant psychiatric disorder like depression or schizophrenia; 
especially if treatment for those has ever been required or is anticipated to be 
required 
b. Clinically significant evidence of extra-pulmonary TB (e.g. miliary TB, TB meningitis, 
but not limited lymph node involvement) 
c. Serious lung conditions other than TB, or significant respiratory impairment in the 
discretion of the investigator 
d.  Any diabetes mellitus 
e. Cardiovascular disease such as myocardial infarction, heart failure, coronary heart 
disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension 
f. Arterial hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood 
pressure of ≥90 mmHg on two occasions during screening).  
g. Long QT syndrome or family history of long QT syndrome or family history of sudden 
death of unknown or cardiac-related cause 
h. Alcohol or other drug abuse that is sufficient to significantly compromise the safety 
or cooperation of the patient, that includes substances prohibited by the protocol or 
has led to significant organ damage at the discretion of the investigator. 
8. Any of the following laboratory findings at screening: 
a. Serum amino aspartate transferase (AST) and/or  
 alanine aminotransferase (ALT) >3x the upper limit of normal (ULN),  
b. Serum alkaline phosphatase or y-glutamyl transferase > 2.5x the ULN,  
c. Serum total bilirubin level >1.5x the ULN  
d. Estimated creatinine clearance (eCrCl; using the Cockroft and Gault formula [57] 
lower than 30 ml/min  
e. Serum albumin < 2.8 g/dl 
f. Haemoglobin level <7.0 g/dl 
g. Platelet count <50,000/mm3,  


 
 
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h. Serum potassium below the lower level of normal for the laboratory 
i. 
Blood glucose at screening of less than 70mg/dL (3.9mmol/L) 
9. ECG findings in the screening ECG: (one or more): 
a. QTcF of >0.450 s  
b. Atrioventricular (AV) block with PR interval > 0.20 s,  
c. QRS complex > 120 milliseconds  
d. Any other changes in the ECG that are clinically relevant as per discretion of the 
investigator 
10. Restricted medication: 
a. Treatment with any other investigational drug within 1 month prior to enrolment or 
enrolment into other clinical (intervention) trials during participation. 
b. Previous anti-TB treatment with drugs active against MTB within the last 3 months 
prior to screening.  
c. Unable or unwilling to abide by the requirements regarding restricted medication or 
have taken restricted medication as described under section 12.6, page 59. 
Restricted medication includes the following drug classes: 
 
Anti-TB drugs other than study drugs 
 
Medication that lowers the threshold for epileptic seizures 
 
Medication that prolongs the QTc interval 
 
Drugs that affect monoaminooxidase or serotonin metabolism 
 
CYP 450 inhibitors or inducers, including grapefruit containing foods / 
beverages and St. John’s Wort 
 
10.5 Schedule of events  
The trial consists of the following periods: 
 
Screening period: Visit SCR (Day -8 to 0)  
 
Experimental Treatment Period: Weekly visits from Visit WK00 (Day 01) to WK16 (Day 
112 ± 2 days).  
 
Follow-up period: Visit WK18 (Day 126 ± 4 days), WK26 (Day 182 ± 7 days), WK38 (Day 
266 ± 7 days), WK52 (Day 364 ± 7 days) 
A tabular overview of the individual timing and details of the respective procedures and laboratory 
samples to be done at each visit can be found in the Schedule of Events,  p.13. 


 
 
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10.5.1 Screening Period  
Visit SCR (day -8 to 0) 
Administrative & regulatory  
 
Written informed consent 
 
Assign participant screening number 
Clinical  
 
Demographic data:  Date of birth, ethnic group, sex 
 
Medical history, incl. treatment history and current concomitant 
medication  
 
Physical examination, Vital signs (temperature, blood pressure, 
pulse, pulse oxymetry and respiratory rate) after 10 mins supine 
rest 
 
Weight (kg)/height (m) 
 
Neurological examination, vision testing 
Laboratory  
Blood 
 
Serum pregnancy test (blood sample of 7.5mL), if female of 
childbearing potential 
 
HIV test and CD4 count (blood sample of 7.5mL) 
 
Host biomarker and pharmacogenomics blood sample, if consent 
for this sub study is given 
 
Screening laboratory (blood sample of 12.5mL) 
Urine 
 
Urine drug screening 
 
Urinalysis  
Microbiology 
 
Spontaneously produced sputum 
 
Ziehl-Neelsen smear from concentrated sample 
 
Susceptibility testing for RIF and INH by rapid test 
Other  
 
Inclusion and exclusion criteria  
 
Chest X-ray (if no chest X-ray is available no older than 2 weeks) 
 
ECG (12 lead, single) after 10 mins supine rest 
Study drugs 
 
N/A 
 
10.5.2 Treatment Period  
Visits WK 00 – WK 16 (Day 01 – Day 112, each ±2 days with exception of day 14 (-2 days window)) 
Administrative & regulatory  
 
Randomization (before/at WK00 only) 


 
 
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 
Enrolment (WK00 only) 
 
Hospitalization* (WK 02 only) 
Clinical (before intake of IMP) 
 
Physical examination, vital signs, weight  
Additional blood pressure and heart rate measurements  
at WK00: 1h, 2h and 3h (± 10 mins) after intake of IMP,  
at WK02 during hospitalization: 1h, 2h, 3h, 4h, 6h (± 10 ins)  after 
intake of IMP with a meal 
 
Neurological examination/vision testing (not WK 00) 
 
Concomitant medication 
 
Adverse events  
 
Hospitalization: WK02 visit only, for intensive PK sampling after 
dosing together with standardized meal. 
Laboratory  
(before intake of 
IMP) 
Blood 
 
Safety Lab (WK01-09, WK11, WK13, WK16): haematology and 
biochemistry (blood sample of 9.5mL), Coagulation only at WK 
02 and if clinically indicated (additional blood sample of 3mL); to 
be sampled before study treatment administration 
 
Serum pregnancy test (blood sample of 7.5mL), if female of 
childbearing potential (WK09 only) 
 
Host biomarker blood sampling only at WK02, WK04, WK07, 
WK11, WK13 and WK16, if consent for this sub study is given 
 
Intensive PK sampling DZD (WK02 only): 0 (within 1h before 
dosing), 1, 2, 4, 8, 12, (± 10 mins) and 24 hours (± 30 mins) after 
dosing 
Urine 
 
Urinalysis (WK01-09, WK11, WK13, WK16): per dipstick,  
additional microscopy on abnormal dipstick results 
Microbiology 
 
Sputum (3  samples per visit, one of which may be an early 
morning sample – to be specified in the microbiology laboratory 
manual)  
 
AFB smear from screening and WK16 samples 
 
Culture in BD MGIT liquid media from 2 spot sputum samples 
 
Culture on LJ solid media from 2 samples (WK00, WK08, WK12 
and WK16 only) 
 
Susceptibility testing: minimum inhibitory concentration (MIC) 
for drugs the participant is receiving will be tested on a 
representative MTB isolate from baseline and from WK08 or 
later, if any growth detected 
 
Storage of the 3rd sputum sample 


 
 
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 
Storage of an isolate obtained at baseline, isolates from 
treatment visits, and from all cultures positive after WK08 will be 
stored as specified in the TB Lab Manual 
 
Analysis by MBLA and/or sputum LAM, if capacity/budget 
permits 
Other 
 
ECG (12-lead, triplicate at WK00, single at WK01-WK09, WK11, 
WK13, WK16): pre-dose, after 10 minutes lying down, before 
any other assessment.  
If a QTcF of >480ms, or a QTc-prolongation over baseline of 
>50ms is seen in a single ECG during experimental treatment, 
two more ECGs should be registered, to obtain a more precise, 
average QTcF measurement. 
Study drugs 
 
drug dispensing of weekly supply as specified in the Drug 
Management Plan (DMP) 
 
intake of the morning dose of study drug 
 
drug accountability (except for Wk00) 
 
Compliance assessment 
 
 
 


 
 
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10.5.3 Follow-up Period  
Visits FU 1 at WK18 (Day 126 ±4 days): all patients 
FU 2,3 at WK26, WK38 (Day 182, Day 266, each ±7 days): only patients with sputum culture conversion 
who end treatment after week 16. 
FU 4 at WK52: all patients (Day 364 ± 7 days): all patients 
All reasonable efforts should be made to achieve on-site visits being conducted. Should this not be 
possible, a home visit by a study team shall be performed, or, if this is again not possible, telephonic visits 
will be conducted to obtain health status, information on TB treatment outcome and eventual re-
treatment, and pregnancy status if the patient is a woman of childbearing potential. 
Administrative & regulatory  
 
N/A 
Clinical  
 
Physical examination, vital signs at FU 1 (WK18); at FU 2-4 (WK26, 
WK38, WK52) symptom orientated physical examination only or 
to follow up on (S)AEs 
 
Neurological examination/vision testing at FU 1 (WK18); at FU 2-
4 (WK26, WK38, WK52) symptom orientated neurological  
examination only or to follow up on (S)AEs 
 
 Concomitant medication 
 
Adverse events  
Laboratory  
Blood 
 
Safety laboratory (blood sample of 9.5mL) at FU 1 (WK18) 
 
Serum pregnancy test (blood sample of 7.5mL), if female of 
childbearing potential at FU 1 (WK18) only 
Urine 
 
Urinalysis at FU 1 (WK18) only 
Microbiology 
 
Spot sputum (2 sample) 
 
Ziehl-Neelsen smear from concentrated sample 
 
Culture in BD MGIT liquid media 
 
Culture on LJ solid media 
 
Analysis by MBLA and/or sputum LAM, if capacity/budget 
permits 
Study drugs 
 
Standard of care TB treatment from government health system 
outside of the study, if patient did not meet the definition for 
sustained culture conversion by week 08. 
 
 
 


 
 
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11 TRIAL ASSESSMENTS 
The following trial assessments will be performed at the timing indicated in the Schedule of Events 
table on page 13. Below is a detailed description of what each assessment entails.  
11.1 Demographic and background assessments 
 
Written informed consent 
 
Demographic data:  Date of birth, ethnic group, sex 
 
Medical history, incl. treatment history and current medication  
 
Chest X-ray (X-ray images performed at non-study facilities may be accepted, if there is 
reasonable certainty that the patients ID is correct, and if they are not older than 2 weeks) 
 
Method of birth control, both for male and female subjects. 
11.2 Efficacy assessments  
The assessments of efficacy will be done at multiple fixed time-points during treatment and 
follow-up phase as follows:  
Spot sputum  
o Method: Participants will be shown images of what good quality sputum samples 
should look like, which reportedly has led to better sample quality and higher 
detection rates of MTB.  
o Before producing a sample, participants should first rinse their mouth with clean 
water. Then, they should deeply inhale three times and cough deeply to produce 
a good quality sample, trying to avoid saliva and nasal secretions. 1 sample is 
collected at screening visit (SCR), 3 samples are collected per experimental 
treatment phase visit and two samples during follow-up phase at each visit.  
o From two spot sputum samples at visits WK00 to WK16, cultures will be done in 
MGIT liquid media. At WK00, WK08 and WK12, LJ solid media cultures will be 
performed from two samples as well. Additionally, the MBLA, a novel assay to 
measure mycobacterial load by quantifying 16S rRNA from sputum samples, will 
be performed on stored aliquots of sputum samples collected at all study visits; 
and evaluation of LAM concentration will be performed as experimental 
determination of bacterial load, both depending on test availability. 
o During follow-up phase at visits FU 1-4 the two spot sputum samples will be 
processed for mycobacterial culture MGIT liquid culture, Ziehl-Neelsen stained 
sputum smear and for LJ on solid media.   
o If the volume of sputum sampled is too small for all tests to be done, culture in 
MGIT liquid media will be prioritised as these data are required for evaluation of 
the primary study end-point.   


 
 
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o The infecting isolate will be stored from a positive culture of a sample obtained 
prior to treatment start, from visits during experimental treatment, and from 
every positive culture obtained at or after visit WK08, for assessments of MICs 
and typing by molecular bacteriology, to be specified in the Laboratory Manual. 
o The methodology will be described in detail in the Laboratory Manual, which will 
be supplied to the trial sites before study start. 
11.3 Safety assessments  
Electrocardiography  
ECGs are to be performed after a period of at least 10 minutes of recumbent (lying down) rest; 
and before any other procedures are done.  
At visit WK00, a 12-lead ECGs will be performed in triplicate. At all other visits, a single ECG will 
suffice, unless the following is observed: 
If a QTcF of >480ms, or a prolongation over baseline of >50ms is seen in a single on-treatment or 
unscheduled ECG, two more ECGs should be registered, to obtain an average QTcF measurement 
that will be more precise than the estimate from a single ECG. 
12-lead ECG analysis will be performed. The following ECG variables will be assessed for safety 
endpoint: Heart rate, PQ interval, QRS, QT, and QT corrected for heart rate using Fridericia 
correction (QTcF), morphological abnormalities.  
o Method: Single ECGs will be recorded for at least 10 seconds pre-dose at 
50mm/second or greater. Timing and registration technique for ECGs will be 
standardized for all participants.  Patients should be lying down (recumbent) for 
at least 10 minutes prior to each 12-lead ECG evaluation. For each participant, 
the ECG should be collected at around the same time of day, preferably within 2 
hours before dosing. 
o ECGs will be analysed immediately by site investigators to ascertain patient 
safety.  
Screening/Safety laboratory tests 
Samples for laboratory tests are to be taken before the day’s dose of study treatment is 
administered. 
 
Urine:  
o Urine drug screening by a rapid test for opiates, amphetamines, cannabinoids, 
cocaine, benzodiazepines and barbiturates. 
o Urinalysis*: Dipstick for pH, protein, glucose, ketones, urobilinogen, blood and 
leukocytes.   
o Urine microscopy on abnormal dipstick results as per the investigator’s decision.  


 
 
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 
Blood:  
o Serum pregnancy test, if female of childbearing potential (SCR, WK09 and WK18) 
o HIV test (CD4 count if HIV positive, additionally viral load, if patient is on ARVs, 
additionally genotypic resistance testing, if viral load is >1,000 copies/µL ) and 
patient would have to be switched to a non-dolutegravir ART regimen after end 
of study (SCR) 
o Haematology*: Complete blood count with differential and platelets 
o Biochemistry*: ALT, AST, gamma-glutamyl transferase (yGT), alkaline 
Phosphatase (aP), lipase, direct and total bilirubin, albumin, serum creatinine, 
electrolytes (Na+, K+, Serum Calcium, Magnesium, Cl-, PO43-), random glucose 
o Coagulation: aPTT, PT, INR 
*performed during safety laboratory assessment, complete list of tests done during screening only  
Physical examination 
Details about the conduct of physical examination will be laid out in the Manual of Procedures 
(MOP) 
 
Weight (kg)/height (m) 
 
Physical examination 
 
Additionally, the Hunter criteria for early detection of serotonin syndrome will be 
assessed: 
o Spontaneous clonus 
o Inducible clonus  
o Ocular clonus 
o Tremor  
o Hyperreflexia 
o Agitation  
o Diaphoresis 
o Hyperthermia above 38ºC  
Serotonin syndrome is diagnosed according to the following decision rule, which will prompt 
stopping a subject from receiving study drug if fulfilled. The Hunter Serotonin Toxicity Criteria 
are fulfilled if any of the following is fulfilled: 
o Spontaneous clonus 
o Inducible clonus PLUS agitation or diaphoresis 
o Ocular clonus PLUS agitation or diaphoresis 


 
 
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o Tremor PLUS hyperreflexia 
o Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus 
In the case of presence of newly appearing symptoms “inducible clonus”, “ocular clonus”, or 
“tremor”, which would not fulfil Hunter criteria on their own, close observation of the participant 
(ideally daily) is warranted while continuing on medication, and the sponsor medical expert should 
be notified. 
 
Vital signs (temperature (degrees Celsius), blood pressure (systolic and diastolic, in 
mmHg), pulse (bpm), pulse oxymetry, and respiratory rate (breaths/minute)). 
Measurements for blood pressure and pulse rate will be performed in the supine position 
after at least 10 minutes rest using an oscillometric method. As far as possible, 
measurement will always be performed on the same arm.  
 
On visits WK00 and WK02, additional blood pressure measurements will be performed: 
WK00: after 1h, 2h and 3h (± 10 mins) after IMP is taken;  
WK02: 1h, 2h, 3h, 4h, 6h (± 10 mins) after intake of IMP 
Detailed neurological examination  
The detailed neurological examination will be laid out in the Manual of Procedures (MOP) 
 
Neurological examination including the following assessments:  
o Cranial nerves 
 
Test both pupillary responses to light 
 
Eye movements in all directions 
 
Palatal movement 
 
Tongue movement 
o Reflexes: Biceps, Achilles’ and patellar tendon reflexes bilaterally 
o Sensory: Vibration sensitivity, pin prick, light touch 
Vision testing  
The vision testing will be laid out in the Manual of Procedures (MOP) 
 
Visual acuity testing according to Snellen  
 
Vision testing for colour deficiencies according to Ishihara  
Compliance assessment for food and beverage restrictions (at SCR and during experimental 
treatment WK00 – WK16) 
The investigator will assess the risk to the participant by questioning about their usual diet and 
drinking habits, and about their understanding of which beverages they usually take are not 
permitted in the study. 


 
 
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The investigator will have to come to the conclusion at screening that the participant will likely 
comply, for a participant to be eligible to study participation. 
11.4 Assessments when Recurrence is Suspected 
During follow-up, patients who are experiencing complaints, or have laboratory events suggesting 
a recurrence of disease, will be evaluated in a standardized manner that has been described for 
the TBTC study 31 [58]. 
Triggers for the assessment will be the following events: 
- 
A positive culture confirmed as M. tuberculosis from a sputum specimen collected at or after 
the WK16 visit 
- 
Worsening signs and/or symptoms consistent with tuberculosis at or after WK16 
- 
The site investigator is considering an extension of tuberculosis therapy beyond 16 weeks 
The following procedures shall be conducted: 
- 
Assessment of symptoms 
- 
Review interval medical history 
- 
Weight, vital signs and physical examination 
- 
Obtain 3 sputum specimens for smear and MGIT plus LJ culture, 2 specimens at least 4h apart. 
If M. tuberculosis is isolated, the isolate is to be stored frozen. 
- 
Chest radiograph 
- 
Review participant’ s contact information, and update if indicated 
- 
Contact sponsor medical expert to review procedures, results and decide on management 
The outcome of this assessment will be twofold: 
- 
to define whether the patient will have met the endpoint of “relapse”, conditional on a 
matching of baseline and recurrence isolate, if available; 
- 
to transfer the patient to the government TB treatment programme to receive treatment for 
recurrent disease 
11.5 Pharmacokinetic assessments  
The exact time of drug administration will be recorded on the day of PK sampling and will be 
defined as 0h for the following PK sampling procedures. The timing of drug administration on the 
two preceding days will also be recorded.  
Delpazolid 
All patients will undergo intensive PK sampling at Day 14 (WK02) visit. A sample will be drawn 
within 1h before administration of the DZD morning dose (0 h). 
The DZD morning dose will be administered with a standardized meal. Blood draws thereafter will 
be performed at 1, 2, 4, 8, 12 (± 10 mins) and 24 hours (± 30 mins) after DZD morning dose. The 
exact time of meal and DZD administration at the day of PK sampling will be recorded. 
Standardized food and fluid intake will be monitored and noted throughout the PK days. 


 
 
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Procedures for sample connection, storage and transportation will be described in the Laboratory 
Manual. Assaying of DZD, BDQ and DLM plus main metabolites, and MXF will be conducted 
centrally at the Department of Pharmacy, Radboudumc, the Netherlands, with validated LC-
MS/MS methods.  
Pharmacokinetic parameters will be assessed using non-compartmental techniques and non-
linear mixed effects methodology. The latter will be utilized to develop a population PK model 
describing DZD, which will be linked to safety and efficacy parameters. Secondary PK parameters 
to be reported are listed in section 9.2.3. 
11.6 Additional biomarker assessments 
The main evaluation of treatment response biomarkers in this study focus on sputum 
microbiology (via serial MGIT and LJ cultures); and the experimental assessments for LAM, and 
the MBLA). Collection and appropriate storage of plasma and whole blood samples will permit 
exploratory evaluation of host immunological and transcriptomic biomarkers as sub-studies. In 
addition, a sample for pharmacogenomics analyses will be stored at screening (see section 
20.3.3). Sampling for these sub-studies will be conditional on participant approval to storage, 
and genetic testing.    
 


 
 
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12 STUDY TREATMENT 
12.1 Study drug regimens  
The study will recruit into the following arms: 
Arm 1 (D0):  BDM   
(bedaquiline, delamanid, moxifloxacin) 
Arm 2 (D400): BDM + DZD  
(bedaquiline, delamanid, moxifloxacin, delpazolid 400 mg OD) 
Arm 3 (D800): BDM + DZD  
(bedaquiline, delamanid, moxifloxacin, delpazolid 800 mg OD) 
Arm 4 (D1200): BDM + DZD 
(bedaquiline, delamanid, moxifloxacin, delpazolid 1200 mg OD) 
Arm 5 (D800-BD): BDM + DZD  (bedaquiline, delamanid, moxifloxacin, delpazolid 800 mg BID) 
BDQ, DLM, MXF are approved drugs. Product Information Leaflets for these drugs will be provided 
to investigators.  
DZD is not an approved drug. It will be manufactured and tested according to Good Manufacturing 
Practice (GMP) requirements. The Sponsor will provide Ethical Review Boards and site 
investigators with a set of documents, as required by the local regulatory authority, that provides 
information on the manufacture and quality control of the raw substance and the medicinal 
product; Certificates of Analysis (CoA) of the batches to be used; and an Investigational Brochure 
(IB) that summarizes preclinical and clinical data with respect to DZD.  
 
12.2 Study drug dosage and administration  
The experimental and control treatment as described above will be administered daily for 16 
weeks (see Table 1. Daily Dosing of Study Medication), together with food. 
 
Bedaquiline: will be dosed as per the licensed dose: 400 mg orally once daily for the first 
14 days, then 200 mg three times a week.  
 
Delamanid: will be dosed as per the licensed dose: 200 mg orally in two daily doses of 
100 mg. 
 
Moxifloxacin: will be dosed as per the licensed dose: 400 mg orally once daily 
 
Delpazolid - not licensed:  
o Dose: will be according to randomization to dosing arm: 
 
Arm 1: 15 participants will receive 0 mg of DZD 
 
Arm 2: 15 participants will receive 400 mg DZD orally once daily 
 
Arm 3: 15 participants will receive 800 mg DZD orally once daily 
 
Arm 4: 15 participants will receive 1200 mg DZD orally once daily 
 
Arm 5: 15 participants will receive 800 mg DZD orally twice daily 


 
 
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The daily dose of study drug for participants will be dependent on the subjects’ experimental 
arm as shown in the following table:  
Table 1. Daily Dosing of Study Medication 
 
Bedaquiline 
(Sirturo®)  
100 mg tablet 
Delamanid  
50 mg tablet 
Moxifloxacin 400 
mg tablet 
Delpazolid 400 mg 
tablet 
Arm 1 (D0): 
 
BDM 
Day 01-14: 
4 tablets to be 
taken orally once 
per day in the 
mornings 
 
Day 15-112:  
2 tablets to be 
taken orally 3 times 
per week in the 
mornings 
Day 01-112: 
2 tablets to be 
taken orally  2 
times per day 
(mornings and 
evenings) 
Day 01-112: 
1 tablet to be taken 
orally once per day 
in the mornings 
 
Arm 2 (D400):  
 
BDM-DZD  
 
Day 01-14: 
4 tablets to be 
taken orally once 
per day in the 
mornings 
 
Day 15-112:  
2 tablets to be 
taken orally 3 times 
per week in the 
mornings 
Day 01-112: 
2 tablets to be 
taken orally  2 
times per day 
(mornings and 
evenings) 
Day 01-112: 
1 tablet to be taken 
orally once per day 
in the mornings 
Day 01-112:  
1 tablet to be taken 
orally once per day 
in the mornings 
Arm 3 (D800-OD):  
 
BDM-DZD 
Day 01-14: 
4 tablets to be 
taken orally once 
per day in the 
mornings 
 
Day 15-112:  
2 tablets to be 
taken orally 3 times 
per week in the 
mornings 
Day 01-112: 
2 tablets to be 
taken orally  2 
times per day 
(mornings and 
evenings) 
Day 01-112: 
1 tablet to be taken 
orally once per day 
in the mornings 
Day 01-112:  
2 tablets to be 
taken orally once 
per day in the 
mornings 
Arm 4 (D1200):  
 
BDM-DZD 
Day 01-14: 
4 tablets to be 
taken orally once 
per day in the 
mornings 
 
Day 15-112:  
2 tablets to be 
taken orally 3 times 
Day 01-112: 
2 tablets to be 
taken orally  2 
times per day 
(mornings and 
evenings) 
Day 01-112: 
1 tablet to be taken 
orally once per day 
in the mornings 
Day 01-112: 
3 tablets to be 
taken orally  once 
per day in the 
mornings 


 
 
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per week in the 
mornings 
Arm 5 (D800-BD):  
 
BDM-DZD 
Day 01-14: 
4 tablets to be 
taken orally once 
per day in the 
mornings 
 
Day 15-112:  
2 tablet to be taken 
orally 3 times per 
week in the 
mornings 
Day 01-112: 
2 tablets to be 
taken orally  2 
times per day 
(mornings and 
evenings) 
Day 01-112: 
1 tablet to be taken 
orally once per day 
in the mornings 
Day 01-112: 
2 tablets to be 
taken orally  2 
times per day 
(mornings and 
evenings) 
 
DZD can be taken with or without food. The bioavailability of BDQ and DLM strongly increases 
when taken with food. MXF can be taken with or without food. As a result, all anti-TB drugs 
have to be taken with food and a glass of water in the mornings and evenings. 
During pharmacokinetic sampling days, the anti-TB drugs are taken with standardized meals. 
As specified under sections 10.4 (page 42) and 12.6.2 (page 60), HIV patients in need of ART will 
be treated with a dolutegravir-based ART regimen during the study. Dolutegravir in a fixed-dose 
combination, containing Dolutegravir (50 mg), Lamivudine (300mg) and Tenofovir Disoproxil 
Fumarate (300mg), will be provided following local clinical practice/procedures and specific 
recommendations on initiating these drugs. Therefore, this is considered as concomitant 
medication and not study medication (see also section 12.6). 
 
12.3 Study drug management   
A Study Drug Management Plan (DMP) will describe all aspects of drug management in this study, 
including details on packaging, labelling, storage conditions, distribution, drug-dispensing, drug 
accountability and other drug-related procedures. A team of pharmacists, including a pharmacist 
at each study site, will be responsible for study drug management.   
The Sponsor will supply the study drugs to allow completion of this study including spare drugs.  
The overall intent of the labelling of the study drugs is to ensure the protection of the trial 
participants, to ensure traceability and identification of the drugs and trial at all times, to facilitate 
the proper use of the drugs, and to comply with national and international regulations on 
investigational drugs. The study drugs will be labelled for the study according to The Rules 
Governing Medicinal Products in the European Union, Annex 13 of GMP, and to national labelling 
requirements of the study sites. 
All study medication must be kept in secure cabinets or rooms with access restricted to designated 
study personnel. Medication will be stored at appropriate conditions at designated temperatures, 


 
 
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protected from light and moisture. A temperature monitoring system will be in place to monitor 
appropriate storage conditions and record possible deviations. 
The dispensing of study drugs for individual patients will be performed and recorded as described 
in the DMP. Dispensing at each site will be supervised by a pharmacist. Dispensing will only be 
performed by licensed and trained study personnel.  
12.3.1 Quality check and product release 
DZD tablets will be released for the study by a designated qualified person. At the study sites, trial 
pharmacists will verify once more the identity and quantities of all drugs supplied. This will be an 
administrative check. 
12.3.2 Study Drug Accountability 
The study pharmacists will be responsible for maintaining accurate records of receipt and 
destruction of study medication in the “Study Drug Inventory Log”. The records should reflect the 
overall quantity of study drugs at site. Furthermore, the pharmacist will maintain individual 
records of study drug dispensing and return for each patient (Study Drug Dispensing and 
Accountability Forms).   
Upon completion of the study, all unused DZD will be returned to the sponsor or a CRO designated 
by the sponsor or is destroyed, once drug accountability is completed and checked by the monitor. 
All other unused study medication may be used by the sites in routine patient care, if the brand of 
the drug is approved by host country’s regulatory authority and after approval of the sponsor. If 
this is not the case, the same provisions for return and destruction as described for DZD will take 
place. 
12.3.3 Retention of Testing Samples 
Sufficient quantities of each study medication will need to be kept to reconfirm specifications 
should the need arise. These samples should be retained until the analysis of trial data is complete 
or as required by applicable regulations, whichever is longer. After this period, retention samples 
will be destroyed following national regulations. 
12.4 Treatment after End of Study Therapy (Post-study Access to Treatment)  
The strategy recommended for participants to continue their TB treatment within the government 
health system is informed by two previous phase 2b TB trials with a 2-month experimental 
treatment, and the solution found for patients in Tanzania in collaboration with the national TB 
program in those past trials [27, 56, 59]. 
Patients who achieve two successive negative liquid media cultures, with no positives to follow by 
WK16 visit, the first of which is at or before WK 08, will NOT receive standard of care TB-treatment 
according to national guidelines as continuation phase to complete 6 months of treatment. Their 
planned post-treatment follow-up visits at WK 18, WK26, WK38 and WK52 will serve to determine 


 
 
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whether they have achieved lasting cure. Patients who will NOT fulfil at least one of these criteria 
will receive standard of care TB-treatment according to national guidelines until WK26 at a 
government health facility (continuation Phase).  
They will be invited to return to the WK52 follow-up visit to determine their wellbeing and 
treatment outcome.  
The review of culture results, and decision to discontinue or continue treatment will be made on 
the day before the WK16 visit. Should sufficient culture results to take this decision not be 
available by this timepoint, but available culture results indicate good response to treatment in 
the view of the investigator, this decision, and the start of continuation phase treatment, may be 
delayed until latest to WK16 (day112) + 6 days. 
Should positive results become available after a decision is taken to discontinue treatment after 
WK16, the investigator should discuss these with the sponsor medical expert to come to a 
conclusion of whether the management of the patient should be changed, which should be done 
only in exceptions. 
12.5 Measurement of Adherence to Study Treatment 
Study treatment intake will be observed by study staff during the study visits in the morning and 
will be administered at home on the other days. Facility-based directly observed treatment (DOT) 
or community-based DOT (i.e. a friend or relative of the participant will act as a treatment 
supervisor) will be in place in order to maximize adherence. The method and person chosen will 
be noted in the participant’s source documents. Furthermore, treatment adherence will be 
assessed by pill counting at every visit.  
12.6 Concomitant and Prohibited Medication 
12.6.1 Drug-Drug-Interactions 
BDQ and, to a lesser extent, DLM are metabolized by CYP3A4. MXF is metabolized by uridine 
diphosphate (UDP)-glucuronosyltransferases (UGT).  
A change in activity of these hepatic enzymes can change the drug concentrations in blood and 
tissue and thereby influence safety and efficacy readouts. All drugs that would lead to a substantial 
change in activity of these enzymes are prohibited; and participants may not be included into the 
study if receiving such drugs at screening or if it is likely that these drugs will be needed during 
study treatment. Patients who are enrolled and on study medication, and a need arises to treat 
with any of those drugs during the treatment phase of the trial need to be discussed with the 
sponsor medical expert. Their experimental treatment may be stopped, and they may be 
continued on standard TB treatment according to national guidelines. An overview of drugs 
allowed as concomitant medication and prohibited medication can be found in the following 
description:  


 
 
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12.6.2 Antiretroviral treatment (ART) 
Drug-drug interactions: 
Nucleosidic reverse transcriptase inhibitors are permitted as concomitant medications. Most 
patients will have 2 drugs of this category in their regimen.  The third drug of choice during study 
treatment is dolutegravir due to its limited potential for drug-drug-interactions with the TB drug 
regimen under study; and participants who are on ART or starting on ART will receive this drug as 
part of their ART regimens. 
Protease inhibitors as part of antiretroviral treatment regimens: because of the unfavourable 
interaction potential [60, 61], protease inhibitors need to be stopped at least 3 days before the 
start of study treatment (Day 01) for a patient to be eligible. Patients will be switched to 
dolutegravir-based ART regimens. 
Efavirenz as part of antiretroviral treatment regimens: will have to be stopped at least 14 days 
before the start of study treatment (Day 01) for a patient to be eligible; so that the CYP3A4 enzyme 
induction caused by efavirenz can wear off before starting study drugs [62, 63].  
If a patient has taken efavirenz within 14 days of the planned Day 01, they will not be eligible for 
participation in the study, unless three or fewer daily doses have been taken and there is approval 
from the sponsor medical expert that the patient may be enrolled.  
Patients will be switched to dolutegravir-based ART regimens during the study. Dolutegravir will 
be provided as part of the local available fixed-dose combination, containing also Lamivudine 
(300mg) and Tenofovir Disoproxil Fumarate (300mg). Dolutegravir is an HIV-integrase inhibitor 
recommended as first-line treatment together with a nucleoside reverse transcriptase inhibitor 
(NRTI) backbone in many international guidelines [64, 65]. The main route by which dolutegravir 
is metabolized is by phase II metabolism in the liver involving glucuronidation by uridine 
diphosphate glucuronosyltransferase (UGT) 1A1. Minor contributions in glucuronidation come 
from UGT1A3 and UGT1A9. A small portion (<10%) is metabolised by the cytochrome P450 (CYP) 
3A4 through oxidation (phase I metabolism). In theory, drugs that induce or inhibit UGT1A1 or 
CYP3A4 can lead to drug interactions, but clinically significant interactions via CYP3A4 have not 
been reported. Dolutegravir itself has no clinically relevant inhibition or induction effects on main 
CYP-enzymes, and can therefore be applied together with our study medication. 
ART experienced patients: 
The occurrence of TB in a patient on ARVs may be a symptom of an ARV treatment failure; which 
could be due to resistance of the HIV strain, or to suboptimal compliance.  
The study related switch of ARV regimen to dolutegravir would be beneficial to such patients; as 
dolutegravir is very likely a new drug for them with no viral resistance. However, in case of 
treatment failure, it needs to be ensured that they will not be switched back to their previous, 
failing ARV regimen after end of study participation.  


 
 
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Thus, ART experienced patients will have HIV viral load testing during screening. Should the viral 
load exceed 1,000/µl, this will be rated insufficient virologic control. If there is a foreseeable need 
for switching patients back to an ARV regimen that does not contain dolutegravir after the end of 
study participation, a genotypic HIV resistance screening against the ART regimen taken at 
screening is to be performed, in all other cases of insufficient virologic control, it is highly 
recommended.  
The patient’s ART regimen after end of study is to be designed based on the results of resistance 
testing and on local availability of drugs.  
ART naïve patients: 
Patients who, at the time of screening for this study, are not on ARVs may enter the study if they 
have a CD4+ count of ≥220 \µl, and the enrolling physician feels that ARVs can be safely withheld 
for two months. After two months of study TB treatment, patients may start on ARVs. 
Based on a review of available studies, we conclude that withholding ARVs in patients with >50 
CD4 cells/µl is safe – based mainly on the NIMR/WHO TDR study from Tanzania, that was the 
largest and most rigorous (double blinded, placebo controlled) study. This study found no 
difference in survival or IRIS in patients with >220 CD4 cells/µl, whether ARVs were started after 
2 weeks or after 6 months of anti-TB treatment [66, 67]. 
The SAPiT study in South Africa randomized 642 South African HIV+TB patients with CD4 counts 
<500/µl to 1 of 3 times to initiate ART at either, 1) <4 weeks, 2) 8-12 weeks, or 3) 6 months. The 
median CD4 count was 145; 231 subjects had >200 CD4 cells (relevant to this proposed study). 
SAPiT was terminated early due to reduced mortality in combined groups 1&2 vs group 3 (HR= 
0.44) [68]. However, 12.4% of patients in groups 1&2 had IRIS, vs 3.8% in group 3 (P<.001). A 
second report from SAPiT found reduced mortality in group 1 vs 2 only in patients with CD4 counts 
<50 (HR= 0.32), whereas there was no effect on mortality in patients with ≥50 CD4 cells [60]. 
However, patients with ≥50 CD4 cells in group 1 had a 2-fold increased risk of IRIS vs group 2 (P= 
.02). In many of these cases TB-IRIS was severe and required hospitalization. Thus, for the patients 
we propose to recruit in this trial (CD4 >220/µl) SAPiT found 8-12 weeks to be the optimal time 
point to start ART. 
12.6.3 Prohibited medication: anti-tuberculosis agents  
Use of drugs with an action on MTB complex, in addition to study treatment, is prohibited while 
participants are receiving study treatment in both groups, intervention and control arm. This 
includes, but is not limited to amikacin and other aminoglycosides, cycloserine, EMB, INH, LZD, 
para-aminosalicylic acid, RIF, rifabutin, rifapentine pyrazinamide, streptomycin, kanamycin, 
thioacetazone, capreomycin, fluoroquinolones, and thioamides. Significant concomitant use of 
one or more of these agents will be evaluated by the sponsor medical expert and may lead to 
exclusion of the patient from treatment. Excluded patients will be taken off-IP and will be follow-
up according to protocol. These patients’ data will be analysed in an ITT-analysis. 


 
 
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12.6.4 Prohibited medication: drugs that can induce epileptic seizures 
Around 4-10% of all persons experience an epileptic seizure during their lifetime [62, 64, 69]; 
therefore unprovoked seizures are not a rare event.  
Since epileptic seizures in a participant might thus either be independent of study treatment, but 
could also constitute a safety signal of DZD.  
Drugs that lower the threshold for epileptic seizures and provoke such an event could generate a 
false safety signal and are thus prohibited in study participants. 
These include, but are not limited to atomoxetine, aminophylline, theophylline, tramadol, 
penicillins, tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamino 
oxidase inhibitors.  
12.6.5 Prohibited medication: QT prolonging medication  
Concurrent treatment with QTc-prolonging agents (other than the study drugs) is prohibited for 
participants in all treatment arms in this study until visit WK 16, as this could influence the safety 
assessments of novel treatment combinations and put participants at risk. QTc- prolonging agents 
include but are not limited to amiodarone, bepridil chloroquine, chlorpromazine, cisapride, 
clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, 
haloperidol, ibutilide, levomethadyl, lumefantrine, mefloquine, mesoridazine, methadone, 
pentamidine, pimozide, procainamide, quinidine, quinine, sotalol, sparfloxacin, terfenadine, 
thioridazine, and voriconazole during study participation.  
Participants having received such drugs within 30 days prior to dosing, are not eligible for this 
study. Exceptions may be made for individuals who have received 3 daily doses or less, and at least 
5 elimination half-lives of the drug have passed before first dose of study treatment. Such 
exceptions should be discussed with the sponsor medical expert. 
Due to the extended half-life of BDQ and DLM metabolites, QTc-prolonging drugs which are 
administered after end of study treatment should be given with caution and with ECG controls. 
We advise the sponsor medical expert be contacted about this prior to such administration.   
Significant concomitant use of one or more of these agents will be evaluated by the sponsor 
medical expert and may lead to exclusion of the patient from treatment. Excluded patients will be 
taken off-IP and will be follow-up according to protocol.  
12.6.6 Prohibited medication: drugs affecting monoamine oxidase (MAO) 
Drugs affecting monoamine oxidase (MAO), or are metabolized by MAO:  If participants require 
treatment, or have had treatment within 30 days before start of study treatment, with drugs which 
are mainly metabolized by, or affecting activity of MAO - A or  B; such as α-methyldopa, or MAO 
inhibitors, then these participants are excluded from treatment. These include, but are not limited 
to rasagiline, safinamide, selegiline, moclobemide, tranylcypromine, phenelzine and isocarboxazid.   


 
 
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Significant concomitant use of one or more of these agents will be evaluated by the sponsor 
medical expert and may lead to exclusion of the patient from treatment.  
Exceptions may be made for individuals who have received 3 daily doses or less, and at least 5 
elimination half-lives of the drug have passed before first dose of study treatment. Such 
exceptions should be discussed with the sponsor medical expert. 
12.6.7 Prohibited medication: Serotonin agonists  
Participants may not be included into the study or will be excluded from treatment if they are 
taking drugs that have agonistic effects to serotonin action. These include, but are not limited to, 
serotonin reuptake inhibitors such as fluoxetine, citalopram, or serotonin agonists such as 
sumatriptane, dextromethorphan, or opiate analgesics (mainly fentanyl). 
Significant concomitant use of one or more of these agents will be evaluated by the sponsor 
medical expert and may lead to exclusion of the patient from treatment. Excluded patients will be 
taken off-IP and will be follow-up according to protocol. These patients’ data will be analysed in 
an ITT-analysis. 
12.6.8 Prohibited medication: CYP450 inhibitors/inducers 
Patients requiring treatment with any drug(s) or substance(s) known to be strong inhibitors or 
inducers of cytochrome P450 enzymes, or specific inhibitors/inducers of CYP3A4 may not be 
included in the study. This also applies to patients who having received such medications in the 
30 days prior to starting study treatment. This may be subject to exceptions after consultation 
with the sponsor medical expert for participants who have received 3 days or less of one of these 
drugs or substances, if there has been a wash-out period equivalent to at least 5 half-lives of that 
drug or substance. 
Also, such drugs may not be given to participants while they are on study treatment.  
HIV protease inhibitors or efavirenz are drugs that influence CYP 450 activity; and provisions on 
how to deal with those drugs is made above under 12.6.2.  
12.6.9 Antimalarials  
If a patient is diagnosed with uncomplicated malaria (microscopic confirmation) 
Atovaquone/Proguanil is an option for the treatment of uncomplicated malaria that is compatible 
with study treatment.  
Severe malaria is a life-threatening emergency, treatment of which has priority over continuation 
of participants in the trial.  The currently recommended first choice of intravenous artesunate is 
compatible with study treatment.  
 
The following antimalarials are incompatible with BDQ, DLM and MXF due to their inherent 
QT prolonging effect: Primaquine (recommendation: to delay primaquine admission until 
after end of study treatment, in case of a plasmodium vivax or ovale infection), 
Artemether/Iumefantrin (ALU), Quinine, and Chloroquine. 


 
 
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12.6.10 
Dosing precautions 
Iron supplements: orally administered iron supplements decrease the absorption of many drugs, 
therefore should be administered 4h before or 2h after study treatment. 
12.6.11 
Antinausea and antipeptic drugs 
The anti-nausea drug of choice in patients on study treatment is metoclopramide due to a low 
potential for interaction (for background, see Appendix, chapter 21.1, page 98). However, since 
metoclopramide shows potential to affect the QT interval, if given i.v. in higher doses, and may 
cause akathisia and seizures, it should therefore be used very restrictively only by low dose oral 
administration. 
The anti-peptic drugs of choice for participants in this study are ranitidine (1st choice) or 
omeprazole (2nd choice; see Appendix, chapter 21.2)  
Orally administered aluminium or magnesium containing antacids interfere with bioavailability of 
many drugs and are therefore prohibited in this study.  
12.6.12 
Substance abuse 
Patients who are regular abusers of opiates are not eligible for this study. Other substance abuse 
is covered by exclusion criterion 7, and special caution is to be taken to exclude persons whose 
abuse can lead to seizures during withdrawal, including but not limited to alcohol, met-
/amphetamines or tramadol. 
12.6.13 
Food restrictions 
Dietary tyramine can, in the presence of substantial inhibition of enteric monoaminooxidase A, 
cause an increase in blood pressure. Study participants need to agree to forgo the consumption 
of certain foods while taking study medication. A list of those foods is provided in Appendix 20.2, 
page 95.  
13 PARTICIPANT ENROLMENT 
Patients will be invited to be screened for inclusion in the trial if they are suspected to have 
pulmonary TB or have an established diagnosis by smear microscopy, GeneXpert or chest X-ray, 
done within the government or private health sector.  
Participants will be enrolled and assigned to randomized study treatment only if they meet all of 
the inclusion criteria and none of the exclusion criteria.  
13.1 Recruitment procedures 
Recruitment can be enhanced by individual and community awareness of the study and/or TB in 
general, through the following materials, but not limited to these: 
 
Public announcements through advertisements, posters and radio announcements 


 
 
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 
Information leaflets distributed to healthcare providers, to be handed to newly 
diagnosed TB patients 
Recruitment materials will be used only upon approval of the ethics committees relevant for this 
trial. 
13.2 Informed consent  
Patients will be given a patient information sheet about the trial and the anticipated benefits, 
where, among other information, the potential risks associated with the protocol procedures will 
be explained. The investigator or a person designated by the investigator will inform the patient 
or the patient’s legally acceptable representative. The language used will be as non-technical as 
possible, and the patient will not unduly be influenced to participate in the trial.  
Written informed consent must be obtained from every patient prior to any procedures being 
done specifically for the study. For illiterate patients, study information is given in the presence of 
an impartial, literate witness, who will read the information sheet to the patient or will witness 
the complete reading of the information sheet to the patient. The patient will give consent by 
thumb printing the ICF. The witness states that free, informed consent has been given by his/her 
signature on the ICF. An original or a photocopy of the signed informed consent form will be 
provided to the patient or to the patient’s legally acceptable representative, depending on locally 
applicable regulations. A signed original will be kept with the patient’s medical records at the site.  
Participants will be informed that screening includes collecting sputum samples for smear and 
culture, chest X-ray and ECG registration, blood and urine samples, pregnancy testing, if 
applicable, and testing for HIV. Patient will be encouraged to receive their HIV results but may 
choose not to be informed. HIV seropositive individuals will be referred to the local HIV services. 
Participants will be informed that agreeing to be screened does not mean that they must join the 
trial, however that participation in the trial will require good adherence. Patients will be informed 
that they will be free to withdraw from the study at any time, and that withdrawal will have no 
negative effects on them receiving standard care afterwards. 
The site will document the name and position of those study personnel at the site who have 
received appropriate Good Clinical Practice (GCP) training in advance are responsible for obtaining 
informed consent. No other staff will perform the informed consent process.   
The informed consent template will be provided to the investigator by the Sponsor. If any 
modifications to the informed consent form are proposed by the site, the consent form must be 
submitted to the Sponsor for approval prior to submission to the ethics committee. The informed 
consent form will be revised whenever new important information becomes available.  Each 
consent form revised during the course of the study will need to be reviewed by an ethics 
committee. The ICF can only be used after approval of the ethics committee. After approval of a 
revised informed consent, all active participants must sign the revised informed consent form to 
be able to continue study participation.  


 
 
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13.3 Exclusion of particular groups 
Minors below 18 years are excluded from the study. TB in children is different in diagnosis and 
disease course from adult disease. Therefore, this age group will not participate in this trial. 
13.4 Vulnerable participants  
Patients who are unable to give free, informed consent (e.g. mentally impaired persons, prisoners) 
will be excluded from the trial, as their uncoerced agreement to study participation and 
procedures cannot be ascertained, and compliance may be suboptimal. 
13.5 Procedures to assign participants to treatment groups  
Patients who have given informed consent and who have been found eligible for participation 
(meeting all inclusion criteria and no exclusion criterion) based on results from screening visit, will 
be randomly assigned to one out of five treatment arms with a 1:1:1:1:1 allocation. Randomization 
must be performed when all screening results are available but not before eligibility for study 
participation is proven. 
Randomization will be performed through centralized assignment of patients by means of an 
Interactive Web Response System (IWRS), a web-based randomization system. Patient 
characteristics will be used to balance the composition of the treatment arms with regards to 
prognostic factors.  
These characteristics will be:  
 
site  
 
HIV status 
 
bacterial load in sputum as measured by GeneXpert cycle threshold 
13.6 Methods of avoiding bias  
This study will be open-label, patients and physicians will be aware of treatment allocation. To 
ensure unbiased assessment of efficacy endpoints, the personnel assessing patients’ outcomes, 
like the microbiology laboratory staff or the sponsor medical expert discussing the possibility of 
recurrent disease, will remain blinded to treatment assignment throughout the whole study. Every 
effort will be made to maintain this blinding.  
Further, there will not be any cumulative summary of study data by randomized treatment arms 
generated, except for data to be provided to the independent data safety monitoring board 
(DSMB) by the unblinded statistician. Such analysis may not be distributed outside of the DSMB. 
Determination of MICs for the experimental treatment allocated to the patients will only be made 
after all other assessments of patient samples have been completed in the respective laboratory 
or will be done at a different specialised laboratory.  


 
 
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13.7 Participant withdrawal  
A patient may decide to withdraw consent and therefore withdraw from the trial at any time and 
for any reason. The investigator may also withdraw a patient from study treatment or the entire 
trial for any of the following reasons: 
 
A major protocol violation caused by the patient 
 
If, for any reason, the investigator concludes that continued participation in the trial 
would not be in the participant’s best interest. 
 
Requires medication that is prohibited by the protocol 
The investigator will also withdraw a patient upon request of the Sponsor or if the study is 
terminated. If a serious adverse event occurs, the Principal Investigator will discuss it with the 
sponsor. A patient who is discontinued due to an AE, will be followed up as described under 
“Adverse Events”.  
In general, patients who withdraw or are withdrawn from treatment (but still maintain consent to 
continue in the study) shall continue to follow study assessments as laid down in the schedule of 
events, in order to make them evaluable in the ITT population.  
When a patient is withdrawn from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page of the case report form (CRF). When a patient withdraws 
from the study on his/her own decision, it is up to the patient to provide a reason thereof. The 
investigator shall at least ask for the reason and point out that the collection of all withdrawal 
reasons is of great importance for the sponsor from a medical and scientific point of view. 
On the date of withdrawal and in the interest of participants’ safety, if consent to this is still 
maintained, participants should have all assessments scheduled for Day 112 (WK16) completed at 
the day they leave the study. These include vital signs, complete physical examination, including 
neurological examination and vision testing, safety lab, 12-lead ECG, concomitant medication and 
assessments of AEs. 
Recent safety laboratory results should be available to make sure that no adverse findings are 
missed that could put the participant at risk. In a female participant of childbearing potential, a 
serum pregnancy test should be requested, if possible. 
If a continuation following the schedule of assessments is not possible, and if the participant 
agrees, a follow-up visit should be scheduled 14 days (+/-4 days) after withdrawal. During this visit 
all procedures as described in section 10.5.3, page 48, “Follow-up Period”, of the protocol should 
be carried out, i.e. vital signs, symptom related physical examination, follow-up of former AEs and 
assessments of new AEs, incl. blood tests to follow up on past abnormal results and new AEs, as 
per investigators discretion. 
For patients who withdraw from the study, every attempt should be made to perform all or as 
many as possible of the follow-up assessments.   


 
 
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Patients who do not return for final assessments will be contacted by site personnel in an attempt 
to complete the follow-up assessments. 
All attempts gearing towards the completion of the study visits should be documented in the 
patients’s study file. 
13.8 Adjustment of sample size during the study 
The number of patients, who withdraw or are withdrawn from the study for any reason after 
intake of at least one dose of study medication will be monitored by the Sponsor. If dropouts 
due to withdrawal are higher than expected, the sample size will be reviewed and might be 
revised by the responsible biometrician. Due to these revisions, adjustments to recruitment 
numbers might be necessary, which could lead to recruitment of more participants than 
currently planned. 
13.9 Safety: expedited safety data review  
An independent data safety monitoring board (DSMB) will be convened for the trial. The DSMB 
will review safety data at regular intervals as defined in the DSMB Charter, but will also perform 
expedited review if the following conditions are met: 
 
Three or more patients experience a grade 3 or higher AE (CTCAE 5.0) in the same organ 
system that are at least possibly related to one of the study drugs, and qualify as 
“unexpected” by being more severe than in previous experience with the drug in 
question. 
 
Two or more patients experience a grade 4 or higher AE (CTCAE 5.0) in the same organ 
system that are at least possibly related to one of the study drugs, and qualify as 
“unexpected” by being more severe than in previous experience with the drug in 
question. 
 
One patient experiences a grade 5 AE (death) that is at least possibly related to one of 
the study drugs 
13.10 Additional safety considerations: individual patient stopping criteria for 
safety 
 
Hepatotoxicity stopping criteria: these follow the FDA guidance on evaluation of drug-
induced liver injury [66]. More detail on patient management in case of liver toxicity 
including intensifying the assessment schedule, is provided under 20.1, page 93.  
A patient should discontinue study drug if: 
o ALT or AST >8xULN  
o ALT or AST >5xULN for more than 2 weeks  
o ALT or AST >3xULN and (total bilirubin (TBL) >2xULN or INR >1.5  


 
 
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o ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
As soon as symptoms resolve and elevated ALT/AST are below 2x ULN, reintroduction of 
study treatment is to be discussed with the sponsor medical expert. Study treatment will 
be reintroduced (all drugs simultaneously). Close, at least biweekly monitoring of 
symptoms and laboratory parameters is needed to identify repeated DILI. Should this 
occur, the study regimen will be permanently stopped and the participant be continued 
on a regimen that is considered non-toxic. 
All participants who discontinue study treatment should be followed up as described for 
follow-up of adverse events classified as “severe” (grade 3 and above). 
 
ECG stopping criterion: Participants will stop treatment if their on-treatment ECG shows 
a prolongation of the Fridericia  corrected QT interval (QTcF) on average in triplicate ECGs 
to grade 3 as defined under 14.6. 
 
In this case, the patient will be hospitalized and monitored closely with at least daily ECGs 
until the abnormality abates.  Study drugs and other potentially offending drugs will be 
withheld. Blood electrolytes (mainly Mg+, Ca++, K+) will be measured and abnormalities 
corrected, after discussion with the sponsor medical expert.   
 
As soon as the AE improves to grade 2 or less, study drugs might be restarted in close 
discussion with the sponsor medical expert, unless QTcF prolongation resulted in 
dangerous arrhythmias (grade 4 QTcF prolongation as defined under 14.6 Table 2 – in 
this case, the patient will be discontinued from study treatment..  
 
Neuropathy stopping criterion: Participants will stop treatment with DZD in case they 
develop clinically significant signs of motor or sensory neuropathy, i.e. loss of muscle 
strength, loss of sensation, loss of vibration sensitivity, or loss of visual acuity or colour 
vision.  
In this case, treatment with BDQ, DLM and MXF may continue as scheduled. Since 
neuropathy may be associated to MXF in rare events, a discontinuation of MXF may be 
advised in severe cases of neuropathy or if neuropathy does not improve after DZD is 
discontinued. 
 
Hypertension (tyramine pressor effect) stopping criterion:  
BP systolic >160 mmHg, or diastolic >100 mmHg:  
o Re-assessment: Participants who develop significant hypertension with systolic 
blood pressure (BP) averages of three measurements of ≥ 160 mm Hg, and/or 
diastolic BP of ≥ 100 mm Hg, but less than 180/110 mmHg, will be re-assessed on 
2 separate occasions.  
They should be re-counselled as to the foods and drink to be avoided with study 
treatment, as non-compliance to this could be an important aspect to the 
hypertension. 


 
 
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o If this evaluation supports the conclusion of a significant increase in blood 
pressure, the investigator will assess potential causes. If the increase is 
determined to be associated with study treatment, a de-challenge/re-challenge 
will be performed: participants will discontinue DZD. If, after ≥ 10 h (> 5 x t1/2 of 
DZD) after the last dose, BP has dropped significantly, a re-challenge with daily 
BP measurements will be considered.  
o Treatment with BDQ, DLM and MXF should continue throughout.  
o Continued hypertension after re-assessment: participants who develop 
persistent hypertension ≥ 160/100 mmHg after evaluation and adequate 
antihypertensive treatment, including those who have undergone a re-challenge 
with DZD, will discontinue all study treatment and complete TB treatment 
according to national TB program guidelines. These participants will receive 
follow-up to determine whether the condition normalizes after discontinuation 
of study treatment.    
BP systolic >180 mmHg, or diastolic >110 mmHg: 
o Immediate stop: Participants who develop hypertension with systolic blood 
pressure (BP) averages of three measurements of ≥ 180 mm Hg, and/or diastolic 
BP of ≥ 110, will stop study treatments immediately, and receive antihypertensive 
treatment. During follow-up, investigators should attempt to determine whether 
the condition normalizes after discontinuation of study treatment, in order to 
better judge relatedness to IMP.   
 
Pregnancy stopping criterion: a female patient will stop treatment immediately, if a 
pregnancy test is positive at any time. Further management is described under Chap. 
14.11.. 
 
Serotonin syndrome stopping criterion: A patient will stop treatment with DZD if at least 
one of the following criteria are fulfilled, which are indicative of serotonin syndrome 
(Hunter Serotonin Toxicity Criteria): 
o Spontaneous clonus 
o Inducible clonus PLUS agitation or diaphoresis 
o Ocular clonus PLUS agitation or diaphoresis 
o Tremor PLUS hyperreflexia 
o Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus 
 
Convulsions/seizures stopping criterion: A patient will stop study treatment if clinically 
significant convulsions are observed in the discretion of the investigator. 
In such a case, the following examinations should be done as soon as possible, after 
stabilisation of the participant’ s condition, to assess the aetiology and contributing 
factors to the event in order to assess relatedness to study drugs. 


 
 
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o Clinical assessment: ventilation pattern, neurological abnormalities, body 
temperature, blood pressure, heart rate 
o Quick bed-side test: glucose 
o ECG 
o Question on concomitant medications, including herbal or over-the-counter 
preparations 
o Question on alcohol or other drug intake, regular abuse and changes in pattern 
of use that might have led to a withdrawal 
o Re- question on own and family history of seizures (to be done at screening, but 
repeated in this case) 
o Draw safety blood sample, including all safety blood tests that are done as per 
schedule of events  
PLUS:  
Malaria microscopy and rapid test, if in a malaria endemic area; to exclude 
cerebral malaria 
o Cerebral imaging like computed tomography (CT) or magnetic resonance imaging 
(MRI) are indicated; to be conducted urgently if cerebral haemorrhage is 
suspected as the underlying cause. It is to be noted that CT is suboptimally 
sensitive to describe a stroke during the first 24h but is highly sensitive to describe 
haemorrhage. 
o Electroencephalography (EEG) should be conducted when patient is stable. 
 
In addition, a seizure can be a symptom of CNS infection such as meningitis or 
encephalitis. If this is suspected, a lumbar puncture may be seen to be in the patient’ s 
best interest, after elevated intracranial pressure has been duly excluded by 
ophthalmoscopy or cerebral imaging.  
 
The information obtained by these diagnostics will be transmitted to the sponsor medical 
expert on the immediately reportable event form within 24h, and any updates 
transmitted and discussed in a timely manner.  
 
14 REPORTING ADVERSE EVENTS 
14.1 Definitions  
For safety monitoring and reporting purposes, a drug related AE is defined as an adverse event 
that is judged to be definitely, probably or possibly related to (one of) the study drug(s).  Adverse 
events will be graded for severity according to the CTCAE 5.0 grading system.  
 
Proportion of adverse events of Grade 3 or Grade 4 severity  


 
 
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 
Proportion of adverse events possibly, probably or definitely related to study drugs.  
 
Proportion of treatment discontinuations or interruptions related to adverse events  
 
Specific ECG endpoints:  
o Frequency, severity and type of ECG alterations 
o Changes to PR, RR, QRS, QT, Fridericia-corrected QT [QTcF] 
o Proportion of participants with QTcF > 500ms on treatment 
o Proportion of participants who experience a prolongation of QTcF >  grade 3 
 
Term 
Definition 
Adverse Event (AE) 
 
Any untoward medical occurrence in a patient or clinical trial subject to 
whom a medicinal product has been administered including occurrences 
which are not necessarily caused by or related to that product. 
Adverse Reaction (AR) 
 
Any untoward and unintended response to an investigational medicinal 
product related to any dose administered. 
Unexpected Adverse Reaction 
(UAR) 
An adverse reaction, the nature or severity of which is not consistent with 
the information about the medicinal product in question set out in the 
summary of product characteristics (or Investigator brochure) for that 
product. 
Serious Adverse Event (SAE) or 
Serious Adverse Reaction (SAR) 
or Suspected Unexpected 
Serious Adverse Reaction 
(SUSAR) 
Respectively any adverse event, adverse reaction or unexpected adverse 
reaction that:  
 
results in death 
 
is life-threatening* 
 
requires 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation** 
 
results in persistent or significant disability or incapacity 
 
consists of a congenital anomaly or birth defect  
 
is medically significant*** 
*The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient 
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. 
**Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalisation is a precautionary measure for continued observation. Hospitalisations for a pre-
existing condition (including elective procedures that have not worsened) do not constitute an 
SAE. Due to the seriousness of the disease in this study, some patients may be admitted to hospital 
for the initial Phase of their trial treatment. This would not qualify as an SAE, although if that 
hospitalisation had to be prolonged beyond the normal length of admission, then it would be an 
SAE. 


 
 
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***A medically serious event is one which does not fit the other outcomes, but the event may 
jeopardize the patient and may require medical or surgical intervention (treatment) to prevent 
one of the other outcomes.  An example might include allergic bronchospasm, haemoptysis, or 
seizure requiring treatment in an emergency room, that do not result in hospitalization. 
 
14.2 Clarifications and exceptions 
Occurrences will be registered as AE from administration of the first dose of study drugs. All events 
that occur or are elicited before administering any study drugs, e.g. screening laboratory 
abnormalities qualifying as Adverse Events, will be recorded as medical history. If such events 
meet criteria for seriousness, they will nevertheless be reported as SAEs. 
Abnormalities which are not clinically significant as per the qualified judgement of the investigator 
do not constitute adverse events and are not recorded and reported as such. However, these 
abnormalities may be analysed and reported in the study report. 
14.3 Additional immediately reportable events  
The following events are notable events and need to be reported to the Sponsor within 24 hours 
of the site becoming aware of the event:  
 
Pregnancy while on study treatment,  
 
QTc prolongation meeting a stopping criterion 
 
any toxicity or condition that leads to a planned deviation from study medication 
 
any grade 4 event that is defined as probably or definitely related to study treatment by 
the investigator, and does not meet criteria for seriousness or other immediately 
reportable events 
14.4 Eliciting adverse event information  
Patients will be instructed during informed consent to report occurrence of adverse events to the 
investigator, also between study visits and if not directly asked for.  
Patients will be instructed to contact the investigator outside the schedule in case of a new 
complaint, or worsening of an existing complaint, that they feel is severe. 
At every study visit, patients will be asked to describe their complaints, and report new 
occurrences.  
Physical examination findings, weight, vital signs, ECG and laboratory information will be gathered 
as described by the study schedule of events. Additional investigations will be ordered by the 
investigator, if they are in the subject`s best interest. 


 
 
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14.5 Assessment of Causality 
The Investigator will review each AE and assess its relationship to study treatment based on all 
available information at the time of the completion of the CRF.  
Each sign or symptom reported will be graded on a 5-point severity scale (see below). Additionally, 
the date and time of onset, relationship to the study medication, duration, action taken, and 
outcome (resolved, improved, unchanged, worse, fatal, or unknown (lost to follow-up) of each 
event will be noted. 
The following definitions for rating attribution/causality will be applied: 
Relationship 
Description 
Event 
Type 
(if 
Serious) 
Unrelated 
There is no evidence of any causal relationship 
Unrelated SAE 
Unlikely 
There is little evidence to suggest there is a causal relationship 
(e.g. the event did not occur within a reasonable time after 
administration of the trial medication).  There is another 
reasonable explanation for the event (e.g. the patient’s 
clinical condition, other concomitant treatment). 
Unrelated SAE 
Possible 
There is some evidence to suggest a causal relationship (e.g. 
because the event occurs within a reasonable time after 
administration of the trial medication).  However, the 
influence of other factors may have contributed to the event 
(e.g. the patient’s clinical condition, other concomitant 
treatments). 
SAR 
Probable 
There is evidence to suggest a causal relationship and the 
influence of other factors is unlikely. 
SAR 
Definitely 
There is clear evidence to suggest a causal relationship and 
other possible contributing factors can be ruled out. 
SAR 
 
Factors to be considered in judging relatedness include: 
 
The temporal sequence from drug administration. 
 
Recovery on discontinuation (de-challenge), recurrence on re-administration (re-
challenge). 
 
Underlying, concomitant, intercurrent disease. 
 
Concomitant medication or treatment. 
 
Known response pattern for the classes of drug the participant is receiving 
 
Exposure to physical and/or mental stresses. 
 
The pharmacology and PK of the medication used. 


 
 
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14.6 Assessment of Severity 
Severity of AEs will be classified following the U.S. National Institutes of Health Common 
Terminology 
Criteria 
for 
Adverse 
Events 
5.0 
(CTCAE), 
available 
online 
at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf , published: November 27, 2017, with the exception of QTc prolongation, 
which will be graded as specified .in table 3. If the specific event is not contained in this 
compendium, the following generic definition, which is also contained in CTCAE 5.0 for such 
events, will apply:  
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily life (ADL)*. 
 
Grade 3: Severe; significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
Grade 5: Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, work or 
farming, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
 
Table 2: definition of severity grading of QTcF prolongation 
This deviation from the CTCAE severity grading is necessary due to the specific situation of TB 
patients; a population in whom a change in QTc over baseline is difficult to assess. Before 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
(1) Absolute QTcF 
>480 and ≤500 ms 
and 
QTcF 
change 
from baseline >0 ms 
and ≤30 ms; or 
(1) Absolute QTcF 
>480 ms and ≤500 
ms and QTcF change 
from baseline >30 ms 
and ≤ 60 ms; or  
1) 
Absolute 
QTcF 
>500 ms; or 
Life-threatening 
consequence, 
e.g., 
torsades de pointes 
or other associated 
serious 
ventricular 
dysrhythmia. 
- 
(2) absolute QTcF 
≤480 ms and QTcF 
change 
from 
baseline >30 and ≤60 
ms 
(2) absolute QTcF 
≤480 
and 
QTcF 
change 
from 
baseline >60 ms. 
(2) absolute QTcF 
>480 
and 
QTcF 
change 
from 
baseline >60 ms. 
 
 
- 


 
 
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treatment starts, they are sick, have elevated temperature and are distressed by their first contact 
with the trial team, which influences the QT interval, through elevated heart rate and possibly 
other mechanisms.  
In a specific analysis of the Oflotub phase III study, it was confirmed that the elevated heart rates 
at baseline were associated with lower QTcF; and that specifically at baseline, QTcF correction 
undercorrects at these high heart rates of TB patients [76]. 
Further, QTc at baseline and late during treatment were compared. A mean increase in QTcF of 
11.2 ms was found in the Gatifloxacin arm, and 9.8 ms in the control arm; despite the fact that for 
none of the drugs, a correlation between Cmax and QTc prolongation could be described.  
Due to this limitation, there is a risk that an incorrect signal of QTcF prolongation over baseline in 
a patient will occur that in itself will not show a safety hazard to the patient, but will result in 
lifesaving drugs being withheld. Therefore, assessment of severity of QTcF prolongation and the 
stopping of treatment in this study as laid out in Table 2: definition of severity grading of QTcF 
prolongation, follows the precedent of the ACTG A5343 trial mentioned above; where a 
combination of bedaquiline and delamanid was trialled and assessed for its potential to prolong 
the QT interval [77].  
Here, in order to prevent a false signal that might be due to a change in heart rate between 
assessments, a higher grade QTcF prolongation is defined as a combination of QTcF prolongation 
from baseline with an elevated absolute value, not a prolongation alone. 
 
14.7 Other AE definitions  
The following definitions will be used for AE Reporting: 
Action Taken with Study Drugs  
 
IMP unchanged 
 
IMP interrupted 
 
IMP stopped 
 
Non – IMP study drug unchanged 
 
Non – IMP study drugs interrupted 
 
Non – IMP study drugs stopped 
 
Not applicable  
Other Action Taken 
 
None 
 
Medication given 
 
Hospitalisation or prolongation of hospitalisation 
 
Therapeutic or diagnostic procedure 
Outcome 
 
Resolved 
 
Improved 


 
 
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 
Unchanged 
 
Worse 
 
Fatal 
 
Unknown 
Occurrence  
 
Once 
 
Intermittent  
 
Continuous 
 
14.8 Adverse event reporting  
Adverse events will be recorded by the investigator from the time a participant signs the informed 
consent form.  
Any AE (serious or non-serious) observed by the investigator or reported by the subject will be 
recorded in the source data and on the Adverse Event electronic case report form (eCRF). The 
Investigator will review each AE and assess its relationship to the study treatment based on all 
available information at the time of the visit. The following information will be recorded for each 
AE reported: 
 
Diagnosis of the AE, if possible. In the case where an overall diagnosis cannot be made, 
each specific sign and/or symptom will be recorded as individual AEs; where possible the 
wording in the CTCAE should be used. 
 
Date of onset 
 
Stop date (duration) if applicable 
 
Severity (grade) 
 
Action taken with IMP/non-IMP study drugs 
 
Other action taken 
 
Outcome 
 
Relationship to IMP/non-IMP study drugs 
 
Occurrence 
 
Seriousness 
14.9 Serious adverse event reporting  
Any AE that occurs which is serious, or which is potentially serious, but a decision cannot be taken 
due to a lack of information, must be reported by the investigator to the study monitor and to the 
sponsor medical expert within 24 hours of the site first being aware of the SAE, whether or not 
the serious event is deemed drug-related. Medical Review will be done by the Sponsor Medical 
Expert. Furthermore, any SAE will be reported to Otsuka Novel Products GmbH, with its principal 
recipient in the United States, and secondary at Erika-Mann-Strasse 21, 80636 Munich, Germany. 


 
 
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In addition, the investigator will provide a detailed, signed, written, and complete SAE Form, 
including the investigator’s estimates of the relationship with the study drug and seriousness of 
the AE in question to the study monitor and sponsor medical expert within 24 hours of becoming 
aware of the SAE. The investigator will ensure that the participant in the report is identified by an 
anonymous code rather than by personal details. 
The study monitor will confirm receipt of the SAE Form with the Investigator and review the initial 
information on the SAE Form for diagnosis, consistency and completeness of data. To update or 
add information to a reported SAE, the Investigator will provide the study monitor and sponsor 
medical expert with a newly completed Serious Adverse Event Form, designated as a follow-up 
report. This will be submitted to the study monitor and Sponsor Medical Monitor within 24 hours 
of the Investigator receiving the information. 
If additional information is needed to complete the profile of the reported SAE, the additional 
information will be requested from the Investigator, if necessary, to complete the profile of the 
SAE reported. After evaluation of the SAE Form for expectedness and possible relation to study 
drug, the sponsor/designee will complete a standardized form by the Council for International 
Organizations of Medical Sciences (CIOMS) for unexpected treatment-emergent SAEs (SUSARs), 
which are forwarded to the investigator. All SAEs and SUSARs will be submitted to all IECs/IRBs 
and regulatory bodies in accordance with local requirements and ICH-GCP guidelines.   
14.10 Clinical Laboratory adverse events 
Changes in the results of the clinical laboratory assessment, 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 if this is a clinically 
significant change from baseline for that individual patient. 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 negative, clinically significant 
change from baseline for that patient, it is an adverse event. 
14.11 Pregnancy as adverse event 
All women of childbearing potential will be instructed to contact the investigator immediately if 
they suspect they might be pregnant during the trial (for example, missed or late menses). If 
pregnancy is suspected while the patient is receiving experimental study treatment, this will be 
withheld immediately until pregnancy can be ruled out with certainty.  


 
 
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If pregnancy is confirmed, experimental treatment will be permanently discontinued in an 
appropriate manner. The patient should complete her TB treatment course following the host 
country’s national guidelines. 
The investigator must immediately notify the sponsor of any pregnancy in a study subject. The 
pregnancy must be recorded on the pregnancy form and forwarded to the sponsor. Expedited 
reporting of pregnancy to regulatory authorities is necessary in case of a pregnancy complication 
fulfilling the criteria for Serious Adverse Events.  
Protocol-required procedures for trial discontinuation must be performed unless contraindicated 
by the pregnancy. Other appropriate pregnancy follow-up procedures should be considered if 
indicated. In addition, the investigator must report to the sponsor for follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome. Infants must be 
followed for a minimum of 6 months. Congenital malformations are to be reported as Serious 
Adverse Events. 
14.12 Disease under study 
Symptoms of the disease under study (i.e. TB) experienced by the subject whilst on the study will 
be assessed by the Investigator. If the symptom has worsened whilst the subject is on the study, 
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 subject’s TB and not 
clinically significant, it will not be recorded as an AE, and this will be noted in the patient’s source 
documentation. If the Investigator is unsure as to whether the symptom is clinically significant or 
not, it is to be classified as significant and reported as an AE. 
If during follow-up phase, the participants is found to have at least one spot sputum sample that 
is found to be associated with relapse or re-infection with a different strain of MTB, this is to be 
recorded as adverse event.  
 
14.13 Follow-up of adverse events  
14.13.1 
General Follow-up of Adverse Events 
During and following a patient’s participation in a clinical trial, the Investigator must ensure that 
adequate medical care is provided to the patient for all AEs, including significant abnormal 
laboratory values. The investigator should inform the patient when medical care is needed for any 
AEs, he/she becomes aware of. 
All non-serious AEs classified as severe and probably/possibly related to IMP must be followed 
until the AE has resolved, or until there is no further change likely to the participants’ condition. 
Cases of pre-existing chronic conditions or if the patient dies from another event can be closed 
with an outcome of “unchanged”. 


 
 
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All other non-serious AEs must be followed until the outcome of the event is “improved” (for 
chronic conditions), “resolved” or until the last scheduled study visit, and all queries on these AEs 
have been resolved. If the patient dies from another event, the case can be closed with an 
outcome of “unchanged”. 
All SAEs must be followed until the outcome of the event is deemed “resolved”, “unchanged” or 
“fatal” and until all queries have been resolved. Cases of chronic conditions, cancer or if the patient 
dies from another event can be closed with an outcome of “unchanged”.  
14.13.2 
Follow-up of Post-Trial Adverse Events 
Any new SAEs reported by the patient to the Investigator that occur after the last scheduled 
contact, that are determined by the Investigator to be causally related or possibly related to the 
use of the IMP, will be reported to the study monitor and sponsor medical Expert, IEC/IRB and 
regulatory authorities on an expedited basis as required. 
15 STATISTICAL CONSIDERATIONS  
15.1 Sample size determination 
15 participants per arm with a total of 75 participants, and a wide range of DZD doses (from 0mg 
to 800mg BID) has been determined as an adequate sample size for population PK modelling, and 
for exposure response modelling to detect a clinically meaningful dose-dependent relationship. 
Furthermore, the planned sample size of 15 subjects per treatment group is in keeping with other 
trials of this type and accounts for the possibility of up to 3 drop-outs per group, which based on 
previous studies of this type conducted at these sites, represents a conservative estimate of the 
expected drop-out rate.  
Previous Phase IIA (EBA) studies indicate that the between patient standard deviation of logCFU 
can be approximately 0.2. Therefore, assuming similar variability in this trial the expected standard 
errors of group mean EBA and corresponding width of 95% confidence intervals are 0.052 and 
0.101 respectively for a group size of 15 and 0.063 and 0.124 respectively for a group size of 10. 
This level of precision with a group size of 15 is considered adequate.  
15.2 Populations to be analysed  
The final analysis populations will be described in the Statistical Analysis Plan (SAP), which will be 
signed off before database lock.  
15.2.1 Intent-to treat (ITT) population 
The ITT population will consist of all randomized patients in the groups to which they were 
randomly assigned, and who have taken at least one dose of study treatment. 


 
 
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15.2.2 Adequate adherence (AA) population: 
The AA population will be the same as the ITT population with the following patients excluded: 
 
Randomised patients not meeting the eligibility criteria 
 
Patients having missed 10 or more doses of their allocated treatment in the first 16 weeks 
of their treatment. 
15.2.3 Safety Population 
The safety population will be defined as all patients who received any dose of study medication. 
 
15.3 Analysis of safety endpoints  
The safety analysis population will be used for all safety analyses.  
15.3.1 ECG analysis 
QT and QTc data will be analysed categorically based on the number and percentage of patients 
classified in each category by treatment group. QTc data will be presented for Friderica’s 
corrections. 
Post-baseline QT- and QTc-intervals will be classified into the following categories:   
 
QT/QTc<450 ms 
 
450 ms <QT/QTc <480 ms 
 
480 ms < QT/QTc < 500 ms 
 
QT/QTc > 500 ms   
QTc-changes from baseline will be classified into the following categories: 
 
decrease (an increase < 0 ms) 
 
increase < 30 ms 
 
>30 ms and < 60 ms 
 
increase >60 ms  
15.3.2 Adverse Events 
The incidence of treatment – emergent adverse events, defined as all AEs that occur after the 
administration of IMP, and their relatedness to experimental treatment will be summarised by 
treatment group, by system organ class and preferred term, maximum severity, and potential 
relationship to IMP, as well as TEAEs with an outcome of death, serious TEAEs, and 
discontinuations due to TEAEs. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. 


 
 
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15.3.3 Other safety variables 
Binary and categorical variables will be tabulated by treatment arm. Continuous variables will be 
summarised with location (such as mean or median) and precision (such as standard error or inter-
quartile range) summary estimates.  
Patients with worsening condition from baseline on any variable will be described and tabulated. 
The following variables will be analysed: 
 
Laboratory Parameters: a list of safety laboratory parameters collected in the trial is described 
under section 11.3.  
 
Ophthalmologic Variables: Visual Acuity (Snellen) and Colour Vision (Ishihara) tests 
 
Physical Examination incl. neurological examination; esp. presence of Hunter score criteria 
 
Vital signs 
15.4 Analysis of primary efficacy endpoint 
The primary efficacy endpoint of this study will be change in mycobacterial load over time on 
treatment as quantified by time to positivity in BD MGIT 960® liquid culture and described by 
nonlinear mixed-effects methodology. All patients in the ITT analysis population will be included 
in this analysis  
This endpoint will be analysed by non-linear mixed effects modelling. 
15.5 Procedure for accounting for missing, unused and spurious data 
Study data will, after being entered, be checked for consistency and completeness through 
programmed checks by the database, which will raise automatic queries. Further completeness 
and consistency checks will be performed by data management and any resulting queries will be 
sent through the database query system so as to leave an audit trail. 
15.6 Procedure for reporting any deviations from the original statistical plan  
Any deviations from the Statistical Analysis Plan will be reported and explained in the Clinical Study 
Report.  
15.7 Timing of analyses 
Analysis for the primary endpoints, and secondary endpoints unrelated to disease recurrence or 
relapse, will be performed after data are available (allowing for time for culture growth) after the 
last patient completed their WK16 (or otherwise last treatment) visit. A partial database lock will 
be performed for this purpose, with a final database lock at the end of study after all long-term 
outcome data are available. 
16 DATA HANDLING AND QUALITY ASSURANCE  


 
 
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16.1 Data collection 
The investigator agrees to maintain accurate source documentation and CRFs. For each patient 
screened, an electronic CRF (eCRF) will be completed, even if the patient drops out at any time 
point during the study. All eCRF information for the completed visits must be completed.  
All applicable eCRF pages must be completed for each participant, who has received any dose of 
study drug and has completed the study.  
For participants who are prematurely withdrawn, the visits up to withdrawal plus the withdrawal 
visit need to be completed.  
In the case of necessary corrections, all changes will be effectuated such that the first version is 
still legible, and the change is initialled and dated by the correcting person. Each completed eCRF 
must be reviewed, signed and dated by the responsible Principal Investigator or the sub-
investigator in a timely manner. 
16.2 Source documents 
Source data 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, electronic data, screening logs and recorded data from automated instruments. 
Study data will be collected and entered into the eCRF. Some data may still be captured entirely 
or partially on paper source documents and will manually be entered into an eCRF, including but 
not limited to:  
 
Informed Consents 
 
Chest X-ray images and reviews 
 
Sample collection data (will be on Lab Forms except for HIV and malaria test results) 
 
Safety and microbiology laboratory results and their review by the investigator. 
All paper source documents and the electronic source documents pertaining to this trial will be 
maintained by the investigators. The investigator will be obliged to permit trial-related monitoring, 
audits, Independent Ethics Committee/Institutional Review Board (IEC/IRB) review and regulatory 
inspections, providing authorized persons direct access to source data/documents. 
16.3 Study monitoring  
One or more study monitors will be assigned to the study. The monitor, as a representative of the 
Sponsor, has the obligation to follow the study closely. The monitor will visit the site at regular 
intervals and will be in contact by phone and written communication, as required.  
Site investigators and designated study personnel will allow the study monitors to inspect study 
documents, pertinent hospital or clinic records as well as site facilities, as required. All aspects of 


 
 
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the study will be carefully monitored in order to ensure compliance with GCP and all applicable 
regulatory guidelines. The monitor will be responsible for verification of: 
 
adequacy of study personnel’s qualifications as well as facilities  
 
informed consent procedures and patient eligibility 
 
the accuracy and completeness of the (e)CRF entries, source data and other trial-related 
records against each other  
 
appropriate study drug storage, usage and accountability  
 
appropriate adverse event reporting 
 
maintenance of the essential documents 
 
all other aspects of the trial relating to protection of the rights and well-being of patients, 
accuracy of trial data and adherence to the protocol, GCP and applicable regulatory 
requirements 
Source data verification will be carried out according to the monitoring plan.  
The sponsor will provide a framework for maintenance of quality in performance and reporting of 
laboratory procedures through the laboratory monitoring plan. 
The study database will only be locked after the data have been monitored by the sponsor and all 
queries issued through data cleaning activities have been completed and resolutions documented.  
16.4 Inspection of records 
The investigator will allow the Sponsor, the Sponsor’s Representative, Regulatory Agencies and 
Ethics Committees access to all study records, if requested. The investigator will promptly notify 
the sponsor of any audits scheduled by regulatory authorities or ethics committees and promptly 
forward copies of any audit reports received to the sponsor. 
16.5 Records retention 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in the International Conference on Harmonization (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product, or for not 
less than 10 years after trial completion, whichever is longer.  
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be 
retained. 


 
 
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16.6 Confidentiality of personal data  
All patient records, lab specimen etc. will be identified in appropriate manner to maintain patients’ 
confidentiality and will be kept in a secure storage area with limited access. Clinical data will not 
be released without the written agreement of the patient (or their legal guardian), except as 
necessary for monitoring and auditing by the sponsor or its representative, regulatory authorities 
or ethics committees.   
For those participants who gave consent to store genetic samples for future testing an analysis, 
their samples will be labelled using anonymous codes. Results of any genetic tests will not be 
disclosed to anybody not involved with the study, in particular not to immediate relatives without 
prior consent of the patient. 
This confidentiality will be in accordance to the recently instated EU Data protection Law 
(Regulation (EU) 2016/679).  
17 ETHICAL CONSIDERATIONS 
17.1 Basic principles  
This study will be performed in accordance with the protocol, the principles laid down in the ICH 
harmonized tripartite guideline regarding GCP (Consolidated Guideline E6, July 2002), the 
Declaration of Helsinki (Sixth Revision, October 2008), as well as any other applicable national and 
international regulatory guidelines. 
17.2 Involvement of ethical committees  
The protocol and the informed consent document to be used in this study must be submitted to 
the Investigator’s Ethics Review Committee/IRB, regulatory authority, and the sponsor IRB for 
approval. Written documentation of approval of both, the protocol and the informed consent, 
must be provided to the sponsor before starting the study. 
The Investigator will ensure that the purpose of the study is explained to the patient and that 
written consent is obtained prior to participation in the study. The patient and the Investigator or 
his/her delegate will sign the consent prior to entry into the study.  
The Investigator will promptly report to the Ethics Committee/IRB of all changes in the research 
activity and all unanticipated problems involving risks to human participants or others and will not 
make changes in the research without Ethics Committee/IRB approval, except where necessary to 
eliminate apparent immediate hazards to human participants. 
17.3 Regulatory authorities  
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs and Serious 
Unexpected Adverse Drug Reactions (SUSARs), and the Integrated Clinical Trial Report according 


 
 
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to national regulations. Written approval will be obtained from the Regulatory Authorities prior 
to commencement of the trial. 
17.4 Investigators view of the ethical issues and considerations 
The investigator(s) participating in this trial, as listed above, have had the opportunity to review 
the protocol outline. Their concerns and suggestions have been included into the final protocol. 
17.5 Falsification of data 
Any proven evidence of falsification of data will be dealt with in accordance with the policy of the 
sponsor and appropriate action will be taken.  
18 ADMINISTRATIVE CONSIDERATIONS 
18.1 Trial committees 
18.1.1 Trial Oversight: Trial Steering Committee (TSC)  
The role of the Trial Steering Committee (TSC) is to provide overall supervision of the trial and 
ensure that the trial is conducted in accordance with GCP and GCLP principles. The Trial Steering 
Committee will formally report to the Sponsor. TSC specifics will be detailed and justified in the 
TSC charter. The TSC will at least consist of a sponsor representative person, the sponsor medical 
expert, the trial statistician, and a principal investigator (PI).  
18.1.2 Data Safety Management Board (DSMB) 
To include an element of expert advice that is independent of the PIs and the sponsor, an 
independent Data Safety Monitoring Board (DSMB) will be installed. The DSMB will safeguard the 
interests of trial participants. The DSMB will review data and will make recommendations to the 
TSC regarding stopping of certain arms, or the whole trial if trial participation is an undue risk to 
participants and will use the safety review guidelines in their consideration. The DSMB are not 
executive, any decision regarding early termination of arms or the whole trial will be made by the 
TSC and sponsor. A DSMB charter will be established that describes the roles and responsibilities 
of this independent committee for the trial. 
18.2 Trial registration  
Before study start, the trial will be registered in clinicaltrials.gov, a WHO recognized clinical trials 
registry. 
In addition, the trial will be registered in the South African National Clinical Trials Registry. 


 
 
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18.3 Financing  
The study sponsor is LegoChem Biosciences, Inc. The trial is conducted under the umbrella of 
PanACEA, the PanAfrican Consortium for the Evaluation of anti-TB Antibiotics. PanACEA is a not-
for-profit consortium with the goal of shortening the treatment regimen of drug-sensitive TB. 
LegoChem Biosciences ensures that sufficient funding of this study is available.   
LegoChem Biosciences, Inc. will contribute sufficient DZD 400mg tablets Biosciences to ensure 
conduct of this study.  
18.4 Patient insurance  
The sponsor certifies that it has obtained or will obtain clinical trial insurance in line with the 
requirements in each country prior to study start. 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. 
18.5 Patient compensation for trial-related expenditures 
Trial participants will receive a flat sum per trial visit (and per day spent in hospital) for out of 
pocket expenses, which covers loss of salary, travel to/from site and other miscellaneous cost, 
depending on the vote of the trial sites’ ethics committee. This sum will be laid down in the sites’ 
informed consent documents to follow local practice and be approved by sites’ ethics committees. 
Should a trial participant have higher travelling expenses, these can be reimbursed at the 
discretion of the investigator. In such cases, receipts and considerations should be documented in 
the participant’s records. 
Since these payments are reimbursements of estimated cost, they do not constitute an undue 
incentive for trial participation. 
18.6 Publication Policy  
After completion of the study, the data may be considered for reporting at a scientific conference 
and/or publication in scientific journals. LMU will be responsible for these activities and will 
collaborate with the investigators to determine how the manuscript is written and edited, the 
number and order of authors, the journal to which it will be submitted and other related issues.  
The results of the study will be published independent of the outcome - positive or negative - of 
the study. 
Under certain circumstances, i.e. when the publication of particular findings (of an 
epidemiological, sociological or genetics study) may present a risk to the interest of a community 
or population or a racially or ethnically defined group of people, it may be considered 
inappropriate to publish findings. 


 
 
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18.7 Protocol amendment policy  
Any change to the protocol will be made 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 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 for notification purposes as appropriate. 
 
 


 
 
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Gillespie, S.H., et al., Four-Month Moxifloxacin-Based Regimens for Drug-Sensitive 
Tuberculosis. New England Journal of Medicine, 2014. 371(17): p. 1577-1587. 


 
 
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20 APPENDIX 
20.1 Management and classification of liver toxicity 
Since treatments in this study do not include standard of care for DS-TB, we decided to 
recommend testing for and management of drug-induced liver injury (DILI) following the FDA’ s 
guidance that provides a synthesis of patient protection considerations, and adequate 
characterisation of the treatment regimen’ s risk for DILI [66], rather than follow TB-specific 
guidelines. 
20.1.1 Prevention: Participant awareness  
Remind the participant to avoid substances with the potential to cause liver damage: 
including alcohol and other medications such as paracetamol. 
The participant must be informed about signs that might indicate worsening abnormalities 
or evidence of drug reaction (e.g. loss of appetite, fever, nausea, vomiting, rash, jaundice) 
and know to present emergently should any of these be noticed. 
20.1.2 Closer observation: AST/ALT > 3xULN 
It is critical to initiate close observation immediately upon detection and confirmation of early 
signals of possible DILI, and not to wait until the next scheduled visit or monitoring interval.  
A threshold of aminotransferase levels greater than 3xULN is recommended for closer 
observations, as lesser elevations are common and nonspecific, if participant is asymptomatic 
regarding clinical signs of DILI AND bilirubin AND INR are not elevated.   
Other laboratory findings that do not meet these criteria but raise the investigator’s concern 
should be discussed with the sponsor medical expert.  
If additional testing, beyond that specified in the trial protocol, is carried out, it is important that 
the subject’s information be added to the CRFs and database.  
Close observation includes:  
 
Repeating liver enzyme, serum bilirubin tests and coagulation tests two or three times 
weekly. Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize or the trial drug has been discontinued and the subject is asymptomatic.  
 
Obtaining a more detailed history of symptoms and prior or concurrent diseases.  


 
 
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 
Obtaining a history of concomitant drug use (including non-prescription medications and 
herbal and dietary supplement preparations), but especially alcohol use, recreational 
drug use, and special diets.  
 
Ruling out acute viral hepatitis types A, B, C, D, and E; hypoxic/ischemic hepatopathy as 
much as possible; and biliary tract disease. Ultrasound should be performed for the 
latter.   
 
Obtaining a history of exposure to environmental chemical agents.  
 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).  
20.1.3 Pausing treatment 
Pausing of study treatment should be considered if:  
 
ALT or AST >8xULN  
 
ALT or AST >5xULN for more than 2 weeks  
 
ALT or AST >3xULN and (TBL >2xULN or INR >1.5)  
 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
20.1.4 Re-challenge with study treatment: 
 
As soon as symptoms resolve and elevated ALT/AST are below 2x ULN, 
reintroduction of study treatment is to be discussed with the sponsor medical 
expert. Study treatment will be reintroduced (all drugs simultaneously). Close, 
biweekly monitoring of symptoms and laboratory parameters is then needed to 
identify repeated DILI. Should this occur, the study regimen will be permanently 
stopped and the participant be continued on a regimen that is considered non-toxic. 
 
Inform the participant: The participant must be informed about signs that might 
indicate worsening abnormalities or evidence of drug reaction (e.g. loss of appetite, 
fever, nausea, vomiting, rash, jaundice) and know to present emergently should any 
of these be noticed. 
 
The participant must be informed on avoiding alcohol and other liver toxic co-
medications or drugs.  
20.1.5 Follow-up of liver toxicities 
 
 All participants who discontinue study treatment should be followed up as 
described for follow-up of adverse events classified as “severe” (grade 3 and above).  
 
 


 
 
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20.2 MAO inhibitor food restriction list 
 
Food Classification 
Foods to avoid 
Cheeses 
Strong, aged cheeses (i.e. aged cheddar, Swiss and parmesan)  
Blue cheeses (i.e. Stilton and Gorgonzola), Brie, Camembert, 
feta, mascarpone.  
Meat, Fish or Substitute  
Beef or chicken livers (aged), 
Cured meats (i.e. meats treated with salt and nitrate or 
nitrite, such as dry-type summer sausages, pepperoni and 
salami).  
Raw meats and fish if stored outside the refrigerator 
Beverages 
Especially beer from the tap, red wine 
All alcoholic beverages should be avoided for the reason of 
hepatotoxicity. 
Miscellaneous 
Yeast Extracts such as Marmite, soy sauce  
Leftovers 
Do not eat after 48 hours. 
 
 


 
 
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20.3 Sub-studies 
This study provides the opportunity to advance the scientific understanding of TB disease and 
treatment, within a well-controlled clinical trial generating valuable data on treatment response 
in a large cohort of participants, with GCP-related quality control and assurance producing high 
data quality. 
It is therefore ethically mandated to use this opportunity to advance the science around TB and 
TB treatment by making use of this resource, in order to accelerate future developments to the 
benefit of TB patients and persons at risk of TB diseases. 
During this trial, retention samples will be collected as described below. These samples may be 
used in the following proposed sub-studies, including possible genetic analysis. Collection of these 
samples will only be done if the site’s ethics committee has accepted the conduct of these sub-
studies, and if a study participant provides separate consent, on forms separate from consent for 
the main trial. Study participants will be able to refuse retention sample collection and/or genetic 
testing while still participating in the main trial.  
Sample(s) will be kept until they are all used up or destroyed at the Sponsor’ s discretion, which 
may take up to fifteen years, with extension if needed. If the specimens are going to be stored for 
longer, we will ask permission from the local ethics committee. 
The use of these samples will be decided on by the PanACEA Executive group, upon applications 
of individual researchers or teams for use of trial samples. Results of these analyses will not be 
incorporated into the trial reports, and will not be disclosed to investigators before the completion 
of the trial. 
Retention samples will be whole blood for genetic analysis, serum, sputum and urine samples to 
analyse for potential correlates of treatment success and bacterial load. Storage and analysis of 
these samples may be performed outside of the countries hosting the trial site(s). The possibility 
of sample transport and analysis abroad will be included into the information provided to the 
patient before consenting. 
All use of stored samples, which is not identical with intentions and/or methods described in this 
protocol, shall be submitted to the relevant IRBs before any sample is used. 
20.3.1 Rationale: New Markers for Treatment Response 
Background: Monitoring of TB treatment response in an individual, as well as for later-stage 
clinical trials of new regimens, is currently hampered by limitations in the predictive methods 
used. 2-month culture status is widely accepted as a surrogate marker for the efficacy of a regimen 
in a Phase II trial. However, on an individual basis, the sensitivity of a positive 2-month culture to 
predict relapse was less than 50%, thus cannot be used for identifying patients at risk who would 
benefit from intensified therapy [70]. In Phase II clinical trials, lengthy time to availability of culture 
results are problematic in terms of adaptive trial designs, which require these data for efficient 
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In later stage clinical trials, the gold standard for efficacy is currently the rate of treatment failure 
and relapse, which requires an 18-month follow up with all consequences including cost, losses to 
follow-up, slow progress of clinical development etc. [34]. 
New bacterial and host markers are therefore urgently required and need to be validated for their 
use in individualized therapy and clinical trials. If feasible, research on these markers will include 
research on coinfection of TB with other pulmonary pathogens by next generation sequencing, as 
coinfections may modify TB disease course, and culture is an insufficient method to identify all 
potential co-infecting pathogens, which was demonstrated recently by the description of 
cryptomycota, a completely new phylum of single-cell fungi [71-73].  
Further, the association of pharmacokinetics of standard anti-TB drugs with treatment success is 
still incompletely understood [74]. 
In this study, a number of potential biomarkers derived from the pathogen and the host will be 
examined:  
20.3.2 Methods to assess the infecting pathogen: 
 
Differential Staining methods will be performed on sputum smears to determine the 
frequency of e.g. mycobacterial persister phenotype as described by Garton et al [75], 
and to correlate phenotypes with treatment response as measured by the primary and 
secondary study endpoints. 
 
Sputum bacterial transcriptomics, proteomics and metabolism may be assessed in order 
to define and assess innovative endpoints linked to the diagnosis of TB or to TB treatment 
success. 
 
Bacterial antigens: novel bacterial antigens may be analysed from the preserved 
materials in order to validate new tests with a potential to be used as surrogates for 
treatment success. 
 
Molecular bacteriology: assessments using molecular bacteriologic measures may be 
done during screening and during treatment course. This will be done to evaluate novel 
PCR-based diagnostics, and parameters to determine treatment success such as 
mycobacterial RNA, and mycobacterial antigens. Sequencing of mycobacterial DNA and 
RNA may be included. 
 
Molecular epidemiology: strain typing of the pathogen e.g. through Spoligo-typing, 
MIRU-VNTR or sequencing of parts or the entire bacterial genome or transcriptome may 
be done in order to establish molecular strain epidemiology, an association of strains 
with treatment response, severity of infection, or of the genotype with drug resistance. 
20.3.3 Methods to assess Host Markers and Co-infections: 
 
Serological and Immunological markers: sera, whole blood will be preserved to later 
allow analysis of host markers for possible surrogates for a diagnosis of active TB, and for 
primary and secondary endpoints of this study. Markers assessed will include 


 
 
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mycobacterial and other antigens, immunological parameters including those assessed 
by flow cytometry, and evaluation of concurrent viral and parasitic infections, among 
others.  
 
Co-infections: the role of coinfections in TB patients regarding disease symptoms and 
treatment response shall be investigated. These will be analyzed by standard 
microbiological methods including culture, staining and antigen detection, but also by 
molecular detection including next-generation sequencing from stored patient materials. 
 
Genetic Markers associated with TB treatment outcome: Patient DNA and RNA will be 
stored identified with a code, to allow for future analysis of host genetic/transcription 
markers associated with study endpoints and/or PK parameters (pharmacogenomics), 
among others. Novel technologies for analysis of genome and transcriptome, like next 
generation sequencing and nucleic acid chip analysis may be used for this purpose. 
21 POSSIBLE DRUG INTERACTIONS 
21.1 Anti-TB drugs in PanACEA-DECODE and anti-nausea / anti-emetic drugs 
21.1.1 Metoclopramide  
Background on metoclopramide (MCP): MCP is a phenothiazine-derived anti-emetic. Few data suggest 
that MCP is a substrate of CYP2D6. More specifically, studies in human liver microsomes suggest that 
MCP is both a substrate and an inhibitor of CYP2D6 [76]. In vitro, CYPs 1A2, 2C9, 2C19, and 3A4 also 
metabolized metoclopramide. A pharmacokinetic interaction study between the strong CYP2D6 
inhibitor fluoxetine and MCP in humans shows that MCP is a CYP2D6 substrate indeed. MCP interacts 
with many other CYP2D6 substrates (e.g. antidepressants), resulting in an increased risk of 
extrapyramidal symptoms and neuroleptic syndrome, and this may (partially) be a reflection of a 
pharmacokinetic interaction on MCP.  
Metoclopramide hydrochloride promotes motility in the upper gastrointestinal tract by sensitizing 
tissues to the action of acetylcholine, which is independent from intact vagal innervation and does not 
stimulate biliary, gastric, or pancreatic secretions. It hastens gastric emptying and intestinal transit by 
increasing tone and amplitude of gastric contractions, relaxing the pyloric sphincter and duodenal 
bulb, and enhancing peristalsis of the duodenum and jejunum. It also has antiemetic property which 
is attributed to the central and peripheral dopamine receptor inhibition. Some interactions between 
MCP and other drugs are mediated by increased gastric motility. 
Supraventricular tachycardia, bradycardia, and possible atrioventricular block have been reported 
very rarely, mostly with intravenous administration of MCP. However, there are no formal 
cardiological contra-indications for MCP. In Micromedex, concurrent use of metoclopramide and 
serotonin norepinephrine reuptake inhibitors is contra-indicated, as it may result in an increased risk 
of extrapyramidal reactions and neuroleptic malignant syndrome. Case reports are available 
describing serotonin syndrome when MCP was combined with a SSRI, possibly due to a small 5-HT3 
receptor blocking effect of MCP [77]. 


 
 
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Interaction between MCP and study drugs: a pharmacokinetic interaction between MCP and the drugs 
in DECODE is unlikely, since none of the study drugs are metabolized via CYP2D6 or interact with 
CYP2D6. Furthermore, plasma protein binding of MCP is low (~30-40%), making plasma protein 
displacement less likely and relevant. Apart from the pharmacokinetic interaction, monitoring of the 
ECG may be a precaution measure, when higher than standard doses of MCP are combined with 
MXF/DLM/BDQ or when these drugs are combined for a longer period. MCP is a phenothiazine-
derivative, and some phenothiazines have been noted to enhance the QT interval prolongation effect 
of MXF, but QT prolongation is not seen with MCP. Concurrent use of metoclopramide and serotonin 
norepinephrine reuptake inhibitors is contra-indicated, and MCP may increase the risk of serotonin 
syndrome, but the risks for this adverse effect seems of minor clinical relevance. 
Conclusion:  Upon repeated use and with higher doses of metoclopamide, at least ECG should be 
monitored. No data are available. It is advised that MCP can be combined with the study drugs, but 
with caution (see arguments listed above). This means that MCP is started at a low dose (10 mg BID 
orally or rectally), that possible dose increases occur with small steps and with careful monitoring of 
adverse effects, that the standard dose of 3-4x10mg/day is not exceeded, and that MCP is used as 
short as possible. A next dose step would be to 10 mg twice daily.       
 
21.1.2 Domperidone 
Background on domperidone: domperidone is another phenothiazine-derived anti-emetic. It is 
metabolized by CYP3A4, CYP1A2 and CYP2E1. QT interval prolongation is a known adverse effect to 
domperidone.  For this reason, domperidone may not be used in this study.  
Conclusion: Domperidone is not allowed to be given in this study per protocol due to QT prolongation.   
 
21.1.3 Cyclizine 
Background on cyclizine: cyclizine is an antihistaminic anti-emetic with weakly sedating, weakly 
anticholinergic and strong anti-emetic properties. It is not often used as an anti-emetic. Cyclizine is 
metabolized in the liver mainly to the largely inactive metabolite nor-cyclizine, formed by a 
demethylation reaction. Its pharmacokinetics have been poorly studied, and its metabolic pathway is 
unknown, but it has been suggested that the CYP2D6 enzyme has a role in the metabolism of 
cyclizine[78]. The antihistamine hydroxyzine, which is the same class of antihistamine (piperazine) as 
cyclizine, is metabolized by CYP2D6. Cyclizine inhibits CYP2D6 based on a human liver microsome 
study [79]. The elimination half-life of cyclizine is long (24 h). It can cause tachycardia. Very few 
interactions have been described.  
Interaction between cyclizine and study drugs: a pharmacokinetic interaction between cyclizine and 
the drugs in DECODE is unlikely, since none of the study drugs are metabolized via CYP2D6 or interact 
with CYP2D6.  
Conclusion: no interaction of the study drugs and cyclizine has been described and it is not 
anticipated. Cyclizine would have disadvantages as a first-choice anti-emetic in PanACEA-DECODE: 
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has a long elimination half-life which is a disadvantage in case of an interaction, and this old drug may 
not be available everywhere. For this reason, the use of cyclizine is not recommended in study 
patients. 
 
21.1.4 Promethazine  
Background on promethazine: promethazine is an antihistaminic / phenothiazine-derived anti-emetic. 
It has strongly sedating, weakly anticholinergic and strong anti-emetic properties. The sedating effect 
is a disadvantage for its use as an anti-emetic. Promethazine is metabolized in the liver to the main 
metabolites promethazine-sulphoxide and desmethylpromethazine. It is metabolized predominantly 
by CYP2D6 [80]. It also inhibits CYP2D6 based on human liver microsome studies [79] and studies in 
humans [81]. The elimination half-life is 10-14 h. It can cause bradycardia, tachycardia and (when 
administered i.v.) prolonged QT interval. 
Interaction between promethazine and study drugs: a pharmacokinetic interaction with the drugs in 
DECODE is unlikely, since none of the study drugs are metabolized via CYP2D6 or interact with CYP2D6. 
Apart from the pharmacokinetic interaction, monitoring for cardiotoxicity may be a precaution when 
promethazine would be used in this study (possible increased risk of QT interval prolongation). 
Micromedex on the combination with MXF: use with caution, e.g. start with lowest dose and titrate 
the dose.  
Conclusion: the use of promethazine is not recommended in study patients due to the strong sedative 
effect, which may put participants at risk of accidents, and the QT-prolonging potential, which has 
however only been reported for iv use.  
    
21.1.5 Dimenhydrinate 
Background on dimenhydrinate: dimenhydrinate is another antihistaminic anti-emetic. It is a salt of 
diphenhydramine 
(diphenhydramine 
theophyllinate). 
Dimenhydrinate 
dissociates 
to 
diphenhydramine and 8-chlorotheophylline upon administration. Diphenhydramine is an active 
metabolite and is well absorbed from the gastrointestinal tract with a bioavailability of 42 to 62%. 
Diphenhydramine experiences extensive first pass hepatic n-demethylation via CYP2D6; minor 
demethylation via CYP1A2, 2C9 and 2C19; and smaller degrees of metabolism in pulmonary and renal 
systems. Next to being a substrate for CYP2D6, it inhibits CYP2D6 based on human liver microsome 
studies and [82] and studies in humans [83]. The drug is widely distributed throughout the body, 
including the CNS, with protein binding ranging from 78 to 98.5%. Half-life is 4-8 h. It is not commonly 
used for nausea and vomiting. Eg for chemotherapy-induced nausea and vomiting, diphenhydramine 
may be a useful adjunct to other anti-emetics but is not recommended as a single agent. 
Interaction between dimenhydrinate and study drugs: a pharmacokinetic interaction with the drugs 
in DECODE is unlikely, since none of the study drugs are metabolized via CYP2D6 or interact with 
CYP2D6.  
Conclusion: dimenhydrinate is not recommended as anti-emetic in this study, since data on actual 
interactions of dimenhydrinate and licensed drugs are scarce. There is much less experience with the 


 
 
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use of dimenhydrinate as an anti-emetic compared to MCP, it may be a weakly acting drug mainly 
suitable as an adjunct, and this old drug may not be available everywhere.  
 
21.1.6 Ondansetron 
Background on ondansetron: ondansetron is a 5-HT3 (serotonine) receptor antagonist. Hepatic 
elimination is responsible for 95% of ondansetron clearance and < 5% is recovered unchanged in urine. 
Ondansetron is moderately hydrophobic organic cation, and human organic cation transporter 1 
(OCT1) is responsible for its hepatic cellular uptake. The primary metabolic pathway involves CYP3A 
(CYP3A4, CYP3A5), whereas CYP2D6, CYP1A2 and CYP2E1 constitute the secondary pathway. 
Arrhythmia and bradycardia may occur seldomly (<1%) and QT interval prolongation may occur after 
i.v. administration. Use should be avoided in patients with congenital long QT syndrome, monitoring 
is recommended in patients with electrolyte abnormalities, bradyarrhythmias, congestive heart 
failure, and those taking concomitant medications that prolong the QT interval. In Micromedex, 
simultaneous use with other CYP3A4 substrates and inhibitors is contra-indicated. Moreover, 
concurrent use with other serotonergic agents may result in increased risk of serotonin syndrome, 
therefore, these drugs are prohibited from use in all trial participants. 
Interaction between ondansetron and study drugs: a pharmacokinetic interaction between 
ondansetron and the CYP3A4 substrates in this study (BDQ, DLM and DZD) has not been described but 
may be possible, as it is the main metabolic enzyme of ondansetron. In addition, there may be an 
increased risk of QT interval prolongation and serotonin syndrome.  
Conclusion: Ondansetron (a serotonin receptor antagonist) is not allowed to be given in this study per 
protocol due to increased risk of QT interval prolongation, serotonin syndrome and pharmacokinetic 
drug-drug interactions (via CYP3A4). 
 
21.2 Anti-TB drugs in PanACEA-DECODE and antacids / H2-antagonists / proton pump 
inhibitors 
 
21.2.1 Aluminium and magnesium containing antacids 
Background on aluminium and magnesium containing antacids: These drugs do not interfere with 
metabolic enzymes. However, an elevation in the pH of the stomach and or interaction with cations 
may decrease the absorption to other drugs. These drugs are prohibited from use in all trial 
participants.  
 
Interaction between aluminium and magnesium containing antacids and study drugs: No 
pharmacokinetic interaction through metabolic enzymes is expected. It is unknown whether lower pH 
in the stomach may affect the absorption of BDQ, DLM or DZD. When combined with MXF, a 40% 
decrease in exposure occurs. MXF should be administered at least four hours before or eight hours 
after an aluminum or magnesium containing product. 
 


 
 
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Conclusion: no relevant interactions are expected with BDQ, DLM or DZD, but this has not been 
confirmed in patients. MXF should be separated in time from antacids. Still these drugs are prohibited 
from use in all trial participants.  
 
21.2.2 Ranitidine 
Background on ranitidine: ranitidine a histamine H2-receptor antagonist and is metabolized in the liver 
to at least 3 metabolites. No involvement or clinically relevant inhibition/induction of CYP enzymes is 
anticipated. In vitro, ranitidine did not inhibit CYP3A activity (Martinez et al., 1999), although in 
Micromedex CYP3A4 substrates and inhibitors are contra-indicated. 
Interaction between ranitidine and study drugs: No pharmacokinetic interaction through metabolic 
enzymes is expected. It is unknown whether gastric acid secretion affects the absorption of BDQ, DLM 
and DZD. The bioavailability of MXF is not affected by concurrent administration of ranitidine (Stass 
et al., 2001). 
 
Conclusion: no pharmacokinetic interactions through metabolic enzymes are expected with ranitidine 
in this study.  It is unknown whether gastric acid secretion affects the absorption of some of the study 
drugs, nevertheless, ranitidine is the drug of first choice in these patients. 
 
21.2.3 Omeprazole 
Background on omeprazole: omeprazole is metabolized by CYP2C19 and CYP3A4. Omeprazole is 
metabolized directly in part by CYP3A4 to omeprazole sulfone, then transformed into 5-
hydroxyomeprazole sulfone by CYP2C19. The metabolism of esomeprazole and omeprazole is 
essentially similar, except that the rate of 5'-hydroxylation is slower in the case of esomeprazole than 
in the racemic mixture. It is inhibiting CYP2C19, CYP3A4 and P-gp, and induces CYP1A2 and. 
Interaction between omeprazole and study drugs: a pharmacokinetic interaction between 
omeprazole and BDQ, DLM and DZD may occur, as they are CYP3A4 substrates, and their exposure 
may be increased as a result. MXF is a P-gp substrate, but this interaction is probably of minor clinical 
relevance.  
Conclusion: limited pharmacokinetic interactions through metabolic enzymes are expected with 
omeprazole in this study. Therefore, it is proposed to administer omeprazole as second choice in this 
study. Of note, it is unknown whether gastric acid secretion affects the absorption of some of the 
study drugs. 
 
21.2.4 Other proton pump inhibitors – esomepromazole, lansoprazole, rabeprazole, 
pantoprazole 
The metabolic profile of these protone pump inhibitors is similar to that of omeprazole. They are all 
metabolized by CYP3A4 and/or CYP2C19: interactions with study drugs via CYP3A4 therefore cannot 
be excluded.   
 

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