A Phase 2/3, Multicenter, Randomized, Open-label, Active-controlled Study to Evaluate the Efficacy and Safety of Bedaquiline Administered as Part of a Treatment Regimen With Clarithromycin and Ethambutol in Adult Patients With Treatment-refractory Mycobacterium Avium Complex-lung Disease (MAC-LD)
Phase: PHASE2
Conditions: Treatment-refractory Mycobacterium Avium Complex-lung Disease (MAC-LD)
Sponsor: Janssen Pharmaceutical K.K.

 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 8 December 2022
Janssen Pharmaceutical K.K. *
 
Clinical Protocol
 
Protocol Title
A Phase 2/3, Multicenter, Randomized, Open-label, Active-controlled Study to Evaluate
the Efficacy and Safety of Bedaquiline Administered as Part of a Treatment Regimen
With Clarithromycin and Ethambutol in Adult Patients With Treatment-refractory
Mycobacterium Avium Complex-lung Disease (MAC-LD)
Short Title
Bedaquiline/CAM/EB Study in Treatment-refractory MAC-LD Patients
 
Protocol TMC207NTM3002; Phase 2/3
AMENDMENT 8
 
TMC207 (Bedaquiline)
 
*This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used
throughout the protocol to represent Janssen Pharmaceutical K.K.
Status: 
Approved
Date: 
8 December 2022
Prepared by: Janssen Pharmaceutical K.K.
EDMS number: 
EDMS-ERI-206741399, 9.0
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date: 8 December 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 8 
08-Dec-2022
Amendment 7 
30-June-2022
Amendment 6 
20-Apr-2022
Amendment 5 
09-Dec-2021
Amendment 4 
30-Sep-2021
Amendment 3 
08-Jul-2021
Amendment 2 
14-Apr-2021
Amendment 1 
21-Oct-2020
Original Protocol 
01-Jul-2020
Amendment 8 (8 December 2022)
Overall Rationale for the Amendment: The major rationale for the amendment is to change in the study
design from Japan study to a multi-country study taking into participation of South Korea and Taiwan, to
reconsideration the inclusion/exclusion criteria, and to change the sample size based on the changing the
statistical power. In accordance with these changes, the statistical analysis plan is also revised.
The changes made to the clinical protocol TMC207NTM3002 as part of Protocol Amendment 8 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Section 10.8 Appendix 8: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.2 Schema
1.3 Schedule of
Activities (SoA)
4.1 Overall Design
5 Study Population
6.8 Concomitant
Therapy
•
The study will consist of a screening period of 6370 days (910
weeks)
•
-W9-W10  63-70 to 0 (figure omitted)
•
Footnote a. Screening evaluations must be performed within 6370
days (910 weeks) prior to baseline (Day 1). These 910 weeks
include 14 days of rifamycin W/O for participants to whom it is
applicable. If screening period exceeds 910 weeks for reasons
such as time required to obtain the result of microbiology
assessment of screening, the screening period may be extended
up to 1415 weeks.
•
Screening for eligible participants will be performed within 910
weeks before administration of the study intervention.
•
Concomitant therapies administered after signing informed
consent (6370 days before first dose of study intervention,
including the extension period if screening period is extended)
and prestudy therapies for pulmonary MAC disease administered
prior to signin  g informed consent must be recorded at screening.
1-week extension
in consideration
of transportation
period of samples
from South Korea
and Taiwan
1.1 Synopsis
4.1 Overall Design
9.2 Sample Size
Determination
•
A target of 180124 participants with treatment-refractory MAC-
LD will be enrolled in this study.
•
A sample size of 180124 participants (9062 in Group A: the BDQ
containing regimen, 9062 in Group B: the rifamycin-containing
regimen) will have a power of about 9080% to show superiority
for a 20% difference in proportion of participants having sputum
conversion at Week 24 based on a chi-square test (at the 5% 2-
sided significance level) on the intent-to-treat (ITT) population.
Change in target
sample size
according to
change in
statistical power
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3
Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
4.1 Overall Design 
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding
• Participants who meet all the eligibility criteria will be 
randomized in a 1:1 (Treatment Group A [Group A]: Treatment 
Group B [Group B]) ratio stratified by country: 
• The randomization will be balanced by using randomly permuted 
blocks and will be stratified by country. 
Stratification by
country for the
enrollment in
multi-country
study
1.3 Schedule of 
Activities (SoA) 
Footnote c. Assessments planned on Day 1 except for blood sampling 
for PK which is performed after dosing must generally be performed 
prior to first dose of stud y intervention.
Clarification of
applicable tests
Footnote m. Two sputum samples should be collected at each visit 
time point except for Week 2, 6, and 10. One should be collected in 
the early morning (at home or at the study site) and the other 
sample(s) at the study site. If sputum collection at home is
impossible, 2 samples will be collected at the study site. If sputum
can be produced more easily in the evening/night than in the early
morning, it is acceptable to store the sample obtained in the previous
day of visit in a refrigerator, bring it to the study site, and submit it on
the following day. Samples collected at home or the study site can be
spontaneous, or induced or aspirated. In case 2 sputum sample
collection is not feasible at Week 2, 6, and 10, either no sample or 1
sample collection is allowed. Sputum samples will be shipped to the
central microbiology laboratory where all cultures will be performed
on solid and on liquid media. The same applies to sputum collections
at OPW 2, 6 and 10 in the optional cohort. And in case a sputum
sample is collected in routine clinical practice before obtaining
informed consent on the day of informed consent, it is acceptable to
submit as a sputum sample for the study after obtaining the
participant's consent and recorded.
Clarification of
sputum collection
methods, etc.
Footnote v. Extra visits will be required for participants meeting 
certain grading thresholds for changes in QTcF. All ECGs will be 
performed in triplicate (3 ECGs within 5 minutes) and must be of
good quality (stable baseline, free of interference and artefact). The
ECG machine dedicated for this study must be used. All tracings will
be transmitted for blinded central analysis. ECG at 2-4 hours post-
dose of BDQ and CAM will be obtained at Week 2, Week 12, Week
24 and Week 48. ECG at pre-dose of BDQ and CAM (0 hours) will
be obtained at Day 1, Week 4, Week 6, Week 8, Week 16 and Week
32. Those ECG should be performed within 20 minutes prior to PK
blood sampling at every time point whenever possible. ECG will be
performed before blood sampling at the other visit where time points
of ECG measurement are not specified.
Clarification of
target drugs
2 Introduction 
In South Korea, "KOREAN GUIDELINE FOR TUBERCULOSIS 
4th EDITION" is published in 2020,50 and in Taiwan, "Consensus 
Statement of Nontuberculous Mycobacterial Lung Disease in 
Taiwan" is published in 2020.51 Both diagnostic criteria for NTM-LD 
and chemotherapy for MAC-LD in both countries are in accordance 
with an official ATS/IDSA statement,14 and chemotherapy mainly 
with 3 drugs consisted of macrolide (CAM or AZM), rifamycin (RFP 
or RBT), and EB, is recommended as the standard therapy.
Addition current
status of the
diagnostic criteria
and chemotherapy
for MAC-LD in
South Korea and
Taiwan
2.1 Study Rationale 
The diagnostic criteria and chemotherapy for MAC-LD in the world 
are in accordance with an official ATS/IDSA statement,14 and there is 
no difference in the diagnostic criteria. For chemotherapy, regimen 
consisting of 3 drugs such as macrolide (CAM or AZM), rifamycin 
(RFP or RBT), and EB is recommended as SOC. Although there are
some differences in the dosage and administration of drugs among
countries, it is not a major factor that causes differences in the efficacy.
Addition the
rationale on the
change to multi-
country study
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4
Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
Therefore, it may be considered that there is no major regional
difference in the therapeutic outcome for MAC-LD.
In April 2020, a post-phase II study consultation was held with the
Pharmaceuticals and Medical Devices Agency (PMDA), and the
study was started as a Japan study. However, in view of the severe
circumstance for the progress of the study due to the repeated
outbreaks of COVID-19 etc., additional PMDA consultation was held
in November 2022. Based on the advice from PMDA, the study
design is changed to conduct as a multi-country clinical study
includin  g the investigational sites in South Korea and Taiwan.
2 Introduction  
2.2 Background 
2.2.1 Comparator/ 
Combination 
Therapy 
2.3 Benefit-risk 
Assessment 
4.1 Overall Design 
• For the most comprehensive nonclinical and clinical information 
regarding BDQ, refer to the latest version of the Investigator’s 
Brochure (IB)40 addendum, and Japanese local package insert of 
SIRTURO (BDQ). 
• For the most comprehensive nonclinical and clinical information 
regarding BDQ, refer to the latest version of the IB,40 addendum,
and the Japanese local package insert to support the use of BDQ
for the chemotherapy for NTM LD.
• Rifampicin RFP and RBT have been approved for TB and NTM-
LD including MAC-LD or recommended for use in local
guidelines in Japan, South Korea and Taiwan.41, 50, 51
• Clarithromycin CAM is one of the macrolide antibiotics and
approved for broader infectious disease including MAC infection
or recommended for use in local guidelines in Japan, South
Korea and Taiwan.41, 50, 51
• Ethambutol EB has been approved for TB and NTM including
MAC or recommended for use in local guidelines in Japan, South
Korea and Taiwan.41, 50, 51
• For further information regarding above drugs, refer to each
Japanese local package insert.
• More detailed information about the known and expected benefits
and risks of BDQ may be found in the IB,40 addendum, and
Japanese local package insert of SIRTURO (BDQ).
• Upon completion of the 60-week study intervention period, the
study is completed, but the participant may continue SOC of
Japanese local guidelines or medical practice at each study site
for at least 1 year after culture conversion at the discretion of the
investigators.
Revision in
association with
the change to
multi-country
study
4.2 Scientific 
Rationale for Study 
Design 
• The South Korean and Taiwanese guidelines recommend a 3-drug 
regimen consisting of macrolide (CAM or AZM), RFP or RBT, 
and EB as the SOC. 50, 51 Therefore, this3-drug regimen, 
consisting of CAM as macrolide  is selected as control arm. 
• The Japanese local guidelines for MAC-LD treatment in Japan, 
South Korea ,Taiwan and an Official ATS/IDSA statement
currently recommend treating until patients have been on SOC
for 1 year after culture conversion, but there is no evidence to
support this treatment duration.41, 50, 51, 14
• Upon completion of the 60-week study intervention period, the
study is completed, but the participant may continue SOC of
Japanese local guidelines in Japan, South Korea and Taiwan or
medical practice at each study site for least 1 year after culture
conversion at the discretion of the investigators after study
completion.
Addition in
association with
the change to
multi-country
study
4.4 End of Study 
Definition 
Following completion of the study, the participant may continue the
SOC per Japanese local guidelines or medical practice at each study
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
site for at least 1 year after culture conversion, at the discretion of the
investigator.
4.2 Scientific 
Rationale for Study 
Design 
5.1 Inclusion 
Criteria 
• The present study will enroll patients with treatment-refractory 
MAC-LD defined as participants who are sputum culture positive 
for MAC despite at least 6 months and no more than 36 months 
of MAC-LD treatment (at least 2 antibiotics for MAC, including 
a macrolide), that is either ongoing or has stopped within the last 
12 months. 
• 5.1 Criterion modified per Amendment 8. 
5.2 Has at least 2 positive sputum cultures of MAC (sputum 
cultures to be taken at least 4 weeks apart): 
· one obtained within 12 months prior to screening, which was
documented while being treated for MAC-LD for a total of at
least 6 months and no longer than 36 months.
· one at screening (by central microbiology laboratory).
• 6.1 Criterion modified per Amendment 8.
6.2 Received at least 6 months and no more than 36 months of
consecutive MAC-LD treatment (at least 2 antibiotics for MAC,
including a macrolide), that is either ongoing or has stopped within
12 months prior to screening.
Note: Participants must be compliant with medication intake for
at least 75% of the total doses for prescribed SOC (including
intermittent regimen) recommended by local guidelines a given
treatment.
Elimination of
upper limit of
prior treatment
period in
Inclusion
Criterion 5, and
modification of
related
descriptions
5.2 Exclusion 
Criteria 
5. Criterion modified per Amendment 8. 
5.1 Treatment already includes an injectable/inhaled aminoglycoside 
within 3 months prior to screening or the investigator deems the 
participant to be a candidate for an injectable/inhaled aminoglycoside
at durin  g screening period or at Da y 1.
Clarified language
regarding use of
aminoglycosides
6. Criterion modified per Amendment 8. 
6.1 Has a history of documented macrolide-resistant MAC strain 
within 24 months prior to screening or at screening. For CAM, MIC of 
≥32 μg/mL indicates resistance according to the Clinical and 
Laboratory Standards Institute [CLSI] M24 guidelines.9,46,47
Note: In case a subject has ≥2 documented DST results within 24
months prior to screening, the subject is eligible if the latest result is
susceptible and DST at screenin  g is confirmed susceptible.
Addition of note
on handling of
multiple records
of DST
15. Criterion modified per Amendment 8. 
15.1 Has contraindications to the use of CAM, EB, RFP or RBT per 
Japanese local prescribing information in Japan, South Korea or 
Taiwan. 
Revision in
association with
the change to
multi-country
study 
5.4 Screening 
Failures 
Individuals who do not meet the criteria for participation in this study 
(screen failure) may be rescreened, including candidates whose 
microbiological testing at screening is not eligible, such as culture
negative, resistance to CAM, etc.
Clarification of
rescreening rules
6.1 Study 
Interventions 
Administered 
Rifamycin (RFP or RBT) will be taken according to the investigator's 
instructions as per Japanese package insert. Combination drugs will 
not be provided by the sponsor and marketed product at study sites 
should be administered. Participants will be instructed to take their 
assigned dose of the study intervention or comparator and 
combination drugs, per Table 2. 
Additions to Table 2 (dosage and administration, etc. of study 
interventions in South Korea and Taiwan) are omitted. 
Revision in
association with
the change to
multi-country
study, and
addition of dosage
and
administration etc.
of study
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6
Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
interventions in
South Korea and
Taiwan
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
In order to maintain the blind, the investigator should not perform 
microbiological tests for acid-fast bacillus at the study site after Day 
1 until completion of the assessments other than microbiological 
assessments at the Week 24 except in emergency situations related to 
subject safet y or chemotherapy. 
Clarification of
microbiological
testing rules
during the blinded
period
6.7 Treatment of 
Overdose 
Refer to the Japanese local package insert of the comparator 
rifamycin (RFP or RBT) for advice on treatment of overdose. 
Revision in
association with
the change to
multi-country
study 
6.8 Concomitant 
Therapy 
• Antibacterial drugs, such as fluoroquinolones, linezolid that may 
be effective for MAC-LD other than the specified concomitant 
medications are prohibited during the study treatment period. 
• clofazimine (increased QT prolongation is reported in co- 
administration with BDQ) 
Addition of
prohibition of
antibacterial drugs
that may be
effective for
MAC-LD, and
clofazimine
8.1.2 Clinical 
Assessments in 
MAC-LD 
This is to calculate the percentage of participants who have changed to 
an individualized treatment regimen in accordance with SOC of 
Japanese guidelines or medical practice at each study site as defined 
by SOC of local guidelines or protocol (Section 6.8.1) in both groups 
and participants who have switched to BDQ-containing regimen in 
Group B. 
Revision in
association with
the change to
multi-country
study and
modification
based on
consistency of
description
8.2.3 
Electrocardiograms 
• If triplicate ECGs confirm a mean QTcF ≥500 ms or an increase 
from baseline of >60 ms, the following will be done: 
• if after 2 weeks mean QTcF is ≥500 ms or increase from baseline 
of >60 ms, the investigator must permanently stop the study 
intervention, and continue weekly triplicate ECGs until
resolution.
Weekly triplicate ECG monitoring for participants who have
recovered from QTcF ≥500 ms or increase from baseline of >60 ms
may be discontinued if over 3 consecutive weeks the triplicate ECGs
demonstrate a mean QTcF <500 ms or one time increase of ≤60 ms.
Participants who meet these criteria can be switched to less frequent
ECG monitoring per Section 1.3, Schedule of Activities (SoA). If
mean QTcF <500 ms or increase of ≤60 ms is not demonstrated, then
weekly triplicate ECGs will be continued at least until the end of the
last dose of BDQ plus 4 weeks due to the long half-life of BDQ. At
that point, if mean QTcF <500 ms or increase of ≤60 ms is
demonstrated, weekly triplicate ECGs can be switched to less
frequent ECG monitoring per Section 1.3, Schedule of Activities
(SoA). Otherwise if mean QTcF <500 ms or increase of ≤60 ms is
not demonstrated, the investigator judges whether weekly triplicate
ECGs will be continued or be switched to less frequent ECG
monitorin  g per Section 1.3, Schedule of Activities (SoA).
Clarification of
response to
increase of
>60 ms
1.1 Synopsis 
9.4.3 Primary 
Endpoint 
The Cochran-Mantel-Haenszel chi square test stratified by region 
(Japan, non-Japan) at the 5% 2-sided significance level will be used 
to compare sputum culture conversion rate in MGIT at Week 24. 
Reconsideration
of the statistical
analysis plan in
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
7
Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
9.4.4 Secondary 
Endpoints 
• The percentage of participants with sputum culture conversion 
(defined as 3 consecutive negative sputum cultures taken at least 
25 days apart) in MGIT and 7H10 or 7H11 agar media will be 
calculated after Week 4. The percentage of participants who 
achieved sputum culture conversion at Week 24 and completed
48-week BDQ-containing regimen and achieved sputum culture
conversion at Week 60 in Group A will be compared with the
percentage of participants who completed 60-week SOC regimen
and achieved sputum culture conversion at Week 60 in Group B
using the Cochran-Mantel-Haenszel test stratified by region
(Japan, non-Japan) chi square test (the Fisher's exact test will be
used in case of rare events).
• The percentage of participants with sputum culture negativity in
MGIT and 7H10 or 7H11 agar media will be calculated at each
visit after Week 2, respectively. A generalized linear model
including treatment, region (Japan, non-Japan), time, and
treatment-by-time interaction as fixed effects will be applied for
the number of negative culture participants and the number of all
participants at each timepoint and comparison between treatment
groups will be performed using the appropriate contrast for the
percentage of negative culture participants at Week 24.
• Kaplan-Meier estimates will be generated for the time to sputum
culture conversion up to Week 24 and Week 48. The difference
between the treatment groups will be compared using the log-
rank test stratified by region (Japan, non-Japan) for the time to
sputum culture conversion up to Week 24.
association with
the change to
multi-country
study
Throughout the 
protocol 
Minor changes and clarifications were made. 
Minor errors and
unclear
descriptions were
noted.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
8
Status: Approved, Date: 8 December 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................. 2
TABLE OF CONTENTS .......................................................................................................................... 8
LIST OF IN-TEXT TABLES AND FIGURES .......................................................................................... 10
1. 
PROTOCOL SUMMARY .............................................................................................................. 11
1.1. 
Synopsis ................................................................................................................................... 11
1.2. 
Schema .................................................................................................................................... 16
1.3. 
Schedule of Activities (SoA) ...................................................................................................... 17
1.3.1. 
Schedule of Activities (SoA) in the Optional Cohort ................................................................ 19
2. 
INTRODUCTION .......................................................................................................................... 22
2.1. 
Study Rationale......................................................................................................................... 24
2.2. 
Background............................................................................................................................... 26
2.2.1. 
Comparator/Combination Therapy ......................................................................................... 30
2.3. 
Benefit-risk Assessment ............................................................................................................ 30
2.3.1. 
Risks for Study Participation .................................................................................................. 31
2.3.2. 
Benefits for Study Participation .............................................................................................. 32
2.3.3. 
Benefit-risk Assessment for Study Participation ...................................................................... 32
3. 
OBJECTIVES AND ENDPOINTS ................................................................................................. 33
4. 
STUDY DESIGN ........................................................................................................................... 36
4.1. 
Overall Design .......................................................................................................................... 36
4.2. 
Scientific Rationale for Study Design ......................................................................................... 38
4.2.1. 
Study-specific Ethical Design Considerations ......................................................................... 40
4.3. 
Justification for Dose ................................................................................................................. 41
4.4. 
End of Study Definition .............................................................................................................. 43
5. 
STUDY POPULATION ................................................................................................................. 43
5.1. 
Inclusion Criteria ....................................................................................................................... 43
5.2. 
Exclusion Criteria ...................................................................................................................... 45
5.3. 
Lifestyle Considerations ............................................................................................................ 48
5.3.1. 
Activity ................................................................................................................................... 48
5.4. 
Screen Failures ......................................................................................................................... 49
5.5. 
Criteria for Temporarily Delaying Enrollment/Randomization/Administration of Study
Intervention ............................................................................................................................... 49
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY ......................................................... 49
6.1. 
Study Interventions Administered .............................................................................................. 49
6.2. 
Preparation/Handling/Storage/Accountability ............................................................................. 50
6.3. 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 51
6.4. 
Study Intervention Compliance .................................................................................................. 52
6.5. 
Dose Modification ..................................................................................................................... 53
6.6. 
Continued Access to Study Intervention After the End of the Study............................................ 54
6.7. 
Treatment of Overdose ............................................................................................................. 54
6.8. 
Concomitant Therapy ................................................................................................................ 54
6.8.1. 
Individualized Treatment Regimen ......................................................................................... 57
6.8.2. 
Optional Cohort ..................................................................................................................... 58
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ........................................................................................... 58
7.1. 
Discontinuation of Study Intervention ........................................................................................ 58
7.1.1. 
Liver Chemistry Stopping Criteria ........................................................................................... 59
7.1.2. 
QTc Stopping Criteria ............................................................................................................ 59
7.1.3. 
Temporary Discontinuation .................................................................................................... 59
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
7.1.4. 
Rechallenge .......................................................................................................................... 59
7.2. 
Participant Discontinuation/Withdrawal From the Study ............................................................. 59
7.2.1. 
Withdrawal From the Use of Research Samples .................................................................... 60
7.3. 
Lost to Follow-up ....................................................................................................................... 60
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................ 61
8.1. 
Efficacy Assessments ............................................................................................................... 63
8.1.1. 
Microbiology Assessments (MAC-LD Treatment Outcome) .................................................... 63
8.1.2. 
Clinical Assessments in MAC-LD ........................................................................................... 63
8.2. 
Safety Assessments .................................................................................................................. 65
8.2.1. 
Physical Examinations ........................................................................................................... 65
8.2.2. 
Vital Signs ............................................................................................................................. 65
8.2.3. 
Electrocardiograms ................................................................................................................ 66
8.2.4. 
Clinical Safety Laboratory Assessments ................................................................................. 67
8.2.5. 
Pregnancy Testing ................................................................................................................. 67
8.2.6. 
Management of Common Expected Toxicities ........................................................................ 67
8.2.7. 
Other Safety Evaluations ....................................................................................................... 70
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting...................................... 70
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information ............................................................................................................................ 70
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ......................................... 71
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ..................................................... 71
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ........................................... 71
8.3.5. 
Pregnancy ............................................................................................................................. 71
8.3.6. 
Disease-related Events and Disease-related Outcomes not Qualifying as Adverse
Events or Serious Adverse Events ......................................................................................... 71
8.3.7. 
Adverse Events of Special Interest ......................................................................................... 72
8.4. 
Pharmacokinetics ...................................................................................................................... 72
8.4.1. 
Evaluations ............................................................................................................................ 72
8.4.2. 
Analytical Procedures ............................................................................................................ 72
8.4.3. 
Pharmacokinetic Parameters and Evaluations........................................................................ 73
8.5. 
Genetics and Pharmacogenomics ............................................................................................. 73
8.6. 
Biomarkers ............................................................................................................................... 73
8.7. 
Immunogenicity Assessments ................................................................................................... 73
8.8. 
Health Economics or Medical Resource Utilization and Health Economics................................. 73
9. 
STATISTICAL CONSIDERATIONS .............................................................................................. 73
9.1. 
Statistical Hypothesis ................................................................................................................ 73
9.2. 
Sample Size Determination ....................................................................................................... 74
9.3. 
Populations for Analysis Sets .................................................................................................... 74
9.4. 
Statistical Analyses ................................................................................................................... 74
9.4.1. 
General Considerations ......................................................................................................... 74
9.4.2. 
Primary Estimand .................................................................................................................. 74
9.4.3. 
Primary Endpoint ................................................................................................................... 75
9.4.4. 
Secondary Endpoints ............................................................................................................. 75
9.4.5. 
Tertiary/Exploratory Endpoint ................................................................................................. 76
9.4.6. 
Safety Analyses ..................................................................................................................... 76
9.4.7. 
Other Analyses ...................................................................................................................... 78
9.5. 
Interim Analysis......................................................................................................................... 79
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................... 80
10.1. 
Appendix 1: Abbreviations ......................................................................................................... 80
10.2. 
Appendix 2: Clinical Laboratory Tests........................................................................................ 82
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations ....................................... 84
10.3.1. 
Regulatory and Ethical Considerations ................................................................................... 84
10.3.2. 
Financial Disclosure ............................................................................................................... 87
10.3.3. 
Informed Consent Process ..................................................................................................... 87
10.3.4. 
Data Protection ...................................................................................................................... 88
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
10
Status: Approved, Date: 8 December 2022
10.3.5. 
Long-term Retention of Samples for Additional Future Research ............................................ 88
10.3.6. 
Committees Structure ............................................................................................................ 88
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data .......................................................... 89
10.3.8. 
Data Quality Assurance ......................................................................................................... 90
10.3.9. 
Case Report Form Completion ............................................................................................... 90
10.3.10. Source Documents ................................................................................................................ 91
10.3.11. Monitoring.............................................................................................................................. 92
10.3.12. On-site Audits ........................................................................................................................ 93
10.3.13. Record Retention ................................................................................................................... 93
10.3.14. Study and Site Start and Closure ........................................................................................... 93
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting ........................................................................................................................... 95
10.4.1. 
Adverse Event Definitions And Classifications ........................................................................ 95
10.4.2. 
Attribution Definitions ............................................................................................................. 96
10.4.3. 
Severity Criteria ..................................................................................................................... 96
10.4.4. 
Special Reporting Situations .................................................................................................. 97
10.4.5. 
Procedures ............................................................................................................................ 97
10.4.6. 
Product Quality Complaint Handling ....................................................................................... 99
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality ........................................... 99
10.5. 
Appendix 5: Contraceptive Guidance ...................................................................................... 100
10.6. 
Appendix 6: Patient-reporting Questionnaires .......................................................................... 102
10.7. 
Appendix 7: A Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity
Table (November 2007) .......................................................................................................... 115
10.8. 
Appendix 8: Protocol Amendment History................................................................................ 121
11. REFERENCES ........................................................................................................................... 144
INVESTIGATOR AGREEMENT .......................................................................................................... 148
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
The Ratios of Mean BDQ Exposures From Simulations of the Dose and
Administration of BDQ for the Patients With MDR-TB (MDR-TB regimen) and the
Dose and Administration of BDQ for the Patients With MAC-LD in This Study (MAC-
LD regimen) ......................................................................................................................... 42
Table 2: 
Dosage and Administration Table for Study Interventions and Combination Drugs ................ 50
Table 3: 
BDQ Missed Dose and Interruption Instructions ................................................................... 53
Table 4: 
Volume of Blood to be Collected From Each Participant ....................................................... 62
FIGURES
Figure 1: Schematic Overview of the Study ......................................................................................... 16
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
11
Status: Approved, Date: 8 December 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2/3, Multicenter, Randomized, Open-label, Active-controlled Study to Evaluate the Efficacy and
Safety of Bedaquiline Administered as Part of a Treatment Regimen With Clarithromycin and Ethambutol
in Adult Patients With Treatment-refractory Mycobacterium Avium Complex-lung Disease (MAC-LD)
Short Title: Bedaquiline (BDQ)/CAM/EB Study in Treatment-refractory MAC-LD patients.
(Bedaquiline) TMC207 is a diarylquinoline derivative and a novel antimycobacterial agent, with in vitro
activity against a wide range of Mycobacterium (M) species, including Mycobacterium tuberculosis
(M. tuberculosis), M. avium complex (MAC), M. kansasii, and M. abscessus. Infection with the latter
3 nontuberculous organisms can result in nontuberculous mycobacterial (NTM) lung disease (LD), which
is distinct from the pulmonary infection caused by M. tuberculosis, for which BDQ is currently indicated.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary 
 
Microbiological assessment in MGIT: To evaluate the
efficacy of BDQ compared with rifamycin when
administered as part of a treatment regimen with
CAM and EB in adult participants with treatment-
refractory MAC-LD at Week 24.
 
Percentage of participants with
sputum culture conversion (defined
as 3 consecutive negative sputum
cultures taken at least 25 days apart)
in MGIT at Week 24.
Secondary
 
Microbiological assessment in 7H10 or 7H11 agar
media: To evaluate the efficacy of BDQ compared
with rifamycin when administered as part of a
treatment regimen with CAM and EB in adult
participants with treatment-refractory MAC-LD at
Week 24.
 
Percentage of participants with
sputum culture conversion (defined
as 3 consecutive negative sputum
cultures taken at least 25 days apart)
in 7H10 or 7H11 agar media at
Week 24.
 
Clinical assessment: To evaluate the efficacy of BDQ
compared with rifamycin when administered as part
of a treatment regimen with CAM and EB in adult
participants with treatment-refractory MAC-LD at
Week 24.
 
Change from baseline in patient-
reported health status on total score
of SGRQ at Week 24.
 
Microbiological assessment: To evaluate the efficacy
of BDQ compared with rifamycin when administered
as part of a treatment regimen with CAM and EB in
adult participants with treatment-refractory MAC-LD
up to Week 48.
 
Percentage of participants with
sputum culture conversion (defined
as 3 consecutive negative sputum
cultures taken at least 25 days apart)
in MGIT and 7H10 or 7H11 agar
media at Week 48.
 
Percentage of participants with
sputum culture negativity in MGIT
and 7H10 or 7H11 agar media,
respectively, at each visit after
Week 2 per Schedule of Activities.
 
Time to sputum culture conversion
(defined as 3 consecutive negative
sputum cultures taken at least
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
12
Status: Approved, Date: 8 December 2022
Objectives 
Endpoints
25 days apart) in MGIT up to
Week 48.
 
Time to positivity in MGIT up to
Week 48.
 
Clinical assessment: To evaluate the efficacy of BDQ
compared with rifamycin when administered as part
of a treatment regimen with CAM and EB in adult
participants with treatment-refractory MAC-LD.
 
Change from baseline in
patient-reported health status on
total score of SGRQ at Weeks 48
and 60.
 
Change from baseline in lung
function parameters at Weeks 24,
48, and 60.
 
Percentage of participants who
undergo a change in their MAC-LD
treatment regimen by Week 24, by
Week 48 (Group A) and by
Week 60 (Group B).
 
Microbiological assessment: To evaluate the efficacy
of BDQ compared with rifamycin when administered
as part of a treatment regimen with CAM and EB in
adult participants with treatment-refractory MAC-LD
at Week 60.
 
Percentage of participants with
sputum culture conversion (defined
as 3 consecutive negative sputum
cultures taken at least 25 days apart)
in MGIT and 7H10 or 7H11 agar
media at Week 60.
 
To evaluate the safety and tolerability of BDQ
compared with rifamycin when administered as part
of a treatment regimen with CAM and EB in adult
participants with treatment-refractory MAC-LD.
 
Safety and tolerability based on
assessment of AEs, clinical
laboratory assessments, 12-lead
ECG, vital signs, physical
examination, visual examination,
and audiology up to Week 60.
 
To evaluate the PK of BDQ (and metabolite M2), and
CAM (and metabolite 4-OH-CAM [optional]).
 
PK exposures of BDQ (and
metabolite M2 [optional]) at Day 1,
Weeks 2, 8, 12, 24, and 48, and
CAM (and metabolite 4-OH-CAM
[optional]) at Day 1, Weeks 2, 8, 12,
and 24.
Exploratory
 
Clinical assessment: To evaluate the efficacy of BDQ
compared with rifamycin when administered as part
of a treatment regimen with CAM and EB in adult
participants with treatment refractory MAC - LD
assessed by QOL-B NTM module.
 
Change from baseline in patient
reported health status on score of
QOL-B NTM module at Weeks 24,
48, and 60.
 
To evaluate the occurrence of culture reversion
(relapse or reinfection) in participants who previously
had sputum conversion.
 
Rate of culture reversion (relapse or
reinfection) up to Week 60.
 
Microbiological assessment: To evaluate the efficacy
of BDQ compared with rifamycin when administered
 
Percentage of participants having
MAC isolates with acquired
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
13
Status: Approved, Date: 8 December 2022
Objectives 
Endpoints
as part of a treatment regimen with CAM and EB in 
adult participants with treatment-refractory MAC-LD. 
resistance to CAM detected by a
phenotypic method up to Week 60.
 
Percentage of participants having
MAC isolates with increased MICs
to BDQ (at least 4 fold increase) up
to Week 60.
 
To evaluate PK/PD relationships for safety and 
efficacy of BDQ (and CAM [optional]). 
 
Exposure, and safety and efficacy
(PK/PD) relationship assessments of
BDQ (and CAM [optional]) by
Week 24.
 
To determine the mechanisms of resistance in 
participants’ MAC isolates with increased BDQ MICs 
by sequencing both atpE, mmpT5 and other genes (if 
available).
 
Evolution of the atpE, mmpT5 and
other gene sequences up to
Week 60.
 
Clinical assessment: To evaluate the efficacy of BDQ 
compared with rifamycin when administered as part 
of a treatment regimen with CAM and EB  for 
participants who achieved sputum culture conversion 
(at Weeks 24, 48, and 60).
 
Change from baseline in
patient-reported health status on
total score of SGRQ at Weeks 24,
48, and 60.
 
Change from baseline in patient
reported health status on score of
QOL-B NTM module at Weeks 24,
48, and 60.
 
Change from baseline in lung
function parameters at Weeks 24,
48, and 60.
 
Change from baseline in chest CT
findings at Weeks 24, 48, and 60.
Note:
1) Although not included in the above objectives and endpoints, the efficacy and safety at OPW24 (Week 24 of
study intervention treatment) and OPW48 (the last dose of study intervention) in the optional cohort will be
evaluated as additional analysis in the similar manner with efficacy and safety at Week 24 and Week 48.
2) Group A= Treatment group consisting of BDQ + CAM + EB
3) Group B= Treatment group consisting of rifamycin (RFP or RBT) + CAM + EB
Key: AEs=adverse event; atpE=ATP synthase subunit c; BDQ=bedaquiline; CAM=clarithromycin; CT=computed
tomography; EB=ethambutol; ECG=electrocardiogram; MAC=Mycobacterium avium complex; MAC-LD=MAC
lung disease; MGIT=mycobacterium growth indicator tube; MIC=minimal inhibitory concentration;
mmpT5=mycobacterial membrane protein transporter-5; NTM=nontuberculous mycobacterial; OPW=week in
optional cohort; PD=pharmacodynamics; PK=pharmacokinetics; QOL-B=Quality of Life-Bronchiectasis;
RBT=rifabutin; RFP=rifampicin; SoA=schedule of activities; SGRQ= St. George’s Respiratory Questionnaire.
Hypothesis
The hypothesis of this study is that BDQ -containing regimen is superior to rifamycin-containing regimen
and increases the proportion of participants with sputum culture conversion in mycobacteria growth
indicator tube (MGIT) at Week 24 as compared to rifamycin-containing regimen.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
14
Status: Approved, Date: 8 December 2022
OVERALL DESIGN
This is a multicenter, randomized, open-label, active-controlled study to evaluate efficacy and safety of
BDQ compared with rifamycin administered as part of a treatment regimen with clarithromycin (CAM)
and ethambutol (EB) for 48 weeks in adult participants with treatment -refractory MAC-LD. The study will
consist of a screening period of 70 days (10 weeks) (including rifamycin washout period of 14 days for
participants to whom this is applicable), an open-label treatment period of 48 weeks (baseline visit [Day 1]
to Week 48) in Group A or 60 weeks (Day 1 to Week 60) in Group B, and follow-up period of 12 weeks in
Group A. Participants will return for study visits biweekly in the first 12 weeks, and then every 4 weeks
until Week 60. In addition, this study provides an option to receive BDQ -containing regimen for non-
converters in Group B based on the result of microbiological test up to Week 24 as the optional cohort.
OPW-2 in optional cohort will be initiation of 2-week washout period in optional cohort.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study.
A futility analysis will be implemented to evaluate early the benefit/risk balance by assessing safety and
efficacy in the first 60 participants (about 30 participants from both groups) who reach the Week-24 time
point or discontinued earlier or switched to individualized treatment regimen. This futility analysis is
nonbinding and the IDMC will recommend the continuation or termination of the study based on the whole
package of information, which also includes other efficacy and safety assessments. Sponsor will decide the
continuation or termination of the study based on the recommendation by IDMC.
NUMBER OF PARTICIPANTS
A target of 124 participants with treatment-refractory MAC-LD will be enrolled in this study.
TREATMENT GROUPS AND DURATION
Participants who meet all the eligibility criteria will be randomized in a 1:1 (Treatment Group A
[Group A]: Treatment Group B [Group B]) ratio stratified by country:
 
Group A: BDQ + CAM + EB
 
Group B: rifamycin (rifampicin [RFP] or rifabutin [RBT]) + CAM + EB
EFFICACY EVALUATIONS
Microbiology assessments (MAC-LD Treatment Outcome), clinical assessments in MAC-LD, percentage
of participants who undergo a change in their MAC-LD treatment regimen, and a lung function assessment
using a spirometry test, will be performed in this study.
PHARMACOKINETIC EVALUATIONS
Pharmacokinetic (PK) assessments for BDQ (and its active metabolite M2 [optional]) will be based on
sparse sampling and will be performed using a Bayesian PK approach. A validated population PK model
for BDQ and M2 has been developed that allows estimation of the main PK parameters (maximum plasma
concentration [Cmax], area under plasma concentration time curve [AUC], and minimum plasma
concentration between 0 hour and the dosing interval τ [Ctrough]) based on sparse samples drawn on various
study visits. The plasma concentration of CAM and its active metabolite 4-OH CAM will be determined
predose and around peak via predose and postdose blood sampling.
SAFETY EVALUATIONS
Safety assessments will include all adverse events (AEs), physical examination, measurement of body
weight, visual examination and audiology, vital signs, electrocardiograms (ECGs), and clinical laboratory
tests.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
15
Status: Approved, Date: 8 December 2022
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A sample size of
124 participants (62 in Group A: the BDQ containing regimen, 62 in Group B: the rifamycin-containing
regimen) will have a power of about 80% to show superiority for a 20% difference in proportion of
participants having sputum conversion at Week 24 based on a chi-square test (at the 5% 2-sided significance
level) on the intent-to-treat (ITT) population.
All efficacy and safety data will be summarized by treatment groups (Groups A and B). For the Group B,
data from optional cohort will be analyzed separately.
The Cochran-Mantel-Haenszel test stratified by region (Japan, non-Japan) at the 5% 2-sided significance
level will be used to compare sputum culture conversion rate in MGIT at Week 24. A generalized linear
model including treatment, region (Japan, non-Japan), time, and treatment-by-time interaction as fixed
effects will be applied for the number of sputum culture negative participants and the number of all
participants at each timepoint and comparison between treatment groups will be performed using the
appropriate contrast for the percentage of negative participants at Week 24. Kaplan Meier estimates will be
generated for the time to sputum culture conversion up to Week 24 and Week 48. The changes from baseline
in total score of St. George’s Respiratory Questionnaire (SGRQ) and respective domain scores will be
summarized descriptively at Weeks 24, 48, and 60.
For each AE, the percentage of participants who experience at least 1 occurrence of the given event will be
summarized by treatment group. Descriptive statistics will be calculated for each laboratory analyte at
baseline and for observed values and changes from baseline at each scheduled time point. Changes from
baseline results will be presented in pre- versus postintervention cross-tabulations (with classes for below,
within, and above normal ranges). Frequency tabulations of the laboratory abnormalities will be made. The
effects on cardiovascular variables will be evaluated by means of descriptive statistics and frequency
tabulations. Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be
calculated at baseline and for observed values and changes from baseline at each scheduled time point.
Frequency tabulations of the abnormalities will be made. Vital signs including temperature (axillary), heart
rate, respiratory rate, oxygen saturation, and blood pressure (systolic and diastolic) values and their changes
from baseline, including percentage of participants with values beyond clinically important limits will be
summarized. Physical examination findings, visual acuity, color discrimination, visual field, fundoscopy,
and audiometry data will also be descriptively presented.
The pharmacokinetic/pharmacodynamic (PK/PD) analyses may be performed at earlier time points as
necessary to support efficacy and safety findings. If there is any visual trend in graphical analysis, suitable
models will be applied to describe the PK/PD relationships. For each intervention group, descriptive
statistics, including arithmetic mean, SD, coefficient of variation, median, minimum, and maximum will be
calculated for all individual derived PK parameters including exposure information of BDQ and M2 (if
applicable) for Group A, and will be calculated for predose and 2 to 4 hours postdose plasma concentrations
on Day 1, Weeks 2, 8, 12, 24, and 48 of BDQ, and CAM and 4-OH CAM for both Groups A and B.
The Statistical Analysis Plan (SAP) will describe the planned interim (futility) analyses in detail. Details of
the futility analysis (including classification of lack of efficacy) and criterion will be included in the IDMC
charter and SAP.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
16
Status: Approved, Date: 8 December 2022
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
Key: BDQ=bedaquiline; CAM=clarithromycin; CT=computed tomography; EB=ethambutol; IDMC=Independent
Data Monitoring Committee; MAC=Mycobacterium avium complex; MAC-LD=MAC lung disease;
max=maximum; OPW=week in optional cohort; RBT=rifabutin; RFP= rifampicin; W=Week; W/O=washout
Note:
1) OPW-2 - Initiation of 2-week washout period in optional cohort
2) OPD1 - Date of starting dose in optional cohort
3) OPW24 - Week 24 in optional cohort
4) OPW48 - Week 48 in optional cohort
a Prior to Week 24, participants who are judged to have difficulty continuing their designated treatment regimen
due to failure to respond (based on non-conversion and clinical worsening) or the occurrence of AE will be
considered treatment failures and can switch to an individualized treatment regimen (see Section 6.8.1), at the
discretion of the investigator in consultation with IDMC.
b After Week 24 assessment, all participants who are judged to have difficulty continuing their designated
treatment regimen due to failure to respond (based on non-conversion and clinical worsening) or the occurrence
of AE will be considered treatment failures and will be given the option to switch to an individualized treatment
regimen (see Section 6.8.1) at the discretion of the investigator.
c After completion of 48-week treatment, converters who achieved culture conversion at Week 48 in the Group A
will be followed for 12 weeks as drug-free period. Participants who failed to achieve sputum culture conversion
(non-converters) by Week 48 and continue chemotherapy will be discontinued from the study and switched to
another treatment regimen.
d At Week 24, non-converters in the Group B, will be considered to switch to BDQ-containing regimen at the
discretion of the investigators. When the investigator changes to BDQ-containing regimen, 2-week washout of
used rifamycin is required before initiation of BDQ-containing regimen.
e All participants who are judged to have difficulty continuing their BDQ-containing regimen due to failure to
respond (based on non-conversion and clinical worsening) or the occurrence of AE will be considered treatment
failures and will be given the option to switch to an individualized treatment regimen (see Section 6.8.1) at the
discretion of the investigators.
NCT04630145

NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
18
Status: Approved, Date: 8 December 2022
 
Screening
a 
Investigation b
Follow-up (Group 
A)/ Investigation 
(Group B) 
Early
discon-
tinuation/
Switch to
ITR f
Day (D)/Week (W)
-W10 to
D0
Baseline 
D1 c 
W2 
W4 
W6 
W8 
W10 W12 W16d W20d W24d W28d W32d W36d W40d W44d W48d,e W52d W56d W60 d
Study day 
-70 to 0 
1 
15±2 29±2 43±2 57±2 71±2 85±2 113±3 141±3 169±3 197±4 225±4 253±4 281±4 309±4 337±4 365±4 393±4 421±4 before W60
Audiology, visual examinations y 
X 
 
Xee  
Xee 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
(X)
Fundoscopy  
 dd  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
(X)
Note: (X)=If available
Key: CAM=clarithromycin; CT=computed tomography; D=day; ECG=electrocardiogram; FSH=follicle-stimulating hormone; HIV= human immunodeficiency virus, ITR=Individualized treatment regimen;
MGIT=mycobacterium growth indicator tube; MIC= minimal inhibitory concentration; NTM=nontuberculous mycobacterial; PK=pharmacokinetics; QOL-B=Quality of Life-Bronchiectasis; SGRQ= St.
George’s Respiratory Questionnaire; SoA=schedule of activities; VNTR: variable number tandem repeat, W=week; WGS: whole genome sequencing; WOCBP: woman of childbearing potential.
NCT04630145

NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
20
Status: Approved, Date: 8 December 2022
a. Screening evaluations must be performed within 70 days (10 weeks) prior to baseline (Day 1). These 10 weeks include 14 days of rifamycin W/O for participants to whom it is applicable. If screening period
exceeds 10 weeks for reasons such as time required to obtain the result of microbiology assessment of screening, the screening period may be extended up to 15 weeks.
b. If required during the 48-week treatment period, participants can have a change in their treatment regimen, in which MAC-LD treatment may continue in accordance with standard of care or NTM treatment
guidelines. All decisions on treatment regimen change should be made based on clinical worsening supported by microbiology data by the investigator. Participants requiring a treatment regimen change will
be followed up for safety only, but all assessments should be performed according to the protocol.
c. Assessments planned on Day 1 except for blood sampling for PK which is performed after dosing must generally be performed prior to first dose of study intervention.
d. Every 4-week visit must be scheduled after more than 25 days from the previous visit.
e. The participants who have been treated with BDQ-containing regimen (Group A) through Week 48 and culture converted, will transfer to the follow-up period. The participants who have been treated with
rifamycin-containing regimen (Group B) through Week 48 will continue to be treated up to Week 60.
f. 
Early discontinuation visit is to be scheduled within 7 days of the investigator’s discretion to discontinue treatment with study intervention  (including the day of discontinuation, other than withdrawal of
consent). Visit for switch to individualized treatment regimen is to be scheduled within 7 days after discontinuing the assigned treatment regimen (including the day of switch) and before the start of
individualized treatment regimen.
g. Must be signed before first study-related activity.
h. Investigators should ensure that all study enrollment criteria have been met at screening. If a participant’s clinical status changes (including any available laboratory results or receipt of additional medical
records) after screening but before the first dose of study intervention is given such that he or she no longer meets all eligibility criteria, then the participant should be excluded from participation in the study.
i. 
Medical and surgical history, including NTM exposure history, NTM treatment history, and MAC-LD.
j. 
β-hCG test will be performed only at screening and Day 1 whereas urine pregnancy test at timepoints described in SoA other than screening and Day 1.
k. FSH test is performed only for postmenopausal women.
l. 
After Week 48, only participants in Group B will continue to administer study intervention, and study intervention accountability will be continued up to Week 60.
m. Two sputum samples should be collected at each visit time point except for Week 2, 6, and 10. One should be collected in the early morning at home and the other sample(s) at the study site. If sputum
collection at home is impossible, 2 samples will be collected at the study site. If sputum can be produced more easily in the evening/night than in the early morning, it is acceptable to store the sample
obtained in the previous day of visit in a refrigerator, bring it to the study site, and submit it on the following day. Samples collected at home or the study site can be spontaneous, induced or aspirated. In
case 2 sputum sample collection is not feasible at Week 2, 6, and 10, either no sample or 1 sample collection is allowed. Sputum samples will be shipped to the central microbiology laboratory where all
cultures will be performed on solid and on liquid media. The same applies to sputum collections at OPW 2, 6 and 10 in the optional cohort. And in case a sputum sample is collected in routine clinical
practice before obtaining informed consent on the day of informed consent, it is acceptable to submit as a sputum sample for the study after obtaining the participant's consent and recorded.
n. Identification and speciation of MAC will be done by MALDI-TOF MS at screening, baseline, and postbaseline for all positive sputum culture(s)
o. BACTEC MGIT™ will be used for qualitative culturing in an automated mycobacterial detection system.
p. Drug susceptibility testing (DST) will be done on culture positive isolates at screening, baseline, and at Week 24. The testing will be done on the last culture positive isolates in case of participants with non-
conversion and recurrence (relapse/reinfection).  In addition, the testing will be done on positive isolates at early discontinuation (if available). In the optional cohort, DST will be done on the last culture
positive isolates in case of participants with non-conversion and recurrence (relapse/reinfection), as well as positive isolates at early discontinuation (if available).
q. In case of recurrence (relapse/reinfection) or in case of acquired resistance (at least 4-fold increased MIC) to BDQ is indicated by DST result, baseline and postbaseline isolates will be identified using WGS
or VNTR if necessary. If more than 1 postbaseline positive culture (isolate) showing resistant is available the last culture positive sample will be tested for VNTR and/or WGS in addition to the baseline
culture positive sample.
r. 
Lung function test on Day 1 will be acceptable within 1 week prior to Day 1.
s. Chest CT scans taken within 6 months prior to screening are acceptable.
t. 
Single sparse blood samples will be collected for measurement of plasma concentrations of BDQ (and M2 [optional]). These samples can be taken at any time after intake of BDQ on the day, but the date and
time of the second to last and the last administration of BDQ and CAM, respectively, and the date and time of blood draw must be recorded.
u. Two blood samples will be drawn: one just before intake of BDQ or first intake of CAM in the visit, and the second sample between 2 to 4 hours after the intake. The date and time of the last study drug
administrations of BDQ and CAM, respectively, prior to the first PK samples and the date and time of the study drug administrations immediately after the first PK samples must be recorded. The date and
time of the blood draw must be recorded.
v. Extra visits will be required for participants meeting certain grading thresholds for changes in QTcF. All ECGs will be performed in triplicate (3 ECGs within 5 minutes) and must be of good quality (stable
baseline, free of interference and artefact). The ECG machine dedicated for this study must be used. All tracings will be transmitted for blinded central analysis. ECG at 2-4 hours post-dose of BDQ and
CAM will be obtained at Week 2, Week 12, Week 24 and Week 48. ECG at pre-dose of BDQ and CAM will be obtained at Day 1, Week 4, Week 6, Week 8, Week 16 and Week 32. Those ECG should be
performed within 20 minutes prior to PK blood sampling at every time point whenever possible. ECG will be performed before blood sampling at the other visit where time points of ECG measurement are
not specified.
w. Examination of height (screening only), body weight measurement, observation for skin events/reactions, assessments performed as part of the clinical course of NTM related disease (body temperature,
heart rate, respiratory rate, and oxygen saturation) and additional assessments (systolic blood pressure and diastolic blood pressure). Physical examination and vital signs will be performed before intake of
study intervention and blood sampling.
x. Including hematology, chemistry and urinalysis.
y. Including visual acuity, color discrimination, visual field. Audiology and visual examinations within 4 week prior to Day 1 and within 4 days prior or after each visit other than Day 1 will be acceptable.
z. After Week 24 assessment, all participants in the Group B who are non-conversion and well-tolerated, will be considered to receive the BDQ-containing regimen at the discretion of the investigators. When
the investigator changes to BDQ-containing regimen, 2-week washout of treated rifamycin must be given before initiation of BDQ-containing regimen. The investigators can postpone the decision to transfer
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to the optional cohort for up to Week 32 in order to confirm a sputum culture positive at Week 24, if necessary. If decision to transfer to the optional cohort exceeds Week 32 for reasons such as time
required to obtain the result of microbiology assessment of Week 24, the period may be extended. If necessary, consider study date of OPD1 by adding the number of days required to switch to the optional
cohort to study date of Week 24.
aa. OPD1 is Day 1 for participants who are transferred to optional cohort. Assessments planned on OPD1 must be performed prior to first dose of BDQ. The investigators can postpone the decision to switch to
the optional cohort for up to Week 32 in order to confirm sputum culture positive at Week 24. If decision to transfer to the optional cohort exceeds Week 32 for reasons such as time required to obtain the
result of microbiology assessment of Week 24, the period may be extended.
bb. Upon completion of the 48-week optional treatment period, the observation of each participant will be completed.
cc. In principle, testing data at Week 24 will be used as that of OPD1, so it is not necessary to perform another test as OPD1. If the transition period is extended due to confirmation of the result of sputum
culture, the result of microbiology assessment of Week 24 will be used as that of OPD1, the latest data (Week 28, etc) will be used when specified testing other than the microbiology assessment have been
performed after Week 24 in Group B.
dd. Fundoscopy within 4 week prior to Day 1 and within 4 days prior or after each visit other than Day 1 will be acceptable.
ee. Audiology must be done only in subjects who are taking aminoglycoside
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2. 
INTRODUCTION
Bedaquiline (BDQ) is a Mycobacterium-specific adenosine 5'-triphosphate (ATP) synthase
inhibitor that was developed as part of a combination therapy for pulmonary tuberculosis (TB) due
to infection with multi-drug resistant (MDR) Mycobacterium tuberculosis (M. tuberculosis).
Bedaquiline fumarate (TMC207) was first approved on 28 December 2012 in the United States
(US) under the provisions of accelerated approval regulations. Conditional Marketing
Authorization in the European Union (EU) was granted on 5 March 2014, approval for market
authorization in Japan was on 19 January 2018, and over 60 approvals worldwide for the treatment
of pulmonary MDR-TB in adults as of part of combination therapy have been granted. Bedaquiline
is marketed under the trade name SIRTURO®.
Bedaquiline is a diarylquinoline derivative and a novel antimycobacterial agent, with in vitro
activity against a wide range of Mycobacterium (M) species, including M. tuberculosis, M. avium
complex (MAC), M. kansasii, and M. abscessus. Infection with the latter 3 nontuberculous
organisms can result in nontuberculous mycobacterial lung disease (NTM-LD), which is distinct
from the pulmonary infection caused by M. tuberculosis, for which BDQ is currently indicated.
Nontuberculous mycobacteria are a collection of naturally occurring organisms with the potential
to cause hard-to-treat pulmonary infections. The bacteria exist in the environment, commonly in
water and soil, and often colonize natural water sources such as indoor water systems, hot tubs,
and pools.8,13
Mycobacterium avium complex comprises a group of slow growing mycobacteria including
M. avium and M. intracellulare. Infection with MAC is the most common cause of NTM-LD
worldwide (although there are regional differences). The prevalence and incidence of NTM-LD
associated with MAC are increasing worldwide in both immunocompromised and
immunocompetent individuals, with and without preexisting lung disease.1,18,34 The incidence rate
of NTM-LD in Japan in 2014 was estimated to be 14.7 cases per 100,000 person-years, which is
approximately 2.6 times the incidence rate reported in 2007,35 and the rate of MAC infection in
NTM-LD was 88%.26 Japan is a high-burden country of NTM-LD.
MAC lung disease (MAC-LD) has 2 main clinical presentations: one is nodular-bronchiectatic
(NB) type which tends to affect the middle-aged, postmenopausal, and elderly female population;
and the other is fibro-cavitary (FC) type which is most often seen in patients with underlying lung
disease such as cystic fibrosis, bronchiectasis, previous TB, and chronic obstructive pulmonary
disease (COPD).27,44 Some patients with predominantly NB type may also have cavities, which is
referred to as cavitary NB type.12,22,29 This mixed clinical presentation is however not considered
as a separate category. Clinical symptoms vary in scope and intensity but commonly include
chronic recurrent cough, often with purulent sputum and/or hemoptysis, and dyspnea. Systemic
symptoms include malaise, fatigue, weight loss, fever, and chest pain in advanced disease.28 The
diagnosis of NTM-LD is based on the following 2 criteria in Japan; clinical criteria (radiological
findings, exclusion of other diagnosis) and bacteriology criteria (eg, positive culture results).42
However, both an official ATS/IDSA statement (published by the American Thoracic Society
[ATS] and the Infectious Diseases Society of America [IDSA] in 2007) and the Japanese
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guidelines (published by the Japanese Society for Tuberculosis and the Japanese Respiratory
Society in 2012) state that treatment need not necessarily commence as soon as the diagnostic
criteria are met.14,41 The decision to initiate treatment should be based on an assessment of the
potential risks and benefits of a prolonged course of multiple antibiotics for the individual patient.41
Treatment of MAC-LD remains challenging and involves prolonged antibiotic therapy, with a
combination of at least 3 antibiotics. In an official ATS/IDSA statement, it is stated that the
cornerstones of MAC therapy are the macrolides (clarithromycin [CAM] or azithromycin [AZM])
and ethambutol (EB), and then these agents are combined with companion drugs, usually rifamycin
(rifampicin [RFP] or rifabutin [RBT]), and possibly an injectable aminoglycoside.14 The British
Thoracic Society guidelines published in 2017, also recommend the treatment with RFP, EB, CAM
or AZM, and intravenous or nebulised amikacin (AMK) (consideration of use) for MAC-LD.16
However, the macrolides, rifamycin, and EB are not approved for the treatment of NTM-LD in the
US and EU, but are used off-label as these drugs are approved for the treatment of disseminated
MAC disease in human immunodeficiency virus (HIV) positive patients.14,16
On the other hand, the Japanese guidelines recommend a treatment regimen for MAC-LD based
on CAM, RFP (RBT is as an alternative to RFP), and EB; if necessary injectable
aminoglycosides (streptomycin [SM] or kanamycin [KM]) can be added.41 In Japan, CAM, RFP,
RBT, EB, SM, and AMK liposome inhalation suspension (ALIS) are approved for the treatment
of MAC-LD. Kanamycin is listed in the Japanese guidelines, but KM is not approved for the
treatment of MAC-LD.41 Amikacin is not listed in the Japanese guidelines, but injectable AMK
is reimbursed for the treatment of MAC-LD as from February 2019 and ALIS is approved for the
treatment of MAC-LD in March 2021.33 In addition, AZM is recommended as one of macrolides
in US and UK, but the Japanese guidelines do not recommend the use of AZM, as it is approved
for the prophylaxis and treatment of disseminated MAC disease with acquired
immunodeficiency syndrome (AIDS), but is not approved for the treatment of MAC-LD without
AIDS (but reimbursement for MAC-LD is acceptable in Japan from 26 February 2020).41 In
conclusion, there are limited antibiotics approved for the treatment of MAC-LD in Japan.
In South Korea, "KOREAN GUIDELINE FOR TUBERCULOSIS 4th EDITION" is published in
2020,50 and in Taiwan, "Consensus Statement of Nontuberculous Mycobacterial Lung Disease in
Taiwan" is published in 2020.51 Both diagnostic criteria for NTM-LD and chemotherapy for MAC-
LD in both countries are in accordance with an official ATS/IDSA statement,14 and chemotherapy
mainly with 3 drugs consisted of macrolide (CAM or AZM), rifamycin (RFP or RBT), and EB, is
recommended as the standard therapy.
In addition, the inclusion of RBT or RFP, a moderate or strong inducer of hepatic cytochrome
P450 (CYP) 3A4 enzymes, in the MAC-LD treatment regimen complicates the administration of
other important drugs to treat underlying conditions in patients with MAC-LD.
For the most comprehensive nonclinical and clinical information regarding BDQ, refer to the latest
version of the Investigator’s Brochure (IB)40 addendum, and local package insert of SIRTURO
(BDQ).
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The term “study drug” throughout the protocol refers to BDQ. The term “study intervention”
throughout the protocol refers to BDQ and rifamycin (RFP or RBT) as defined in Section 6.1,
Study Interventions Administered.
The term "sponsor" used throughout this document refers to the entities listed in the Protocol
Supplementary Information, which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject".
2.1. 
Study Rationale
MAC-LD can vary widely in severity, ranging from asymptomatic to severe, the disease is
frequently (but slowly) progressive and can lead to deterioration in lung function, reduced physical
function and health-related quality of life (HRQOL), and an increased risk of mortality.11,28
Patients with MAC-LD, particularly those with poor lung function or cavitary disease, have been
shown to have a significantly impaired HRQOL.19 Management and complete eradication of the
infection remains extremely challenging; despite treatment, the persistence of the underlying
disease and the presence of the organism in the environment often renders patients susceptible to
recurrence. Other comorbid factors and adverse side effects combined with toxicity due to the
treatment drugs lead to poor quality of life for patients.
In general, standard treatment for MAC-LD is long and frequently associated with drug-related
toxicities,3,24 with the most common toxicities of the recommended regimen including
gastrointestinal disorders, liver disorders, and eye disorders.13,41 The Japanese guidelines currently
recommend a 3-drug regimen, consisting of CAM, RFP or RBT, and EB, as standard of care
(SOC).41 Although limited by variable and inconsistent drug combinations, the relationship
between in vitro macrolide susceptibility and clinical response (based on sputum conversion) for
MAC-LD was demonstrated in the CAM monotherapy and CAM-containing regimens in
HIV-negative patients with MAC-LD.13,41 Most first-line anti-TB drugs have 10 to 100 times less
in vitro activity against MAC isolates than against M. tuberculosis.13 With the exception of CAM,
drug susceptibility testing (DST), from which the therapeutic efficacy of agents used in the
treatment of MAC-LD, has not been established.13,41
As isolates of MAC have only a single copy of the ribosomal ribonucleic acid operon in their
genome, macrolide monotherapy carries a significant risk for the development of mutational
resistance, which is extremely difficult to treat.13 Hence, it is crucial to include companion drugs
with the macrolide in order to prevent the emergence of macrolide-resistant MAC isolates.
Therefore, drugs with less activity against MAC are included in the recommended treatment
regimen. The contribution of EB to the efficacy of the regimen is unknown but may be minimal,
although EB was shown to delay the emergence of resistance in a mouse study.6 Rifamycins have
been shown to have a lower bactericidal activity against MAC than against M. tuberculosis in vitro.
The minimal inhibitory concentration (MIC) of RFP was demonstrated to be 16 μg/mL for MAC
compared to 0.2 μg/mL for M. tuberculosis for several strains.20 Additionally, in chemotherapeutic
experiments in beige mice infected with MAC, RFP, and RBT displayed no reduction in the
colony-forming unit (CFU) counts in the organs of the beige mouse model after 28 days of
treatment, while CAM resulted in a reduced CFU count of more than 1 log10 unit from the
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pretreatment values after 28 days of treatment.20 Moreover, the inclusion in a regimen of any
rifamycin, all of which are potent inducers of CYP3A4 enzymes, can result in drug-drug
interactions (DDIs), which further complicates therapy.
Overall, the treatment success rate in treatment-refractory patients with the current treatment has
been unsatisfactory and many patients remain culture positive despite prolonged therapy.24 The
Japanese guidelines for MAC-LD treatment currently recommend treating until patients have been
on SOC for 1 year after culture conversion, but there is no evidence to support this treatment
duration.41
As mentioned, the treatment of MAC-LD is essentially empirical as there are very few published
randomized controlled trials, specifically a lack of trials evaluating treatment in patients who are
not infected with HIV.13,41 Given the issues and lack of robustness of the current recommended
treatment regimen, the inclusion of a single new antibiotic with activity against MAC could have
a significant impact on overall treatment efficacy and safety. Due to its novel mode of action
(inhibition of ATP synthase), BDQ defines a new class of anti-TB compounds. Currently, no other
drugs belonging to the same pharmacologic class are available and therefore the potential for cross-
resistance is minimal. Because of the conserved nature of ATP synthase in mycobacteria, BDQ
also shows activity against other mycobacteria including MAC2 and BDQ has shown to have
activity against MAC in an experimental murine model.30 Studies have also shown that BDQ has
a low MIC with regard to MAC7,23, and that the minimal bactericidal concentration ranges between
1 to 2 mg/L for some clinical strains31 and >128 mg/L for MAC 101 strain,30 suggesting it has at
least bacteriostatic activity against MAC.
The standard duration of administration with BDQ for the treatment of MDR-TB with a known
bactericidal effect is 24 weeks, whereas the duration of administration with BDQ for MAC-LD,
which has been suggested to have a bacteriostatic effect, needs to be longer, and is therefore set at
48 weeks.
The sponsor expects that the substitution of BDQ for rifamycin in the MAC-LD treatment regimen
with CAM and EB will show higher culture conversion rate and enable shortening of the MAC-LD
treatment period (as well as avoid DDIs caused by rifamycin). Hence, the present study
(TMC207NTM3002) will evaluate the efficacy and safety of BDQ as part of a regimen including
CAM and EB after 48 weeks of treatment of the study intervention. This 48-week BDQ treatment
period is same as the maximum duration in the sponsor-initiated clinical study in Japanese
participants with MDR-TB (Study TMC207TBC2001).43
The diagnostic criteria and chemotherapy for MAC-LD in the world are in accordance with an
official ATS/IDSA statement,14 and there is no difference in the diagnostic criteria. For
chemotherapy, regimen consisting of 3 drugs such as macrolide (CAM or AZM), rifamycin (RFP
or RBT), and EB is recommended as SOC. Although there are some differences in the dosage and
administration of drugs among countries, it is not a major factor that causes differences in the
efficacy. Therefore, it may be considered that there is no major regional difference in the
therapeutic outcome for MAC-LD.
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In April 2020, a post-phase II study consultation was held with the Pharmaceuticals and Medical
Devices Agency (PMDA), and the study was started as a Japan study. However, in view of the
severe circumstance for the progress of the study due to the repeated outbreaks of COVID-19 etc.,
additional PMDA consultation was held in November 2022. Based on the advice from PMDA, the
study design is changed to conduct as a multi-country clinical study including the investigational
sites in South Korea and Taiwan.
2.2. 
Background
Bedaquiline Nonclinical Studies
Microbiologic Profile
Bedaquiline is a potent inhibitor of MAC in vitro with a MIC lower than that of approved
antimycobacterial agents. Its spectrum is unique in its specificity to mycobacteria, including
species important in humans such as M. tuberculosis, M. kansasii, and the fast growers
M. fortuitum and M. abscessus. The target and mechanism of action of BDQ are different from
those of other anti-TB agents. In BDQ mutant strains (M. tuberculosis, MAC, and M. smegmatis),
the atpE gene, which encodes a part of the F0 subunit of ATP synthase, was affected. This indicates
that BDQ inhibits the proton pump of M. tuberculosis ATP synthase. Furthermore, the distinct
target of BDQ means that there is no cross-resistance with existing antimycobacterial drugs.
Bedaquiline has potent bacteriostatic activity after 1 month of treatment in the MAC-established
infection mouse model. Four months of treatment improved the activity of AMK alone,
CAM+AMK, AMK+BDQ, and CAM+AMK+BDQ, all achieving bactericidal activity. The
activity of BDQ monotherapy did not improve and was still bacteriostatic. The triple combination
CAM+AMK+BDQ activity was better when compared to CAM alone or BDQ alone but not to
AMK alone.
Toxicology
Repeated dose toxicity studies were performed up to 3 months in mice, up to 6 months in rats, and
up to 9 months in dogs. Recovery was studied in rats and dogs.
Bedaquiline and its N-monodesmethyl metabolite (N-monodesmethylbedaquiline [M2]) have the
characteristics of a cationic amphiphilic drug and therefore induce phospholipidosis, mainly in
cells of the mononuclear phagocytic system. Changes in the mononuclear phagocytic system were
seen in all species and consisted of the accumulation of pigment-laden and/or foamy macrophages
in various tissues, but mostly in lymphoid tissue (lymph nodes and spleen), lungs, liver, stomach,
skeletal muscle, pancreas, and/or uterus. Ultrastructural examination was done on numerous
tissues from mice, rats, and dogs. Phospholipidosis is mainly regarded as an adaptive phenomenon
rather than a toxic response. It is described to be slowly reversible upon treatment cessation and
this was confirmed for BDQ by at least partial recovery seen in dog and rat studies.
A main target organ of toxicity was the skeletal muscle, which showed degenerative/necrotic
lesions in mice, rats, and dogs. The changes have been described as varying from multifocal to
widespread and were accompanied by clear increases in aspartate aminotransferase (AST), total
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creatine phosphokinase (CPK), and myoglobin. This myopathy only occurred after prolonged or
high dose administration and was usually reversible after treatment cessation or a decrease in dose.
Pharmacokinetic Profile
After single oral administration in rats, mice, dogs, and monkeys, absorption of BDQ was rather
rapid. Oral bioavailability was approximately 70% to 80% in mice and rats and 40% in dogs and
monkeys. The plasma concentration profiles of BDQ showed a multiphasic decline with a long
terminal elimination half-life (t1/2 term) ranging from 1 to 3 days in mice to 40 days in dogs. The
dose was slowly excreted in urine and feces after oral administration of 14C-labeled BDQ to rats,
dogs, and monkeys, most of the dose being recovered in feces. The overall recovery of
radioactivity was 56% in dogs and 71% in monkeys at 2 weeks after dosing, and 90% in male rats
and 72% in female rats at 216 hours.
After repeated oral administration, the systemic exposure to M2 in mice (area under the plasma
concentration-time curve [AUC]) was 2 to 7 times higher than that to unchanged BDQ.
Bedaquiline exposure increased less than dose proportionally and M2 exposure increased almost
dose proportionally. In rats and dogs, the exposure to M2 was either comparable or up to 2 times
lower than that to BDQ and the exposure of the 2 compounds increased dose proportionally to less
than dose proportionally. The N-didesmethyl metabolite (M3) plasma levels represented about
10% of those of BDQ in dogs and at least 25% in rats. The M3 metabolite was not investigated in
mice.
Tissue uptake was low in the brain after single oral administration of 14C-labeled BDQ in
pigmented male rats and monkeys. High tissue concentrations were associated with the adrenal
gland, lung, spleen, and liver. The decline of the concentrations of total radioactive substances in
most tissues was parallel to the plasma concentration decline. Following repeated oral
administration of BDQ to mouse, rat, and dog, the BDQ trough concentration ratios tissue/blood
(T/B) were above 30 in lung, spleen, lymph nodes, and thymus, and the tissue concentrations of
M2 were generally higher than those of unchanged BDQ. The tissue concentrations of the
2 compounds increased more than dose proportionally at high dose levels.
In vitro and in vivo metabolism studies showed that BDQ was subjected primarily to oxidative
metabolism leading mainly to M2. Cytochrome P450 3A4 (CYP3A4) was the major CYP form
involved in vitro in the metabolism of BDQ and the further metabolism of M2. In juvenile rats,
BDQ was less extensively metabolized than in adult rats, in agreement with CYP3A ontogeny.
No induction of CYP1A2, CYP3A4, CYP2C9, and CYP2C19 activities at concentrations up to
10 μM of BDQ was observed in cultures of cryopreserved primary human hepatocytes.
Investigation of the BDQ-mediated inhibition of CYP activity in a pooled batch of human liver
microsomes demonstrated slight or no direct inhibition of the CYP activity and no
mechanism-based inhibition was observed. M2 showed some moderate potential to inhibit CYP
activity using human liver microsomes, mainly CYP2B6, CYP2D6, and CYP2C19
(50% inhibitory concentration=3-13 μM). However, inhibition of CYP activity by M2 in vivo in
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humans should be limited since exposure to M2 in humans is low (maximum concentration [Cmax]
<0.5 μg/mL or 0.9 μM).
Clinical Studies
Phase 1 Studies
Pooled analyses were done for 8 Phase 1 studies in healthy subjects (5 single-dose studies and
3 multiple-dose studies). The pooled analysis included data from 217 healthy subjects, of whom,
189 received at least 1 dose of BDQ up to 700 mg. Five studies were not included in the Phase 1
pooled analysis: C117 was an open-label, DDI study in 16 HIV-1 infected subjects (without
TB infection). This single-sequence DDI Phase 1 study was conducted to investigate the potential
interaction between steady-state nevirapine and a single-dose of 400 mg BDQ. C112 was an
open-label, single-dose study in 8 healthy subjects and in 8 subjects with moderate hepatic
impairment. TBC1003 was a double-blind, single-dose study in 88 healthy subjects to evaluate the
effect of a single supratherapeutic (800 mg) dose BDQ on the QT/corrected QT (QTc) interval. A
total of 44 subjects received BDQ. TBC1002 was an open-label 3-way crossover study in 36
healthy adults to assess the relative bioavailability of 2 pediatric formulations of BDQ after
single-dose administration of 100 mg, with and without food. NTM1001 was an open-label, DDI
study in 16 healthy subjects. This single-sequence DDI Phase 1 study was conducted to investigate
the potential interaction between steady-state CAM and a single-dose of 100 mg BDQ.
Bedaquiline was well absorbed with tmax at approximately 5 hours postdose. The Cmax and AUC
increased proportionally up to the highest doses studied (700 mg single dose and 400 mg once
daily [qd] multiple doses). Accumulation from Day 1 to Day 14 was approximately 2-fold
expressed as increase in AUC, corresponding to an effective half-life of about 24 hours. From
Phase 2 study, 4 weeks after ceasing BDQ intake, the mean BDQ and M2 concentrations were
reduced by approximately 40% compared to the end of the BDQ treatment period. At the last
follow-up visit (Week 120), BDQ and M2 plasma concentrations were approximately 15% and
20% of the median Week 24 plasma concentrations, respectively. The average t1/2 term of BDQ and
M2, was estimated as 5.5 months and 5.3 months, respectively.
Administration of BDQ as the tablet formulation with food increased the relative bioavailability
(by 95%) compared to administration without food.
Drug-drug interaction studies confirmed the role of CYP3A4 in the metabolism of BDQ to M2. A
study with RFP (a CYP3A4 inducer) showed that the exposure (AUC336h) to single dose BDQ as
well as M2 was significantly reduced (by 52% and 25%, respectively). Furthermore, co-
administration of ketoconazole, lopinavir/low-dose ritonavir (LPV/rtv), or CAM (CYP3A4
inhibitors) increased the systemic exposure to BDQ. After 3 days of co-administration with
ketoconazole, exposure (AUC24h) to BDQ increased by 22%, without a significant effect on M2.
The combined intake of a single-dose of BDQ and LPV/rtv caused an increase in exposure
(AUClast) of BDQ by 22%, while for M2 exposure was decreased by 41% compared to intake of
BDQ alone. After 5 days of co-administration with CAM, no impact on rate and extent of
absorption (Cmax and tmax) of BDQ were observed, while it led to an increase in BDQ plasma
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exposure of 12% for AUC72h and 14% for AUC240h and to a decrease of 52% for Cmax and 51%
and 42% for AUC72h and AUC240h, respectively, of M2.
In the pooled Phase 1 studies, BDQ was generally safe and well tolerated. In the pooled group of
subjects treated with BDQ alone, adverse event (AEs) were reported in 60.3% of subjects and most
frequently related to system organ class of nervous system disorders (24.3%) and gastrointestinal
disorders (16.9%). Within these classes, the most frequent AE was headache (18.0%). In the
single-dose BDQ alone pooled treatment group, AEs were most frequently (in at least 15% of
subjects) related to the system organ class of nervous system disorders (25.0%). The most
frequently reported AE was headache (18.9%). Except for nasal congestion and nasopharyngitis,
which were reported in 5.3% of subjects, all other AEs were reported in less than 5% of subjects.
In the pooling of the multiple-dose studies, the number of subjects with at least 1 AE was 55.6%.
Adverse events were most frequently related to the system organ classes of gastrointestinal
disorders (28.9%), nervous system disorders (17.8%), and general disorders and administration
site conditions (15.6%). Within these classes, the most frequently reported AEs were headache
(15.6%) and dry mouth (11.1%).
Efficacy/Safety Studies
There are a few publications about the use of BDQ in patients with NTM-LD. However, no
controlled studies by the sponsor have been conducted to investigate the efficacy and safety of
BDQ in MAC-LD.
Overall clinical safety of BDQ administered as 400 mg once daily for 2 weeks and 200 mg dosed
thrice a week up to an additional 22 weeks was generally safe and well tolerated in adults as part
of combination therapy of pulmonary TB due to MDR M. tuberculosis.
Upon analysis of the placebo-controlled Phase 2b study C208 Stage 2, an imbalance in the number
of deaths was identified between the BDQ group (n=10; 12.7%) and the placebo group (n=3; 3.7%)
despite better microbiologic outcomes in the BDQ group. The reason for the increased overall
mortality in the BDQ group in this study is as yet unclear given that the causes of death were varied
(TB was the only cause of death reported in more than 1 subject), and there was a wide range in
time to death since last intake of BDQ/placebo (range, 2-911 days). In addition, all deaths in the
BDQ arm were considered not related to study intervention by the investigator. Overall,
16 subjects (6.9%) died during or after participation in study C209; all deaths were considered not
or doubtfully related to BDQ by the investigator. Three (5.3%) subjects died during the completed
TBC3001 study, all after the end of the Investigational Treatment phase, all 3 fatal serious adverse
events (SAEs) were assessed as not related to BDQ by the investigator.
Based on review as confirmed by an external hepatologist,10 it can be concluded that BDQ has a
signal for liver injury manifested by increases in AST and to a lesser extent alanine transaminase
(ALT). Transaminase elevations are not unexpected given the number of other hepatotoxic drugs
in the background regimen and based on the publication by Keshavjee et al (2012),22 which
describes a 16.5% incidence of hepatotoxicity during MDR-TB treatment. There were no
significant changes or treatment-related effects in other clinical laboratory tests, vital signs, and
most electrocardiogram (ECG) parameters. The QT corrected according to Fridericia's formula
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(QTcF) interval was shown to increase modestly (mean 10-15 ms increase from baseline) after
treatment with BDQ.
For the most comprehensive nonclinical and clinical information regarding BDQ, refer to the latest
version of the IB,40 addendum, and the local package insert.
2.2.1. 
Comparator/Combination Therapy
Comparator:
Rifampicin (RFP)/Rifabutin (RBT)
RFP and RBT have been approved for TB and NTM-LD including MAC-LD or recommended for
use in local guidelines in Japan, South Korea and Taiwan.41, 50, 51 Rifampicin and RBT are strong
or moderate inducers of CYP3A4 enzymes. Frequent AEs of RFP are gastrointestinal disorders,
AST increased, ALT increased, rash, liver disorder, pyrexia, thrombocytopenia, and headache.
Frequent AEs of RBT are nausea, leukopenia, pancytopenia, hypertriglyceridemia, and immune
reconstitution inflammatory syndrome.
Combination:
Clarithromycin (CAM)
CAM is one of the macrolide antibiotics and approved for broader infectious disease including
MAC infection or recommended for use in local guidelines in Japan, South Korea and Taiwan.41,
50, 51 Frequent AEs of CAM are gastrointestinal symptoms such as abdominal pain and diarrhea.
The major laboratory changes were ALT increased, AST increased, and eosinophils increased.
Ethambutol (EB)
EB has been approved for TB and NTM including MAC or recommended for use in local
guidelines in Japan, South Korea and Taiwan.41, 50, 51 Known clinically significant AEs are visual
impairment, severe liver disorder, shock, anaphylactic shock, interstitial pneumonia, eosinophilic
pneumonia, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythroderma, and
thrombocytopenia.
For further information regarding above drugs, refer to each local package insert.
2.3. 
Benefit-risk Assessment
Although BDQ has demonstrated antimicrobial activity against MAC in vitro and in the mouse
model, clinical efficacy of BDQ in MAC-LD patients has not been established yet. Participants in
this study may experience clinical benefit from the treatment of MAC-LD. Result from these
studies may be useful in developing novel therapy for treatment-refractory MAC-LD.
The following adverse drug reactions related to BDQ therapy were identified:
 
Very common: nausea, arthralgia, headache, vomiting, and dizziness.
 
Common: ECG QT prolonged, diarrhea, transaminases increased, and myalgia
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More detailed information about the known and expected benefits and risks of BDQ may be found
in the IB,40 addendum, and local package insert of SIRTURO  
 (BDQ).
2.3.1. 
Risks for Study Participation
Potential Risks of Clinical
Significance
Summary of Data/
Rationale for Risk 
Mitigation Strategy
Benefit of BDQ-containing regimen
regarding the clinical course of
MAC-LD might not be shown.
Clinical efficacy of BDQ in
treatment-refractory MAC-LD
patients has not been evaluated in
human clinical study yet and
efficacy is not demonstrated.
 A futility analysis will be
implemented to evaluate early
the benefit/risk balance by
assessing safety and efficacy in
the first 60 participants (about
30 participants from both
groups) to minimize the number
of exposure participants in case
benefit/risk balance are
unfavorable.
 Unblinding IDMC review will
be implemented.
 Investigator can switch to
individual regimen based on the
result of non-conversion and
clinical worsening.
Participants who are randomized to
treatment Group B need to continue
SOC by Week 24 regardless of the
low culture conversion rates.
Based on the result of clinical study
in AMK liposome inhalation
suspension (ALIS, Arikayce®),
culture conversion rate in SOC
were about 10%.15
 Non-converter in treatment
Group B will be assigned to
optional cohort to receive the
BDQ containing regimen.
 Investigator can switch to
individual regimen based on the
result of based on non-
conversion and clinical
worsening.
Risks Due to Study Intervention (BDQ and RFP/RBT) and Combination Drugs (CAM and EB)
QT prolongation due to
administration of BDQ and/or
CAM
QT prolongation was identified as
known risk and has been observed
in nonclinical and clinical studies in
MDR-TB patients (see IB40).
 Triplicate ECG will be assessed
and monitored by IDMC
frequently.
 Discontinuation of study
intervention and combination
drugs will be required based on
the result of ECG.
Risks Due to Study Procedures
Blood sampling will be increased
compared to standard medication.
Blood drawing may cause pain,
tenderness, bruising, bleeding,
dizziness, vasovagal response,
syncope, and, rarely, infection at
the site where the blood is taken.
As with all clinical studies
requiring blood sampling, there are
risks associated with venipuncture
and multiple blood sample
collection.
The total blood volume to be
collected is considered to be an
acceptable amount of blood over
this time period from the population
in this study.
Risks Due to Other Causes
Risk for emerging BDQ-resistant
MAC.
Risk for emerging BDQ-resistant
strains in MAC-LD patients is
possible and will be evaluated in
 Emergence of resistance will be
evaluated in non-converters.
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Status: Approved, Date: 8 December 2022
Potential Risks of Clinical
Significance
Summary of Data/
Rationale for Risk 
Mitigation Strategy
this study. Appropriateness of
dosage and treatment duration will
be evaluated in this study.
BDQ resistant strains were
identified in clinical studies in
MDR-TB patients.
 Switch to individualized
treatment based on the result of
microbiological assessment and
clinical worsening is allowed in
this study.
 Conduct drug susceptibility test
and gene analysis to detect the
resistance.
Visual impairment is a known risk 
in EB. 
- 
Visual examinations and
fundoscop y will be assessed.
For an individualized treatment 
regimen in treatment Group A, 
aminoglycosides may be added to 
the BDQ-containing regimen. 
The antimicrobial activity of BDQ 
in combination with 
aminoglycosides against MAC has 
been confirmed from the results of 
a nonclinical study,30 but its clinical
efficacy has not been evaluated yet
and its efficacy has not been
demonstrated. In multidrug therapy
approved for the treatment of
pulmonary MDR-TB in Japan and
overseas, aminoglycosides have
been recommended as one of the
agents to be used concomitantly
with multidrug therapy including
BDQ48,49, and no safety issues have
been observed. However, the
clinical safety in patients with
pulmonary MAC disease has not
yet been evaluated and its safety
has not been demonstrated.
During the study, study visits are
scheduled at least once every 4
weeks to perform specified safety
assessments.
Key: AMK=amikacin; BDQ=bedaquiline; CAM=clarithromycin; EB=ethambutol; ECG=electrocardiogram;
IB=investigator’s brochure; IDMC=Independent Data Monitoring Committee; MDR-TB=multi-drug resistant
tuberculosis; MAC-LD=Mycobacterium avium complex-lung disease; SOC=standard of care.
2.3.2. 
Benefits for Study Participation
As described in Section 2.1, the treatment options for the target population are very limited and
there is an unmet medical need. BDQ-containing treatment regimens may be a new treatment
option for treatment-refractory patients. From this perspective, study participation may provide the
benefit for participants to potentially improve their clinical course. The contribution to participate
in this study may be useful to develop new therapy in MAC-LD.
2.3.3. 
Benefit-risk Assessment for Study Participation
Based on the available data and proposed safety measures, the overall benefit/risk assessment for
this study is acceptable for the following reasons:
 
Only participants who meet all inclusion criteria and none of the exclusion criteria (specified
in Section 5) will be allowed to participate in this study, The selection criteria include
adequate provisions to minimize the risk and protect the well-being of participants in the study.
 
Safety will be closely monitored throughout the study:
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 
In general, safety evaluations will be performed at scheduled visits during the study as
indicated in the Section 1.3.
 
Triplicate ECG will be assessed at scheduled visits during the study. The result of ECG
will be read by not only investigators but also central ECG monitors. Independent Data
Monitoring Committee (IDMC) will review the data frequently.
 
A futility analysis will be implemented to evaluate early the benefit/risk balance.
 
Optional cohort is planned to ensure the opportunity to receive the BDQ containing regimen
for Group B participants who could not achieve sputum culture conversion at Week 24.
 
Participants can switch to individualized treatment based on the result of microbiological
assessment and clinical worsening at the discretion of investigators.
 
Any clinically significant abnormalities (including those persisting at the end of the
study/early withdrawal) will be followed by the investigator until resolution or until a
clinically stable endpoint is reached.
Taking into account the measures taken to minimize risk to participants of this study, the potential
risks identified in association with BDQ are justified by the anticipated benefits that may be
afforded to participants with MAC-LD.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
Microbiological assessment in MGIT: To
evaluate the efficacy of BDQ compared with
rifamycin when administered as part of a
treatment regimen with CAM and EB in adult
participants with treatment-refractory MAC-LD at
Week 24.
 
Percentage of participants with sputum
culture conversion (defined as 3
consecutive negative sputum cultures
taken at least 25 days apart) in MGIT at
Week 24.
Secondary
 
Microbiological assessment in 7H10 or 7H11 agar
media: To evaluate the efficacy of BDQ
compared with rifamycin when administered as
part of a treatment regimen with CAM and EB in
adult participants with treatment-refractory MAC-
LD at Week 24.
 
Percentage of participants with sputum
culture conversion (defined as 3
consecutive negative sputum cultures
taken at least 25 days apart) in 7H10 or
7H11 agar media at Week 24.
 
Clinical assessment: To evaluate the efficacy of
BDQ compared with rifamycin when
administered as part of a treatment regimen with
CAM and EB in adult participants with treatment-
refractory MAC-LD at Week 24.
 
Change from baseline in patient-
reported health status on total score of
SGRQ at Week 24.
 
Microbiological assessment: To evaluate the
efficacy of BDQ compared with rifamycin when
administered as part of a treatment regimen with
CAM and EB in adult participants with
treatment-refractory MAC-LD up to Week 48.
 
Percentage of participants with sputum
culture conversion (defined as 3
consecutive negative sputum cultures
taken at least 25 days apart) in MGIT
and 7H10 or 7H11 agar media at
Week 48.
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Status: Approved, Date: 8 December 2022
Objectives 
Endpoints
 
Percentage of participants with sputum
culture negativity in MGIT and 7H10 or
7H11 agar media, respectively, at each
visit after Week 2 per SoA.
 
Time to sputum culture conversion
(defined as 3 consecutive negative
sputum cultures taken at least 25 days
apart) in MGIT up to Week 48.
 
Time to positivity in MGIT up to Week
48.
 
Clinical assessment: To evaluate the efficacy of
BDQ compared with rifamycin when
administered as part of a treatment regimen with
CAM and EB in adult participants with
treatment-refractory MAC-LD.
 
Change from baseline in
patient-reported health status on total
score of SGRQ at Weeks 48 and 60.
 
Change from baseline in lung function
parameters at Weeks 24, 48, and 60.
 
Percentage of participants who undergo
a change in their MAC-LD treatment
regimen by Week 24, by Week 48
(Group A), and by Week 60 (Group B).
 
Microbiological assessment: To evaluate the
efficacy of BDQ compared with rifamycin when
administered as part of a treatment regimen with
CAM and EB in adult participants with
treatment-refractory MAC-LD at Week 60.
 
Percentage of participants with sputum
culture conversion (defined as 3
consecutive negative sputum cultures
taken at least 25 days apart) in MGIT
and 7H10 or 7H11 agar media at
Week 60.
 
To evaluate the safety and tolerability of BDQ
compared with rifamycin when administered as
part of a treatment regimen with CAM and EB in
adult participants with treatment-refractory MAC-
LD.
 
Safety and tolerability based on
assessment of AEs, clinical laboratory
assessments, 12-lead ECG, vital signs,
physical examination, visual
examination, and audiology up to
Week 60.
 
To evaluate the PK of BDQ (and metabolite M2),
and CAM (and metabolite 4-OH-CAM
[optional]).
 
PK exposures of BDQ (and metabolite
M2 [optional]) at Day 1, Weeks 2, 8, 12,
24, and 48, and CAM (and metabolite 4-
OH-CAM [optional]) at Day 1, Weeks
2, 8, 12, and 24.
Exploratory
 
Clinical assessment: To evaluate the efficacy of
BDQ compared with rifamycin when
administered as part of a treatment regimen with
CAM and EB in adult participants with treatment
refractory MAC-LD assessed by QOL-B NTM
module.
 
Change from baseline in patient reported
health status on score of QOL-B NTM
module at Weeks 24, 48, and 60.
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Status: Approved, Date: 8 December 2022
Objectives 
Endpoints
 
To evaluate the occurrence of culture reversion
(relapse or reinfection) in participants who
previously had sputum conversion.
 
Rate of culture reversion (relapse or
reinfection) up to Week 60.
 
Microbiological assessment: To evaluate the
efficacy of BDQ compared with rifamycin when
administered as part of a treatment regimen with
CAM and EB in adult participants with
treatment-refractory MAC-LD.
 
Percentage of participants having MAC
isolates with acquired resistance to
CAM detected by a phenotypic method
up to Week 60.
 
Percentage of participants having MAC
isolates with increased MICs to BDQ (at
least 4-fold increase) up to Week 60.
 
To evaluate PK/PD relationships for safety and
efficacy of BDQ (and CAM [optional]).
 
Exposure, and safety and efficacy
(PK/PD) relationship assessments of
BDQ (and CAM [optional]) by Week
24.
 
To determine the mechanisms of resistance in
participants’ MAC isolates with increased BDQ
MICs by sequencing both atpE, mmpT5 and other
genes (if available).
 
Evolution of the atpE   mmpT5 and other
gene sequences up to Weeks 60.
 
Clinical assessment: To evaluate the efficacy of
BDQ compared with rifamycin when
administered as part of a treatment regimen with
CAM and EB for participants who achieved
sputum culture conversion (at Weeks 24, 48, and
60).
 
Change from baseline in
patient-reported health status on total
score of SGRQ at Weeks 24, 48, and 60.
 
Change from baseline in patient reported
health status on score of QOL-B NTM
module at Weeks 24, 48, and 60.
 
Change from baseline in lung function
parameters at Weeks 24, 48, and 60.
 
Change from baseline in chest CT
findings at Weeks 24, 48, and 60.
Note:
1) Although not included in the above Objectives and Endpoints, the efficacy and safety at OPW24 (Week 24 of
study intervention treatment) and OPW48 (the last dose of study intervention) in the optional cohort will be
evaluated as additional analysis in the similar manner with efficacy and safety at Week 24 and Week 48.
2) Group A=Treatment group consisting of BDQ + CAM + EB
3) Group B=Treatment group consisting of rifamycin (RFP or RBT) + CAM + EB
Key: AEs=adverse event; atpE=ATP synthase subunit c; BDQ=bedaquiline; CAM=clarithromycin; CT=computed
tomography; EB=ethambutol; ECG=electrocardiogram; MAC=Mycobacterium avium complex; MAC-LD=MAC
lung disease; MGIT=mycobacterium growth indicator tube; MIC=minimal inhibitory concentration;
mmpT5=mycobacterial membrane protein transporter-5; NTM=nontuberculous mycobacterial; OPW=week in
optional cohort; PD=pharmacodynamics; PK=pharmacokinetics; QOL-B=Quality of Life-Bronchiectasis;
RBT=rifabutin; RFP=rifampicin; SoA=schedule of activities; SGRQ= St. George’s Respiratory Questionnaire.
 
Refer to Section 8, STUDY ASSESSMENTS AND PROCEDURES for evaluations related to
endpoints.
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TMC207 (Bedaquiline)  
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Status: Approved, Date: 8 December 2022
HYPOTHESIS
The hypothesis of this study is that BDQ-containing regimen is superior to rifamycin-containing
regimen and increases the proportion of participants with sputum culture conversion in MGIT at
Week 24 as compared to rifamycin-containing regimen.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a multicenter, randomized, open-label, active-controlled study to evaluate efficacy and
safety of BDQ compared with rifamycin administered as part of a treatment regimen with CAM
and EB for 48 weeks in adult participants with treatment-refractory MAC-LD.
 
A target of 124 participants with treatment-refractory MAC-LD will be enrolled in this study.
Participants who meet all the eligibility criteria will be randomized in a 1:1 (Treatment Group
A [Group A]: Treatment Group B [Group B]) ratio:
 
Group A: BDQ + CAM + EB
 
Group B: rifamycin (RFP or RBT) + CAM + EB
For dosing details, refer to Section 6, STUDY INTERVENTION AND CONCOMITANT
THERAPY.
Participants will be randomly assigned to 1 of 2 treatment groups based on a computer-generated
randomization schedule prepared before the study by or under the supervision of the sponsor. The
randomization will be balanced by using randomly permuted blocks and will be stratified by
country. The investigator and participant will be blinded for microbiological assessments until
each participant has completed the other assessments at Week 24. If during the treatment period,
the participant presents with clinical worsening, unblinding for microbiology assessments is
allowed at the discretion of the investigator. For the microbiological blinding procedures, refer
Section 6.3.
Participants who are taking rifamycin before start of the study intervention will be required to
discontinue rifamycin to allow for a minimum of 14-day washout period. This safety measure is
implemented to avoid DDIs between rifamycin and BDQ. Bedaquiline is a substrate of CYP3A4
(which is the main metabolic pathway for elimination) and co-administration with strong inducers
such as rifamycin are contraindicated as they substantially reduce BDQ levels.
The study will consist of a screening period of 70 days (10 weeks) (including rifamycin washout
period of 14 days for participants to whom this is applicable), an open-label treatment period of
48 weeks (baseline visit [Day 1] to Week 48) in Group A or 60 weeks (Day 1 to Week 60) in
Group B, and a follow-up period of 12 weeks in Group A. Participants will return for study visits
biweekly in the first 12 weeks and then every 4 weeks until Week 60. In addition, this study
provides an option to receive BDQ-containing regimen for non-converters in Group B at Week 24
as the optional cohort. OPW-2 in optional cohort will be initiation of 2-week washout period in
optional cohort.
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Status: Approved, Date: 8 December 2022
Participants requiring a treatment regimen change will be considered treatment failures for
subsequent endpoints and will be followed up for safety only, but all assessments should be
performed according to the protocol. In addition to the option to switch to the optional cohort in
Group B and withdrawal from the study, individualized treatment regimen was set up to as a
regimen that may be used when participants are judged to have difficulty continuing their
designated treatment regimen due to failure to respond (based on non-conversion supported by
microbiological results, and clinical worsening of symptoms related to MAC-LD supported by the
results such as chest computed tomography [CT] scan) or the occurrence of AE. Since the
microbiological results are blinded, if the investigators consider the regimen change based on the
clinical worsening of symptoms related to MAC-LD supported by the result of chest CT scan and
so on, the investigators can consult with IDMC before the change. Specific switching criteria,
treatment options, visits and assessments before and after switching, and follow-up will be detailed
in Section 6.8.1, Individualized Treatment Regimen.
Upon completion of the 48-week treatment period, the participants in Group A who achieved
culture conversion will transfer to the follow-up period of 12 weeks. During the follow-up period,
the convertors will be treatment free for MAC-LD in order to confirm the durability of culture
conversion. Non-converters at Week 48 in Group A will be discontinued from the study and
switched to another treatment regimen if they continue chemotherapy because the duration of BDQ
treatment is 48 weeks. On the other hand, the participants in Group B will continue the study
intervention up to Week 60. Upon completion of the 60-week study intervention period, the study
is completed, but the participant may continue SOC of local guidelines or medical practice at each
study site for at least 1 year after culture conversion at the discretion of the investigators.
In addition, this study provides an option to receive BDQ-containing regimen
(BDQ + CAM + EB) for non-converters in Group B at Week 24 as the optional cohort. The
participants may continue Group B regimen, switch to an individualized treatment regimen, or
BDQ-containing regimen in the optional cohort at the discretion of the investigators. The criteria
for switching to optional cohort after Week 24 are detailed in Section 6.8.2. When the investigator
changes to BDQ-containing regimen, 2-week washout of rifamycin is required before initiation of
BDQ-containing regimen. The participants switching to BDQ-containing regimen will be
considered treatment failures for rifamycin-containing regimen and will be followed up for
efficacy and safety for BDQ-containing regimen.
In this optional cohort, during the 48-week treatment period (from Day 1 in optional cohort
[OPD1] to Week 48 in optional cohort [OPW48]) of the study, participants may be changed to
individualized treatment regimen. The investigators can postpone the decision to transfer to the
optional cohort for up to Week 32 in order to confirm a sputum culture positive at Week 24, if
necessary. Regardless of delay in the transition phase, the treatment duration of the optional cohort
will be for 48 weeks.
All participants who switched to the optional cohort will be considered as treatment failure to
rifamycin-containing regimen.
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Status: Approved, Date: 8 December 2022
Key efficacy assessments include sputum culture conversion in MGIT and 7H10 or 7H11, St.
George’s Respiratory Questionnaire (SGRQ), and lung function (refer to Section 8.1, Efficacy
Assessments). Key safety assessments will include the monitoring of AEs, physical examinations,
measurement of body weight, vital sign measurements, clinical laboratory tests, 12-lead ECGs,
and visual/audiology test (refer to Section 8.2, Safety Assessments).
An IDMC will be commissioned for this study. Refer to Committees Structure in Section 10.3,
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations for details.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
Study Population
A recent study in treatment-refractory patients (including cavitary patients) documented a sputum
culture conversion rate of 8.9% by month 6 of guideline-based therapy.15 This patient population
therefore represents not only an area of unmet medical need, but also a suitable group to establish
whether BDQ is active against human MAC infections. The present study will enroll patients with
treatment-refractory MAC-LD defined as participants who are sputum culture positive for MAC
despite at least 6 months of MAC-LD treatment (at least 2 antibiotics for MAC, including a
macrolide), that is either ongoing or has stopped within the last 12 months.
Regardless of the predominant radiographical MAC-LD clinical presentation (FC type or NB type),
the presence of cavities may be correlated with different treatment outcome compared to the
noncavitary NB type.25 Additionally, cavity size may be negatively correlated with treatment
outcome, as demonstrated in participants with drug susceptible TB.5,39 To uniformly evaluate
clinical efficacy, participants with one or more cavities ≥2 cm on a chest CT scan taken within the
last 6 months will be excluded from this study. Patients with large cavity have a poor prognosis
and surgical therapy in addition to chemotherapy can be considered immediately after diagnosis.
Dose Selection
Refer to Section 4.3, Justification for Dose.
Blinding, Control, Study Phase/Periods, Treatment Groups
The Japanese guidelines currently recommend a 3-drug regimen, consisting of CAM, RFP or RBT,
and EB, as SOC.41 The South Korean and Taiwanese guidelines recommend a 3-drug regimen
consisting of macrolide (CAM or AZM), RFP or RBT, and EB as the SOC. 50, 51 Therefore, 3-drug
regimen, consisting of CAM as macrolide is selected as control arm.
This study will be conducted by an open-label design. Because rifamycin, which is included in the
control regimen, is known to cause a reddish coloration of the urine, feces, sputum, sweat, serum,
and discoloration of soft contact lenses, blinding of the study drug/comparator is practically
impossible due to the wide area of coloration effects. The primary endpoint at Week 24 is sputum
culture conversion, which will be assessed based on the results of culture at the central
microbiology laboratory. These microbiological results will be blinded to the investigator and
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
participants until the completion of the other assessments at Week 24. Randomization will be used
to minimize bias in the assignment of participants to treatment groups, to increase the likelihood
that known and unknown participant attributes (eg, demographic and baseline characteristics) are
evenly balanced across treatment groups, and to enhance the validity of statistical comparisons
across treatment groups.
The planned treatment duration of BDQ (48-week BDQ treatment period) is same as the maximum
duration in the sponsor-conducted clinical study in Japanese participants with MDR-TB (Study
TMC207TBC2001).43 Overall, the treatment success rate in treatment-refractory patients with the
current treatment has been unsatisfactory and many patients remain culture positive despite
prolonged therapy.24 The local guidelines for MAC-LD treatment in Japan, South Korea ,Taiwan
and an Official ATS/IDSA statement currently recommend treating until patients have been on
SOC for 1 year after culture conversion, but there is no evidence to support this treatment
duration.41, 50, 51, 14
The standard duration of administration with BDQ for the treatment of MDR-TB with a known
bactericidal effect is 24 weeks, whereas the duration of administration with BDQ for MAC-LD,
where a bacteriostatic effect is suggested, needs to be longer, and is therefore set at 48 weeks and
drug free follow-up period for 3 months is planned to evaluate the recurrences after completion of
treatment to evaluate appropriate treatment duration. On the other hand, the participants in Group
B who achieved culture conversion at Week 24 will continue up to Week 60. This 60-week
duration is consistent with the end of follow-up period in Group A. Upon completion of the 60-
week study intervention period, the study is completed, but the participant may continue SOC of
local guidelines in Japan, South Korea and Taiwan or medical practice at each study site for least
1 year after culture conversion at the discretion of the investigators after study completion.
In addition, participants who have not achieved culture conversion in Group A (BDQ-containing
regimen) will continue their assigned regimen until Week 48, unless they have difficulty
continuing due to failure to respond (see Section 6.8.1, based on non-conversion and clinical
worsening) or the occurrence of AE related to the regimen. If participants were judged to have
difficulty continuing due to failure to respond to the regimen or the occurrence of the regimen
related AE, at the discretion of investigators, there will be options to discontinue from the study
or switch to an individualized treatment regimen (in principle, add on injectable SM, injectable or
inhalation suspension of AMK).
The participants in Group B (rifamycin-containing regimen) who do not achieve culture
conversion up to Week 24 and continue the study, will have the option, at discretion of investigator,
to (1) continue rifamycin-containing regimen, (2) switch to individualized treatment regimen (see
Section 6.8.1, in principle, add on injectable SM, injectable or inhalation suspension of AMK ),
(3) switch to BDQ-containing regimen after 2-week washout of rifamycin. The latter option is
called the "optional cohort" (see Section 6.8.2). The target population is refractory participants,
who received at least 6-month SOC before this study and received the rifamycin-containing
regimen up to Week 24 and SOC for at least 1 year but could not achieve culture conversion.
Therefore, in consideration of the benefits for non-converters in Group B, an opportunity to switch
to the optional cohort at Week 24 after the completion of the assessments will be provided. All
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
participants switched to individualized treatment regimen or the optional cohort will be considered
as “treatment failures”.
Efficacy Measures
To date, the surrogate markers predictive of clinical treatment response in MAC-LD have not been
established. In 2018, a consensus paper on treatment outcome definitions was released which
proposed key outcome parameters to be used in the treatment of NTM-LD.44 The microbiological
consensus definition for culture conversion is the finding of at least 3 consecutive negative
mycobacterial cultures from respiratory samples, collected at least 4 weeks apart (at least 25 days
apart in consideration of allowed visiting window), during antimycobacterial treatment (the
sampling date of the first negative culture is then the date of culture conversion).44 In the present
study, the primary endpoint for the primary analysis at Week 24 is the percentage of participants
achieving sputum culture conversion (defined as 3 consecutive negative sputum cultures taken at
least 25 days apart) (ie, 6 months after start of study intervention). The recent study using
semiquantitative cultures to monitor treatment effect suggests that a lack of microbiological
response after 6 months of treatment is a very accurate predictor of treatment failure (nonresponse)
at 12 months and beyond. The percentage of participants achieving sputum culture conversion at
Week 48 (ie, 12 months after start of study intervention) is the secondary efficacy endpoint for the
assessment of the sustainability of sputum culture conversion. In addition, the secondary efficacy
endpoint for clinical assessment is the change from baseline in patient-reported health status on
the total score of SGRQ and the extrapolatory efficacy endpoint for clinical assessment is the
change from baseline in patient-reported health status on the score of QOL-B NTM module at
Weeks 24, 48, and 60.14
The burden of living with MAC-LD and the complicated, prolonged therapy associated with its
treatment has a significant impact on patient’s HRQOL. Assessing HRQOL is an important aspect
of patient assessment and management, which involves evaluating a patient’s satisfaction with
domains of health, including the perception of performance in physical function, emotional state,
social interaction, and somatic sensation domains.4,32 The present study will evaluate the HRQOL
in participants with MAC-LD using the SGRQ21,45 and the QOL-B NTM module.17,38 The SGRQ
is a disease-specific instrument designed to measure impact on overall health, daily life, and
perceived well-being in participants with obstructive airway disease.21,45 The NTM module was
developed specifically for NTM symptoms and consists of NTM symptoms, body image, digestive
symptoms, and eating problems.17,38 However, as QOL-B NTM module has only been
preliminarily validated and no consensus has been reached at present, this will be handled as an
exploratory measurement tool in this study.
4.2.1. 
Study-specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may
be withdrawn at any time with no reason given and without penalty or loss of benefits to which
they would otherwise be entitled. Only participants who are fully able to understand the risks,
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 8 December 2022
The primary ethical concern is to continue the standard regimen which may not be effective in
treatment-refractory MAC-LD for at least Week 24 in case participants will be randomized to
Group B. Although this study plans to perform the primary analysis at Week 24, an optional cohort
of participants randomized to standard therapy who have not achieved culture conversion at
Week 24 will be provided in which they will receive the BDQ combination regimen. Participants
who are not converted at Week 24 will be selected at the discretion of the investigator to either
continue with the treatment regimen used through Week 24, switch to an individualized treatment
regimen, or proceed to an optional cohort and receive the BDQ combination regimen. All
participants, except those who continue on the same treatment regimen through Week 24, will be
treated as failures. This cohort was set as a rescue measure for participants assigned to the standard
therapy because the sputum culture conversion rate by the standard therapy was low and the
likelihood of conversion was low even if the treatment was continued for longer than 24 weeks.
Addition of aminoglycosides (injectable SM, injectable or inhalation suspension of AMK) is
permitted as an individualized treatment regimen in either treatment group if participants are
judged to have difficulty continuing the designated treatment regimen due to failure to respond
(based on non-conversion and clinical worsening) or the occurrence of the regimen related AE, at
the discretion of investigators. Addition of aminoglycosides in Group B is recommended by the
Japanese guideline,41 and is expected to be clinically efficacious in participants with clinical
worsening. On the other hand, addition of aminoglycosides to the regimen in Group A has been
confirmed to have antimicrobial activity based on nonclinical studies, but its clinical efficacy has
not been confirmed at present. Regarding safety, in the Japanese and oversea guidelines on
approved drug therapies for the treatment of pulmonary MDR-TB,48,49 AMK and SM are
recommended as agents to be used in combination with multiple drug therapies including BDQ,
and there have been no reports of any problems concerning drug interactions and new adverse
reactions associated with the combination use. However, experience in the treatment of pulmonary
MAC disease is limited, and safety monitoring participants will be performed at least every 4
weeks until study completion or early discontinuation according to Section 1.3, Schedule of
Activities (SoA), Since treatment options for participants who failed to respond are limited,
addition of aminoglycosides, which is expected to convert and improve clinical symptoms, was
selected as an individualized treatment regimen.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
Japanese Red Cross Society.
4.3. 
Justification for Dose
The dosage and administration of BDQ of this study in adult participants with treatment-refractory
MAC-LD (BDQ 400 mg once daily in the first 2 weeks, followed by BDQ 200 mg twice weekly
in Weeks 3-48) was determined based on the PK results of DDI study between CAM and BDQ
and simulation using the previously developed population pharmacokinetic (popPK) model of
BDQ.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 8 December 2022
In this study, the replacement of RFP in the current standard therapy regimen (CAM + EB + RFP)
with BDQ (CAM + EB + BDQ) for the participants with treatment-refractory MAC-LD is planned.
BDQ is a CYP3A4 substrate and co-administration with CAM (CYP3A4 inhibitor), one of the
standard therapies for MAC-LD, increases BDQ exposure. Thus, a popPK model was developed
to simulate the exposure of BDQ in combination with CAM. As the popPK model of BDQ, a
model based on the non-Japanese data from Phase 1 and Phase 2 studies conducted at the timing
of development for the participants with MDR-TB was used. Applying this model to the results
from NTM1001, a 37% decrease in BDQ clearance was estimated when CAM was co-
administered. The model was used to explore the dosage and administration of BDQ in this study.
Bedaquiline exposures were targeted to be similar to those expected with the MDR-TB dosing
regimen (BDQ 400 mg once daily in the first 2 weeks, followed by BDQ 200 mg three times
weekly in Weeks 3-24) for the following reasons:
 
There were no safety concerns in the Phase 2 clinical studies in non-Japanese and Japanese
participants with MDR-TB.
 
Based on the postmarketing safety information of BDQ in Japan, there has been no safety
concern in participants with MDR-TB, even when administered for longer than 24 weeks.
In this assessment, several dose regimens were simulated. When BDQ PK was simulated for
1,000 participants under the dose regimen of “BDQ 400 mg once daily in the first 2 weeks,
followed by BDQ 200 mg twice weekly in Weeks 3 to 48 (in combination with CAM 500 mg
twice daily)”, the exposure was consistent with that expected with the dosage regimen for
pulmonary MDR-TB (Table 1).
Table 1: 
The Ratios of Mean BDQ Exposures From Simulations of the Dose and Administration of BDQ
for the Patients With MDR-TB (MDR-TB regimen) and the Dose and Administration of BDQ
for the Patients With MAC-LD in This Study (MAC-LD regimen)
Time since first BDQ dose 
The ratioa of Ctroughb 
The ratioa of Cmax 
The ratioa of AUC  
Week 2 
1.15 
1.06 
1.11c
Week 24 
0.97 
0.98 
0.93d
Week 48 
0.99 
0.99 
0.95d
Key: AUC=area under curve; CAM=clarithromycin; Cmax=maximum plasma concentration; Ctrough=minimum plasma
concentration between 0 hour and the dosing interval τ; MAC-LD=Mycobacterium avium complex-lung disease;
MDR-TB=multi-drug resistant tuberculosis.
Note: In MDR-TB regimen, BDQ was administered as 400 mg once daily in the first 2 weeks, followed by BDQ 200 mg three
times weekly in Weeks 3 to 24 (without co-administration of CAM).
MAC-LD regimen: BDQ 400 mg once daily in the first 2 weeks, followed by BDQ 200 mg twice weekly in Week 3 to 48 (with
co-administration of CAM [500 mg twice daily]).
a: The mean exposure of MAC-LD regimen/ the mean exposure of MDR-TB regimen
b: Plasma trough concentration
c: AUC24h
d: AUC168h.
As a result, BDQ dosing regimen for this study was proposed as “400 mg once daily for the first
2 weeks in combination with CAM followed by BDQ administered at 200 mg twice weekly for
the next 46 weeks, with an interval of at least 72 hours”.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last visit for the last participant in the study. The final data
from the study site will be sent to the sponsor (or designee) after completion of the final participant
visit at that study site, in the time frame specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed
assessments at Week 60 of the open-label phase or at OPW48 of the optional cohort. Following
completion of the study, the participant may continue the SOC per local guidelines or medical
practice at each study site for at least 1 year after culture conversion, at the discretion of the
investigator.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 10 weeks before administration of the
study intervention.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Male or female.
2. 
20 to 79 years of age, inclusive.
3. 
Has body weight ≥40 kg at screening and on Day 1.
4. 
Has radiological evidence consistent with NTM-LD based on a chest CT scan taken
within 6 months prior to screening or at screening.
5. 
5.1 
5.2 
Criterion modified per Amendment 4.
Criterion modified per Amendment 8.
Has at least 2 positive sputum cultures of MAC (sputum cultures to be taken at least
4 weeks apart):
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
 one obtained within 12 months prior to screening, which was documented while
being treated for MAC-LD for a total of at least 6 months.
 one at screening (by central microbiology laboratory).
6. 
6.1 
6.2 
Criterion modified per Amendment 4.
Criterion modified per Amendment 8.
Received at least 6 months of consecutive MAC-LD treatment (at least 2 antibiotics for
MAC, including a macrolide), that is either ongoing or has stopped within 12 months
prior to screening.
Note: Participants must be compliant with medication intake for at least 75% of the total
doses for prescribed SOC (including intermittent regimen) recommended by local
guidelines. Participants who have missed more than 25% of their doses during a given
treatment period for any reason (including noncompliance by participants, interruption
due to an AE at the discretion of physician, and others) can only be enrolled if approved
by the sponsor’s medical monitor.
7. 
No presence of cognitive dysfunction that would impact the completion of the
patient-reported outcome (PRO) assessments.
8. 
Must sign an informed consent form (ICF) indicating that he or she understands the
purpose of, and procedures required for, the study and is willing to participate in the
study.
9. 
A woman of childbearing potential must have a negative highly sensitive serum
(-human chorionic gonadotropin [-hCG]) test at screening and on Day 1.
10. 
A woman using oral contraceptives must use an additional contraceptive method (as
required in Inclusion Criterion 11).
11. 
A woman must be (as defined in Section 10.5, Appendix 5: Contraceptive Guidance).
a. Not of childbearing potential
b. Of childbearing potential and
o 
Practicing a highly effective method of contraception (failure rate of <1%
per year when used consistently and correctly) and agrees to remain on a
highly effective method while receiving study intervention and until 90
days after last dose - the end of relevant systemic exposure. The
investigator should evaluate the potential for contraceptive method failure
(eg, noncompliance, recently initiated) in relationship to the first dose of
the study intervention. Examples of highly effective methods of
contraception are located in Section 10.5, Appendix 5: Contraceptive
Guidance.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 8 December 2022
12. 
a woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the
purposes of assisted reproduction during the study and for at least 90 days after
receiving the last dose of study intervention.
13. 
a male participant must wear a condom when engaging in any activity that allows for
passage of ejaculate to another person during the study and for at least 90 days after
receiving the last dose of study intervention (male participants should also be advised
of the benefit for a female partner to use a highly effective method of contraception as
condom may break or leak).
14. 
a male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum 90 days after receiving the last dose of study intervention.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Had previous exposure to BDQ.
2. 
Has active TB disease.
3. 
Has cystic fibrosis, medically unstable respiratory disease (eg, COPD, bronchiectasis,
asthma).
Note: Medically unstable respiratory disease is defined as their symptom/sign are not
controlled with medication for their respiratory disease and exacerbation was observed
within 6 months prior to screening.
4. 
Has one or more cavities ≥2 cm in diameter on a chest CT scan taken within 6 months
prior to screening or at screening.
5. 
5.1 
Criterion modified per Amendment 8.
Treatment already includes an injectable/inhaled aminoglycoside within 3 months prior
to screening or the investigator deems the participant to be a candidate for an
injectable/inhaled aminoglycoside during screening period or at Day 1.
6. 
6.1 
Criterion modified per Amendment 8.
Has a history of documented macrolide-resistant MAC strain within 24 months prior to
screening or at screening. For CAM, MIC of ≥32 μg/mL indicates resistance according
to the Clinical and Laboratory Standards Institute [CLSI] M24 guidelines.9,46,47
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Note: In case a subject has ≥2 documented DST results within 24 months prior to
screening, the subject is eligible if the latest result is susceptible and DST at screening
is confirmed susceptible.
7. 
Has a history of a myocardial infarction, or a presence of any clinically significant
cardiac disease, as determined by the investigator.
8. 
Has experienced one or more of the following risk factors for QT prolongation:
 
personal or family history of Long QT Syndrome
 
personal history of cardiac disease, symptomatic or asymptomatic arrhythmias,
with the exception of sinus arrhythmia
 
a confirmed prolongation of the QT or QT interval corrected according to QTcF
≥450 milliseconds (ms) in the screening ECG (retesting to reassess eligibility will
be allowed once using an unscheduled visit during the screening period)
 
pathologic Q-waves (defined as Q-wave >40 ms or depth >0.4-0.5 mV)
 
evidence of ventricular pre-excitation (eg, Wolff Parkinson White syndrome)
 
electrocardiographic evidence of complete or clinically significant incomplete left
bundle branch block or right bundle branch block
 
evidence of second- or third-degree heart block
 
intraventricular conduction delay with QRS duration >120 ms
 
bradycardia as defined by sinus rate less than 50 beats per minute
 
syncope (ie, cardiac syncope not including syncope due to vasovagal or epileptic
causes)
 
risk factors for Torsades de Pointes (eg, heart failure, hypokalemia, or
hypomagnesemia)
9. 
Has a relevant history or current condition that might interfere with drug absorption,
distribution, metabolism, or excretion such as malabsorption syndrome or renal, or
hepatic disease.
10. 
Has active malignancy (primary or metastatic) or any other malignancy requiring
chemotherapy or radiotherapy within 1 year before screening (exceptions are squamous
and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy,
which is considered cured with minimal risk of recurrence).
11. 
Has known allergies, hypersensitivity, or intolerance to BDQ, CAM, EB, RFP or RBT
(refer to IB40 and addendum of BDQ, and package insert of each drug).
12. 
Has the following toxicities during the screening period:
 
Serum creatinine is >1.5 × upper limit of normal (ULN)
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
 
Aspartate aminotransferase (AST) is >3.0 × ULN
 
Alanine aminotransferase (ALT) is >3.0 × ULN
 
Alkaline phosphatase (ALP) is >3.0 × ULN
 
Total bilirubin is >2.0 × ULN or >1.5 × ULN when accompanied by any increase
over ULN in other liver function test
13. 
Has a history of HIV antibody positive, tests positive for HIV at screening, a history of
hepatitis B surface antigen (HBsAg), or hepatitis C antibody (anti-HCV) positive, or
other clinically active liver disease, or tests positive for HBsAg or anti-HCV at
screening. A participant who has completed treatment for hepatitis C and has been cured
is eligible.
14. 
Has a history of drug or alcohol abuse that, in the investigator’s opinion, would
compromise the participant’s safety or compliance to the study protocol procedures.
15. 
15.1 
Criterion modified per Amendment 8.
Has contraindications to the use of CAM, EB, RFP or RBT per local prescribing
information in Japan, South Korea or Taiwan.
16. 
Has taken any prohibited therapies as noted in Section 6.8, Concomitant Therapy before
the planned first dose of study intervention.
17. 
Received an investigational study intervention or used an invasive investigational
medical device within 60 days before the planned first dose of study intervention or is
currently enrolled in an investigational study.
18. 
Is pregnant, or breast-feeding, while enrolled in this study or within 90 days after the
last dose of study intervention.
19. 
Plans to father a child while enrolled in this study or within 90 days after the last dose
of study intervention or who is unwilling to use acceptable methods of contraception as
outlined in Section 10.5, Appendix 5: Contraceptive Guidance.
20. 
Has any condition for which, in the opinion of the investigator, participation would not
be in the best interest of the participant (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments.
21. 
Has preplanned surgery or procedures that would interfere with the conduct of the study.
Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate.
22. 
Employee of the investigator or study site, with direct involvement in the proposed
study or other studies under the direction of that investigator or study site, as well as
family members of the employees or the investigator.
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TMC207 (Bedaquiline)  
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CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 8 December 2022
23. 
Is co-infected with NTM species other than MAC on sputum culture at screening.
Note: If both MAC and NTM species other than MAC were detected on screening
sputum culture, and previous test result(s) suggested possible contamination such as
NTM species other than MAC was not detected before screening, a retesting of
screening sputum culture (repeat of sputum collection and sputum culture) will be
allowed once. The time required for retesting will not be included in the duration of the
screening period (9 weeks).
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening
and at baseline (Day 1). If a participant's clinical status changes (including any available laboratory
results or receipt of additional medical records) after screening but before the first dose of study
intervention is given such that he or she no longer meets all eligibility criteria, then the participant
should be excluded from participation in the study.
NOTE: Retesting of abnormal laboratory, ECG and physical examination values that may lead to
exclusion will be allowed once. Retesting will take place during an unscheduled visit in the
screening period. If the repeat test meets the study enrollment criteria, the participant can be
included in the study.
NOTE: If a subject is excluded due to COVID-19 related circumstances during the screening
period, the reason for screen failure should be recorded as exclusion criterion number 25 on the
eCRF (refer to COVID-19 Appendix).
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Refer to Section 6.8, Concomitant Therapy for details regarding prohibited therapy
during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.3.1. 
Activity
1. 
Participants will abstain from strenuous exercise for 24 hours before each blood
collection for clinical laboratory tests. Participants may participate in light recreational
activities during studies (eg, watching television, reading).
2. 
Strenuous exercise may affect study specified assessments and safety laboratory results;
for this reason, strenuous exercise should be avoided within 24 hours before all planned
study visits and during stays in the study site.
3. 
Avoid donating blood for at least 30 days after last dose of BDQ of the study.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened, including candidates whose microbiological testing at screening is not eligible, such
as culture negative, resistance to CAM, etc. Rescreened participants should be assigned a different
participant number with the initial screening.
5.5. 
Criteria for Temporarily Delaying
Enrollment/Randomization/Administration of Study Intervention
Not applicable.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Interventions Administered
The study drug BDQ and the comparator rifamycin (RFP and RBT) will be provided as tablets for
oral administration. BDQ will be taken with food in the morning at approximately the same time
each day, depending on visit and visit assessments. Rifamycin (RFP or RBT) will be taken
according to the investigator's instructions. Combination drugs will not be provided by the sponsor
and marketed product at study sites should be administered. Participants will be instructed to take
their assigned dose of the study intervention or comparator and combination drugs, per Table 2.
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Status: Approved, Date: 8 December 2022
Table 2: 
Dosage and Administration Table for Study Interventions and Combination Drugs
Group 
Group A 
Group B 
Group A and Group B
Intervention Name 
BDQ (TMC207) a,b
Rifamycin  
a,b,c
clarithromycin 
(CAM) 
ethambutol
(EB)
rifampicin 
(RFP) 
rifabutin 
(RBT)
Category 
Study Interventions  
(Investigational Medicinal Product) 
Non-Investigational Medicinal
Product
Stud y drug 
Comparator 
Combination drugs
Formulation and 
strengths 
100 mg tablet 
150 mg 
capsule 
150 mg 
capsule 
200 or 250 mg
tablet
125, 250, 400
or 800 mg
tablet
Dosage level(s) 
JP, SK, TW: 
Loading phase 
(Week 1-2): 
400 mg qd, 
Maintenance phase 
(Week 3-48): 
200 mg biw with at 
least 72 hours 
between doses 
JP, SK, 
TW: 
450 mg qd, 
Maximum 
daily dose 
600 mg 
JP: 300 mg 
qd 
SK, TW: 
150 or 
300 mg qd 
 
JP: 
800 mg/day d  
(400 mg bid) 
SK, TW: 
1,000 mg/day d  
(500 mg bid) 
JP:
500-750 mg
qd,
Maximum
daily dose
1.0 g
SK, TW:
15 mg/kg e
qd
Route of administration 
Oral 
Ora l 
Oral 
Oral 
Oral
Sourcing 
Provided centrally by the sponsor 
Provided locally by the trial site
a Participants who are taking rifamycin before start of treatment with BDQ will be required to discontinue
rifamycin to allow for a minimum 14-day washout period to avoid DDIs between rifamycin and BDQ.
b Bedaquiline and rifamycin (RFP/RBT) will be provided under the responsibility of the sponsor.
c RFP is basically administered in all countries, but RBT will be considered if RFP is ineffective or cannot be
used in Japan or at the discretion of the investigator in South Korea and Taiwan. The dose of RBT is based on
the recommended dose in each country; 300 mg/day in Japan, and 300 mg/day for ≥50 kg and 150 mg/day for
<50 kg in South Korea and Taiwan.
d Daily dose of CAM on Day 1 is 800 mg (400 mg bid) in Japan and 1,000 mg (500 mg bid) in South Korea and
Taiwan. If a dose reduction is required due to AEs after the start of treatment, the daily dose of CAM may be
reduced to 750 mg (South Korea and Taiwan) or 600 mg (Japan) at the discretion of the investigator.
e Based on 15 mg/kg, the daily dose will be determined at the discretion of the investigator.
 
Key: JP=Japan; SK=South Korea; TW=Taiwan; AE=adverse event; BDQ=bedaquiline; bid: bis in die (twice a
day), biw: bis in week (twice a week); qd: quaque die (once a day), CAM=clarithromycin; EB=ethambutol;
RBT=rifabutin; RFP=rifampicin; DDI= drug-dru  g interactions
 
Study intervention administration must be captured in the source documents and the electronic
case report form (eCRF).
BDQ will be manufactured and provided under the responsibility of the sponsor. Refer to the IB40
for a list of excipients of BDQ. Rifamycin (RFP or RBT) will be provided under the responsibility
of the sponsor. Refer to the respective Japanese package insert for a list of excipients of Rifamycin
(RFP or RBT).
For a definition of study intervention overdose, refer to Section 6.7, Treatment of Overdose.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored in the original blister sheet or container within the designated
temperature range indicated by label of the kit in order to protect from light.
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Status: Approved, Date: 8 December 2022
Refer to the pharmacy manual/study intervention and procedures manual for additional guidance
on study intervention preparation, handling, and storage.
Preparation, handling, and storage of combination drugs (CAM and EB) will be in accordance
with procedures of the study sites.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The dispensing of study intervention to the
participant and the return of study intervention from the participant must be documented on the
study intervention accountability form. Participants must be instructed to return all original
containers, whether empty or containing study intervention. The participants must return unused
study intervention to the study site.
Study intervention must be handled in strict accordance with the protocol and the container label
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention and study intervention returned by the
participant must be available for verification by the sponsor's study site monitor during on-site
monitoring visits. The return to the sponsor of unused study intervention or used returned study
intervention for destruction will be documented on the study intervention return form. When the
study site is an authorized destruction unit and study intervention supplies are destroyed on-site,
this must also be documented on the study intervention return form.
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even to the same participant. Whenever a participant brings his or her study
intervention to the study site for pill count, this is not seen as a return of supplies. Study
intervention may not be relabeled or reassigned for use by other participants. The investigator
agrees neither to dispense the study intervention from, nor store it at, any site other than the study
sites agreed upon with the sponsor. Further guidance and information for the final disposition of
unused study interventions are provided in the pharmacy manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
It is an open-label study; however, participants will be randomly assigned to 1 of 2 treatment
groups based on a computer-generated randomization schedule prepared before the study. The
randomization will be balanced by using randomly permuted blocks and will be stratified by
country.
Blinding
As this is an open-label study, blinding procedures are not applicable. However, the
microbiological results from Week 2 to Week 24 will be blinded to the investigators, site staffs
and participants until the completion of the other assessments at Week 24 by the investigators. In
order to maintain the blind, the investigator should not perform microbiological tests for acid-fast
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bacillus at the study site after Day 1 until completion of the assessments other than microbiological
assessments at the Week 24 except in emergency situations related to subject safety or
chemotherapy. In case the investigators need to know the microbiological result to decide if
participants should be switched to an individualized treatment regimen or continue the study
treatment regimen, due to clinical worsening, the investigators can access the microbiological
result from the central laboratory (for the detailed procedure, refer to the Procedure for
Confirmation and Reporting of Results of Blinded Sputum Culture Including Collection of
Samples for Microbiology Test). Sponsor except for specific personnel listed below must keep the
blinding of all the microbiological assessment after Week 2 until unblinding takes place for the
primary analysis.
In addition, sponsor personnel involved in monitoring of the study sites and personnel involved in
management operation of the central laboratory etc. are excluded from maintenance of blinding
for microbiology assessments, taking into account that sponsor needs to confirm that investigators
and etc. comply with the protocol and the decision to switch to individualized treatment regimen
and the optional cohort is made based on the appropriate process. Details will be provided in the
statistical analysis plan (SAP).
The interim (futility) analysis is detailed in Section 9.5, Interim Analysis.
6.4. 
Study Intervention Compliance
Table 3 provides instructions for when BDQ doses are missed or interrupted. Bedaquiline in the
optional cohort will be administered according to Group A regimen. Interruption or missing dose
of comparator or combination drug will be managed by investigators based on local practice and
labeling.
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Table 3: 
BDQ Missed Dose and Interruption Instructions
BDQ Missed Dose 
BDQ Interruption
Loadin  g Phase (Weeks 1-2) 
Loadin  g Phase (Weeks 1-2)
Participant notices missed 
dose within 12 hours of 
planned intake time 
 
 
Participant notices missed 
dose 12 hours or later 
after planned intake time
BDQ interruption 
≤14 days 
 
BDQ interruption
>14 days
Take missed dose and 
then resume dosing 
schedule 
Do not take missed dose 
and resume dosing 
schedule 
Continue dosing from last 
dose taken to complete 
total doses required in 
Loading Phase (previous 
doses taken into account) 
Restart from beginning of
Loading Phase to
complete total doses
required in Loading Phase
(previous doses not taken
into account)
 
More than 1 interruption is not allowed (considered as
treatment failures, 1 interruption is acceptable)
Restarting is not permitted after interruptions of
>30 days (considered as treatment failures)
Maintenance Phase (Weeks 3-48) 
Maintenance Phase (Weeks 3-48)
Participant notices missed 
dose in same dosing week 
of missed dose 
Participant notices missed 
dose after dosing week of 
missed dose
BDQ interruption ≤14 
days 
BDQ interruption
between 15 to 30 days
Take missed dose as soon
as possible and then
resume dosing schedule
Do not take missed dose
and resume dosing
schedule
Dosing can be resumed after interruptions of up to
30 days. All interruptions must be reported to the
sponsor within 3 working days of the study site
becoming aware
More than 1 interruption of 15 to 30 days is not
allowed (considered as treatment failures, 1
interruption is acceptable)
Restarting is not permitted after interruptions of
>30 days (considered as treatment failures)
Note: BDQ in the optional cohort will be administered according to Group A regimen.
Study intervention compliance will be assessed by counting tablets and/or capsules returned and
using participant diary during the site visits and documented in the source documents. The use of
study intervention captured in participant diary will be recorded in the eCRF.
Combination drug compliance will be assessed by participant diary during the site visits and
documented in the source documents. The use of combination drug captured in participant diary
will be recorded in the eCRF.
6.5. 
Dose Modification
Any dose/dosage adjustment as described in Section 6.1, Study Interventions Administered,
should be overseen by medically-qualified study-site personnel (principal or subinvestigator unless
an immediate safety risk appears to be present).
In case a dose reduction is necessary, the study drug will be administered per Section 6.1.
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6.6. 
Continued Access to Study Intervention After the End of the Study
Participants will be instructed that study intervention will not be made available to them after they
have completed/discontinued study intervention and that they should return to their primary
physician to determine standard of care.
6.7. 
Treatment of Overdose
There is no experience with the treatment of acute overdose with BDQ.
For this study, any dose of BDQ greater than 400 mg within a 24-hour time period (-12 hour) from
first day to 14 days after the first dose and 200 mg within a 72-hour time period (-24 hour) from
15 days will be considered an overdose. The sponsor does not recommend specific intervention
for an overdose. Removal of unabsorbed BDQ may be achieved by gastric lavage or aided by the
administration of activated charcoal. Since BDQ is highly protein-bound, dialysis is not likely to
significantly remove BDQ from plasma.
Refer to the local package insert of the comparator rifamycin (RFP or RBT) for advice on treatment
of overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Evaluate the participant to determine, in consultation with Medical Monitor, whether study
intervention should be interrupted or dose should be reduced.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities. General measures
to support basic vital functions including monitoring of vital signs and ECG (QT interval)
should be taken in case of deliberate or accidental overdose.
 
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study
intervention if requested by the Medical Monitor (determined on a case-by-case basis).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the Medical Monitor based on the clinical evaluation of the participant.
6.8. 
Concomitant Therapy
Concomitant therapies administered after signing informed consent (70 days before first dose of
study intervention, including the extension period if screening period is extended) and prestudy
therapies for pulmonary MAC disease administered prior to signing informed consent must be
recorded at screening.
Concomitant therapies must be recorded throughout the study from signing of the ICF up to the
last study visit. Concomitant therapies should also be recorded beyond the last follow-up visit only
in conjunction with new or worsening AEs and SAEs that meet the criteria outlined in Serious
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Adverse Events in Section 8.3.1, Time Period and Frequency for Collecting Adverse Event and
Serious Adverse Event Information.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; nonpharmacologic therapies such as electrical stimulation, acupuncture, special diets,
exercise regimens, or other specific categories of interest) different from the study intervention
must be recorded in the Concomitant Therapy Section of the eCRF. Recorded information will
include a description of the type of therapy, duration of use, dosing regimen, route of
administration, and indication. For any concomitant therapy given as a treatment for a new
condition or worsening of an existing condition, the condition must be documented in the Adverse
Event Section of the eCRF. Modification of an effective preexisting therapy should not be made
for the explicit purpose of entering a participant into the study.
It is important to record the use of biotin because of its potential to affect certain laboratory assays
when high levels of biotin are present in serum/plasma samples, leading to incorrect test results
for certain laboratory parameters. All prior and concomitant treatment with MAC-LD drugs will
be recorded. For participants who were previously diagnosed with MAC-LD and are being treated
or will start treatment at screening, the start date and details of their treatment regimen must be
recorded. Participants who are taking rifamycin before start of the study intervention will be
required to discontinue rifamycin to allow for a minimum 14-day washout period (to avoid DDIs
between rifamycins and BDQ). Participants who are transferred to the optional cohort will be
required to discontinue rifamycin to allow for a minimum 14-day washout period before start of
the BDQ-containing regimen.
If contraindicated medication(s) listed in each package insert of comparator/combination drugs
(RFP, RBT, CAM, or EB) are received during screening, the contraindicated medication(s) are
prohibited from 7 days prior to Day 1 up to the last dose of the medications including study
intervention.
Antibacterial drugs, such as fluoroquinolones, linezolid that may be effective for MAC-LD other
than the specified concomitant medications are prohibited during the study treatment period.
When injectable aminoglycoside is used as part of an individualized treatment regimen, injectable
KM is prohibited throughout the study period, because it is not approved for the treatment of
NTM-LD. Injectable SM, injectable or inhalation suspension of AMK is acceptable as part of an
individualized treatment regimen. The use of injectable SM, injectable or inhalation suspension of
AMK for any purposes other than as part of an individualized treatment regimen is prohibited.
The following medications are prohibited from 2 weeks prior to Day 1 up to the last dose of study
intervention (see note):
 
systemic use of moderate and strong CYP3A4 inhibitors (eg, azole antifungals: ketoconazole,
fluconazole, voriconazole, itraconazole; ketolides such as telithromycin; and macrolide
antibiotics [except CAM]) for more than 2 weeks.
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 
systemic use of strong CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbital,
St. John’s wort [Hypericum perforatum], and systemic, multiple dosing of dexamethasone),
except rifamycins for those randomized to the rifamycin-containing regimen.
NOTE: For participants receiving BDQ, the above prohibited medication can be (re-)started
1 month after stopping BDQ.
NOTE: The examples of potent CYP3A4 inhibitors and inducers do not form a complete list. The
investigator should consult the prescribing information for study interventions and combination
drugs (CAM and EB) and, if necessary, contact the appropriate sponsor representative.
The following medications are prohibited because of their potential for QTc prolongation. These
medications are not allowed from 7 days prior to Day 1 up to the last dose of study interventions
and combination drugs (CAM and EB) (including individualized treatment regimens):
 
antiarrhythmics Class IA (eg, quinidine, hydroquinidine, disopyramide)
 
antiarrhythmics Class III (eg, amiodarone, sotalol, dofetilide, ibutilide)
 
neuroleptics: phenothiazines thioridazine, haloperidol, chlorpromazine, trifluoperazine,
pericycline, prochlorperazine, fluphenazine, sertindole, and pimozide
 
quinolone antimalarials (eg, chloroquine and quinacrine)
 
moxifloxacin (prohibited from the initiation date of BDQ treatment up to 1 month after the
last dose of BDQ)
 
antimicrobials: erythromycin intravenous (IV), pentamidine, delamanid
 
tricyclic antidepressants, including amitriptyline, doxepin, desipramine, imipramine, and
clomipramine
 
prokinetic cisapride
 
nonsedating antihistamines: astemizole, terfenadine, and mizolastine
 
clofazimine (increased QT prolongation is reported in co-administration with BDQ)
NOTE: The above list of drugs with known risk of QT prolongation is based on drugs that may
be commonly used during the treatment of NTM-LD. The investigator should consult current
publicly available drug information to identify other drugs with potential QT prolongation. The
list of potential QT prolonging drugs is long and subject to change. Clinical interpretation of known
and potential additive risks is required.
The following medications are prohibited because of their potential for muscle damage (myopathy)
from 7 days prior to Day 1 up to the last dose of study interventions and combination drugs (CAM
and EB) (including individualized treatment regimens) (see note):
 
3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins)
 
griseofulvin
NOTE: All prohibited medications with a risk for muscle damage (myopathy) can be (re-)started
1 month after BDQ discontinuation.
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Status: Approved, Date: 8 December 2022
Hepatotoxic medications should be used with caution, especially during the treatment period in
participants with signs of hepatotoxicity (eg, participants with transaminase elevations).
Alternative medications should be used if possible.
For participants who change their treatment regimen, latest package inserts should be consulted
for contraindicated medication(s) or medication(s) that is not recommended for concomitant use.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.8.1. 
Individualized Treatment Regimen
In addition to the option to switch to the optional cohort in Group B and withdrawal from the study,
individualized treatment regimen was set up to as a regimen that may be used when participants
are judged to have difficulty continuing their designated treatment regimen due to failure to
respond (based on non-conversion supported by microbiological results, and clinical worsening of
symptoms related to MAC-LD supported by the results such as chest computed tomography [CT]
scan) or the occurrence of AE.
During the study, if deemed necessary by the investigator to switch to individualized treatment
regimen (in principle, add on SM, injectable or inhalation suspension of AMK. Regimens that may
be selected for each treatment group are listed below) and continue treatment, it can be done by
obtaining re-consent from the participant (refer to Sections 1.2 and 4.1). Participants should meet
one of the following criteria to switch to individualized treatment regimen. (Note: Refer to
Section 6.3 for blinding method of the microbiological assessment result).
 
Continuation of assigned treatment regimen is difficult because participants are non-
converters based on the result of microbiological test (ie, positive) and have clinical worsening
of symptom associated with MAC-LD based on the findings in chest CT scan and so on, at
the discretion of investigators.
 
Continuation of assigned treatment regimen is difficult due to AE related to drug in assigned
regimen, at the discretion of investigators.
Individualized treatment regimens permitted in this study are described in below. Investigators
should select the appropriate regimens for participants in each treatment group or if no regimen is
considered appropriate the participants should be discontinued from the study.
Group A (Assigned treatment regimen: BDQ + CAM + EB)
 
BDQ + CAM + EB + aminoglycosides (add one of injectable SM, injectable or inhalation
suspension of AMK)
 
BDQ + CAM + aminoglycosides (same as above)
 
BDQ + CAM (when difficult to continue treatment with EB and no clinical worsening)
Group B (Assigned treatment regimen: Rifamycin + CAM + EB)
 
Rifamycin + CAM + EB + aminoglycoside (same as above)
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 
Rifamycin+ CAM + aminoglycoside (same as above)
 
Rifamycin + CAM (when difficult to continue treatment with EB and no clinical worsening)
Note: From the viewpoint of preventing the development of CAM resistance, a regimen with EB
discontinuation should be carefully considered.
If an investigator judges that it is necessary to use treatment regimens other than those listed above,
such as discontinuation of study intervention, discontinuation of CAM or switching CAM to AZM
(prohibited medication), the participant should be discontinued from the study and treatment
regimens available at the study site will be provided.
Prior to switching to an individualized treatment regimen, visit and assessments for switch to
individualized treatment regimen must be done as shown in Section 1.3, Schedule of Activities
(SoA). After switching, a participants will continue their usual schedule for assigned treatment
regimen. Note that participants in Group A who have switched to individualized treatment regimen
can continue up to Week 48, participants in Group B can continue up to Week 60.
6.8.2. 
Optional Cohort
To maximize the benefit and minimize the risk, participants in treatment Group B can switch to
optional cohort after completion of Week 24 assessment. The decision to switch to optional cohort
can be made by Week 32 (refer to Sections 1.2, 1.3 and 4.1). Participants must meet all of the
following criteria at the timing of the decision to switch to optional cohort. Before starting BDQ
administration, a washout of rifamycin for 2 weeks is required and BDQ administration in optional
cohort should start by OPD1.
 
Participants are non-converter based on the result of microbiological test (ie, positive) up to
Week 24.
 
Participants do not have condition described in Section 7.1.
 
Participants do not experience any AE associated with CAM and/or EB that causes
discontinuation of CAM and/or EB at the discretion of investigators.
Switching from an individualized treatment regimen to the optional cohort is not permitted.
Switching to an individualized treatment regimen is permitted if the criteria described in
Section 6.8.1 are met, even after switching to the optional cohort.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:
 
The participant withdraws consent to receive study intervention.
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention.
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Status: Approved, Date: 8 December 2022
 
The participant has a QTcF prolongation (defined as a QTcF value ≥500 ms, or an increase
from baseline of >60 ms) at any given time point (confirmed by repeat ECGs).
 
The participant requires treatment with any of the prohibited medications listed in Section 6.8,
Concomitant Therapy.
 
The participant becomes pregnant. Refer to Section 10.5, Appendix 5: Contraceptive
Guidance.
 
Noncompliance with study intervention administration as defined in Table 3.
 
The participants discontinued administration of study intervention before Week 48 in Group A,
Week 60 in Group B or OPW48 in optional cohort.
If a participant discontinues study intervention before Week 48 in Group A, Week 60 in Group B
or OPW48 in the optional cohort, the participant will receive the assessments of early
discontinuation or withdrawal.
The early discontinuation visit assessment will be performed within 7 days of the investigator’s
discretion to discontinue treatment with study intervention, unless the participant withdraws
consent. Study intervention assigned to the participant who discontinued study intervention may
not be assigned to another participant.
7.1.1. 
Liver Chemistry Stopping Criteria
Refer to Section 8.2.6 Management of Common Expected Toxicities.
7.1.2. 
QTc Stopping Criteria
Refer to Section 8.2.3, Electrocardiograms.
7.1.3. 
Temporary Discontinuation
Participants will be temporarily discontinued from study treatment at the investigator’s discretion.
Few situations are specified in Section 8.2.3, Electrocardiograms and Section 8.2.6 Management
of Common Expected Toxicities.
7.1.4. 
Rechallenge
Instructions on BDQ interruption and resumption are specified in Table 3.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will NOT be automatically withdrawn from the study if he or she has to discontinue
study intervention before Week 48 (Group A), Week 60 (Group B), or OPW48 (the optional
cohort). A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Death
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When a participant withdraws before study completion, the reason for withdrawal is to be
documented in the eCRF and in the source document.
Participants will be encouraged to complete the early discontinuation visit assessments, which is
to be scheduled within 7 days of investigator’s discretion to discontinue treatment with study
intervention. If the reason for withdrawal from the study is withdrawal of consent, then no
additional assessments are allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply (eg, consult with family members, contacting the participant’s other physicians,
medical records, database searches, use of locator agencies at study completion,) as local
regulations permit.
7.2.1. 
Withdrawal From the Use of Research Samples
Collection of optional samples for research is not planned in the study.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
attempts should be made to obtain contact information from each participant, eg, home, work, and
mobile telephone numbers, and email addresses for both the participant as well as appropriate
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study-site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 
Before a participant is deemed lost to follow up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, telephone calls, e-
mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.
 
Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
 
Should a study site close, eg, for operational, financial, or other reasons, and the investigator
cannot reach the participant to inform them, their contact information will be transferred to
another study site.
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Status: Approved, Date: 8 December 2022
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (SoA) summarizes the frequency and timing of efficacy, PK, and safety
measurements applicable to this study.
The following time windows are allowed:
 
For visit Weeks 2, 4, 6, 8, 10, and 12 (±2 days)
 
For visit Weeks 16, 20, and 24 (±3 days)
 
For visit Weeks 28, 32, 36, 40, 44, 48, 52, 56, and 60 (±4 days)
In case of scheduling visit according to above time windows, the investigators should ensure that
4-week sputum collection interval does not fall below 25 days.
All PRO (SGRQ and QOL-B NTM module) assessments should be conducted/completed before
any tests, procedures, or other consultations to prevent influencing participant perceptions. The
questionnaires will be completed by the investigator after interviewing the participant and the data
will be entered into the eCRF by the investigator/study-site personnel. Refer to the PRO
completion guidelines for instructions on the administration of PROs.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: noninvasive procedures should be collected first before
invasive 
procedure 
(questionnaire/interview/ECG, 
vital 
sign/physical 
examination/CT
scan/audiology/visual examinations/fundoscopy, then sputum sample collection, and blood
sampling). ECG and blood collections for PK assessments should be kept as close to the specified
time as possible. Other measurements may be done earlier than specified timepoints if needed.
Actual dates and times of assessments will be recorded in the source documentation and eCRF.
The total blood volume for the study is approximately 68 to 115.5 mL (52 mL [Group A] for
pharmacokinetics and 20 mL [Group B], and 2 mL for pregnancy testing [women of childbearing
potential only]).
The total blood volume to be collected from each participant will be approximately 68 to 115.5 mL.
For each participant, the maximum amount of blood drawn from each participant in this study will
not exceed 115.5 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
If the unscheduled PK samples are taken, the date and the time of the blood draw must be recorded.
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Status: Approved, Date: 8 December 2022
Table 4: 
Volume of Blood to be Collected From Each Participant
Type of Sample 
Volume per 
Sample (mL) 
Number of 
Samples per 
Participant 
Approximate
Total Volume
of Blood (mL)a
Safet y (includin  g screenin  g and posttreatment assessments) 
 
 - Hematology 
2d  
9-12 
18-24
 - Serum chemistryb 
2.5 
9-12 
22.5-30
 
Serology (HIV, hepatitis) 
7.5 
1 
7.5
 
Serum -hCG pregnancy tests (for women of 
child-bearin  g potential only)
1 
2 
2
Pharmacokinetic samples 
2 
10-26 
20-52
Approximate Totalc 
 
 
68-115.5
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Serum chemistry excludes serology (HIV, hepatitis) and serum -hCG pregnancy tests.
c. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
d. Depending on local laboratory.
Key: -hCG=beta human chorionic gonadotropin; HIV=human immunodeficienc y virus
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form.
Refer to the Section 1.3, Schedule of Activities (SoA) for the timing and frequency of all sample
collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the laboratory manual. Procedures for the collection, handling, and shipment of microbiological
samples (sputum), as well as disclosure of blinded data are described in the Procedure for
Confirmation and Reporting of Results of Blinded Sputum Culture Including Collection of
Samples for Microbiology Test.
Study-specific Materials
The investigator will be provided with the following supplies:
 
IB and IB Addendum
 
Pharmacy manual/study intervention and procedures manual
 
Laboratory manual
 
Procedure for Confirmation and Reporting of Results of Blinded Sputum Culture, Including
Collection of Samples for Microbiology Test
 
PRO questionnaires and PRO completion guidelines
 
eCRF completion guidelines
 
ICF
 
Protocol Supplementary Information
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Status: Approved, Date: 8 December 2022
8.1. 
Efficacy Assessments
Microbiology assessments (MAC-LD Treatment Outcome), clinical assessments in MAC-LD,
percentage of participants who undergo a change in their MAC-LD treatment regimen, and a lung
function assessment using a spirometry test, will be performed in this study.
8.1.1. 
Microbiology Assessments (MAC-LD Treatment Outcome)
Sputum sample will be collected at the timepoints shown in Section 1.3, Schedule of Activities
(SoA). Instructions for the collection, handling, storage, and shipment of samples for
microbiological assessment can be found in the Procedure for Confirmation and Reporting of
Results of Blinded Sputum Culture, Including Collection of Samples for Microbiology Test. All
sample collection and processing will be performed according to the approved operating
procedures.
Qualitative Culture for MAC (Mycobacteria Growth Indicator Tube [MGIT])
This is to assess participants’ response to treatment by measuring the microbiological response
(culture positive or negative) using liquid medium in MGIT. In addition, time to sputum culture
conversion and time to positivity are calculated for MGIT.
Qualitative Culture for MAC (7H10 or 7H11 Agar Media)
This is to assess participants’ response to treatment by measuring the microbiological response
(culture positive or negative) using 7H10 or 7H11 agar media.
Identification and Speciation Of MAC
This is for identification and speciation of MAC by matrix-assisted laser desorption ionization
time of flight mass spectrometry (MALDI-TOF MS) for MAC from MGIT, 7H10 or 7H11 agar,
and positive sputum cultures.
Resistance Determinations
This is to determine susceptibility of MAC isolates to BDQ, CAM, EB, rifamycins, and other NTM
drugs (if possible) by DST using the broth-based microdilution method according to the Clinical
and Laboratory Standards Institute [CLSI] M24 guidelines.9,46,47
Genotyping or Fingerprinting of Isolates
This is to assess if baseline and postbaseline isolates are the same or different in case of resistance
occurring at postbaseline and in case cultures become positive after having been negative,
genotyping using variable number tandem repeat (VNTR) or whole genome sequencing (WGS)
will be performed.
8.1.2. 
Clinical Assessments in MAC-LD
SGRQ
CCI
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Lung function assessment
The lung function parameters including forced expiratory volume in one second, forced vital
capacity, inspiratory capacity, functional residual capacity, and total lung capacity, will be
assessed.
Change from baseline in chest CT findings
The change from baseline in chest CT findings (improved, no change, or worsened) will be
assessed and their respective percentages will be calculated. The investigators will evaluate
comprehensively based on the spread of opacities, number/size of cavitary opacities, degree of
bronchiectasis, etc.
8.2. 
Safety Assessments
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards
until the last study-related activity (end of study/early withdrawal).
An IDMC will be established for this study to monitor the safety of participants. Details regarding
the IDMC are provided in Committees Structure in Section 10.3, Appendix 3: Regulatory, Ethical,
and Study Oversight Considerations.
Adverse events will be reported and followed by the investigator as specified in Section 8.3,
Adverse Events, Serious Adverse Events, and Other Safety Reporting and Section 10.4, Appendix
4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other Safety
Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early discontinuation
visit will be followed by the investigator until resolution or until a clinically stable condition is
reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in Section 1.3, Schedule of Activities (SoA).
8.2.1. 
Physical Examinations
Physical examination of all body systems (including height and body weight measurement) and
observation for skin events/reactions will be performed before the intake of BDQ and blood
sampling at site visit indicated in Section 1.3, Schedule of Activities (SoA). Height will be
measured at only screening.
8.2.2. 
Vital Signs
Body temperature (axillary), heart rate, respiratory rate, oxygen saturation, blood pressure (systolic
and diastolic) will be assessed, preferably with same position and methodology throughout the
study.
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Blood pressure and heart rate measurements will be assessed supine or sedentary with a completely
automated device. Manual techniques will be used only if an automated device is not available.
Blood pressure and heart rate measurements should be preceded by at least 5 minutes of rest in a
quiet setting without distractions (eg, television, cell phones).
8.2.3. 
Electrocardiograms
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine or sedentary position for at least
5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood
sampling or vital sign measurement is scheduled for the same time point as ECG recording, the
procedures should be performed in the following order: vital signs, ECG(s), blood draw.
At each time point at which triplicate ECGs are required, 3 individual ECG tracings should be
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of
triplicates should be completed within 5 minutes and must be of good quality (stable baseline, free
of interference and artefact). ECGs will be recorded at a paper speed of 25 minute per second until
4 regular consecutive complexes are available. If the record is unclear due to the noise, ECGs will
be repeated after 1 or 2 minutes, and the clearer recording will be adopted as an original recording.
In principle, 2 original ECG recordings will be provided. One original recording will be stored at
the study site and another will be sent to a central cardiologist designated by the sponsor for review.
Submission of ECG to a central cardiologist will be done by transmission or send a hardcopy ECG
if transmission is not possible for any reasons (refer ECG manual for details). The ECG machine
dedicated for this study must be used. All tracings will be transmitted for blinded central analysis.
Participants found to have a QTcF ≥500 ms or an increase from baseline (mean of triplicates on
Day 1) of >60 ms on ECG at any point during the treatment period will be further investigated.
The ECG should be repeated and if confirmed, the investigator should attempt to identify the cause,
including checking and correcting abnormal K+, Ca+2, and Mg+2. If the participant is taking any
drugs suspected of causing QT prolongation, they should be withheld, and the tests repeated after
sufficiently long washout to try to identify the cause. Any QTcF prolongation to ≥500 ms or an
increase from baseline (mean of triplicates on Day 1) of >60 ms while on study intervention is
considered a notable event and should be reported immediately to the sponsor.
Extra visits will be required for participants meeting certain grading thresholds for changes in
QTcF. Additional unscheduled ECG evaluations may be made at the discretion of the investigator.
QTcF Prolongation
If a single ECG shows QTcF ≥500 ms or an increase from baseline (mean of triplicates on Day 1)
of >60 ms, then complete additional triplicate ECGs, evaluate the mean QTcF, and record results
on an unscheduled visit form.
If triplicate ECGs confirm a mean QTcF ≥500 ms or an increase from baseline of >60 ms, the
following will be done:
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 
the investigator must assess potential causes of the abnormality including at a minimum a
check and correction of electrolyte imbalances (K+, Mg+2, Ca+2), review and adjust
combination medications as necessary (eg, temporarily discontinuation of BDQ and CAM),
and obtain weekly duplicate/triplicate ECGs until resolution,
 
if after 2 weeks mean QTcF is ≥500 ms or increase from baseline of >60 ms, the investigator
must permanently stop the study intervention, and continue weekly triplicate ECGs until
resolution.
Weekly triplicate ECG monitoring for participants who have recovered from QTcF ≥500 ms or
increase from baseline of >60 ms may be discontinued if over 3 consecutive weeks the triplicate
ECGs demonstrate a mean QTcF <500 ms or one time increase of ≤60 ms. Participants who meet
these criteria can be switched to less frequent ECG monitoring per Section 1.3, Schedule of
Activities (SoA). If mean QTcF <500 ms or increase of ≤60 ms is not demonstrated, then weekly
triplicate ECGs will be continued at least until the end of the last dose of BDQ plus 4 weeks due
to the long half-life of BDQ. At that point, if mean QTcF <500 ms or increase of ≤60 ms is
demonstrated, weekly triplicate ECGs can be switched to less frequent ECG monitoring per
Section 1.3, Schedule of Activities (SoA). Otherwise if mean QTcF <500 ms or increase of ≤60
ms is not demonstrated, the investigator judges whether weekly triplicate ECGs will be continued
or be switched to less frequent ECG monitoring per Section 1.3, Schedule of Activities (SoA).
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will
be collected as noted in Section 10.2, Appendix 2: Clinical Laboratory Tests. The investigator
must review the laboratory results, document this review, and record any clinically relevant
changes occurring during the study in the adverse event section of the eCRF. The laboratory reports
must be filed with the source documents. The data of local laboratory test except for HBsAg and
HCV antibody test and HIV test at screening must be recorded in eCRF.
8.2.5. 
Pregnancy Testing
Additional serum or urine pregnancy tests may be performed, as determined necessary by the
investigator or required by local regulation, to establish the absence of pregnancy at any time
during the participation in the study.
8.2.6. 
Management of Common Expected Toxicities
For participants with AST and/or ALT elevations, pancreatic amylase elevation, gastrointestinal
system toxicities, musculoskeletal system and cardiac muscle toxicities, and cardiac rhythm
disturbances, the following should be done (refer Section 10.7, Appendix 7: A Division of
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (November 2007)).
AST and/or ALT Elevation
<5.0 × ULN AST or ALT elevation with normal bilirubin:
Participants may continue to take the study intervention. Participants should be followed until
resolution (return to baseline) or stabilization of AST/ALT elevation. Clinical symptoms, AST,
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ALT, and serum bilirubin should be monitored every 2 weeks until clinically stable as necessary
to manage the participant’s condition.
≥5.0 × ULN but ≤8.0 × ULN AST or ALT elevation or ≥3 ULN accompanied by bilirubin ≥2.0 ×
ULN:
Participants will be permanently discontinued from treatment of the suspected causative
background agent or temporarily withhold study intervention at the investigator’s discretion.
Clinical symptoms, AST, ALT, and serum bilirubin should be monitored every 2 weeks until
clinically stable as necessary to manage the participant’s condition. If ALT, AST, and bilirubin do
not improve or worsens within 2 weeks, the study intervention will be temporarily withheld for up
to 2 weeks per investigator discretion. Additional tests should be performed to evaluate the cause
of hepatitis (eg, hepatitis A, B, C). Liver enzymes, including serum bilirubin should be monitored
as frequently as necessary to manage the participant’s condition. If AST/ALT decreases to
<5.0 × ULN, study intervention can be restarted once. Participants who fail to show improvement,
demonstrated by no improvement in clinical course or persistent AST and ALT ≥5.0 × ULN values,
or persistent AST/ALT ≥3.0 × ULN accompanied by bilirubin ≥2.0 × ULN (over 4 weeks) will
have to permanently discontinue the study intervention. Participants should be followed until
resolution or stabilization (return to baseline) of AST/ALT/bilirubin elevation.
>8.0 × ULN AST or ALT elevation
Per investigator discretion, the study intervention will be temporarily withheld for up to 2 weeks.
Additional tests should be performed to evaluate the cause of hepatitis (eg, hepatitis A, B, C). Liver
enzymes, including serum bilirubin should be monitored as frequently as necessary to manage the
participant’s condition. If AST/ALT decreases to <5.0 × ULN, study intervention can be restarted
one time. Participants who fail to show improvement, demonstrated by no improvement in clinical
course or persistent AST and ALT ≥5.0 × ULN values, or persistent AST/ALT ≥3 × ULN
accompanied by bilirubin ≥2.0 × ULN will have to permanently discontinue the study intervention
but can continue the study procedures. Participants should be followed until resolution or
stabilization (return to baseline) of AST/ALT elevation.
Pancreatic Amylase Elevation
Grade 1 (>1.0 to ≤1.5 × ULN) or Grade 2 (>1.5 to ≤2.0 × ULN):
Participants may continue to take the study intervention and should be carefully evaluated and
followed closely.
Grade 3 (>2.0 to ≤5.0 × ULN) or Grade 4 (>5.0 × ULN):
For asymptomatic Grade 3 pancreatic amylase elevations with no history or concomitant disease
of pancreatitis, participants may continue to take the study intervention but should be carefully
evaluated and followed closely. For confirmed Grade 4 elevations of pancreatic amylase,
participants will have to permanently discontinue the study intervention. If there is clinical
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evidence of pancreatitis and amylase of Grade 3 or higher, participants will have to permanently
discontinue the study intervention.
Gastrointestinal System
In case of Grade 4 nausea (hospitalization required) or Grade 4 vomiting (physiologic
consequences requiring hospitalization or requiring parenteral nutrition), the participant’s
continued participation in the study will be at the investigator’s discretion.
Musculoskeletal System and Cardiac Muscle
Myalgia
Grade 1 (with no limitation of activity):
Participants may continue to take the study intervention and should be carefully evaluated and
followed closely.
Grade 2 (muscle tenderness at site other than injection site or with moderate impairment of
activity) or Grade 3 (severe muscle tenderness with marked impairment of activity) or Grade 4
(frank myonecrosis):
Participants will have to permanently discontinue the study intervention but can continue in the
study. Creatinine phosphokinase should be fractionated for creatine kinase myocardial band (CPK-
MB) subunit. Participants having confirmed ≥Grade 2 myalgia with Grade 3 (3.0 to 6.0 × ULN)
elevation in CPK-MB, or Grade 4 (>6.0 × ULN) elevation in CPK-MB subunit will have to
permanently discontinue the study intervention.
LDH and LDH-isoenzymes
For participants with lactate dehydrogenase (LDH) elevation >2.5 × ULN, LDH-isoenzymes will
be assessed.
Cardiac Rhythm Disturbances
The following text describes the minimum requirements for the management of cardiac rhythm
disturbances; however, additional management decisions are at the investigator’s discretion.
Grade 1 (asymptomatic) or Grade 2 (asymptomatic, transient rhythm abnormality not requiring
any treatment) cardiac rhythm disturbances:
Participants may continue to take the study intervention and should be carefully evaluated and
followed closely.
Grade 3 (recurrent, persistent, symptomatic arrhythmia requiring treatment) or Grade 4 (unstable
dysrhythmia requiring hospitalization and treatment) cardiac rhythm disturbances:
Participants will permanently discontinue the study intervention. QTcF prolongation that results
in discontinuation of the study intervention will be reported as AE term of "QT prolonged" of
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Grade 2 if no symptoms are present. If symptomatic, then a higher grade may be reported as per
the definitions above.
8.2.7. 
Other Safety Evaluations
Visual examination including visual acuity testing, color discrimination, visual field testing, and
fundoscopy and audiology will be assessed at study site visit indicated in Section 1.3, Schedule of
Activities (SoA). The visual examination, audiology test, and fundoscopy at Day 1 can be assessed
within 4 week prior to Day 1 and within 4 days prior or after each visit other than Day 1.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and product quality complaints (PQC) from clinical studies are crucial for the protection of
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide.
The sponsor has established Standard Operating Procedures in conformity with regulatory
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver or
surrogate) for the duration of the study.
Further details on AEs, SAEs, and PQC can be found in Section 10.4, Appendix 4: Adverse Events,
Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or nonserious, will be reported from the
time a signed and dated ICF is obtained until completion of the participant's last study-related
procedure, which may include contact for follow-up of safety.
Serious Adverse Events
All SAEs and PQCs occurring during the study must be reported to the appropriate sponsor contact
person by study-site personnel within 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study intervention, must be reported using the Serious Adverse Event Form.
The sponsor will evaluate any safety information that is spontaneously reported by an investigator
beyond the time frame specified in the protocol.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form, which must be completed and signed by a physician from the study site and transmitted to
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by
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facsimile (fax). Telephone reporting should be the exception and the reporter should be asked to
complete the appropriate form(s) first.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, or PQC as
fully as possible. This may include additional laboratory tests or investigations, histopathologic
examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in
Section 10.4, Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints,
and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or
sponsor where required) must report SUSARs to the appropriate Institutional Ethics
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise
required and documented by the IEC/IRB.
8.3.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using the Serious Adverse Event Reporting Form. If a
participant becomes pregnant during the study, a determination regarding study intervention
discontinuation must be made by the investigator in consultation with the sponsor.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.3.6. 
Disease-related Events and Disease-related Outcomes not Qualifying
as Adverse Events or Serious Adverse Events
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they
are protocol-specific assessments.
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8.3.7. 
Adverse Events of Special Interest
The liver, skeletal muscle, heart, pancreas, and stomach have been identified as target organs in
nonclinical toxicology studies. Careful monitoring of these organs should be included in clinical
studies. Any abnormalities in the parameters related to these target organs are therefore considered
as AEs of special interest. Because other compounds for treatment of MAC, with which BDQ will
have to be administered, have been associated with rash, skin events are considered as AEs of
special interest as well in the study.
8.4. 
Pharmacokinetics
Plasma samples will be used to evaluate the PK of BDQ (and M2 or additional metabolites, if
warranted) and CAM (and its active metabolite 4-OH CAM, if warranted). Plasma collected for
PK may additionally be used to evaluate safety or efficacy aspects that address concerns arising
during or after the study period. Genetic analyses will not be performed on these plasma samples.
Participant confidentiality will be maintained.
8.4.1. 
Evaluations
Single sparse blood samples will be collected for measurement of plasma concentrations of BDQ
and M2 at Weeks 4, 6, 16, and 32 in Section 1.3, Schedule of Activities (SoA). On Day 1, Weeks
2, 8, 12, 24, and 48, 2 blood samples will also be drawn: the predose and 2 to 4 hours postdose
plasma concentrations of BDQ and M2 for Group A, and CAM and 4-OH CAM for both Group A
and B. The date and time of the second to last and the last administration of BDQ before the
corresponding sample and the date and time of blood draw must be recorded. The date and time of
the intake of CAM on the day of sampling and the day before sampling should be recorded. Using
these blood samples per participant, the PK exposure of BDQ (if deemed necessary, M2) will be
calculated, during the loading phase as well as during the maintenance phase.
Participant confidentiality will be maintained. Additional information about the collection,
handling, and shipment of biological samples can be found in the Laboratory Manual.
8.4.2. 
Analytical Procedures
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of BDQ, M2, CAM, and 4-OH CAM
using a validated, specific, and sensitive liquid chromatographic-mass spectrometry method by or
under the supervision of the sponsor.
If required, some plasma samples may be analyzed to document the presence of circulating
metabolites of other analytes (eg, circulating metabolites or denatonium) using a qualified research
method. In addition, plasma PK samples may be stored for future analysis of the metabolite profile
or concomitant medications.
The bioanalytical report, including a description of the assay and a summary of the assay
performance data, will be included in the final clinical study report as an addendum.
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8.4.3. 
Pharmacokinetic Parameters and Evaluations
Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the actual
sampling times, PK parameters (Cmax, Ctrough [trough concentration], AUCτ) of BDQ at Day 1,
Weeks 2, 8, 12, 24, and 48 will be derived using population PK modelling. If deemed necessary,
a similar analysis for Cmax, Ctrough, AUCτ will be performed for M2.
Baseline covariates (eg, body weight, age, sex) may be included in the model, if relevant.
The predose and 2 to 4 hours postdose plasma concentrations on Day 1, Weeks 2, 8, 12, 24, and
48 (for Week 48, BDQ and M2 only) of BDQ and M2 for Group A, and CAM and 4-OH CAM
for both Group A and B will be listed.
Pharmacokinetic/Pharmacodynamic Evaluations
The relationship between BDQ (and CAM [optional]) PK and MAC-LD treatment outcome and
safety endpoints may be evaluated as appropriate. Pharmacokinetics/pharmacodynamics analyses
will be performed on the collected data when all participants have reached Week 24 or
discontinued earlier. The PK/PD analyses may be performed at earlier time points as necessary to
support efficacy and safety findings. If there is any visual trend in graphical analysis, suitable
models will be applied to describe the PK/PD relationships. The results of the PK/PD evaluations
will be presented in a separate report.
8.5. 
Genetics and Pharmacogenomics
Not applicable.
8.6. 
Biomarkers
Not applicable.
8.7. 
Immunogenicity Assessments
Not applicable.
8.8. 
Health Economics or Medical Resource Utilization and Health Economics
Not applicable.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1. 
Statistical Hypothesis
The hypothesis of this study is that BDQ-containing regimen is superior to rifamycin-containing
regimen and increases the proportion of participants with sputum culture conversion in MGIT at
Week 24 as compared to the rifamycin-containing regimen.
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9.2. 
Sample Size Determination
Based on the results of 2 clinical trials of ALIS (Phase 236 and Phase 315) in an analogous
population, it is anticipated that the rifamycin-containing regimen in this study will have a sputum
culture conversion rate assumed to be equal to 10% after 24 weeks of treatment.
A sample size of 124 participants (62 in Group A: the BDQ containing regimen, 62 in Group B:
the rifamycin-containing regimen) will have a power of about 80% to show superiority for a 20%
difference in proportion of participants having sputum conversion at Week 24 based on a chi-
square test (at the 5% 2-sided significance level) on the intent-to-treat (ITT) population.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
Description
Enrolled 
All participants who sign the ICF
Randomized 
All participants who were randomized in the study.
Intent-to-treat 
(ITT) 
All randomized participants who take at least 1 dose of study intervention. ITT will be the
primar y population for efficac y analyses.
Per-protocol 
(PP) 
All ITT population with at least 3 consecutive sputum collections taken at least 25 days apart
after baseline.
Participants who have major protocol deviations will be excluded from the PP population.
More details will be provided in the SAP.
Safety 
All participants who take at least 1 dose of stud y intervention.
PK 
All safet y population with at least 1 PK measurement.
9.4. 
Statistical Analyses
The SAP will be finalized prior to DBL and it will include a more technical and detailed description
of the statistical analyses described in this section. This section is a summary of the planned
statistical analyses of the most important endpoints including primary and key secondary endpoints.
9.4.1. 
General Considerations
All efficacy and safety data will be summarized by treatment groups (Groups A and B). For the
Group B, data from optional cohort will be analyzed separately.
9.4.2. 
Primary Estimand
The primary estimand, the main clinical quantity of interest to be estimated in this study, is defined
by the following 5 components:
 
Population: Adult patients with treatment-refractory MAC-LD.
 
Endpoint: Proportion of participants with sputum culture conversion in MGIT at Week 24.
 
Treatment: BDQ-containing regimen versus rifamycin-containing regimen.
 
Intercurrent Events (ICE):
a. Deaths, treatment discontinuation and treatment regimen changes prior to Week 24: all
the ICEs will be handled by a composite strategy to treat the participants as non-
convertors.
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b. Major protocol deviations: all data will be used regardless of the occurrence of major
protocol deviations (treatment policy strategy).
 
Population Level Summary: The difference of proportions between treatment groups.
9.4.3. 
Primary Endpoint
Sputum Culture Conversion in MGIT at Week 24.
The Cochran-Mantel-Haenszel test stratified by region (Japan, non-Japan) at the 5% 2-sided
significance level will be used to compare sputum culture conversion rate in MGIT at Week 24.
Participants with missing sputum samples that impact the ability to assess sputum culture
conversion (ie, 3 consecutive negative sputum cultures taken at least 25 days apart) will be imputed
as non-convertors in the analysis. Participants requiring a treatment regimen change to
individualized regimen will also be considered as non-convertors. A contaminated sputum culture
or failed culture occurring between two negative cultures will be interpreted as “no data”, and will
be ignored for the assessment of the 3 consecutive negative cultures. More details will be provided
in the SAP. Subgroup analyses will be performed for important baseline disease characteristics.
9.4.4. 
Secondary Endpoints
 
Sputum culture conversion in MGIT and 7H10 or 7H11 agar media (other than MGIT at Week
24).
The percentage of participants with sputum culture conversion (defined as 3 consecutive negative
sputum cultures taken at least 25 days apart) in MGIT and 7H10 or 7H11 agar media will be
calculated after Week 4. The percentage of participants who achieved sputum culture conversion
at Week 24 and completed 48-week BDQ-containing regimen and achieved sputum culture
conversion at Week 60 in Group A will be compared with the percentage of participants who
completed 60-week SOC regimen and achieved sputum culture conversion at Week 60 in Group
B using the Cochran-Mantel-Haenszel test stratified by region (Japan, non-Japan).
 
Sputum culture negativity in MGIT and 7H10 or 7H11 agar media.
The percentage of participants with sputum culture negativity in MGIT and 7H10 or 7H11 agar
media will be calculated at each visit after Week 2, respectively. A generalized linear model
including treatment, region (Japan, non-Japan), time, and treatment-by-time interaction as fixed
effects will be applied for the number of negative culture participants and the number of all
participants at each timepoint and comparison between treatment groups will be performed using
the appropriate contrast for the percentage of negative culture participants at Week 24.
 
Time to sputum culture conversion in MGIT.
Time to sputum culture conversion in MGIT is calculated as the interval in days between the
initiation date of the study intervention and the sampling date of the first of the 3 consecutive
negative sputum cultures from sputum samples collected at least 25 days apart.44 Kaplan-Meier
estimates will be generated for the time to sputum culture conversion up to Week 24 and Week 48.
The difference between the treatment groups will be compared using the log-rank test stratified by
region (Japan, non-Japan) for the time to sputum culture conversion up to Week 24. For
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participants with no sputum culture conversion during the analysed period, time to culture
conversion is censored on the last assessment day of the analysed period.
 
Time to positivity in MGIT.
Time to positivity is calculated as the time required to positive signal in MGIT. A recent study
showed a similar correlation between CFU and time to positivity with MAC.37
 
SGRQ.
The changes from baseline in total score of SGRQ and domain scores will be summarized
descriptively at Weeks 24, 48, and 60. For the total score of SGRQ at Week 24, the difference in
the change from baseline between the treatment groups will be provided using an analysis of
covariance (ANCOVA) model.
 
Percentage of participants who undergo a change in their MAC-LD treatment regimen.
The percentage of participants who are changed from randomized treatment regimen to the
individualized treatment regimen, including switched to the optional cohort is calculated.
9.4.5. 
Tertiary/Exploratory Endpoint
The changes from baseline in score of QOL-B NTM module and domain scores will be
summarized descriptively at Weeks 24, 48, and 60.
For participants who achieved sputum culture conversion, the changes from baseline in the total
score of SGRQ, the score of QOL-B NTM module, and chest CT findings will be evaluated.
The relationship between BDQ and CAM PK and MAC-LD treatment outcome and safety
endpoints will be evaluated. PK/PD analyses will be performed on the collected data when all
participants have reached Week 24 or discontinued earlier. The PK/PD analyses may be performed
at earlier time points as necessary to support efficacy and safety findings. If there is any visual
trend in graphical analysis, suitable models will be applied to describe the PK/PD relationships.
The results of the PK/PD evaluations will be presented in a separate report. Other exploratory
endpoints specified in Section 3, OBJECTIVES AND ENDPOINTS will be analyzed descriptively.
9.4.6. 
Safety Analyses
All safety analyses will be made on the Safety Population.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs are AEs with
onset during the treatment period or that are a consequence of a preexisting condition that has
worsened since baseline. All reported treatment-emergent AEs will be included in the analysis.
For each AE, the percentage of participants who experience at least 1 occurrence of the given event
will be summarized by treatment group. In addition, comparisons between treatment groups will
be provided if appropriate.
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Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue study intervention due to an AE, or who experience a severe
AE of at least Grade 3 or an SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the SAP) will be used in the summary of laboratory data. Descriptive
statistics will be calculated for each laboratory analyte at baseline and for observed values and
changes from baseline at each scheduled time point. Changes from baseline results will be
presented in pre- versus postintervention cross-tabulations (with classes for below, within, and
above normal ranges). Frequency tabulations of the laboratory abnormalities will be made. A
listing of participants with any laboratory results outside the reference ranges will be provided. A
listing of participants with any markedly abnormal laboratory results based on DMID scale
(defined in SAP) will also be provided.
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and
frequency tabulations. These tables will include observed values and changes from baseline values
(the predose ECG will be used as baseline).
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be
calculated at baseline and for observed values and changes from baseline at each scheduled time
point. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and
QTc interval using some of the following correction methods: QT corrected according to Bazett's
formula (QTcB), QTcF.
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each
scheduled time point. The percentage of participants with QTc interval >450 milliseconds (ms),
>480 ms, or >500 ms will be summarized, as will the percentage of participants with QTc interval
increases from baseline >30 ms or >60 ms.
All clinically relevant abnormalities in ECG waveform that are changes from the baseline readings
will be reported (eg, changes in T-wave morphology or the occurrence of U-waves).
Vital Signs
Vital signs including temperature (axillary), heart rate, respiratory rate, oxygen saturation, and
blood pressure (systolic and diastolic) (supine or sedentary after at least 5 minutes rest) values and
changes from baseline will be summarized at each scheduled time point. The percentage of
participants with values beyond clinically important limits based on DMID scale (defined in SAP)
will be summarized.
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Physical Examination, Visual Examination, and Audiology
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Physical examination findings will be summarized at each scheduled time point. Descriptive
statistics will be calculated at baseline and for observed values and changes from baseline at each
scheduled time point. Frequency tabulations of the abnormalities will be made. Visual acuity, color
discrimination, visual field, fundoscopy, and audiometry data will be descriptively presented.
9.4.7. 
Other Analyses
An IDMC will be established as noted in Committees Structure in Section 10.3, Appendix 3:
Regulatory, Ethical, and Study Oversight Considerations.
Pharmacokinetic Analyses
If feasible, population PK analysis of plasma BDQ (and M2 [optional]) concentration-time data of
BDQ (and M2 [optional]) may be performed using nonlinear mixed-effects modeling. Data may
be combined with those of other selected studies to support a relevant structural model. Available
baseline participant characteristics (demographics, laboratory variables, genotypes, race, etc) will
be tested as potential covariates affecting PK parameters. Details will be given in a population PK
analysis plan and the results of the population PK analysis will be presented in a separate report.
A snapshot date for PK samples to be analyzed will be defined, if required. Samples collected
before this date will be analyzed for BDQ (and M2 [optional]) and included in the population PK
analysis. Samples collected after the snapshot date will be analyzed at a later date and may be
included in a population PK re-analysis when they become available after database lock.
Data will be listed for all participants with available plasma concentrations per intervention group.
For each intervention group, descriptive statistics, including arithmetic mean, SD, coefficient of
variation, median, minimum, and maximum will be calculated for all individual derived PK
parameters including exposure information of BDQ and M2 (if applicable) for Group A, and will
be calculated for predose and 2 to 4 hours postdose plasma concentrations on Day 1, Weeks 2, 8,
12, 24, and 48 (for Week 48, BDQ and M2 only) of BDQ, and CAM and 4-OH CAM for both
Groups A and B.
All plasma concentrations below the lowest quantifiable concentration or missing data will be
labeled as such in the concentration data presentations or SAS dataset. Concentrations below the
lower quantifiable concentration will be treated as zero in the summary statistics. All participants
and samples excluded from the analysis will be clearly documented in the Clinical Study Report.
Mean and median plasma BDQ, M2, CAM and 4-OH CAM concentration time profiles will be
plotted after the first dose of BDQ, and individual serum concentration time profiles may also be
plotted.
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9.5. 
Interim Analysis
The SAP will describe the planned interim (futility) analyses in greater detail.
A futility analysis will be implemented to evaluate early the benefit/risk balance by assessing
safety and efficacy in the first 60 participants (about 30 participants from both groups) who reach
the Week 24 time point or discontinued earlier or switched to individualized treatment regimen.
This futility analysis is nonbinding and the IDMC will recommend the continuation or termination
of the study based on the whole package of information, which also includes other efficacy and
safety assessments.
In case lack of efficacy is concluded:
 
enrollment in the study will be stopped.
 
participants already enrolled will be switched to a treatment regimen at the discretion of the
investigator.
In case no lack of efficacy is concluded:
 
ongoing enrollment will continue.
Details of the futility analysis (including classification of lack of efficacy) and criterion will be
included in the IDMC charter and SAP. The futility analysis will be prepared by a Statistical
Support Group organized outside of the sponsor.
The primary analysis will be performed when all participants have reached Week 24 or have
discontinued earlier than Week 24.
After the primary analysis, IAs are planned when:
 
all participants have reached Week 48 or discontinued earlier or have switched to the optional
cohort.
 
all participants have reached Week 60 or discontinued earlier or have switched to the optional
cohort.
The primary analysis and the analyses after Week 24 will be conducted by the sponsor. Additional
interim analyses may be performed on request of health authorities or for preparing interactions
with health authorities.
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. 
Appendix 1: Abbreviations
*: The abbreviations for the medications, such as CAM are the one specified in the Japanese
package insert of each medication and Japanese guidelines.
AE(s) 
adverse event(s)
AIDS 
acquired immunodeficiency syndrome
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase
AMK* 
amikacin
ALIS 
amikacin liposome inhalation suspension 
ANCOVA 
analysis of covariance
AST 
aspartate aminotransferase
ATP 
adenosine 5'-triphosphate
ATS 
the American Thoracic Society 
AUC 
area under the plasma concentration-time curve
AZM* 
azithromycin
BDQ 
bedaquiline (TMC207)
-hCG 
-human chorionic gonadotropin
bid 
bis in die (twice a day)
biw 
bis in week (twice a week)
CAM* 
clarithromycin
CFU 
colony forming unit
Cmax 
maximum plasma concentration 
CLSI 
Clinical and Laboratory Standards Institute
COPD 
chronic obstructive pulmonary disease
CPK 
creatine phosphokinase
CPK-MB 
CPK myocardial band 
CT 
computed tomography
Ctrough 
minimum plasma concentration between 0 hour and the dosing interval τ
CYP 
cytochrome P450
DDI 
drug-drug interaction
DMID 
Division of Microbiology And Infectious Diseases
DST 
drug susceptibilit y testing 
EB 
ethambutol
ECG 
electrocardiogram
eCRF 
electronic case report form
FC 
fibro-cavitary
FEV1 
forced expiratory volume in one second 
FSH 
follicle stimulating hormone
GCP 
Good Clinical Practice
GGT 
gamma-glutamyl transferase
HBsAg 
hepatitis B surface antigen
HCV 
hepatitis C virus
HIV 
human immunodeficiency virus
HRQOL 
health-related quality of life
HRT 
hormonal replacement therapy
IB 
investigator’s brochure
ICE 
intercurrent events
ICF 
informed consent form 
ICH 
International Council for Harmonization 
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ICMJE 
International Committee of Medical Journal Editors
IDMC 
Independent Data Monitoring Committee
IDSA 
the Infectious Diseases Society of America
IEC 
Institutional Ethics Committee
IRB 
Institutional Review Board 
ITT 
intent-to treat
KM* 
kanamycin
LD 
lung disease
LDH 
lactic acid dehydrogenase
LPV 
lopinavir
M 
Mycobacterium
MAC 
Mycobacterium avium complex
MALDI-TOF MS 
matrix-assisted laser desorption ionization time of flight mass spectrometry
MDR 
multi-drug resistant
MedDRA 
Medical Dictionary for Regulatory Activities
MGIT 
mycobacteria growth indicator tube
MIC 
minimal inhibitory concentration
NB 
nodular-bronchiectatic
NTM 
nontuberculous mycobacterial
PD 
pharmacodynamic(s)
PK 
pharmacokinetic(s)
PP 
per-protocol
PQC 
product quality complaint
PROs 
patient-reported outcomes
qd 
quaque die (once daily)
QOL-B 
quality of Life-Bronchiectasis
QTc 
corrected QT
QTcB 
QT corrected according to Bazett's formula
QTcF 
QT corrected according to Fridericia’s formula
QTL 
quality tolerance limits
RBC 
red blood cell
RBT* 
rifabutin
RFP* 
rifampicin
rtv 
ritonavir
SAE 
serious adverse event
SAP 
statistical analysis plan
SOC 
standard of care
SGRQ 
St. George’s Respiratory Questionnaire
SM* 
streptomycin 
TB 
tuberculosis
ULN 
upper limit of normal
VNTR 
variable number tandem repeat
WBC 
white blood cell
WGS 
whole genome sequencing
WOCBP 
woman of childbearing potential
Definitions of Terms
Electronic source
system
Contains data traditionally maintained in a hospital or clinic record to document
medical care or data recorded in an eCRF as determined by the protocol. Data in
this system may be considered source documentation.
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10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonization (ICH) guidelines on Good Clinical
Practice (GCP), and applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor; and signed and dated by the
investigator. Protocol amendments must not be implemented without prior Institutional Ethics
Committee (IEC)/Institutional Review Board (IRB) approval, or when the relevant competent
authority has raised any grounds for nonacceptance, except when necessary to eliminate immediate
hazards to the participants, in which case the amendment must be promptly submitted to the
IEC/IRB and relevant competent authority. Documentation of amendment approval by the
investigator and IEC/IRB must be provided to the sponsor. When the change(s) involve only
logistic or administrative aspects of the study, the IEC/IRB (where required) only needs to be
notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Protocol Supplementary Information, which will be provided as a separate document.
Except in emergency situations, this contact should be made before implementing any departure
from the protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss
the situation and agree on an appropriate course of action. The data recorded in the eCRF and
source documents will reflect any departure from the protocol, and the source documents will
describe this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:
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 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
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 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
intervention
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
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At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.3.3. 
Informed Consent Process
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the participant can read and understand. The informed consent
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits,
and potential hazards of the study, and any discomfort participation in the study may entail.
Participants will be informed that their participation is voluntary and that they may withdraw
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the participant will receive for the treatment of his or her disease. Participants will
be told that alternative treatments are available if they refuse to take part and that such refusal will
not prejudice future treatment.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded
by means of the participant's personally dated signature. After having obtained the consent, a copy
of the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
In addition, when switching to an individualized treatment regimen, obtaining re-consent from
participants is required.
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10.3.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
10.3.5. 
Long-term Retention of Samples for Additional Future Research
Not applicable.
10.3.6. 
Committees Structure
Independent Data Monitoring Committee
An IDMC will be established to monitor data on an ongoing basis to ensure the continuing safety
of the participants enrolled in this study and to meet efficacy objectives. This committee will
consist of at least one medical expert in the relevant therapeutic area, at least one medical expert
in cardiology, and at least one statistician; committee membership responsibilities, authorities, and
procedures will be documented in its charter. The committee will meet periodically to review
safety and efficacy data and results. After the review of the interim (futility) analysis results at
Week 24, the IDMC will make recommendations regarding the continuation of the study.
Since the microbiological results are blinded up to Week 24, if the investigators consider the
regimen change based on clinical worsening of the symptoms related to MAC-LD based on the
result of chest CT scan and so on, the investigators can consult with IDMC.
This futility analysis is nonbinding and the IDMC will recommend the continuation or termination
of the study based on the whole package of information, which also includes other efficacy and
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safety assessments. Sponsor will decide the continuation or termination of the study based on the
recommendation by IDMC.
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding BDQ or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including research data, generated as a result of this study, are
considered confidential and remain the sole property of the sponsor. The investigator agrees to
maintain this information in confidence and use this information only to accomplish this study and
will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of BDQ, and thus may be disclosed as
required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and substudy approaches, secondary results generally should not be
published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
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Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 8 December 2022
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
10.3.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Quality tolerance limits (QTLs) will be defined to identify systematic issues that can impact
participant safety and/or reliability of study results. These pre-defined parameters will be
monitored during the study and important deviations from the QTLs and remedial actions taken
will be summarized in the clinical study report.
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's database.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before
the start of the study.
The sponsor will review eCRF for accuracy and completeness during on-site monitoring visits and
after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
10.3.9. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in eCRF. All eCRF entries, corrections, and
alterations must be made by the investigator or authorized study-site personnel. The investigator
must verify that all data entries in the eCRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an
eCRF, if applicable.  Study-specific data will be transmitted in a secure manner to the sponsor.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
eCRF in English. The eCRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, SGRQ and QOL-B NTM module) will be completed by the
same individual who completed the initial baseline.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
 
Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
10.3.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; study intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention or withdrawal from the study,
if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The following data will be recorded directly into the eCRF and will be considered source data:
 
Race
 
History of all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent of e-
cigarettes), cigars, chewing tobacco, patch, gum
 
Blood pressure and heart rate
 
Height and weight
 
Details of physical examination
 
PROs
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
 
Referral letter from treating physician or
 
Complete history of medical notes at the site
 
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
eCRF.
10.3.11. 
Monitoring
The sponsor will use a combination of monitoring techniques central, remote, or on-site monitoring
to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor will compare the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
eCRF are known to the sponsor and study-site personnel and are accessible for verification by the
sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
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Clinical Protocol TMC207NTM3002 Amendment 8
 
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10.3.12. 
On-site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study-site personnel are responsible for being present and available
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
10.3.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
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.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14. 
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
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Status: Approved, Date: 8 December 2022
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 
Inadequate recruitment of participants by the investigator
 
Discontinuation of further study intervention development
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10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions And Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or noninvestigational) product. An AE does not necessarily have
a causal relationship with the study intervention. An AE can therefore be any unfavorable and
unintended sign (including an abnormal finding), symptom, or disease temporally associated with
the use of a medicinal (investigational or noninvestigational) product, whether or not related to
that medicinal (investigational or noninvestigational) product. (Definition per ICH)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information, for time of last adverse event recording).
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for
Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (eg, death from anaphylaxis), the event must be
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reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For BDQ, the expectedness of an AE will be determined by whether
it is listed in the IB.
For rifamycin (RFP or RBT) and combination drugs (CAM and EB) with marketing authorization,
the expectedness of an AE will be determined by whether or not it is listed in the Japanese package
insert.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the investigator. The following
selection should be used to assess all AE. In case AMK is administered as individualized treatment
for MAC-LD, the causal relationship to AMK should be assessed and determined by the
investigator accordingly.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3. 
Severity Criteria
An assessment of severity grade will be made using Section 10.7, Appendix 7: A Division of
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (November 2007). In case of
the event is not listed in DMID table, the severity grade will be made accordingly.
Grade 1 (Mild): Transient or mild discomfort (<48 hours); no medical intervention/therapy
required.
Grade 2 (Moderate): Mild to moderate limitation in activity - some assistance may be needed; no
or minimal medical intervention/therapy required.
Grade 3 (Severe): Marked limitation in activity, some assistance usually required; medical
intervention/therapy required, hospitalizations possible.
Grade 4 (Life-threatening): Extreme limitation in activity, significant assistance required;
significant medical intervention/therapy required, hospitalization or hospice care probable.
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The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study
intervention
 
Unexpected therapeutic or clinical benefit from use of a sponsor study intervention
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
 
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
10.4.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions. If any change in seriousness or severity
of a recorded AE is observed, the investigators must record it as new event in the eCRF.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
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 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the
participant's discontinuation from the study, must be followed until any of the following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
 
For convenience the investigator may choose to hospitalize the participant for the duration of
the treatment period.
The cause of death of a participant in a study within 30 days of the last dose of study intervention,
whether or not the event is expected or associated with the study intervention, is considered an
SAE.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form, which
must be completed and signed by a physician from the study site and transmitted in a secure
manner to the sponsor within 24 hours. The initial and follow-up reports of an SAE should be
made by facsimile (fax). Telephone reporting should be the exception and the reporter should be
asked to complete the appropriate form(s) first.
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10.4.6. 
Product Quality Complaint Handling
Definition
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, reliability, or performance of a distributed product, including its labeling, drug delivery
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential
quality issue during manufacturing, packaging, release testing, stability monitoring, dose
preparation, storage or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Protocol
Supplementary Information, which will be provided as a separate document.
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10.5. 
Appendix 5: Contraceptive Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Section 10.4, Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints,
and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high FSH level (>40 IU/L or mIU/mL) in the postmenopausal range may be used to
confirm a postmenopausal state in women not using hormonal contraception or hormonal
replacement therapy (HRT), however in the absence of 12 months of amenorrhea, a single
FSH measurement is insufficient. If there is a question about menopausal status in women on
HRT, the woman will be required to use one of the nonestrogen-containing hormonal highly
effective contraceptive methods if she wishes to continue HRT during the study.
 
permanently sterile (for the purpose of the study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly.
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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.a
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Bilateral tubal occlusion
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention. The
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the
preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male condom with or without spermicide
 Diaphragm with spermicide
 A combination of male condom with either diaphragm with spermicide (double-barrier methods)
 Periodic abstinence (calendar, symptothermal, postovulation methods)
 Withdrawal (coitus-interruptus)
 Lactational amenorrhea method
a Typical use failure rates may differ from those when used consistently and correctly.
b Hormonal contraception may be susceptible to interaction with the study intervention, which may reduce the
efficacy of the contraceptive method. In addition, consider if the hormonal contraception may interact with
the stud y intervention.
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10.6. 
Appendix 6: Patient-reporting Questionnaires
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QOL-B Questionnaire
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10.7. 
Appendix 7: A Division of Microbiology and Infectious Diseases (DMID)
Adult Toxicity Table (November 2007)
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TMC207 (Bedaquiline)  
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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TMC207 (Bedaquiline)  
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
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TMC207 (Bedaquiline)  
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10.8. 
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 7 (30-Jun-2022)
Overall Rationale for the Amendment: To change text regarding extension of screening period and
timing of visual examination and fundoscopy at Day 1.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of Activities 
(SoA) 
1.3.1. Schedule of Activities 
(SoA) in the Optional Cohort
Updated to allow an extension of the 
screening period up to 14 weeks. 
To specify the upper limit of
allowable extended screening
period.
1.3. Schedule of Activities 
(SoA) 
1.3.1. Schedule of Activities 
(SoA) in the Optional Cohort
8.2.7. Other Safety
Evaluations
Changed timing of visual examinations and 
fundoscopy at Day 1 within 4 weeks prior to 
Day 1 instead of 1 week prior to Day 1.  
To revise the allowable time
window for visual examination
and fundoscopy.
Throughout the protocol 
Minor changes were made. 
Minor errors were noted.
Amendment 6 (20-Apr-2022)
Overall Rationale for the Amendment: To add actions to be taken when it takes time to obtain results
of microbiology assessment of screening and Week 24, to indicate that site personnel involved in
monitoring of the study sites and personnel involved in management operations of the central laboratory
etc. are excluded from maintenance of blinding for microbiology assessment in order to confirm that
switch to individualized treatment regimen and the optional cohort is carried out appropriately based on
the protocol, to correct Japanese translation regarding exclusion criteria on ECG and text regarding ECG
specifications, to clarify data used for OPD1, to clarify interval for early discontinuation visit, to add text
regarding concomitant therapies to be recorded at screening, and to correct text on the QOL-B NTM
module.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of Activities
(SoA)
1.3.1. Schedule of Activities
(SoA) in the Optional Cohort
Changed applicable X notation of OPD1 to
X on Schedule of Activities in the Optional
Cohort.
 
Note: (X)=If available, X=In principle, no
additional test is required as OPD1 as data of
Week 24 will be used as the baseline.
 
Footnote a. Screening evaluations must be
performed within 63 days (9 weeks) prior to
baseline (Day 1). These 9 weeks include 14
days of rifamycin W/O for participants to
whom it is applicable. If screening period
exceeds 9 weeks for reasons such as time
required to obtain the result of microbiology
assessment of screening, the screening
period ma y be extended.
Text was added for actions to be
taken when it takes time to
obtain results of microbiology
assessment of screening and
Week 24. Also, text was added
to clarify the data used for
OPD1 and interval for early
discontinuation visit.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
 
Footnote f. Early discontinuation visit is to
be scheduled within 7 days of the
investigator’s discretion to discontinue
treatment with study intervention after
withdrawal from the study (including the
day of discontinuation withdrawal, other
than withdrawal of consent). Visit for switch
to individualized treatment regimen is to be
scheduled within 7 days after discontinuing
the assigned treatment regimen (including
the day of switch) and before the start of
individualized treatment regimen.
 
Footnote y. Including visual acuity, color
discrimination, visual field. Audiology and
visual examinations within 1 week prior to
Day 1 and within 4 days prior or after each
visit other than Day 1 will be acceptable. If
screening period is extended for reasons
such as time required to obtain the results of
microbiology assessment of screening,
audiology and visual examinations at Day 1
should be reassessed when the extended Day
1 is more than 28 days after the scheduled
test date.
 
Footnote z. After Week 24 assessment, all
participants in the Group B who are
nonconversion and well-tolerated, will be
considered to receive the BDQ-containing
regimen at the discretion of the
investigators. When the investigator changes
to BDQ-containing regimen, 2-week
washout of treated rifamycin must be given
before initiation of BDQ-containing
regimen. The investigators can postpone the
decision to transfer to the optional cohort for
up to Week 32 in order to confirm a sputum
culture positive at Week 24, if necessary. If
decision to transfer to the optional cohort
exceeds Week 32 for reasons such as time
required to obtain the result of microbiology
assessment of Week 24, the period may be
extended. If necessary, consider study date
of OPD1 by adding the number of days
required to switch to the optional cohort to
study date of Week 24.
 
Footnote aa. OPD1 is Day 1 for participants
who are transferred to optional cohort.
Assessments planned on OPD1 must be
performed prior to first dose of BDQ. The
investigators can postpone the decision to
switch to the optional cohort for up to Week
32 in order to confirm sputum culture
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
positive at Week 24. If decision to transfer
to the optional cohort exceeds Week 32 for
reasons such as time required to obtain the
result of microbiology assessment of Week
24, the period may be extended.
 
Footnote cc. In principle, testing data at
Week 24 will be used as that of OPD1, so it
is not necessary to perform another test as
OPD1. If the transition period is extended
due to confirmation of the result of sputum
culture, the result of microbiology
assessment of Week 24 will be used as that
of OPD1, the latest data (Week 28, etc.) will
be used when specified testing other than the
microbiology assessment have been
performed after Week 24 in Group B.
 
Footnote dd. Fundoscopy within 1 week
prior to Day 1 and within 4 days prior or
after each visit other than Day 1 will be
acceptable. If screening period is extended
for reasons such as time required to obtain
the results of microbiology assessment at
screening, visual examinations at Day 1
should be reassessed when the extended Day
1 is more than 28 days after the scheduled
test date.
5.2. Exclusion Criteria 
Japanese translation for Exclusion Criteria 8 
has been corrected.
Corrected Japanese translation.
6.3. Measures to Minimize 
Bias: Randomization and 
Blinding 
As this is an open-label study, blinding 
procedures are not applicable. However, the 
microbiological results from Week 2 to 
Week 24 will be blinded to the investigators, 
site staffs and, participants, and sponsor until 
the completion of the other assessments at 
Week 24 by the investigators. In case the 
investigators need to know the 
microbiological result to decide if 
participants should be switched to an 
individualized treatment regimen or continue 
the study treatment regimen, due to clinical 
worsening, the investigators can access the 
microbiological result from the central 
laboratory (for the detailed procedure, refer 
to the Procedure for Confirmation and 
Reporting of Results of Blinded Sputum 
Culture Including Collection of Samples for 
Microbiology Test). In this case, sSponsor
except for specific personnel listed below
must keep the blinding of all the
microbiological assessment after Week 2
until completion of unblinding takes place
for the primary analysis.
In addition, sponsor personnel involved in
monitorin  g of the stud y sites and personnel
Text was corrected to clearly
describe the duration of blinding
of microbiology assessment
after Week 2 for the sponsor.
In addition, since it is necessary
to confirm that decision to
switch individualized treatment
regimen and the optional cohort
is appropriately carried out
based on the protocol, sponsor
personnel involved in
monitoring of the study sites and
personnel involved in
management operation of the
central laboratory etc. are
excluded from the scope of
blinding for microbiology
assessment.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Section Number 
and Name
Description of Change 
Brief Rationale
involved in management operation of the
central laboratory etc. are excluded from
maintenance of blinding for microbiology
assessments, taking into account that
sponsor needs to confirm that investigators
and etc. comply with the protocol and the
decision to switch to individualized
treatment regimen and the optional cohort is
made based on the appropriate process.
Details will be provided in the statistical
analysis plan (SAP).
6.8. Concomitant Therapy 
Concomitant therapies administered after 
signing informed consent (Prestudy 
therapies administered up to 63 days before 
first dose of study intervention) and prestudy
therapies for pulmonary MAC disease
administered prior to signing informed
consent must be recorded at screening.
Text was added to clarify the
concomitant therapy to be
recorded at screening.
7.1. Discontinuation of Study 
Intervention 
The early discontinuation visit assessment 
will be performed within 7 days of the 
investigator’s discretion to discontinue 
treatment with study intervention after
withdrawal from the study, unless the
participant withdraws consent.
Text was modified to clarify
interval for early discontinuation
visit.
7.2. Participant 
Discontinuation/Withdrawal 
From the Study 
Participants will be encouraged to complete
the early discontinuation visit assessments,
which is to be scheduled within 7 days of
investigator’s discretion to discontinue
treatment with study intervention after
withdrawal from the study.
8.1.2. Clinical Assessments in 
MAC-LD 
The NTM module is developed specifically 
for NTM symptoms and consists mainly of
NTM symptoms (7 items), body image (4
items), digestive symptoms (76 items), and
eatin  g problems (3 items).
Corrected text.
8.2.3. Electrocardiograms 
All tracings will be transmitted for blinded 
central analysis. Participants found to have a 
QT or QTcF ≥500 ms or an increase from 
baseline (mean of triplicates on Day 1) of 
>60 ms on ECG at any point during the 
treatment period will be further investigated. 
Text on QT was removed to
clarify that any participants with
an QTcF ≥ 500 ms or an
increase from baseline of >
60 ms while on study
investigation should be further
investigated, and is considered a
notable event and should be
reported immediately to the
sponsor.
Any QT or QTcF prolongation to ≥500 ms 
or an increase from baseline (mean of 
triplicates on Day 1) of >60 ms while on 
study intervention is considered a notable 
event and should be reported immediately to
the sponsor.
Amendment 5 (09-Dec-2021)
Overall Rationale for the Amendment: To reconsider transition period to the optional cohort (time to
confirm the result of sputum culture), to clarify the reason for setting up the individualized treatment
regimen, to clarify drug susceptibility test and genotyping, as well as to correct minor errors.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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125
Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.1. Synopsis 
In addition, this study provides an option to 
receive BDQ -containing regimen for 
nonconverters in Group B based on the
result of microbiological test up to at Week
24 as the optional cohort.
Text was corrected for
clarification.
A futility analysis will be implemented to 
evaluate early the benefit/risk balance by
assessing safety and efficacy in the first 60
participants (about 30 participants from both
groups) who reach the Week-24 time point
or discontinued earlier or switched to
individualized treatment regimen.
Text was added for clarification.
1.2. Schema 
The following corrections were made to 
Figure 1: Schematic Overview of the Study. 
 
Footnote a. Prior to Week 24, participants
who are judged to have difficulty continuing
their designated treatment regimen due to
failure to respond (based on nonconversion
and clinical worsening) or the occurrence of
AE will be considered treatment failures and
can switch to an individualized treatment
regimen (see Section 6.8.1), at the discretion
of the investigator in consultation with
IDMC.
 
Footnote b. After Week 24 assessment, all
participants who are judged to have
difficulty continuing their designated
treatment regimen due to failure to respond
(based on nonconversion and clinical
worsening) or the occurrence of AE will be
considered treatment failures and will be
given the option to switch to an
individualized treatment regimen (see
Section 6.8.1) at the discretion of the
investigator.
 
Footnote e. All participants who are judged
to have difficulty continuing their BDQ-
containing regimen due to failure to respond
(based on nonconversion and clinical
worsening) or the occurrence of AE will be
considered treatment failures and will be
given the option to switch to an
individualized treatment regimen (see
Section 6.8.1) at the discretion of the
investigators.
Reference was added for
clarification.
1.3. Schedule of Activities 
(SoA) 
1.3.1. Schedule of Activities 
(SoA) in the Optional Cohort 
Drug susceptibility testing after Week 2: The 
testing will be performed on positive isolates 
at Week 24 as well as and at the last visit
with culture positive isolates culture sample
after Week 24, and also in case of
participants with nonconversion and
recurrence (relapse/reinfection). or In
addition, it will be performed on positive
Text was added and corrected
for clarification.
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TMC207 (Bedaquiline)  
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Section Number 
and Name
Description of Change 
Brief Rationale
isolates at early discontinuation (if
available).
 
Drug susceptibility testing after OPW 2 in
the optional cohort: The testing will be
performed on At the last visit with culture
positive isolates culture sample and also in
case of participants with nonconversion and
recurrence (relapse/reinfection). or In
addition, it will be performed on positive
isolates at early discontinuation (if available)
 
VNTR or WGS after Week 2 and after
OPW2 in the optional cohort: In case of
recurrence (relapse/reinfection) culture
reversion, and if acquired resistance or (at
least 4-fold increased MIC) to BDQ any
used drug, VNTR (and/or WGS) will be
performed on both baseline and postbaseline
isolates.
 
Fundoscopy in the optional cohort: footnote
dd was added.
 
Footnote f. Early discontinuation visit is to
be scheduled within 7 days after withdrawal
from the study (including the day of
withdrawal, other than withdrawal of
consent). and or Visit for switch to
individualized treatment regimen is to be
scheduled within 7 days after discontinuing
the assigned treatment regimen (including
the day of switch) and before the start of
switching to individualized treatment
regimen.
 
Footnote p. Drug susceptibility testing
(DST) will be done on culture positive
isolates at screening, baseline, and at Week
24. and at The testing will be done on the
last visit with culture positive isolates
culture sample and also in case of
participants with nonconversion and
recurrence (relapse/reinfection). or In
addition, the testing will be done on positive
isolates at early discontinuation (if
available). In the optional cohort, DST will
be done on at the last visit with culture
positive isolates culture sample and also in
case of participants with nonconversion and
recurrence (relapse/reinfection), or as well as
positive isolates at early discontinuation (if
available).
 
Footnote q. In case of recurrence
(relapse/reinfection a positive culture
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TMC207 (Bedaquiline)  
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Status: Approved, Date: 8 December 2022
Section Number 
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Brief Rationale
occurring after having been negative) or in
case of acquired resistance or (at least 4-fold
increased MIC) to BDQ is indicated by DST
result any used drug, baseline and
postbaseline isolates will be identified
genotyped using WGS or VNTR if
necessary. If WGS is available, it will be
used to identify genetic markers of
resistance and to compare baseline and
postbaseline isolates. If more than 1
postbaseline positive culture (isolate)
showing resistant is available and is
resistant, only the last culture positive
culture sample (isolate) will be tested for
VNTR and/or WGS in addition to the
baseline culture positive sample. culture
(isolate). If more than 1 positive culture
(isolate) is available after having been
negative, only the last positive culture
(isolate) will be tested for VNTR or WGS in
addition to the baseline positive culture
(isolate).
Footnote z. After Week 24 assessment, all 
participants in the Group B who are 
nonconversion and well-tolerated, will be 
considered to receive the BDQ-containing 
regimen at the discretion of the 
investigators. When the investigator changes
to BDQ-containing regimen, 2-week
washout of treated rifamycin must be given
before initiation of BDQ-containing
regimen. The investigators can postpone the
decision to transfer to the optional cohort for
up to Week 32 30 in order to confirm a
sputum culture positive at Week 24, if
necessary. If necessary, consider study date
of OPD1 by adding the number of days
required to switch to the optional cohort to
study date of Week 24.
 
Footnote aa. OPD1 is Day 1 for participants
who are transferred to optional cohort.
Assessments planned on OPD1 must be
performed prior to first dose of BDQ. The
investigators can postpone the decision to
switch to the optional cohort for up to Week
32 30 in order to confirm sputum culture
positive at Week 24.
 
Footnote cc. In principle, testing data at
Week 24 will be used as that of OPD1. Even
If this duration the transition period is
extended up to 6 weeks due to confirmation
of the result of sputum culture, the latest
data will be used when specified testing
Text was corrected as the
transition period (time to
confirm the result of sputum
culture) has been reconsidered
and for clarification.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
have been performed after on Week 24 or
later in Group B will be used for these items.
4.1. Overall Design 
Participants requiring a treatment regimen 
change will be considered treatment failures 
for subsequent endpoints and will be 
followed up for safety only, but all 
assessments should be performed according
to the protocol. In addition to the option to
switch to the optional cohort in Group B and
withdrawal from the study, individualized
treatment regimen was set up to as a regimen
that may be used when participants are
judged to have difficulty continuing their
designated treatment regimen due to failure
to respond (based on nonconversion
supported by microbiological results, and
clinical worsening of symptoms related to
MAC-LD supported by the results such as
chest computed tomography [CT] scan) or
the occurrence of AE. All decisions on
treatment regimen change should be made
when participants are judged to have
difficulty continuing their designated
treatment regimen due to failure to respond
(based on nonconversion supported by
microbiological results, and clinical
worsening of symptoms related to MAC LD
supported by the results such as chest
computed tomography (CT) scan) or the
occurrence of AE, except for switching to
the optional cohort. Since the
microbiological results are blinded, if the
investigators consider the regimen change
based on the clinical worsening of symptoms
related to MAC-LD supported by the result
of chest CT scan and so on, the investigators
can consult with IDMC before the change.
Specific switching criteria, treatment
options, visits and assessments before and
after switching, and follow-up will be
detailed in Section 6.8.1, Individualized
Treatment Regimen.
The text was added and
corrected to clarify the reason
for setting up the individualized
treatment regimen.
In this optional cohort, during the 48-week 
treatment period (from Day 1 in optional 
cohort [OPD1] to Week 48 in optional 
cohort [OPW48]) of the study, participants 
may be changed to individualized treatment
regimen can have a change in their treatment
regimen, in which MAC LD treatment may
continue in accordance with SOC of
Japanese guidelines or medical practice at
each stud y site.
Text was revised according to
the clarification of
individualized treatment
regimen.
The investigators can postpone the decision 
to transfer to the optional cohort for up to 
Week 30 32 in order to confirm a sputum 
culture positive at Week 24, if necessary. 
Text was corrected as the
transition period (time to
confirm the result of sputum
culture) has been reconsidered
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
Regardless of delay in the transition phase
up to 6 weeks, the treatment duration of the
optional cohort will be for 48 weeks.
4.2. Scientific Rationale for 
Study Design 
In addition, participants who have not 
achieved culture conversion in Group A 
(BDQ-containing regimen) will continue
their assigned regimen until Week 48, unless
they have difficulty continuing due to failure
to respond (see Section 6.8.1, based on
nonconversion and clinical worsening) or
the occurrence of AE related to the regimen.
 
The participants in Group B (rifamycin-
containing regimen) who do not achieve
culture conversion up to Week 24 and
continue the study, will have the option, at
discretion of investigator, to (1) continue
rifamycin-containing regimen, (2) switch to
individualized treatment regimen (see
Section 6.8.1, in principle, add on injectable
SM, injectable or inhalation suspension of
AMK ), (3) switch to BDQ-containing
regimen after 2-week washout of rifamycin.
The latter option is called the "optional
cohort" (see Section 6.8.2).
Reference was added for
clarification.
4.4. End of Study Definition 
A participant will be considered to have 
completed the study if he or she has 
completed assessments at Week 60 of the 
open label phase or at OPW48 of the
optional cohort., but Following completion
of the study, the participant may continue
the SOC per Japanese guidelines or medical
practice at each study site for at least 1 year
after culture conversion, at the discretion of
the investigator.
Text was revised to clarify that
the action is to be taken after
completion of the study.
6.3. Measures to Minimize 
Bias: Randomization and 
Blinding 
As this is an open-label study, blinding 
procedures are not applicable. However, the 
microbiological results from Week 2 to
Week 24 will be blinded to the investigator,
participants, and sponsor until the
completion of the other assessments at Week
24. In case the investigators need to know
the microbiological result to decide if
participants should be switched to an
individualized treatment regimen or continue
the study treatment regimen, due to clinical
worsening, the investigators can access the
microbiological result directly from the
central laboratory (for the detailed
procedure, refer to the Procedure for
Confirmation and Reporting of Results of
Blinded Sputum Culture Including
Collection of Samples for Microbiology
Test).
Text was added and deleted for
clarification.
6.8.1. Individualized 
Treatment Regimen 
In addition to the option to switch to the 
optional cohort in Group B and withdrawal 
Text was added and corrected to
clarif y the reason for settin  g up
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
from the study, individualized treatment 
regimen was set up to as a regimen that may 
be used when participants are judged to have
difficulty continuing their designated
treatment regimen due to failure to respond
(based on nonconversion supported by
microbiological results, and clinical
worsening of symptoms related to MAC-LD
supported by the results such as chest
computed tomography [CT] scan) or the
occurrence of AE.
the individualized treatment
regimen.
Group A (Assigned treatment regimen: BDQ 
+ CAM + EB) 
 
BDQ + CAM + EB + aminoglycosides 
(add one of injectable SM, injectable or 
inhalation suspension)
 
BDQ + CAM + aminoglycosides (same
as above)
 
BDQ + CAM (when difficult to
continue treatment with EB and no
clinical worsening)
Group B (Assigned treatment regimen:
Rifamycin + CAM + EB)
 
Rifamycin + CAM + EB +
aminoglycoside (same as above)
 
Rifamycin + CAM + aminoglycoside
(same as above)
 
Rifamycin + CAM (when difficult to
continue treatment with EB and no
clinical worsening)
Note: From the viewpoint of preventing the
development of CAM resistance, a regimen
with EB discontinuation should be carefully
considered.
Text was added for clarification.
Also, a note regarding the
regimen with EB
discontinuation was added.
Prior to switching to an individualized 
treatment regimen, visit and assessments for 
switch to individualized treatment regimen 
must be done as shown in Section 1.3, 
Schedule of Activities (SoA). After
switching, a participants will continue their
usual schedule for assigned treatment
regimen. Note that participants in Group A
who have switched to individualized
treatment regimen can continue up to Week
48, participants in Group B can continue up
to Week 60.
Text was added to clarify before
and after switching to an
individualized treatment
regimen.
6.8.2. Optional cohort 
The decision to switch to optional cohort can 
be made by Week 3230 (refer to Sections 
1.2 and 4.1). 
Text was corrected as the
transition period (time to
confirm the result of sputum
culture) has been reconsidered
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Section Number 
and Name
Description of Change 
Brief Rationale
 
Participants are nonconverter based on 
the result of microbiological test (ie,
positive) up to Week 24.
Text was added for clarification
Switching to an individualized treatment 
regimen is permitted if the criteria described
in Section 6.8.1 are met, even after
switchin  g to the optional cohort.
Text was added for clarification
8.1.1. Microbiology 
Assessment (MAC-LD 
Treatment Outcome) 
Genotyping or Fingerprinting of Isolates 
 
This is to assess if baseline and postbaseline
isolates are the same or different in case of
resistance occurring at postbaseline and in
case cultures become positive after having
been negative, genotyping using variable
number tandem repeat (VNTR) or whole
genome sequencing (WGS) (if available)
will be performed.
Text was deleted for
clarification.
8.2.3. Electrocardiograms 
In principle, 2 original ECG recordings will 
be provided. One original recording will be
stored at the study site and another will be
sent to a central cardiologist designated by
the sponsor for review. Submission of ECG
to a central cardiologist will be done by
transmission or send a hardcopy ECG if
transmission is not possible for any reasons
(refer ECG manual for details).
Text was added for clarification.
9.5. Interim Analysis 
A futility analysis will be implemented to 
evaluate early the benefit/risk balance by
assessing safety and efficacy in the first 60
participants (about 30 participants from both
groups) who reach the Week 24 time point
or discontinued earlier or switched to
individualized treatment regimen.
Text was added for clarification
10.2. Appendix 2: Clinical 
Laboratory Assessments
Hematology (Local laboratory) 
 
Note: A WBC evaluation may include any
abnormal cells, which will then be reported
by the local laboratory. An RBC evaluation
may include abnormalities in the RBC
count, RBC parameters, or RBC
morphology, which will then be reported by
the local laboratory. In addition, any other
abnormal cells in a blood smear will also be
reported.
Text was added for clarification.
Amendment 4 (30-Sep-2021)
Overall Rationale for the Amendment: To revise the Inclusion Criteria 5 and 6, to partially revise a
requirement for sputum collection, to add descriptions regarding individualized treatment regimen, as
well as to correct unclear and inconsistent descriptions.
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Section Number 
and Name
Description of Change 
Brief Rationale
1.2. Schema 
The following corrections were made to 
Figure 1: Schematic Overview of the Study. 
 
Footnote b was added to treatment Group B. 
 
Footnote a. Prior to Week 24, participants 
who are judged to have difficulty continuing 
their designated treatment regimen due to
failure to respond (based on nonconversion
and clinical worsening) or the occurrence of
AE will be considered treatment failure and
can switch to an individualized treatment
regimen based on clinical worsening
supported by microbiology data, symptoms
related to MAC LD and/or the results of
chest CT scan, at the discretion of the
investigator in consultation with IDMC if
needed.
 
Footnote b. After Week 24 assessment, all
participants who are judged to have
difficulty continuing failing their designated
treatment regimen due to failure to respond
(based on nonconversion and clinical
worsening) or the occurrence of AE will be
considered treatment failures and will be
given the option to switch to an
individualized treatment regimen at the
discretion of the investigator.
 
Footnote c. After completion of 48-week
treatment, converters in the Group A will be
followed for 12 weeks as drug-free period.
Participants who failed to achieve sputum
culture conversion (nonconverters) by Week
48 and continue chemotherapy will be
discontinued from the study and will be
switched to another an individualized
treatment regimen.
 
Footnote e. All participants who are judged
to have difficulty continuing failing their
BDQ containing regimen due to failure to
respond (based on nonconversion and
clinical worsening) or the occurrence of AE
will be considered treatment failures and
will be given the option to switch to an
individualized treatment regimen at the
discretion of the investigator.
A footnote associated with
switching to individualized
treatment regimen was added to
treatment Group B. Also,
footnote text was revised to
ensure consistency with Section
6.8.1.
1.3. Schedule of Activities 
(SoA) 
1.3.1. Schedule of Activities 
(SoA) in the Optional Cohort 
Footnote m. At least 2 Two sputum samples 
should be collected at each visit time point 
except for Week 2, 6, and 10. One should be 
collected in the early morning (at home or at 
the study site) and the other sample(s) at the 
study site. Samples collected at the study site 
can be spontaneous or induced. In case 2
To reduce the burden on
participants and study sites, a
requirement for handling
sputum collection at W2, 6, and
10 was eased. Also, text was
added to clarify that handling of
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Section Number 
and Name
Description of Change 
Brief Rationale
sputum sample collection is not feasible at 
Week 2, 6, and 10, either no sample or 1 
sample collection is allowed. Sputum
samples will be shipped to the central
microbiology laboratory where all cultures
will be performed on solid and on liquid
media. The same applies to sputum
collections at OPW 2, 6 and 10 in the
optional cohort.
sputum collections is the same
in the optional cohort.
Footnote t. Single sparse blood samples will 
be collected for measurement of plasma
concentrations of BDQ (and M2 [optional]).
These samples can be taken at any time after
intake of BDQ on the day, but the date and
time of the second to last and the last
administration of BDQ and CAM,
respectively, and the date and time of blood
draw must be recorded.
Text was added for clarification.
2.3.1. Risks for Study 
Participation 
The following text was added to Risks Due 
to Other Causes. 
 
Potential Risks of Clinical Significance: For 
an individualized treatment regimen in 
treatment Group A, aminoglycosides may be 
added to the BDQ-containing regimen.
 
Summary of Data/Rationale for Risk: The
antimicrobial activity of BDQ in
combination with aminoglycosides against
MAC has been confirmed from the results of
a nonclinical study,30 but its clinical efficacy
has not been evaluated and its efficacy has
not been demonstrated. In multidrug therapy
approved for the treatment of pulmonary
MDR-TB in Japan and overseas,
aminoglycosides have been recommended as
one of the agents to be used concomitantly
with multidrug therapy including BDQ48,49
and no safety issues have been observed.
However, the clinical safety in patients with
pulmonary MAC disease has not been
evaluated and its safety has not been
demonstrated.
 
Mitigation Strategy: During the study, study
svisits are scheduled at least once every 4
weeks to perform specified safety
assessments.
Text was added to clarify the
risks for study participation
when aminoglycosides are
added to BDQ-containing
regimen in an individualized
treatment regimen.
4.1. Overall Design 
All decisions on treatment regimen change 
should be made when participants are judged 
to have difficulty continuing their designated 
treatment regimen due to failure to respond
[based on nonconversion clinical worsening
supported by microbiological results, and
clinical worsening of symptoms related to
MAC-LD supported by, and/or the results
Text was revised to ensure
consistency within the
document.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
such as of chest computed tomography (CT)
scan] or the occurrence of AE, except for
switching to the optional cohort. Since the
microbiological results are blinded, if the
investigators consider the regimen change
based on the clinical worsening of symptoms
related to MAC-LD supported by and/or the
result of chest CT scan and so on, the
investigators can consult with IDMC before
the change.
Nonconverters at Week 48 in Group A will 
be discontinued from the study and switched 
to another treatment regimen if they 
continue chemotherapy because the duration
of BDQ treatment is 48 weeks shifted to the
individualized regimen and the study
observations are continued up to Week 60.
Revised to be consistent with
supply of interventional study in
Group A after Week 48.
4.2. Scientific Rationale for 
Study Design 
The present study will enroll patients with 
treatment-refractory MAC-LD defined as 
participants who are sputum culture positive 
for MAC despite at least 6 months and no
more than 36 24 months of MAC-LD
treatment (at least 2 antibiotics for MAC,
including a macrolide), that is either ongoing
or has stopped within the last 12 months.
Text was revised according to
the revision of Inclusion Criteria
5 and 6.
In addition, participants who have not 
achieved culture conversion in Group A 
(BDQ-containing regimen) will continue 
their assigned regimen until Week 48, unless 
they have difficulty continuing due to failure 
to respond (based on nonconversion and
clinical worsening) or the occurrence of AE
related to the regimen. If participants were
judged to have difficulty continuing due to
failure to respond to the regimen or the
occurrence of the regimen related AE, at the
discretion of investigators, there will be
options to discontinue from the study or
switch to an individualized treatment
regimen (in principle, add on injectable SM,
injectable or inhalation suspension of
AMK).
 
Tthe participants in Group B (rifamycin-
containing regimen) who do not achieve
culture conversion up to Week 24 and
continue the study, will have the option, at
discretion of investigator, to (1) continue
rifamycin-containing regimen, (2) switch to
individualized treatment regimen (in
principle, add on which may include
injectable SM, or injectable or inhalation
suspension of AMK or SM), (3) switch to
BDQ-containing regimen after 2-week
washout of rifamycin.
Text was added to clarify
regarding switching to an
individualized treatment
regimen in Group A. Also, text
was revised for clarification.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
4.2.1. Study-specific Ethical 
Design Considerations 
Addition of aminoglycosides (injectable SM, 
injectable or inhalation suspension of AMK) 
is permitted as an individualized treatment 
regimen in either treatment group if 
participants are judged to have difficulty
continuing the designated treatment regimen
due to failure to respond (based on
nonconversion and clinical worsening) or
the occurrence of the regimen related AE, at
the discretion of investigators. Addition of
aminoglycosides in Group B is
recommended by the Japanese guideline,41
and is expected to be clinically efficacious in
participants with clinical worsening. On the
other hand, addition of aminoglycosides to
the regimen in Group A has been confirmed
to have antimicrobial activity based on
nonclinical studies, but its clinical efficacy
has not been confirmed at present.
Regarding safety, in the Japanese and
oversea guidelines on approved drug
therapies for the treatment of pulmonary
MDR-TB,48,49 AMK and SM are
recommended as agents to be used in
combination with multiple drug therapies
including BDQ, and there have been no
reports of any problems concerning drug
interactions and new adverse reactions
associated with the combination use.
However, experience in the treatment of
pulmonary MAC disease is limited, and
safety monitoring participants will be
performed at least every 4 weeks until study
completion or early discontinuation
according to Section 1.3, Schedule of
Activities (SoA). Since treatment options for
participants who failed to respond are
limited, addition of aminoglycosides, which
is expected to convert and improve clinical
symptoms, was selected as an individualized
treatment regimen.
Explanation was added to
clarify ethical consideration of
individualized treatment
regimen.
5.1. Inclusion Criteria 
Inclusion Criteria 5. Criterion modified per 
Amendment 4. 
5.1 Has at least 2 positive sputum cultures 
of MAC (sputum cultures to be taken at 
least 4 weeks apart): 
 one obtained within 12 months prior
to screening, which was documented
while being treated for MAC-LD for
a total of at least 6 months and no
longer than 36 24 months.
one at screening (by central microbiology
laboratory).
The inclusion criterion was
revised considering the
feasibility of subject enrollment
within the range considered to
be a similar target population.
Inclusion Criteria 6: Criterion modified per 
Amendment 4. 
The inclusion criterion was
revised considering the
feasibilit y of subject enrollment
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
6.1 Received at least 6 months and no more 
than 36 24 months of consecutive MAC-LD 
treatment (at least 2 antibiotics for MAC,
including a macrolide), that is either ongoing
or has stopped within 12 months prior to
screening.
within the range considered to
be a similar target population.
6.1. Study Intervention 
Administered 
The following corrections were made to 
Figure 1: Schematic Overview of the Study.
 
Non-Investigational Interventional
Medicinal Product
An error was corrected.
6.8. Concomitant Therapy 
If contraindicated medication(s) listed in 
each package insert of 
comparator/combination drugs (RFP, RBT, 
CAM, or EB) are received during screening,
the contraindicated medication(s) are
prohibited from 7 days prior to Day 1 up to
the last dose of the medications including
study intervention.
 
NOTE: The examples of potent CYP3A4
inhibitors and inducers do not form a
complete list. The investigator should
consult the prescribing information for study
interventions and combination drugs (CAM
and EB) BDQ and, if necessary, contact the
appropriate sponsor representative.
 
The following medications are prohibited
because of their potential for QTc
prolongation. These medications are not
allowed from 7 days prior to Day 1 up to the
last dose of study interventions and
combination drugs (CAM and EB)
(including individualized treatment
regimens):
 
The following medications are prohibited
because of their potential for muscle damage
(myopathy) from 7 days prior to Day 1 up to
the last dose of study interventions and
combination drugs (CAM and EB)
(including individualized treatment
regimens) (see note):
Text was revised in line with the
modified definition of study
drug in Amendment 3.
Injectable SM, or injectable or inhalation 
suspension of SM or AMK is acceptable as 
part of an individualized treatment regimen.
The use of injectable SM, injectable or
inhalation suspension of SM or AMK for
any purposes other than as part of an
individualized treatment regimen is
prohibited.
Text was revised for
clarification.
 
moxifloxacin (prohibited from the 
initiation date durin  g administration of 
Text was revised for
clarification.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
BDQ treatment and up to 1 month after
the last dose of BDQ)
6.8.1. Individualized 
Treatment Regimen 
During the study, if deemed necessary by the 
investigator to Participants can switch to 
individualized treatment regimen (in 
principle, add on which may include
injectable SM, injectable or inhalation
suspension of AMK or SM. Regimens that
may be selected for each treatment group are
listed below) and continue treatment, it can
be done by obtaining re-consent from the
participant at the discretion of investigators
(refer to Sections 1.2 and 4.1). Participants
should meet one of the following criteria to
switch to individualized treatment regimen.
(Note: Refer to Section 6.3 for blinding
method of the microbiological assessment
result). Discontinuation of administration of
BDQ in Group A or optional cohort is not
considered as individualized treatment
regimen in this study.
 
Continuation of assigned treatment
regimen is difficult because
Pparticipants are nonconverters based
on the result of microbiological test (ie,
positive) and have clinical worsening
of symptom associated with MAC-LD
based on the including findings in chest
CT scan and so on, at the discretion of
investigators.
 
Continuation of assigned treatment
regimen is difficult due to AE related
to drug in assigned regimen, at the
discretion of investigators.
Individualized treatment regimens permitted
in this study are described in below.
Investigators should select the appropriate
regimens for participants in each treatment
group or if no regimen is considered
appropriate the participants should be
discontinued from the study.
Group A (BDQ + CAM + EB)
 
BDQ + CAM + EB + aminoglycosides
(add one of injectable SM, injectable or
inhalation suspension)
 
BDQ + CAM + aminoglycosides (same
as above)
 
BDQ + CAM (when difficult to
continue treatment with EB and no
clinical worsening)
Text was added and revised to
clarify individualized treatment
regimens permitted in the study.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
Group B (Rifamycin + CAM + EB)
 
Rifamycin + CAM + EB +
aminoglycoside (same as above)
 
Rifamycin + CAM + aminoglycoside
(same as above)
 
Rifamycin + CAM (when difficult to
continue treatment with EB and no
clinical worsening)
If an investigator judges that it is necessary to
use treatment regimens other than those listed
above, such as discontinuation of study
intervention, discontinuation of CAM or
switching CAM to AZM (prohibited
medication), the participant should be
discontinued from the study and treatment
regimens available at Tthe study site will be
provided supply individualized treatment that
will be obtained locally.
6.8.2. Optional Cohort 
Switching from an individualized treatment 
regimen to the optional cohort is not 
permitted. 
Text was added to clarify that
switching from an
individualized treatment
regimen to the optional cohort is
not permitted.
8.2.3. Electrocardiograms 
Participants found to have a QT or QTcF 
≥500 ms or an increase from baseline (mean
of triplicates on Day 1) of >60 ms on ECG
at any point during the treatment period will
be further investigated.
 
Any QT or QTcF prolongation to ≥500 ms
or an increase from baseline (mean of
triplicates on Day 1) of >60 ms while on
study intervention is considered a notable
event and should be reported immediately to
the sponsor.
Text was added for clarification.
If a single ECG shows QTcF ≥500 ms or an 
increase from baseline (mean of triplicates 
on Day 1) of >60 ms, then complete 
additional triplicate ECGs, evaluate the 
mean QTcF, and record results on an 
unscheduled visit form. 
Text was added to ensure
consistency with the definition
of QTcF prolongation (a QTcF
value ≥500 ms, or an increase
from baseline of >60 ms)
described in Section 7.1.
10.3.3. Informed Consent 
Process 
In addition, when switching to an 
individualized treatment regimen, obtaining 
re-consent from participants is required. 
Text was added to clarify that
obtaining re-consent from
participants is required when
switching to an individualized
treatment regimen.
10.3.6. Committees Structure 
Since the microbiological results are blinded 
up to Week 24, if the investigators consider 
the regimen change based on clinical 
worsening of the symptoms related to MAC-
LD and/or based on the result of chest CT
scan and so on, the investigators can consult
with IDMC.
Text was revised to ensure
consistency within the
document.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
11. REFERENCES 
48. WHO [homepage on the Internet]. WHO 
consolidated guidelines on tuberculosis. 
Module 4: treatment drug-resistant
tuberculosis treatment. Available at:
https://www.who.int/publications/i/item/978
9240007048
49. 日本結核  非結核性抗酸菌症学会治療
委員会. 本邦での多剤耐性結核治療に対
する考え方. Kekkaku. 2020, 95(2):79-84.
Added 2 references which was
used in Section 4.2.1.
Amendment 3 (08-Jul-2021)
Overall Rationale for the Amendment: To describe that the comparator rifamycin (RFP or RBT) will be
supplied by the sponsor and handled in an appropriate manner as a study intervention in accordance with
GCP. Also, the term “study intervention” used throughout this protocol was clarified to refer to the study
drug BDQ and the comparator rifamycin.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
3. OBJECTIVES AND 
ENDPOINTS 
The term “study intervention” was replaced
with “BDQ compared with rifamycin when
administered as part of a treatment regimen
with CAM and EB” throughout the
objectives.
Text was revised to clarify the
objectives in line with the
modified definition of study
intervention.
Microbiological assessment: To evaluate the
efficacy of BDQ compared with rifamycin
when administered as part of a treatment
regimen with CAM and EB the study
intervention in adult participants with
treatment-refractory MAC-LD at up to
Wee k 48.
Text was added to clarify the
evaluation timepoint.
2. INTRODUCTION 
The term “study intervention” throughout
the protocol refers to BDQ, and rifamycin
(RFP or RBT), CAM, and EB, as defined in
Section 6.1, Study Interventions
Administered.
Definition of study intervention
was modified.
In Japan, CAM, RFP, RBT, EB, and SM,
and AMK liposome inhalation suspension
(ALIS) are approved for the treatment of
MAC-LD. Kanamycin is listed in the
Japanese guidelines, but KM is not approved
for the treatment of MAC-LD.41 Amikacin is
not listed in the Japanese guidelines and is
not approved for the treatment of MAC LD,
but injectable AMK is reimbursed for the
treatment of MAC-LD as from February
2019 and ALIS is approved for the treatment
of MAC-LD in March 2021.33
Text was updated based on the
approval of ALIS for the
treatment of MAC-LD.
2.2.1. 
Comparator/Combination 
Therapy 
For further information regarding above
drugs, refer to each Japanese package insert.
Text was added for clarification.
2.3.1. Risks for Study 
Participation 
Risks Due to Study Intervention (BDQ and,
CAM, RFP/RBT, EB) and Combination
Drugs (CAM and EB)
Text was revised in line with the
modified definition of study
intervention.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
Discontinuation of study intervention and
combination drugs will be required based on
the result of ECG.
Investigator can switch to individual 
regimen based on the result of based on 
nonconversion and/or clinical worsening. 
Text was revised to keep
consistency throughout the
document.
4.2. Scientific Rationale for 
Study Design 
Because rifamycin, which is included in the 
control regimen, is known to cause a reddish 
coloration of the urine, feces, sputum, sweat, 
serum, and discoloration of soft contact
lenses, blinding of the study intervention
drug/comparator is practically impossible
due to the wide area of coloration effects.
Text was revised in line with the
modified definition of study
intervention.
In addition, the participants in Group B 
(rifamycin-containing regimen) who do not
achieve culture conversion up to Week 24,
will have the option, at discretion of
investigator, to (1) continue rifamycin-
containing regimen, (2) switch to
individualized treatment regimen (in
principle, add on  injectable or inhalation
suspension of AMK or SM), (3) switch to
BDQ-containing regimen after 2-week
washout of rifamycin.
Text was added for clarification.
6.1 Study Interventions 
Administered 
The study drug BDQ and the comparator 
rifamycin (RFP or RBT) will be provided as 
tablets for oral administration. and BDQ will 
be taken with food in the morning at 
approximately the same time each day, 
depending on visit and visit assessments. 
Rifamycin (RFP or RBT) will be taken 
according to the investigator's instructions as 
per Japanese package insert. Comparator and 
Combination drugs will not be provided by
the sponsor and marketed product at study
sites should be administered.
 
BDQ will be manufactured and provided
under the responsibility of the sponsor.
Refer to the IB40 for a list of excipients of
BDQ. Rifamycin (RFP or RBT) will be
provided under the responsibility of the
sponsor. Refer to the respective Japanese
package insert for a list of excipients of
Rifamycin (RFP or RBT).
 
Corrections were made to Table 2: Dosage
and Administration Table for Study
Interventions and Combination Drugs based
on the above changes.
Text was added to clarify that
the comparator will be provided
by the sponsor. Also, text was
revised in line with the modified
definition of study intervention,
and mistranslation of the term
“study drug” was corrected in
Japanese version of the
document.
6.2. Preparation/Handling/ 
Storage/Accountability 
All study intervention must be stored in the 
original blister sheet or container within the 
designated temperature range indicated by
label of the kit in order to protect from light.
Text was added as comparator
will be provided by the sponsor.
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TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
141
Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
 
Preparation, handling, and storage of 
combination drugs (CAM and EB) will be in 
accordance with procedures of the study 
sites.
Text was added to clarify the
procedures for combination
drugs.
6.3. Measures to Minimize 
Bias: randomization and 
Blinding 
8. Study Assessments and 
Procedures
8.1.1. Microbiology
Assessment (MAC-LD
Treatment Outcome)
microbiology laboratory manual Procedure 
for Confirmation and Reporting of Results 
of Blinded Sputum Culture Including
Collection of Samples for Microbiology Test
Changed the name of procedure
manual
6.4 Study Intervention 
Compliance 
Study intervention compliance will be 
assessed by counting tablets and/or capsules 
returned and using participant diary during 
the site visits and documented in the source 
documents. The use of study intervention
captured in participant diary will be recorded
in the eCRF.
Combination drug compliance will be
assessed by participant diary during the site
visits and documented in the source
documents. The use of combination drug
captured in participant diary will be recorded
in the eCRF.
Text was added to clarify the
assessment of study intervention
and combination drug
compliance.
6.7. Treatment of Overdose 
Refer to the Japanese package insert of the 
comparator rifamycin (RFP or RBT) for 
advice on treatment of overdose. 
Text was added to clarify the
treatment of overdose of
comparator.
6.8 Concomitant Therapy 
Injectable or inhalation suspension of SM or 
AMK is acceptable as part of an
individualized treatment regimen. The use of
injectable or inhalation suspension of SM or
AMK for any purposes other than as part of
an individualized treatment regimen is
prohibited.
Text was added for clarification.
6.8.1 Individualized Treatment 
Regimen 
Participants can switch to individualized 
treatment regimen which may include
injectable or inhalation suspension of AMK
or SM at the discretion of investigators
(refer to Sections 1.2 and 4.1).
Text was added for clarification.
7.1 Discontinuation of Study 
Intervention 
 
The participants discontinued 
administration of study intervention 
BDQ before Week 48 in Group A, 
Week 60 in Group B or OPW48 in
Group A or optional cohort.
Text was revised in line with the
modified definition of study
intervention.
8. STUDY ASSESSMENTS 
AND PROCEDURES 
Procedures for the collection, handling, and 
shipment of microbiological samples 
(sputum), as well as disclosure of blinded 
data are described in the Procedure for 
Confirmation and Reporting of Results of
Blinded Sputum Culture Including
Collection of Samples for Microbiology
Test.
Text was added to clarify the
procedures for handling of
sputum samples and disclosure
of unblinded data.
NCT04630145

TMC207 (Bedaquiline)  
Clinical Protocol TMC207NTM3002 Amendment 8
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
142
Status: Approved, Date: 8 December 2022
Section Number 
and Name
Description of Change 
Brief Rationale
8.1.1. Microbiology 
Assessments (MAC-LD 
Treatment Outcome) 
All sample collection and processing will be 
performed by the staff at the clinical site, 
according to the approved operating 
procedures
Text was revised to keep
consistency throughout the
document.
9.4.7. Other Analyses 
Mean and median plasma BDQ, M2, CAM 
and 4-OH CAM concentration time profiles 
will be plotted after the first dose of BDQ 
study intervention, and individual serum
concentration time profiles may also be
plotted.
Text was revised in line with the
modified definition of study
intervention.
10.1. Appendix 1: 
Abbreviations 
Added amikacin liposome inhalation 
suspension (ALIS). 
ALIS was added according to
the text added.
10.4.1. Adverse Event 
Definitions And 
Classifications 
For rifamycin (RFP or RBT) and 
combination drugs (CAM and EB) with 
marketing authorization, the expectedness of 
an AE will be determined by whether or not 
it is listed in the Japanese package insert. 
Text was added to clarify how
the expectedness of adverse
events are determined for
comparator and combination
drugs.
Throughout the protocol 
Minor changes were made. 
Minor errors were noted.
Amendment 2 (14-Apr-2021)
Overall Rationale for the Amendment: The overall rationale for the amendment is to add the exclusion
criterion of co-infected subject with NTM species other than MAC for clarifying adequate study
population and clinical assessments, and add the methods of self-assessment of PROs (SGRQ, QOL-B
and NTM module) according to each PRO author’s advice.
Section Number 
and Name
Description of Change 
Brief Rationale
5.2 Exclusion Criteria 
 
Added the exclusion criterion of co-infected
subject with NTM species other than MAC.
Clarification for adequate study
population and clinical
assessments.
8.1.2 Clinical Assessments in 
MAC-LD  
Added the methods of self-assessment of
PROs (SGRQ, QOL-B and NTM module).
According to each PRO author’s
advice.
Throughout the protocol 
Minor corrections and clarifications were
done throughout.
Minor errors were noted.
Amendment 1 (21-Oct-2020)
Overall Rationale for the Amendment: The overall rationale for the amendment is to change the
duration of screening period, set the acceptable time window for lung function test, clarify data collection
rule of PK blood samples and data handling rule of primary endpoint, correct inconsistencies and avoid
misinterpretation by the investigators and site staffs.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.2 Schema
1.3 Schedule of Activities
(SoA)
4.1 Overall Design
6.8 Concomitant Therapy 
Changed screening period from maximum 8
weeks to maximum 9 weeks.
Re-estimated the required time
for microbiology testing during
screening period.
1.3 Schedule of Activities
(SoA)
Acceptable time window was set for the
lung function test on Day 1.
It was assumed that lung
function test could not be
performed on Da y 1.
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Section Number 
and Name
Description of Change 
Brief Rationale
Footnotes of drug susceptibility testing and 
optional cohort Da y 1 were corrected.
Correction of inconsistency.
Added how to collect the data for PK blood 
sampling. 
Clarification of data collection
rule for PK blood samples.
7.1 Discontinuation of Study 
Intervention
Corrected errors in referenced sections. 
Mistakes in reference sections.
7.2 Participant 
Discontinuation/Withdrawal
From the Study 
Deleted duplicate text. 
Correction of error.
8. STUDY ASSESSMENTS 
AND PROCEDURES 
Added how to collect the data for 
unscheduled PK blood sampling. 
Clarification of data collection
rule for unscheduled PK blood
samples.
9.4.2 Primary Estimand 
Updated population and intercurrent events. 
Modification and clarification of
the primary estimand in line with
ICH-E9 (R1).
9.4.3 Primary Endpoint 
Added how to handle contaminated sputum 
culture and failed culture in the primary 
analysis. 
Clarification of data handling
rule for contaminated sputum
culture and failed culture.
11 REFERENCES 
Add 2 references. 
Reviewed 2 references
Throughout the protocol 
Minor corrections and clarifications were 
done throughout.
Minor errors were noted.
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11. 
REFERENCES
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Aguilar-Ayala DA, Cnockaert M, André E, et al. In vitro activity of bedaquiline against rapidly
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Aksamit TR, Philley JV, Griffith DE. Nontuberculous mycobacterial (NTM) lung disease: the top
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American Thoracic Society. Health-related quality of life (HRQL). American Thoracic Society
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Bermudez LE, Nash KA, Petrofsky M, Young LS, Inderlied CB. Effect of ethambutol on emergence
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Claeys TA, Robinson RT. The many lives of nontuberculous mycobacteria. J Bacteriol.
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17. Henkle E, Winthrop KL, Ranches GP, Plinkle W, Litvin HK, Quittner AL. Preliminary validation of
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23. Kim DH, Jhun BW, Moon SM, et al. In vitro activity of bedaquiline and delamanid against
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24. Kitada S, Uenami T, Yoshimura K, et al. Long-term radiographic outcome of nodular bronchiectatic
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27. Kwon YS, Koh WJ, Daley CL. Treatment of Mycobacterium avium complex pulmonary disease.
Tuberc Respir Dis (Seoul). 2019;82(1):15-26.
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diseases in humans. In: Velayati AA, Farnia P. Nontuberculous mycobacteria (NTM).
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29. Lee G, Lee KS, Moon JW, et al. Nodular bronchiectatic Mycobacterium avium complex pulmonary
disease. Natural course on serial computed tomographic scans. Ann Am Thorac Soc.
2013;10(4):299-306.
30. Lounis N, Gevers T, Van den Berg J, Vranckx L, Andries K. ATP synthase inhibition of
Mycobacterium avium is not bactericidal. Antimicrob Agents Chemother. 2009;53(11):4927-4929.
31. Martin A, Godino IT, Aquilar-Ayala DA, Mathys V, Lounis N, Villalobos HR. In vitro activity of
bedaquiline against slow-growing nontuberculous mycobacteria. J Med Microbiol.
2019;68(8):1137-1139.
32. Mehta M, Marras TK. Impaired health-related quality of life in pulmonary nontuberculous
mycobacterial disease. Respir Med. 2011;105(11):1718-1725.
33. Ministry of Health, Labour and Welfare [database on the Internet]. 医薬品の適応外使用に係る保
険診療上の取扱いについて(保医発0225 第8 号). Japan: 2019/02/25. Available from:
https://kouseikyoku.mhlw.go.jp/tohoku/shido_kansa/000087975.pdf
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34. Mirsaeidi M, Vu A, Leitman P, et al. A patient-based analysis of the geographic distribution of
Mycobacterium avium complex, Mycobacterium abscessus, and Mycobacterium kansasii infections
in the United States. Chest. 2017;151(4):947-950.
35. Namkoong H, Kurashima A, Morimoto K, et al. Epidemiology of pulmonary nontuberculous
mycobacterial disease, Japan. Emerg Infect Dis. 2016;22(6):1116-1117.
36. Olivier KN, Griffith DE, Eagle G, et al. Randomized trial of liposomal amikacin for inhalation in
nontuberculous mycobacterial lung Disease. Am J Respir Crit Care Med. 2017;195(6):814-823.
37. Pennings LJ, Zweijpfenning S, Ruth MM, et al. Mycobacterium avium complex bacteria remain
viable in sputum during storage and refrigeration. Diagn Microbiol and Infect Dis. 2018;92(4):309-
310.
38. Quittner AL, Madan A, Saez-Flores E, et al. Development of a quality of life module for
nontuberculous mycobacteria (NTM). Eur Respir J. 2015;46:PA2635.
39. Singla R, Osman MM, Khan N, Al-Sharif N, Al-Sayegh MO, Shaikh MA. Factors predicting
persistent sputum smear positivity among pulmonary tuberculosis patients 2 months after treatment.
Int J Tuberc Lung Dis. 2003;7(1):58-64.
40. The Investigator’s Brochure: TMC207 (Bedaquiline), Edition 16, Janssen Research & Development,
October 2022.
41. The Nontuberculous Mycobacteriosis Control Committee of the Japanese Society for Tuberculosis,
The Scientific Assembly for Infection and Tuberculosis of the Japanese Respiratory Society.
Guidelines for chemotherapy of pulmonary nontuberculous mycobacterial diseases – 2012 revised
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42. The Nontuberculous Mycobacteriosis Control Committee of the Japanese Society for Tuberculosis,
The Scientific Assembly for Infection and Tuberculosis of the Japanese Respiratory Society.
Guidelines for the diagnosis of pulmonary nontuberculous mycobacterial diseases - 2008. Kekkaku.
2011;86(1):37-39.
43. Tsuyuguchi K, Sasaki Y, Mitarai S, Kurosawa K, Saito Y, Koh T. Safety, efficacy, and
pharmacokinetics of bedaquiline in Japanese patients with pulmonary multidrug-resistant
tuberculosis: An interim analysis of an open-label, phase 2 study. Respir Invest. 2019;57(4):345-353.
44. van Ingen J, Aksamit T, Andrejak C, et al. Treatment outcome definitions in nontuberculous
mycobacterial pulmonary disease: an NTM-NET consensus statement. Eur Respir J.
2018;51(3):1800170.
45. Winthrop K, Eagle G, Hasegawa N, et al. Patient-reported health status measured by St. George’s
Respiratory Questionnaire improved with sputum culture conversion in patients with nontuberculous
mycobacterial (NTM) lung disease caused by Mycobacterium avium complex (MAC). Am J Respir
Crit Care Med. 2018;197:A7670.
46. Clinical and Laboratory Standards Institute (CLSI). CLSI document M24-A2. Susceptibility testing
of mycobacteria, nocardiae, and other aerobic actinomycetes; approved standard–second edition.
Wayne, PA: Clinical and Laboratory Standards Institute; 2011.
47. Clinical and Laboratory Standards Institute (CLSI). CLSI document M62. Performance standards for
susceptibility testing of mycobacteria, nocardia spp., and other aerobic actinomycetes; 1st edition.
Wayne, PA: Clinical and Laboratory Standards Institute; 2018.
48. WHO [homepage on the Internet]. WHO consolidated guidelines on tuberculosis. Module 4:
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49. 日本結核  非結核性抗酸菌症学会治療委員会. 本邦での多剤耐性結核治療に対する考え方.
Kekkaku. 2020, 95(2):79-84.
50. Joint committee for the revision of Korean guideline for tuberculosis, Korea Centers for Disease
Control and Prevention. Korean guideline for tuberculosis fourth edition. 2020.
51. Taiwan Society of Pulmonary and Critical Care Medicine [homepage on the Internet]. Consensus
statement of nontuberculous mycobacterial lung disease. Taiwan [cited 2022/09/22], Available from:
https://www.tspccm.org.tw/cpage/NTM
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Status: Approved, Date: 8 December 2022
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
 
Date:
  
 
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
 
Date:
  
 
(Day Month Year)
 
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
; MD, PhD
Institution: 
Janssen Pharmaceutical K.K.
Signature: 
electronic signature appended at the end of the protocol 
Date:
  
 
(Day Month Year)
 
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT04630145
PPD

Signature
User 
Date 
Reason
08-Dec-2022
02:23:40
(GMT)
Document Approval
PPD
NCT04630145

 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 18 May 2021
Janssen Pharmaceutical K.K. *
 
Clinical Protocol
 
COVID-19 Appendix Amendment 1
 
Protocol Title
A Phase 2/3, Multicenter, Randomized, Open-label, Active-controlled Study to Evaluate
the Efficacy and Safety of Bedaquiline Administered as Part of a Treatment Regimen
With Clarithromycin and Ethambutol in Adult Patients With Treatment-refractory
Mycobacterium Avium Complex-lung Disease (MAC-LD)
Short Title
Bedaquiline/CAM/EB Study in Treatment-refractory MAC-LD Patients
 
Protocol TMC207NTM3002; Phase 2/3
AMENDMENT 2
 
 TMC207  (Beadquiline) 
 
* This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used
throughout the protocol to represent Janssen Pharmaceutical K.K.
Status: 
Approved 
Date: 
18 May 2021
Prepared by: Janssen Pharmaceutical K.K. 
EDMS number: 
EDMS-RIM-289559, 2.0
 
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04630145

COVID-19 Appendix Amendment 1 
TMC207  (Beadquiline)  
Clinical Protocol TMC207NTM3002 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 18 May 2021
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and
study-site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study
related participant management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements or the clinical judgement of the
investigator to protect the health and well-being of participants and site staff. If, at any time, a
participant’s safety is considered to be at risk, study intervention will be discontinued, and study
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments
should be performed if required and as feasible. Participants will also be questioned regarding
general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow up. Modifications to protocol-required assessments may be
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the
sponsor. Missed assessments/visits will be captured in the clinical trial management system for
protocol deviations. Discontinuations of study interventions and withdrawal from the study should
be documented with the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Modifications
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the
clinical study report.
NCT04630145

COVID-19 Appendix Amendment 1 
TMC207  (Beadquiline)  
Clinical Protocol TMC207NTM3002 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 18 May 2021
IMPORTANT MATTERS RELATED TO COVID-19 AND COORDINATION OF STUDY
CONDUCT
 During the course of COVID-19 pandemic, it may not be possible to visit the study site or
perform tests as specified in the protocol. Temporary measures may therefore be taken if, in
the judgment of the sponsor and the investigator (co-investigator), it is appropriate to
continue the subject's study treatment and to maintain the integrity of the study. Specific
measures may be required and should be implemented in accordance with applicable local
laws, regulations, guidelines and procedures, including:. These deviations will be handled as
"COVID-19 -related".
 If a subject is unable to visit within the acceptable visit window, the subject may visit
outside of the visit window.
 If it becomes necessary to reduce the time spent for tests or if some tests are limited, etc.
at the time of visit to the study site, the following actions are acceptable;
 
Sputum collection at the study site: If sputum collection at home is not possible, 2
collections are required at the study site. In such case, if good sputum specimen can
be collected at the first time at the study site, no second collection will be acceptable 
 
Sputum collection at home: If sputum collection including induced sputum specimen
is not possible or limited at the study site, the submission of at least 1 spontaneous
sputum specimen collected at home is acceptable without second collection at the
study site. And, both sputum specimens at home and at the study site are not obtained
and re-collection at home or at the study site is not possible, the submission of
sputum specimens at this time point may be omitted
 
If two blood samplings for PK will be drawn at the study site, 2nd blood sampling
may be drawn between 30 minutes to 4 hours after the intake. When the timing of 2nd
blood sampling is changed, the timing of ECG measurement should be adjusted
according to the protocol
 
Assessments of the SGRQ and QOL-B NTM module may be self-administered at
home prior to the visit, provided the subject has an environment in place to receive
the explanations to his/her queries to these questionnaires. If both assessments are
performed after site visit, if only one assessment is feasible, the SGRQ assessment
will take precedence and any missing QOL-B NTM module assessment will be
allowed
 
Some or all of the lung function assessments, as well as CT scan, may be obtained on
a different date from the visit if not available at the visit. Deviations due to missed
tests are allowed in situations where the assessment themselves cannot be performed
 
Triplicate ECGs are required; however, if triplicate ECGs are difficult for any reason,
duplicate ECGs or single ECG are acceptable
 
Visual and/or auditory examinations may be performed on different day(s) from the
visit date. In addition, this examination(s) may be omitted only if the subject does not
complain of any visual or auditory abnormalities
 If any deviation other than the above may be occurred, the investigator or co-
investigator will promptly report it to the sponsor and consider necessary measures.
NCT04630145

COVID-19 Appendix Amendment 1 
TMC207  (Beadquiline)  
Clinical Protocol TMC207NTM3002 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4 
Status: Approved,  Date: 18 May 2021
 Unperformed tests, assessments, or visits will be recorded as a protocol deviation in the
clinical trial management system. Discontinuation of investigational product treatment and
withdrawal from the study must be documented on the case report form (CRF) preceded by
the words "COVID-19 -related".
 Other relevant study data affected by the pandemic will also be recorded/displayed as
"COVID-19 -related" on the CRF and/or other study systems, as per sponsor guidance.
This may include missing/late/visit modification/assessment/investigational product
administration and temporary actions as described above.
 The sponsor will assess the overall impact of COVID-19 on the collection of critical study
data and will provide details of the additional data analyses in the study SAP (Statistical
Analysis Plan), if needed.
 Exclusion: Subjects with confirmed SARS-CoV-2 (COVID-19) infection (eg, positive PCR
test) or strongly suspected SARS-CoV-2 infection (No test results recorded but clinical
features present) within 4 weeks before informed consent are basically excluded from the
study. However, patients who meet the following criteria 1 and 2 and in whom a validated
SARS-CoV-2 test result has been recorded as negative can be enrolled in the study;
however, the eligibility will be determined after carefully monitoring the conditions of
candidate patients.
1. A negative test result was obtained at least 2 weeks after disappearance of the condition
presumed to be due to SARS-CoV-2 infection (Key Clinical Features [eg, fever, cough,
dyspnea, etc.])
and
2. No SARS-CoV-2 infection or strongly suspected infection occurs during the screening
period after a negative test result
 COVID-19 related exclusion considerations: 
1. If a subject is excluded due to recent COVID-19 related circumstances, the reason for
screen failure should be recorded on the CRF based on the exclusion criteria regarding a
condition in which the subject's participation would not be in the subject's best interest or
could interfere with the evaluation of the study.
2. Tests related to COVID-19 (Presence of SARS-CoV-2 virus in the body and items related
to immunity to SARS-CoV-2 virus) are rapidly evolving. Additional tests may be
performed at screening and/or during the study as deemed necessary by the Investigator
(co-investigator) and as per regulation/regulatory guidance/standard of care. 
 
NCT04630145

COVID-19 Appendix Amendment 1 
TMC207  (Beadquiline)  
Clinical Protocol TMC207NTM3002 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 18 May 2021
COVID-19 APPENDIX AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document 
Date
Appendix Amendment 1 
18-May-2021
Original Appendix 
08-Jan-2021
Amendment 1 (18-May-2021)
Overall Rationale for the Amendment: The overall rationale for the amendment is to add the
acceptance of the submission of at least 1 sputum specimen collected at home due to limited
sputum collection at the study site.
NCT04630145

COVID-19 Appendix Amendment 1 
TMC207  (Beadquiline)  
Clinical Protocol TMC207NTM3002 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6 
Status: Approved,  Date: 18 May 2021
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study.
I will conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to
me who assist in the conduct of this study. I will discuss this material with them to ensure that they
are fully informed regarding the study intervention, the conduct of the study, and the obligations
of confidentiality.
Principal (Site) Investigator: 
Name (typed or printed): 
Institution and Address: 
Telephone Number: 
Signature: 
 
Date: 
  
 
(Day Month Year)
 
Sponsor's Responsible Medical Officer: 
Name (typed or printed): 
Institution: 
Janssen Pharmaceutical K.K.
Signature: 
[electronic signature appended at the end of the protocol]
Date: 
  
 
(Day Month Year)
 
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT04630145

Signature
User 
Date 
Reason
18-May-2021
07:07:23
(GMT)
Document Approval
PPD
NCT04630145