Conditions: Tuberculosis HIV Infections
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 84
Healthy volunteers: no

Brief summary:
This study evaluated the safety, tolerability, and pharmacokinetics of the anti-tuberculosis (TB) drugs bedaquiline (BDQ) and delamanid (DLM), alone and in combination, among participants (with or without HIV co-infection) taking multidrug treatment for multidrug-resistant tuberculosis (MDR-TB) or rifampin-monoresistant TB (RR-TB).

Detailed description:
Bedaquiline (BDQ) and delamanid (DLM) are two newly approved anti-TB drugs and are both well tolerated. However, the combined effect of these two drugs has not been studied. Combining these two drugs, together with other anti-TB drugs, may improve outcomes for people with MDR-TB or RR-TB. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of BDQ and DLM, alone and in combination, among participants (with or without HIV co-infection) taking multidrug treatment for MDR-TB or RR-TB, and specifically to evaluate the effect of these drugs on the heart.

Participants were randomly assigned to one of three arms: participants in Arm 1 received BDQ, participants in Arm 2 received DLM, and participants in Arm 3 received BDQ and DLM. All participants received their assigned study drugs for 24 weeks together with multidrug background treatment (MBT) for MDR-TB or RR-TB (not provided by the study). HIV-infected participants also received dolutegravir, to be used in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) until study completion. NRTIs were not provided by the study. At study entry participants were initially required to be hospitalized for 2 months, however after an interim analysis, the period of hospitalization was shortened to 2 weeks.

Study visits occurred at entry, each week for 8 weeks after study entry, every other week until week 24, and at weeks 28, 36, 48, 60, 72, 84, 96 and 128. Visits included physical examinations, blood collection, urine collection, sputum sample collection, hair sample collection, chest x-rays, pregnancy testing, electrocardiograms (ECGs), and adherence questionnaires.

Participants were also asked to take part in an optional cerebrospinal fluid sampling study that entailed a lumbar puncture, to be done at weeks 8 or 24.

Arms:
arm 1: Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks.

Participants also received Multidrug Background Treatment (MBT) for TB.

For HIV-positive participants only, one 50 mg tablet of Dolutegravir was taken in combination with two NRTIs until study completion. arm 2: Participants received 100 mg of delamanid twice a day for 24 weeks.

Participants also received Multidrug Background Treatment (MBT) for TB.

For HIV-positive participants only, one 50 mg tablet of Dolutegravir was taken in combination with two NRTIs until study completion. arm 3: Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks.

Participants also received Multidrug Background Treatment (MBT) for TB.

For HIV-positive participants only, one 50 mg tablet of Dolutegravir was taken in combination with two NRTIs until study completion.

Interventions: intervention 1: Bedaquiline intervention 2: Delamanid intervention 3: Dolutegravir intervention 4: Multidrug Background Treatment (MBT) for TB
Intervention descriptions: intervention 1: Four 100 mg tablets (400 mg) orally once a day for 2 weeks, followed by two 100 mg tablets (200 mg) orally three times a week for 22 weeks. intervention 2: Two 50 mg tablets (100 mg) orally with food twice a day for 24 weeks. intervention 3: For HIV-positive participants only: one 50 mg tablet orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs were not provided by the study.) intervention 4: A standardized MBT regimen for MDR- or RR-TB except in cases where a participant had known resistance to one of the components of local standard treatment. MBT was provided by the local program.

Protocol document:
Prot_001.pdf: 
 
A5343 
 
A Trial of the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and 
Delamanid, Alone and in Combination, among Participants Taking Multidrug 
Treatment for Drug-Resistant Pulmonary Tuberculosis 
 
 
A Limited-Center Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
 
 
Industry Support Provided by: 
Janssen Pharmaceuticals, Inc. 
Otsuka Pharmaceutical Company, Ltd. 
ViiV Healthcare, Ltd. 
 
 
IND# 127,382 
 
 
The ACTG Tuberculosis Transformative 
Science Group 
Gavin Churchyard, MBBCh, 
MMED, FCP, PhD, Chair 
 
Protocol Co-Chairs: 
Kelly Dooley, MD, PhD 
 
Gary Maartens, MBChB, MMed 
 
Protocol Vice Chair: 
Francesca Conradie, MD, DTM&H 
 
DAIDS Clinical Representatives: 
Richard Hafner, MD 
Roxana Rustomjee MbChB, 
MMed, FCPhM, FRCP, PhD 
 
Clinical Trials Specialists: 
Laura E. Moran, MPH 
 
Chanelle Houston, BS 
 
 
 
 
FINAL Version 4.0 
June 26, 2018 


A5343 
 
 
FINAL Version 4.0 
 
 
06/26/18 
 
 
A Trial of the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone 
and in Combination, among Participants Taking Multidrug Treatment for Drug-Resistant 
Pulmonary Tuberculosis 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (eg, US National Institutes of Health, Division of AIDS) and institutional 
policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
Name/Title


A5343 
 
 
FINAL Version 4.0 
 
 
06/26/18 
 
 
TABLE OF CONTENTS 
Page 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ........................................................................................................... 10 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 12 
SCHEMA .................................................................................................................................. 14 
1.0 
HYPOTHESES AND STUDY OBJECTIVES.................................................................. 15 
1.1 
Hypotheses ........................................................................................................ 15 
1.2 
Primary Objectives ............................................................................................. 15 
1.3 
Secondary Objectives ........................................................................................ 16 
1.4 
Exploratory Objectives ....................................................................................... 16 
2.0 
INTRODUCTION ........................................................................................................... 17 
2.1 
Background........................................................................................................ 17 
2.2 
Rationale ........................................................................................................... 29 
3.0 
STUDY DESIGN ........................................................................................................... 31 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 33 
4.1 
Inclusion Criteria ................................................................................................ 33 
4.2 
Exclusion Criteria ............................................................................................... 35 
4.3 
Study Enrollment Procedures............................................................................. 37 
4.4 
Co-enrollment Guidelines ................................................................................... 38 
5.0 
STUDY TREATMENT ................................................................................................... 38 
5.1 
Regimens, Administration, and Duration ............................................................ 38 
5.2 
Study Product Formulation and Preparation ....................................................... 39 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 40 
5.4 
Concomitant Medications ................................................................................... 40 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 43 
6.1a 
Schedule of Evaluations (SOE): Screening through Treatment ........................ 43 
6.1b 
SOE: Follow-up and Premature Discontinuation ................................................ 45 
6.2 
Timing of Evaluations ......................................................................................... 46 
6.3 
Instructions for Evaluations ................................................................................ 47 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 56 
7.1 
Specific Management of Toxicities Related to Study-Provided Drugs or MBT .... 57 
7.2 
Toxicity Management – Other ............................................................................ 65 
7.3 
Pregnancy.......................................................................................................... 66 
7.4  
Expected Toxicities of MBT Drugs ..................................................................... 66 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 67 
8.1 
Permanent and Premature Treatment Discontinuation ....................................... 67 


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CONTENTS (Cont’d) 
Page 
 
 
8.2 
Premature Study Discontinuation ....................................................................... 68 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 68 
9.1 
General Design Issues ....................................................................................... 68 
9.2 
Outcome Measures ............................................................................................ 70 
9.3 
Randomization and Stratification ........................................................................ 73 
9.4 
Sample Size and Accrual ................................................................................... 73 
9.5 
Monitoring .......................................................................................................... 76 
9.6 
Analyses ............................................................................................................ 80 
10.0 
PHARMACOLOGY PLAN.............................................................................................. 83 
10.1 
Pharmacology Objectives .................................................................................. 83 
10.2 
Pharmacology Study Design .............................................................................. 83 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis............................... 85 
10.4 
Anticipated Outcomes ........................................................................................ 86 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 86 
11.1 
Records to Be Kept ............................................................................................ 86 
11.2 
Role of Data Management ................................................................................. 86 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 86 
11.4 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 87 
12.0 
HUMAN PARTICIPANTS .............................................................................................. 88 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 88 
12.2 
Participant Confidentiality ................................................................................... 89 
12.3 
Study Discontinuation ........................................................................................ 89 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 89 
14.0 
BIOHAZARD CONTAINMENT....................................................................................... 89 
15.0 
REFERENCES .............................................................................................................. 90 
APPENDIX I: ASSESSMENT OF CEREBROSPINAL FLUID (CSF) 
CONCENTRATIONS OF DELAMANID AND BEDAQUILINE AMONG 
PARTICIPANTS WITH MDR-TB ................................................................................... 96 
APPENDIX II: SAMPLE INFORMED CONSENT .................................................................... 102 
APPENDIX II-A: A5343 STUDY VISITS .................................................................................. 113 
APPENDIX III: CONSENT FOR OPTIONAL LUMBAR PUNCTURE (LP) AT WEEK 8 
OR 24 .......................................................................................................................... 117 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
This is a limited site study open to select non-US sites. The sites that are eligible for 
participation in the study can be found on the A5343 protocol-specific web page (PSWP). 
 
 


 
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PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Kelly Dooley, MD, PhD 
Johns Hopkins Adult AIDS CRS 
600 N. Wolfe Street, Osler 527 
Baltimore, MD 21287 
Phone: 410-955-3100 
Fax: 410-614-9978 
E-mail: kdooley1@jhmi.edu 
 
Gary Maartens, MBChB, MMed 
University of Cape Town 
Division of Clinical Pharmacology 
Observatory 
Anzio Road 
Cape Town, 7925 
SOUTH AFRICA 
Phone: 27-21-4066286 
E-mail: gary.maartens@uct.ac.za 
 
Vice Chair 
Francesca Conradie, MD, DTM&H 
University of Witwatersrand 
Clinical HIV Research Unit 
Postnet Suite 176 
Private Bag X2600 
Houghton 
Johannesburg, Gauteng, 2041 
SOUTH AFRICA 
Phone: 0027-11-2768800 
Phone: 27 11 2768814 
Fax: 27 11 4822130 
E-mail: fconradie@witshealth.co.za 
 
DAIDS Clinical Representatives 
Roxana Rustomjee MbChB, MMed, 
FCPhM, FRCP, PhD 
Senior Scientist 
Tuberculosis Clinical Research Branch 
Therapeutics Research Program 
Division of AIDS/NIAID/NIH/DHHS 
5601 Fishers Lane, Rm 9E31A  
Rockville, MD 20852 
Phone: 240-627-3536 
Mobile: 301-204-9917 
Email: roxana.rustomjee@nih.gov 
DAIDS Clinical Representative (Cont’d) 
Richard Hafner, MD 
TRP, DAIDS, NIAID, NIH  
5601 Fishers Lane 
Room 9E30 
Rockville, MD 20852 
Phone: 301-435-3766 
E-mail: rhafner@niaid.nih.gov 
 
Clinical Trials Specialists 
Laura Moran, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3373 
Fax: 301-628-3302 
E-mail: lmoran@s-3.com 
 
Chanelle Houston, BS 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3367 
Fax: 301-628-3302 
E-mail: chouston@s-3.com 
 
Senior Statistician 
Susan L. Rosenkranz, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health 
900 Commonwealth Avenue, 2nd Floor 
Boston, MA 02215 
Phone: 617-632-5915 
Phone: 617-432-7525 
Fax: 617-632-2001 
E-mail: sue@sdac.harvard.edu 
 
 
 
 
 
 
 


 
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Protocol Statistician 
Yoninah Cramer, MS 
Statistical and Data Analysis Center 
Harvard School of Public Health 
900 Commonwealth Avenue, 2nd Floor 
Boston, MA 02215 
Phone: 617-632-5901 
Fax: 617-632-2001 
E-mail: cramer@sdac.harvard.edu 
 
Data Manager 
Kathleen Donahue, MA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext.7329 
Fax: 716-834-8432 
E-mail: donahue@fstrf.org 
 
DAIDS Pharmacist 
Oladapo Alli, PharmD 
Pharmaceutical Affairs Branch 
DAIDS/OCSO/NIAID/NIH 
5601 Fishers Lane 
Room 9E16 MSC #9832 
Rockville, MD 20852 
Phone: 240-627-3593 
Fax: 240-627-3112 
E-mail: oladapo.alli@nih.gov 
 
Pharmacologist  
Helen McIlleron, MD 
University of Cape Town 
Division of Clinical Pharmacology 
K45-Old Main Building 
Groote Schuur Hospital 
7925 Observatory, Rondebosch 
SOUTH AFRICA 
Phone: 27-21-4066292 
Fax: 27-21-4481989 
E-mail: helen.mcilleron@uct.ac.za 
 
 
 
 
 
Pharmacometrician 
Mats Karlsson, PhD 
Uppsala University 
Box 591 
75124 Uppsala 
SWEDEN 
Phone: +46 18 4714105 
Fax + 46 18 4714003 
E-mail: mats.karlsson@farmbio.uu.se 
 
Cardiologist Consultant 
Joel Morganroth, MD 
ERT, Inc. 
1818 Market Street #1000 
Philadelphia PA 19103 
Phone: 215-840-4961 
E-mail: jmorganroth@ert.com 
 
Investigators 
Andreas Diacon MD, PhD 
Karl Bremer Hospital 
Mike Pienaar Boulevard 
Bellville 7531 
SOUTH AFRICA 
Phone: 27-219-497-751  
Fax: 27-219-181378  
E-mail: ahd@sun.ac.za 
 
Justin Shenje MB ChB, MSc 
South African Tuberculosis Vaccine 
Initiative (SATVI)  
Haarlem Street 
Brewelskloof Hospital 
Worcester, Western Province 6850 
SOUTH AFRICA 
Phone: 27-233-46570 
E-mail: justin.shenje@uct.ac.za 
 
 
 
 
 
 
 
 
 
 


 
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06/26/18 
 
 
Investigators (Cont’d) 
Florian von Groote-Bidlingmaier, Dr med 
(GER) 
TASK Clinical Research Center  
Karl Bremer Hospital 
Belleville, 7530 
Cape Town, 7530 
SOUTH AFRICA 
Phone: 27-21-9497751 
Fax: 27-21-9181378 
E-mail: florianv@sun.ac.za 
 
Field Representative 
Joan Gottesman RN, CCRP 
Vanderbilt Therapeutics (VT) CRS 
One Hundred Oaks 
719 Thompson Lane, Suite 47183 
Nashville, TN 37204 
Phone: 615-936-2664 
Fax: 615-936-2644 
E-mail: joan.gottesman@vanderbilt.edu  
 
Laboratory Technologist 
Gerald L. Tegha, BSc, MSc 
Kamuzu Central Hospital/Tidziwe Centre 
P.O. Box A-104 
100 Mzimba Road 
Kamzu Central Hospital 
Lilongwe  
MALAWI 
Phone: 265-999200668 
Fax: 265-1755954 
E-mail: gtegha@unclilongwe.org 
 
Community Scientific Subcommittee (CSS) 
Representative 
Jacob Tenai 
AMPATH Center and MTRH 
P.O. Box 4606 
Nandi Road 
Eldoret, 30100 
KENYA 
Phone: 254-712285540 
E-mail: jacob.ktenai@gmail.com 
 
 
 
International Site Specialist 
Akbar Shahkolahi, PhD 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3318 
Fax: 301-628-3302 
E-mail: ashahkolahi@s-3.com 
 
Industry Representatives  
Janssen Pharmaceuticals, Inc.:   
Chrispin Kambili, MD 
Janssen Pharmaceutical Inc. 
700 US Highway 202 South 
Raritan, NJ 08869 
Phone: 908-927-5713 
E-mail: ckambili@its.jnj.com 
 
R. Bruce Simonson, BS 
Janssen Pharmaceutical Inc. 
1125 Trenton-Harbourton Road 
Titusville, NJ 08560 
Phone: 609-730-4498  
E-mail: bsimonso@its.jnj.com  
 
Jaylene Allred 
Janssen Pharmaceutical Inc. 
7220 E 157th St. 
Belton, MO 64012 
Phone: 816-425-6033 
E-mail: jallred@its.jnj.com  
 
Manish Doshi, MD 
Janssen Scientific Affairs, LLC 
1125 Trenton-Harbourton Rd 
Titusville, NJ 08560 
Phone: 609-730-6589  
E-mail: mdoshi2@its.jnj.com  
 
 
 
 
 
 
 
 


 
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06/26/18 
 
 
Industry Representatives (Cont’d)  
 
Otsuka Pharmaceutical Company, Ltd 
Jeffrey Hafkin, MD 
Otsuka Pharmaceutical Development and 
Commercialization, Inc. 
Otsuka Novel Products 
2440 Research Boulevard 
Rockville, MD 20850 
Phone: 240-683-3281 
Fax: 301-721-7281 
E-mail: jeffrey.hafkin@otsuka-us.com 
 
Otsuka Pharmaceutical Company, Ltd.: 
Suresh Mallikaarjun, PhD, FCP 
Otsuka Novel Products, OPDC 
2440 Research Boulevard 
Rockville, MD 20879 
Phone: 240-683-3221 
Fax: 301-721-7221 
E-mail: suresh.mallikaarjun@otsuka-us.com 
 
Charles Wells, MD 
Otsuka Pharmaceutical Development and 
Commercialization, Inc. 
Otsuka Novel Products 
2440 Research Boulevard 
Rockville, MD 20850 
Phone: 240-683-3243 
Fax: 301-721-7243 
E-mail: charles.wells@otsuka-us.com 
 
ViiV Healthcare, Ltd.: 
Wendy Snowden, PhD 
ViiV Healthcare UK Limited 
Mailstop CN12, 
GSK House, 980 Great West Road 
Brentford 
Middlesex 
TW8 9GS, UK 
Phone: +44 (0)208 380 6311 
E-mail: 
wendy.x.snowden@viivhealthcare.com 
 
 
 
 
ViiV Healthcare ,Ltd (Cont’d) 
Chris Stainsby, BSc 
ViiV Healthcare 
980 Great West Road 
GSK House CN12 
Brentford TW8 9GS 
United Kingdom  
Phone: +44 07880-179182 
E-mail: 
chris.m.stainsby@viivhealthcare.com  
 
Navdeep Thoofer, PhD 
ViiV Healthcare  
HIV ViiV CSMO  
980 Great West Road  
Brentford, Middlesex TW8 9GS 
United Kingdom 
Phone: +44-20-83086124  
Fax: +44-20-83806201 
E-mail: 
navdeep.k.thoofer@viivhealthcare.com  
 
Laboratory Data Manager 
Laura Hovind, BS, MS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716 834 0900 x 7468 
Fax: 716 833 0655 
E-mail: hovind@fstrf.org 
 
Laboratory Specialist 
Kim Banks, MS, MBA, MT (AMT) 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
Laboratory Science Group 
8757 Georgia Avenue, 12th Floor 
Silver Spring MD 20910 
Phone: 301-628-3404 
Fax: 301-628-3304 
E-mail: kbanks2@s-3.com 
 
 


 
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STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.coreA5343@fstrf.org via e-mail. 
The appropriate team member will respond with a "cc" to actg.coreA5343@fstrf.org. A response 
should generally be received within 24 hours (Monday-Friday). 
 
Protocol E-mail Group 
Sites should contact the Computer Support Group at the Data Management Center (DMC) as 
soon as possible to have the relevant personnel at the site added to the actg.protA5343 e-mail 
group. Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org  
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the protocol team. Send an e-mail message to actg.coreA5343@fstrf.org. 
Include the protocol number, patient identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to pharmacologic laboratory tests, contact the protocol 
pharmacologist. Send an e-mail message to actg.coreA5343@fstrf.org (ATTN: Helen McIlleron). 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRFs), 
the CRF schedule of events, randomization/registration, delinquencies, and other data 
management issues, contact the data manager. CRFs can be downloaded from the FSTRF 
website at www.frontierscience.org. 
• 
For transfers, reference the Patient Transfer from Site to Site SOP 119, and contact 
Kathleen Donahue directly.  
• 
For other questions, send an e-mail message to actg.coreA5343@fstrf.org (ATTN: Kathleen 
Donahue).   
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization  
For randomization questions or problems and study identification number SID lists.  
• 
Send an e-mail message to rando.support@fstrf.org. Call the Statistical and Data Analysis 
Center (SDAC)/DMC Randomization Desk at 716-834-0900 x7301.    
 
Computer and Screen Problems  
Contact the SDAC/DMC programmers. 
• 
Send an e-mail message to actg.support@fstrf.org or call 716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialists. Send an 
e-mail message to actg.coreA5343@fstrf.org (ATTN: Laura Moran and Chanelle Houston). 
 


 
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06/26/18 
 
 
Copies of the Protocol 
To request a hard copy of the protocol, send a message to ACTGNCC@s-3.com (ATTN: Diane 
Delgado) via e-mail. Electronic copies can be downloaded from the ACTG Web site 
(https://www.actgnetwork.org). 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation, contact the clinical trials specialists (Laura Moran 
and Chanelle Houston) or ACTG Site Coordination group at actgsitecoordination@s-3.com.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Oladapo Alli, protocol pharmacist, at 240-627-3593.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
For any questions related to the IND submission, contact the DAIDS RSC at Regulatory@tech-
res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5343 team members. 
• 
Send an e-mail to actg.coreA5343@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
BDQ 
bedaquiline 
 
CMC 
Clinical Management Committee 
 
CNS 
central nervous system 
 
CSF 
cerebrospinal fluid  
 
CBC 
complete blood count 
 
DLM 
delamanid 
 
DR-TB 
drug-resistant tuberculosis 
 
DTG 
dolutegravir 
 
ECG 
electrocardiogram 
 
GCLP 
Good Clinical Laboratory Practices  
 
INH 
isoniazid 
 
INR  
international normalized ratio  
 
LP  
lumbar puncture 
 
MBT 
multidrug background treatment  
 
MDR-TB 
multidrug-resistant tuberculosis 
 
ms 
milliseconds 
 
MTB 
Mycobacterium tuberculosis 
 
NRT 
nucleoside reverse transcriptor inhibitor 
 
NTP 
National Tuberculosis Program 
 
OBR 
optimized background regimen 
 
PK 
pharmacokinetic 


 
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PD 
pharmacodynamic 
 
QTcF 
corrected QT based on the Fridericia correction method 
 
QT Interval 
measure between Q wave and T wave in the heart's electrical cycle 
 
RIF 
rifampin 
 
RR-TB 
rifampin-monoresistant tuberculosis 
 
SMOR 
single molecule-overlapping reads 
 
TB 
tuberculosis 
 
TBM 
tuberculous meningitis 
 
TDR-TB 
totally drug-resistant tuberculosis 
 
TDS 
targeted deep sequencing 
 
TEAE 
treatment-emergent adverse event 
 
XDR-TB 
extensively drug-resistant tuberculosis 
 


 
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SCHEMA 
 
 
A5343 
 
A Trial of the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone 
and in Combination, among Participants Taking Multidrug Treatment for Drug-Resistant 
Pulmonary Tuberculosis 
 
 
DESIGN 
This is a phase II, randomized, open-label, three-arm pharmacokinetic 
and safety trial of the anti-tuberculosis (TB) drugs bedaquiline and 
delamanid. Participants will be randomized to one of three arms. 
Participants in arms 1, 2, and 3 will receive bedaquiline, delamanid, or 
both drugs in combination, respectively, for 24 weeks together with 
multidrug background treatment.  
 
 
 
At any visit prior to and including week 22, participants may be 
asked to take part in an optional nested cerebrospinal fluid (CSF) 
sampling study that will entail a lumbar puncture (LP), to be done at 
weeks 8 or 24.  
 
DURATION 
24 weeks on study TB treatment, followed by 104 weeks of follow-up, for 
a total duration of 128 weeks 
 
SAMPLE SIZE 
84 participants; up to 16 participants will be asked to have an 
optional LP done 
 
POPULATION 
Men and women age 18 or older, with pulmonary multidrug-resistant or 
rifampin-monoresistant TB, with or without HIV co-infection.  
 
STRATIFICATION 
Randomization will be stratified by HIV status, with institutional balancing.  
 
TB REGIMEN 
Arm 1: Bedaquiline 400 mg once daily for 2 weeks followed by 200 mg 
thrice weekly for 22 weeks   
 
 
 
Arm 2: Delamanid 100 mg twice daily for 24 weeks   
 
 
 
Arm 3: Both bedaquiline and delamanid (same doses and duration as in 
Arms 1 and 2) 
 
HIV REGIMEN 
Participants with HIV infection will be offered dolutegravir-based 
antiretroviral treatment. Dolutegravir will be given at a dose of 50 mg once 
daily and must be accompanied by two nucleoside reverse transcriptase 
inhibitors. 
 
 


 
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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 Primary Hypothesis 
 
Co-administration of delamanid (DLM) and bedaquiline (BDQ) (with multidrug 
background treatment [MBT] for multidrug resistant TB infection [MDR-TB] or 
rifampin-monoresistant TB [RR-TB]) will increase the duration of the QT interval 
(QTcF, as measured on electrocardiogram (ECG), adjusted for heart rate using 
the Fridericia correction formula) compared to administration of either drug alone 
(with MBT), but the combined effects on the QT interval will be no greater than 
additive. 
 
1.1.2 Secondary Hypotheses 
 
1.1.2.1 When DLM and BDQ are co-administered with MBT for TB infection, 
clinically significant QTcF prolongation (see section 7.1.1 for definition) 
will be uncommon.   
 
1.1.2.2 Co-administration of BDQ and DLM (in the context of MBT) for MDR-TB 
or RR-TB will not significantly affect concentrations (area under the 
concentration-time curve, or AUC) of either drug (or their main 
metabolites, M2 and DM-6705, respectively). 
 
1.1.3 Exploratory Hypotheses 
 
1.1.3.1 Administration of BDQ and/or DLM for a minimum of 8 weeks in 
patients with RR or MDR pulmonary TB, without TB meningitis, will 
result in measurable drug concentrations (total and unbound) in the 
CSF. 
 
1.1.3.2 BDQ and/or DLM CSF levels will follow a similar concentration curve 
to that found in plasma. 
 
1.2 
Primary Objectives 
 
1.2.1 To estimate the mean changes from baseline (averaged over weeks 8-24) in 
QTcF when DLM and BDQ are co-administered (along with MBT; Arm 3), when 
BDQ is administered without DLM (along with MBT; Arm 1) and when DLM is 
administered without BDQ (along with MBT; Arm 2). 
 
1.2.2 To compare the mean change from baseline (averaged over weeks 8-24) in QTcF 
when BDQ and DLM are co-administered (with MBT) to the mean change 
observed when each drug is administered alone (with MBT) (separate 
comparisons of Arm 3 to Arm 1 and Arm 3 to Arm 2). 
 


 
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1.3 
Secondary Objectives 
 
1.3.1 To estimate the proportion of participants who exhibit QTcF >500 ms at any time 
during study treatment, by arm. 
 
1.3.2 To estimate the proportion of participants who exhibit an increase from baseline 
in QTcF of greater than 60 ms at any time during study treatment, by arm. 
 
1.3.3 To describe visit-specific QTcF changes from baseline while on study drug 
treatment and following completion of study treatment (at week 28), for 
participants in Arm 1 (BDQ), Arm 2 (DLM), and Arm 3 (BDQ and DLM) 
 
 
1.3.4 To estimate, by arm, the proportion of participants for whom the following occurs: 
(a) absolute QTcF >480 and ≤500 ms and (b) (separate measure) QTcF increase 
from baseline of >30 and ≤60 ms. 
 
1.3.5 To compare the pharmacokinetics (PK) of BDQ when given together with DLM 
with MBT for MDR-TB or RR-TB (Arm 3) versus when given alone with MBR for 
MDR-TB or RR-TB (Arm 1). 
 
1.3.6 To compare the PK of DLM when given together with BDQ with MBT for MDR-TB 
or RR-TB (Arm 3) versus when given alone (Arm 2). 
 
1.3.7 To describe the safety and tolerability of study treatment, by arm. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To examine the relationships between plasma concentrations of DLM, its DM-
6705 metabolite, BDQ, its M2 metabolite and QTcF changes from baseline, on 
treatment and post-treatment, using a population pharmacokinetic-
pharmacodynamic (PK-PD) model. 
 
1.4.2 To estimate the proportion of participants with a positive sputum culture at 
baseline who convert their sputum culture to negative by 2 months of study 
treatment and by 6 months of study treatment, by Arm; to report the time-to-
culture conversion, by arm, over 6 months of study treatment.  
 
1.4.3 To measure concentrations of DLM and BDQ and key second-line MBT drugs in 
hair over time. 
 
1.4.4 Among participants with MDR-TB or RR-TB and HIV co-infection initiating 
dolutegravir (DTG) within ±4 weeks of study entry (as part of their antiretroviral 
treatment [ART] regimen), to estimate the proportion of participants with 
suppressed viral load 24 (±6) weeks and 48 (±6) weeks after start of co-
treatment. 
 


 
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1.4.5 To describe the safety and tolerability of dolutegravir-based ART and TB 
treatment among participants co-infected with HIV and MDR-TB or RR-TB. 
 
1.4.6 To estimate the proportion of participants with a favorable TB outcome at week 
128, by arm. 
 
1.4.7 To examine the relationships between plasma and hair concentrations of DLM, 
its DM-6705 metabolite, BDQ, its M2 metabolite, and emergence of drug-
resistant subpopulations during intervention and follow-up phases as 
characterized by targeted deep sequencing (TDS). 
 
1.4.8 To measure plasma and lumbar CSF concentrations of DLM and/or BDQ 
(total and unbound) in up to 16 participants who are receiving one or both 
drugs for treatment of MDR-TB or RR-TB. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Among bacteria, Mycobacterium tuberculosis is the single greatest killer on the planet. 
The World Health Organization (WHO) [1] estimates that over 9 million new cases and 
1.54 million deaths due to tuberculosis (TB) occurred in 2013 
(http://www.who.int/mediacentre/factsheets/fs104/en/) [2]. Multidrug-resistant (MDR) TB, 
TB resistant to isoniazid (INH) and rifampin (RIF), is a growing public health threat, with 
an estimated 480,000 cases in 2013. RR-TB is also on the rise, and, per WHO, must be 
treated with second-line agents, similar to MDR-TB [3]. Extensively drug-resistant (XDR) 
TB, TB resistant to INH, RIF, fluoroquinolones, and injectable anti-TB drugs, has been 
found in every country in which it has been sought [2]. TB resistant to all currently 
available anti-TB drugs is now a reality and threatens a return to the pre-antibiotic era [4-
7]. Therapeutic options for drug-resistant TB are limited in availability, acceptability and 
efficacy. For example, only 1 in 5 patients diagnosed with MDR-TB is started on 
treatment [2]. Current standard treatment for MDR-TB requires 18-24 months of 
multidrug therapy, including at least 6 months of an injectable agent [8], and yet is 
successful in only 48% of patients [9]. Due to inappropriate and/or ineffective MDR-TB 
treatment, nearly 10% of MDR-TB cases now harbor XDR-TB (extensively drug resistant 
TB). Fortunately, for the first time in decades, new drugs are being registered for 
treatment of TB, and there are multiple drugs in the development pipeline. Improved 
treatment of MDR-TB, both to improve clinical outcomes for current patients and to 
prevent XDR- and TDR-TB, is critical. 
 
The WHO recommends two possibilities for treatment of MDR-TB. Patients with RR-TB 
are, per WHO guidelines, also eligible for these regimens. Standard-duration treatment 
regimens must contain at least four drugs to which the organism is likely to be sensitive, 
and these regimens are typically given for 18-24 months [8]. New in 2016, based on 
observational studies [10-13], WHO also provides an option for an alternative short-
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sensitive to fluoroquinolones and injectable agents [3]. In this regimen, seven drugs, 
including an injectable, are given during the intensive phase, and four drugs are given 
during the continuation phase. 
 
It is expected that South Africa will be introducing the WHO shorter-duration MDR-TB 
regimen in 2017. The regimen will include high-dose INH, prothionamide or ethionamide, 
kanamycin or amikacin, moxifloxacin, ethambutol, pyrazinamide, and clofazimine (given 
for 4-6 months, the ‘intensive phase’) followed by moxifloxacin, clofazimine, 
pyrazinamide, and ethambutol (given for 5-7 months, the ‘continuation phase’). 
 
Current MDR-TB treatment regimens (both standard- and short-course regimens), 
however, are poorly-tolerated and have significant toxicities. Regimens, for example, 
may include kanamycin (ototoxicity, which can be irreversible, and poor bactericidal 
activity), a fluoroquinolone, ethionamide or prothionamide (dose-limiting GI toxicity), 
pyrazinamide (risk of resistance, as this drug is a standard part of first-line regimens), 
cycloserine/terizidone (central nervous system [CNS] toxicity), and ethambutol 
(ophthalmologic toxicity risk and risk of resistance, as this drug is a standard part of first-
line regimens).  
 
The evidence base for the treatment of MDR-TB is limited. The guidelines for both 
regimens are based largely on expert opinion and observational cohorts. The first 
randomized controlled trial for an MDR-TB regimen, STREAM 1, is comparing the 18-24 
month regimen to the 9-month regimen. Results will be available in 2018. 
 
Having effective new anti-TB drugs and regimens is, thus, not only important to improve 
cure rates and reduce risk of acquired resistance but also to reduce suffering related to 
common and severe side effects of standard current MDR-TB regimens. As new drugs 
are evaluated and registered, ensuring that they can be used together safely and 
effectively, will build the evidence base needed to test injectable-sparing regimens or 
regimens that do not include highly toxic drugs.  
 
BDQ and DLM are newly registered anti-TB drugs with novel, and distinct mechanisms 
of action. BDQ is a diarylquinoline that inhibits Mycobacterium tuberculosis’ ATP 
synthase [14]. DLM is a nitroimidazole antibiotic with a mechanism of action that 
primarily involves inhibition of mycolic acid synthesis [15]. Separately, BDQ and DLM 
have each been shown to improve sputum culture conversion rates when added to MBT 
compared to MBT alone [16-19]. In phase II clinical trials of BDQ, adding BDQ to MBT 
for 8 weeks (at a dose of 400 mg once daily for 2 weeks followed by 200 mg thrice-
weekly) increased 2-month sputum culture conversion from 9% to 48% compared to 
MBT alone [16], and improved culture conversion was sustained at 6 months [17]. 
When given for 6 months, 24-week culture conversion was improved compared to MBT 
for 6 months without BDQ [20]. Among patients with MDR-TB given MBT alone, MBT 
plus DLM 100 mg twice daily, or MBT plus DLM 200 mg twice daily, 2-month culture 
conversion proportions were 29.6%, 45.4%, and 41.9%, respectively [18]. Long-term 
outcomes with DLM added to MBT for 6 months were favorable in a nonrandomized 
comparison to shorter duration DLM use or MBT alone [19]. Based on these phase II 
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have received regulatory approvals in several countries. Combining these two 
compounds, together with other anti-TB drugs, may improve outcomes for drug-resistant 
TB, as there will not be cross-resistance with other anti-TB drugs. It is also possible that 
use of these drugs together may eventually allow for one or more second-line TB 
drugs in the DR-TB regimen to be dropped. Both have the added benefit of being oral 
agents. It is expected that both BDQ and DLM will be increasingly available globally 
now that both drugs have initial regulatory approvals. The combination of BDQ and 
DLM, though, has not yet been studied in humans. 
 
BDQ is a diarylquinoline with interesting PK properties. It is metabolized by liver 
cytochrome P450 enzyme 3A (CYP3A) to its main metabolite, M2, and it has triphasic 
elimination with an effective half-life of 24 hours, but a prolonged terminal elimination 
half-life of about 5 months. In in vitro human hepatocyte studies, BDQ neither induces 
nor inhibits drug metabolizing enzymes appreciably. M2 is less active than the parent 
drug against M. tuberculosis. DLM’s main route of metabolism is by albumin, and it is 
only partially metabolized by P450 enzymes (CYP3A4); several metabolites have been 
identified in human plasma, including, most prominently, DM-6705 (18%) and DM-6706 
(7%). While the elimination half-life of DLM is 30-38 hours, its metabolites have longer 
terminal half-lives, 121-425 hours. Both BDQ and DLM are relatively well-tolerated (see 
Drug Information below). Each drug modestly increases the QT interval. The combined 
effects of the two drugs on QT have not been studied [BDQ Investigator Brochure 
Janssen Pharmaceuticals, Inc., 2015]. 
 
Nested study of BDQ and DLM CSF penetration 
Tuberculous meningitis (TBM) is a disseminated form of TB most commonly 
affecting children under 5 years and HIV-positive adults [21-24]. Current treatment 
for TBM and multidrug-resistant (MDR) TBM is based on treatment regimens for 
pulmonary TB with many drugs achieving poor CSF penetration and consequently 
poor outcomes. Among patients treated for drug-sensitive (DS) TBM, adults have 
a mortality of 30-50% with 20% mortality in children; among those who survive, 
serious neurologic sequelae are common [25]. MDR TBM confers a 12-fold higher 
risk of death in children [26] and adults [27] with almost 100% mortality in patients 
co-infected with MDR-TB and HIV [28, 29].  
 
With the view to create more effective regimens for the treatment of both DS and 
DR TBM in the future, CSF penetration of new drugs should be evaluated. The 
A5343 study provides a unique opportunity to study the CSF penetration of its two 
novel medications, bedaquiline and delamanid. A5343 participants who consent to 
participate will form part of a nested study to evaluate the CSF penetration of 
these agents. The participants will not have meningitis; thus, CSF concentrations 
will most meaningfully reflect those achieved later in TBM treatment when 
treatment has largely restored the integrity of the blood-brain barrier. This nested 
study will maximize the contribution of the PK data accumulated in A5343 to 
advance what is known about bedaquiline and delamanid CSF penetration.  
 
Further details about the LP for CSF collection are included in Appendix I. 
 


 
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Drug Information 
Bedaquiline 
BDQ is a methoxyquinoline that was FDA-approved in December of 2012 for the 
treatment of MDR-TB. It inhibits the proton pump of Mycobacterium tuberculosis (M. 
tuberculosis) ATP synthase, a novel mechanism of action for an anti-mycobacterial 
drug. It is active in vitro against both replicating and non-replicating bacilli, and it has 
significant bactericidal and sterilizing activity in the murine model of TB infection. In vitro, 
it is equally active against drug-sensitive, MDR, Pre-XDR, and XDR strains of M. 
tuberculosis. The distinct target and mode of action of BDQ minimizes the potential for 
cross-resistance with existing anti-TB drugs [BDQ Investigator Brochure, Janssen 
Pharmaceuticals, Inc., 2015]. 
 
Dose and indications 
BDQ is FDA-approved for the treatment of MDR-TB in combination with MBT. It is also 
approved in South Africa and other countries. For the treatment of TB infection, a dose 
of 400 mg daily (four 100 mg tablets) for 2 weeks, followed by 200 mg three times per 
week (with at least 48 hours between the doses) to complete 6 months of treatment is 
recommended.  
 
Pharmacokinetics 
BDQ is well-absorbed with a Tmax of 5 h. Dose-proportionality of Cmax and AUC was seen 
up to 700 mg with single doses and 400 mg with multiple doses. The average terminal 
elimination half-life of BDQ is 132 days and is 112 days for its M2 metabolite. 
Administration with food increased bioavailability by 95%. BDQ is metabolized by 
oxidative metabolism via the CYP3A4 isoenzyme to its N-desmethyl metabolite, M2. The 
M2 metabolite has activity against M. tuberculosis, but it is 3- to 6-fold less potent [BDQ 
Investigator Brochure Janssen Pharmaceuticals, Inc., 2015]. 
 
Drug-drug interactions 
Based on studies in human hepatocytes, BDQ is likely an inducer of CYP2E1 and a 
weak inducer of CYP2C9 but does not appear to induce other isoenzymes, and it 
demonstrated no inhibition of CYP activity. A drug-drug interaction study of RIF, a 
CYP3A4 inducer, coadministered with BDQ in healthy participants resulted in reduced 
BDQ and M2 concentrations by 52% and 25%, respectively, but reductions in BDQ and 
M2 metabolite concentrations at steady state are expected to be substantially larger [30]. 
Coadministration of BDQ with ketoconazole, a CYP3A4 inhibitor, increased BDQ 
concentrations by 22%. Therefore, coadministration of BDQ with a CYP3A4 inducer or 
inhibitor is likely to affect BDQ exposure. BDQ concentrations are reduced an estimated 
20-50% when given together with efavirenz (EFV); with lopinavir-boosted ritonavir, 
single-dose concentrations are increased 22%, but at steady state, BDQ and M2 
metabolite concentrations are likely to be substantially higher [31]. Nevirapine does not 
appear to have a meaningful impact on BDQ concentrations [31]. Integrase inhibitors like 
raltegravir or dolutegravir have not been tested with BDQ, but given the metabolic 
pathways of these drugs, a clinically significant metabolic drug interaction is unlikely. 
  
Toxicities  
A total of 173 healthy participants participated in six phase I trials with BDQ. In phase I 


 
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trials, BDQ was safe and well tolerated. The most common adverse events (AEs) were 
headache, nasopharyngitis, postural dizziness, and hyperuricemia (the latter a known 
side effect of the coadministered pyrazinamide). Three participants withdrew due to: a 
urinary tract infection, pharyngolaryngeal pain and pyrexia, and increased lipase. In the 
phase IIa trial, the drug-related AEs were diarrhea and rash (two participants) and 
somnolence (one participant). In this study, in which TB patients received 400 mg daily, 
after 7 days, a mean 10 ms increase in QT was seen. In the phase II MDR treatment 
trial, nausea was the only AE seen more frequently in patients in the BDQ arm than in 
patients in the placebo arm (Package Insert, IB). In this study involving prolonged use of 
BDQ at 400 mg daily for 2 weeks followed by 200 mg thrice weekly for 6 weeks in 
participants with TB, a 5-10 ms increase in the QTcF interval compared to placebo 
recipients was seen. There were no clinically relevant changes in laboratory tests. 
However, with prolonged follow-up, an increased risk of death was seen in the BDQ 
treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%), 
based on the 120-week visit window. One death occurred during the 24 weeks of 
administration of BDQ. The imbalance in deaths is unexplained. No discernible pattern 
between death and sputum culture conversion, relapse, sensitivity to other drugs used to 
treat TB, HIV status, or severity of disease was observed.  
 
Combining the phase I and IIa trials, another AE that occurred in three or more people 
was erythema. While ophthalmological findings of conjunctival hyperemia, photophobia, 
or superficial corneal staining were found in some dogs in preclinical studies after 5 
months of daily dosing (though not in other species), there have been no 
ophthalmological side effects related to BDQ in phase I or phase II trials in humans to 
date (IB). More hepatic-related adverse drug reactions were also reported with the use 
of BDQ plus other drugs used to treat TB compared to other drugs used to treat TB 
without the addition of BDQ.  
 
QT effects 
With regard to effects on the QT interval, the proportion of study participants 
experiencing treatment emergent QT abnormalities during study treatment in the phase 
II trial are as follows: 
n (%) 
BDQ/MBT 
Placebo/MBT 
Treatment Phase 
Treatment Phase 
QTcF absolute value, N 
79 
81 
[450 ms – 479 ms] 
23 (29.1) 
10 (12.3) 
[480 ms – 499 ms] 
1 (1.3) 
1 (1.2) 
≥500 ms 
1 (1.3) 
0 
QTcF change in QT, N 
77 
79 
Increase by <30 ms 
22 (28.6) 
48 (60.8) 
Increase by 30-60 ms 
45 (58.4) 
29 (36.7) 


 
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Increase by >60 ms 
10 (13.0) 
2 (2.5) 
 
In Trial C208 Stage 2, the largest mean increase from reference in QTcF during the 24-
week BDQ treatment was 15.7 ms in week 18, compared to 6.2 ms in the comparator 
group at the same time point. This difference persisted, likely because of BDQ and M2’s 
long terminal half-lives. Mean increases in QTcF of ≥10 ms were seen from week 5 
onwards and decreased after week 24 (when study drug was discontinued). Of note, 
mean QTcF changes from baseline at the 5-hour time point (Tmax), were similar to those 
at predose time points, suggesting lack of a direct correlation between plasma 
concentrations and QTcF prolongation, though a delayed effect is possible. The time 
course of QTcF change from baseline with standard BDQ dosing over the 6 months of 
treatment followed by continuation of MBT is summarized in the figure below, from the 
FDA NDA filing: 
 
 
 
Of note, many patients participating in the phase II trials of BDQ were also receiving 
other QT prolonging drugs (like moxifloxacin or clofazimine).  The following summarizes 
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C209. Maximum QTcF for BDQ alone (without other QT-prolonging drugs) was 480 ms. 
 
 
 
Delamanid  
DLM is a nitro-dihydro-imidazooxazole derivative that inhibits mycolic acid synthesis and 
enhances killing by generating nitric oxide in MTB in anaerobic conditions. It is active in 
vitro against actively dividing and dormant mycobacteria with similar MICs against drug-
sensitive and MDR-TB strains. The distinct target and mode of action of DLM minimizes 
the potential for cross-resistance with existing anti-TB drugs [DLM Investigator Brochure, 
Otsuka Pharmaceutical Company, Ltd., 2016]. 
 
Dose and indications 
DLM has been approved by the European Medicines Agency and the Pharmaceuticals 
and Medical Devices Agency (PMDA) in Japan at a dose of 100 mg twice daily with food 
for 6 months for the treatment of MDR-TB.  
 
Pharmacokinetics 
DLM absorption is enhanced by food (and even more so with a high-fat meal), and its 
maximum concentration is reached approximately 4 hours post-dose. DLM exposures 
increase less than proportionally for doses ranging from 50 to 400 mg. DLM is 
extensively protein-bound (>99.5%), as are its primary metabolites DM-6704, DM-6705, 
and DM-6706. DLM is metabolized by albumin. CYP3A4 and CYP1A1 are involved in 
the subsequent metabolism of DLM metabolites. The main circulating metabolites are 
DM-6705 and DM-6706. Following DLM 100 and 200 mg BID for 10 days, all metabolites 
were measurable in plasma and represented <1% to 12% of DLM exposure. The 
elimination half-life of DLM is 30-38 hours; terminal half-life of the metabolites is longer, 
121 to 425 hours. DLM steady state is reached at 10-14 days while DM-6705 steady 
state is reached at 10-14 weeks. Only a small fraction of DLM (3-8%) is eliminated 
renally; the majority of the drug is excreted in feces. Gender, race, age, and renal 
impairment do not affect DLM PK. DLM exposures among patients with MDR-TB were 
similar to those in healthy participants [DLM Investigator Brochure, Otsuka 
Pharmaceutical Company, Ltd., 2016]. 
 


 
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Drug-drug interactions 
DLM and its major metabolites do not show meaningful inhibition of CYP isoenzyme 
activity, including CYP1A1/2, CYP2A6, CYP2B6, CYP2C8/9, CYP2C19, CYP2D6, 
CYP2E1, CYP3A4. DLM is not an inducer of CYP1A2, CYP2C9, CYP3A4/5. Co-
administration of DLM with a combination of first-line anti-TB drugs (INH, RIF, 
pyrazinamide, ethambutol) resulted in a 45% reduction in the concentrations of DLM and 
all its metabolites (likely related to the impaired solubility of DLM in the presence of 
additional drugs and to a much lesser extent due to induction of CYP3A4 and CYP1A1 
by RIF). To enhance drug solubility and absorption, DLM dosing should be separated 
from dosing of other MDR-TB drugs by at least one hour. Ethambutol plasma 
concentrations increased by about 25% when coadministered with DLM. Co-
administration of DLM with lopinavir/ritonavir increased DLM and DM-6705 by about 
25%. DLM did not affect tenofovir, lopinavir, or ritonavir exposures. Coadministration 
with EFV did not affect concentrations of either DLM or EFV. MDR1 (Pgp) inhibition or 
induction does did not appear to affect DLM exposures. No drug interaction studies of 
DLM together with integrase inhibitors have been performed, but based on knowledge of 
metabolic pathways, the risk of metabolic drug interaction potential is expected to be low 
[DLM Investigator Brochure, Otsuka Pharmaceutical Company, Ltd., 2016]. 
 
Toxicities 
As of 31 Jan 2016, 949 adult participants had been exposed to oral doses of DLM in 19 
completed trials in the United Kingdom, Japan, China, South Africa, Peru, Korea, 
Philippines, Egypt, European Union (EU), and United States (US). The safety data for 
patients with TB are provided here.  
 
In a 14-day early bactericidal activity (EBA) trial in participants with drug-sensitive (DS-) 
TB, five treatment-emergent adverse events (TEAEs) considered serious were reported: 
three participants with QT interval prolongation on ECG and two participants with 
increased hepatic transaminases in the DLM 300 mg and 400 mg groups, respectively. 
All five events were mild in severity. Note that additional QT-related information is 
provided in a separate section directly following this. 
 
Trial 204 was a randomized, double-blind trial evaluating DLM 100 mg or 200 mg BID 
orally in combination with an optimized background regimen (OBR) versus placebo with 
OBR for 56 days [18]. Treatment-emergent AEs were reported for >90% of patients in all 
treatment groups (including the placebo + OBR group). Most TEAEs were mild or 
moderate in intensity. In this trial, the incidences of most TEAEs were similar (difference 
<5 percentage points) between the DLM 100 mg BID + OBR group and the placebo + 
OBR group. In Trial 204, there appeared to be a dose response for the following TEAEs 
(>5 percentage points lower in the DLM 100 mg BID + OBR group compared with the 
DLM 200 mg BID + OBR group): vomiting (29.8% vs 36.3%), dyspepsia (3.7% vs 8.8%), 
pyrexia (5.6% vs 11.3%), decreased appetite (14.9% vs 23.1%), hypokalemia (12.4% vs 
19.4%), arthralgia (19.9% vs 26.9%), neck pain (0.6% vs 6.9%), insomnia (26.1% vs 
32.5%), and depression (2.5% vs 8.1%). Chest pain (9.9% vs 4.4%) incidence was 
greater in the DLM 100 mg BID + OBR group and the 200 mg BID + OBR group (8.8% 
vs. 4.4%) compared to placebo + OBR group.  
 


 
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Trial 208 served as a treatment extension trial to provide safety and tolerability data for 
longer-term exposure to DLM for up to 6 additional months beyond the exposure in Trial 
204 [19]. Although DLM was administered for 6 months in this open-label trial (at least 4 
months longer than in previous DLM trials), no new safety concerns were identified when 
the data were compared with previous trials. The incidence of the following TEAEs were 
increased in Trial 208 relative to Trial 204 (>5 percentage points higher in Trial 208 than 
in Trial 204 for the DLM 100 mg BID + OBR group): hyperbilirubinemia (6.6% vs 0.6%), 
nasopharyngitis (8.8% vs 2.5%), upper respiratory infection (URI; 8.0% vs 1.2%), 
increased blood cortisol (8.8% vs 2.5%), and headache (30.7% vs 23.6%). 
 
Trial 210 was designed to evaluate the safety, tolerability, and PK of orally administered 
DLM BID given in sequentially escalated doses for up to 196 days (28 weeks) at each 
dose to individual cohorts of MDR-TB participants refractory to treatment with OBR (9 
months of previous treatment with second-line drugs without achieving sputum culture 
conversion) and to determine the potential dose-limiting factors and, potentially, the 
maximum tolerated dose (MTD) in participants treated with DLM. Drug exposure did not 
increase with these higher doses, apparently due to lack of further absorption. Ten 
participants were enrolled in Trial 210, and all participants reported at least one TEAE. 
Most TEAEs were mild to moderate in severity. The most frequently reported TEAEs (>2 
participants) were hyperglycemia (6/10 participants; 60%), tuberculosis (i.e., progressive 
tuberculosis, 5/10 participants; 50%), viral upper respiratory tract infection (4/10 
participants; 40%), nausea (4/10 participants; 40%), vomiting (3/10 participants; 30%), 
hepatomegaly (3/10 participants; 30%), decreased appetite (3/10 participants; 30%), and 
cough (3/10 participants; 30%).  
 
In trials involving healthy participants without TB or HIV infection, moderate to severe 
psychiatric side effects were seen in some individuals receiving concomitant EFV and 
DLM, including one case of acute delirium in one study participant; one case of severe 
hepatic enzyme elevation was seen in a participant receiving EFV and DLM. In addition, 
the following AEs were reported but were rare: ischemic colitis (occurring more than 2 
weeks after study drug administration ended), hematochezia, and hematemesis. 
 
In summary, DLM at doses of 100 mg BID and 200 mg BID is well-tolerated among 
participants with TB. The most common toxicities among participants with TB included 
gastrointestinal side effects (dyspepsia, nausea, vomiting), fever, headache, chest pain, 
central nervous system side effects, hyperbilirubinemia, and QT prolongation.   
 
QT effect 
In the 14-day early bactericidal activity (EBA) trial in patients with drug-sensitive (DS-) 
TB, 3 patients had ECG QT interval prolongation corrected by Bazett’s formula (i.e., 
QTcB interval ≥450 ms [male] or ≥470 ms [female]) in the DLM 100 mg, 200 mg, and 
300 mg groups, respectively; the concomitant QTcF interval with each of these events 
remained <460 ms. These events were considered mild in severity. 
 
Trial 204, which incorporated specific features of a thorough QT study, assessed serial, 
time-matched ECGs on Days 1, 14, 28, and 56 at 2, 3, 4, 10, 12, and 24 hours post-
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largest effect on time-averaged change in QTcF (relative to baseline and the placebo  
arm) reached 12.1 ms in the 100 mg DLM BID arm and 14.8 ms in the 200 mg DLM BID 
arm. (Note, participants randomized to receive placebo plus OBR (placebo + OBR) had 
a mean increase from baseline of 3 ms). 
 
In terms of categorical ECG assessment, prolonged QT interval incidence—as assessed 
by the local investigator—was greater in the DLM 100 mg BID + OBR group versus the 
placebo + OBR group (9.9% vs 3.8%) and in the 200 mg BID + OBR group compared to 
placebo + OBR group (13.1% vs. 3.8%). The incidence of any QT outliers, though, was 
low: 1 of 161 patients receiving 100 mg BID DLM and 1 of 160 receiving 200 mg BID 
exhibited a QTcF interval >500 ms. Of note, both participants were asymptomatic. In 
addition, there were no cases of torsades de pointes or any clinical events suggestive of 
a proarrhythmia state attributable to DLM. Finally, 3% of participants in the DLM 100 mg 
BID + OBR group and 4% in the DLM 200 mg BID + OBR group had QTcF >60 ms 
change from baseline compared with 0% in the placebo group. 
 
In Trial 208, QTcF data were not calculated from time-matched samples as in Trial 204, 
so caution is necessary when interpreting comparative results. Overall, over 6 months of 
dosing, the mean QTcF interval increased over the first 6 weeks and then stabilized after 
week 6-8; differences from time point to time point were minor and not clinically relevant. 
Only 6 (2.8%) participants had reported TEAEs related to prolonged QT. A low 
percentage of participants (3.8%, 8/213) had a change in QTcF of >60 ms. These data 
suggest that further increases in QTcF duration are not likely to occur with longer-term 
(e.g., 6 months, 26 weeks) dosing of DLM beyond the 2-month (56 days) period in Trial 
204, using the same dose regimen. 
 
QTc interval prolongation appears to be associated with DM-6705 plasma 
concentrations and to a lesser extent with DLM, DM-6704, and DM-6720 plasma 
concentrations. DM-6705 accumulates slowly over time to reach maximal concentrations 
after 2 months of treatment. Key elements of a thorough QTc trial were therefore 
incorporated into Trial 204 to clearly establish a PK/PD relationship for QTc interval 
prolongation. Placebo-corrected mean change from baseline in Fridericia’s corrected QT 
interval [∆∆QTcF] on Day 56 estimated using the linear PK/PD model was 14.24 ms with 
DLM 100 mg BID + OBR at the DM-6705 mean Cmax of 151 ng/mL and 21.98 ms with 
DLM 200 mg BID + OBR at the DM-6705 mean Cmax of 233 ng/mL (Trial 204). A 
slightly (0.5 to 3 ms) lower effect in QTcF prolongation was predicted using an Emax 
model that seemed to fit the data better. The highest DM-6705 concentrations (Cmax) 
and QTc effect were observed on day 56. The QT interval prolongation reversed after 
treatment was discontinued (Trial 204). 
 
Finally, a post hoc multivariate analysis of Trial 204 data suggested that—in addition to 
DLM exposure—hypoalbuminemia (albumin <3.4 mg/dL) hypokalemia, female sex, 
lower heart rate, and older age were each independent risk factors for QTcF 
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Dolutegravir  
DTG is an integrase strand transfer inhibitor (INSTI) that is used for the treatment of 
HIV-1 infection. 
 
Dose and indications 
DTG is approved for use in combination with other antiretrovirals in treatment-naïve and 
treatment-experienced HIV-1 infected adults and children aged 12 years and older and 
weighing at least 40 kg. The recommended dose of DTG in treatment naïve or 
treatment-experienced, integrase-naïve patients is 50 mg QD for most patients (for 
exceptions, see Drug interactions section below). The recommended dose of DTG in 
integrase-experienced patients with certain integrase-associated resistance substitutions 
(L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R) or 
clinically suspected integrase resistance is 50 mg BID. Additionally, in these patients, 
alternative combinations that do not include metabolic inducers should be considered 
when possible.   
 
Pharmacokinetics 
DTG is metabolized by the UGT1A1 metabolic pathway with minor contributions by 
CYP3A4, UGT1A3, and UGT1A9. DTG has a terminal half-life of approximately 14 
hours, and Cmax occurs approximately 2-3 hours postdose. DTG tablets may be taken 
with or without food. DTG is highly protein-bound (approximately 99%) based on in vitro 
data, and in healthy participants, DTG has a mean unbound fraction of approximately 
0.23% [32]. 
 
Drug interactions 
In vitro, DTG does not inhibit or induce cytochrome P450 enzymes. DTG is therefore not 
expected to affect the PK of drugs that are substrates of CYP450. Given that DTG is 
metabolized by UGT1A and CYP3A, when coadministered with potent UGT1A/CYP3A 
inducers such as EFV, fosamprenavir/ritonavir (FPV/r), tipranavir/ritonavir (TPV/r), or 
RIF, a dose adjustment of DTG to 50 mg BID is needed.  In treatment-experienced 
participants with HIV-1 that has integrase resistance mutations as described above, ART 
combinations that do not include metabolic inducers should be considered when 
possible. DTG should not be used with etravirine (ETR) without coadministration of 
atazanavir/ritonavir (ATZ/r), darunavir/ritonavir (DRV/r), or lopinavir/ritonavir (LPV/r, 
Kaletra). Coadministration with nevirapine (NVP) should be avoided because there are 
insufficient data to make dosing recommendations. Coadministration with metabolic 
inducers such as oxcarbazepine, phenytoin, phenobarbital, carbamazepine, and St. 
John’s wort should be avoided because there are insufficient data to make dosing 
recommendations. DTG should be taken 2 hours before or 6 hours after taking cation-
containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium 
supplements, or buffered medications.    
 
In vitro, DTG inhibited the renal organic cation transporter, OCT2 (IC50 = 1.93 μM). In 
vivo, DTG inhibits tubular secretion of creatinine by inhibiting OCT2. Thus, 
coadministration of DTG with dofetilide is contraindicated due to the potential for 
increased dofetilide plasma concentrations and the risk for serious and/or life-
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starting or stopping DTG and metformin together as a dose adjustment may be needed 
for metformin.   
 
Efficacy and toxicity data 
The efficacy of DTG in HIV-1 infected treatment naïve participants was based on 48-
week data from two randomized, international, multicenter, double-blind, active-
controlled trials, SPRING 2 (ING113086) and SINGLE (ING114467). In SPRING 2, 822 
participants were randomized and received either DTG 50 mg QD or raltegravir (RAL) 
400 mg BID, both in combination with fixed-dose dual nucleoside reverse transcriptor 
inhibitor (NRTI) backbone (either abacavir [ABC]/3TC or TDF/FTC) [33]. At 48 weeks, 
the proportion of participants with HIV-1 RNA <50 copies/mL was 88% in the DTG group 
compared with 85% in the RAL group (adjusted difference 2·5%; 95% confidence 
interval (CI) –2·2 to 7·1). The median increase from baseline to week 48 in CD4+ cell 
count was 230 cells/mm3 in both groups. The most common (≥10%) AEs (all grades) for 
DTG vs. RAL groups were nausea (14% vs. 13%), headache (12% vs 12%), 
nasopharyngitis (11% vs 12%), and diarrhea (11% in each group). Few participants had 
drug-related serious AEs (3 [<1%] vs. 5 [1%]), and few discontinued due to AEs (2% in 
each group). Rates of laboratory abnormalities were similar between treatment groups, 
and no clinically significant changes in the fasting lipid profile were noted in either group. 
Nonpathologic inhibition of the organic cation transporter, OCT2, in the proximal renal 
tubules [34] resulted in small, non-progressive increases in serum creatinine early in 
treatment with DTG (weeks 2–4) and then remained stable to week 48, consistent with 
previous findings [35]. No participants on the DTG or the RAL arm discontinued ART 
due to renal AEs. No evidence of treatment-emergent resistance was observed in 
participants with virologic failure on DTG, whereas among RAL-treated participants, one 
had integrase treatment-emergent resistance and four had NRTI treatment-emergent 
resistance.  
 
In SINGLE, 833 participants were randomized and received either DTG 50 mg QD with 
fixed-dose ABC/3TC or fixed-dose TDF/FTC/EFV [36]. At 48 weeks, the proportion of 
participants with HIV-1 RNA <50 copies/mL was 88% on DTG compared with 81% on 
TDF/FTC/EFV (adjusted difference 7.4%; 95% CI 2.5% to 12.3%; p=0.003). The 
adjusted median increase from baseline in CD4+ cell count was 267 cells/mm3 for 
DTG+ABC/3TC vs. 208 cells/mm3 for TDF/FTC/EFV at 48 weeks (adjusted difference 
59%; 95% CI 33% to 84%). The most common (≥10%) AEs for DTG+ABC/3TC vs. 
TDF/FTC/EFV groups were dizziness (7% vs. 32%), nausea (10% vs. 12%), abnormal 
dreams (6% vs. 15%), and insomnia (10% vs. 5%). The number of participants who 
discontinued study due to AEs for DTG+ABC/3TC was 10 (2%) compared with 41 (10%) 
on TDF/FTC/EFV groups. Few participants had drug-related serious AEs (1 [<1%] vs. 8 
[2%]). Renal AEs leading to discontinuation occurred in one participant on 
DTG+ABC/3TC and two participants on TDF/FTC/EFV. At 48 weeks, small increases 
were noted in total, low density lipoprotein (LDL) and high density lipoprotein (HDL) 
cholesterol in both groups but total cholesterol/HDL ratio remained stable; comparable 
increases in triglycerides were observed in both groups. No evidence of treatment-
emergent resistance was observed in participants with virologic failure on DTG, whereas 
among TDF/FTC/EFV-treated participants, four had non-NRTI (NNRTI) treatment-
emergent resistance and one had major NRTI treatment-emergent resistance.  


 
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In May 2018, ViiV Healthcare became aware of a potential safety issue related to 
neural tube defects (NTD) in infants born to women with exposure to dolutegravir 
at the time of conception that was identified from a preliminary unscheduled 
analysis of a study conducted among pregnant women in Botswana (Tsepamo 
study, 4 NTD among 426 pregnancies on dolutegravir). This represented an 
incidence of about 0.9% with an expected background rate of about 0.1%. In the 
reproductive toxicology studies, including embryofetal development studies 
performed in animals prior to drug licensure, there were no adverse development 
outcomes, including NTD, but dolutegravir was found to cross the placenta. Up to 
now, data from the Antiretroviral Pregnancy Registry (APR), clinical trials, and 
post marketing use have not indicated a potential safety issue, but data from 
these sources are limited. The FDA recommends that women of reproductive 
potential have a pregnancy test before starting dolutegravir and that women of 
childbearing age who decide to take a dolutegravir-containing regimen 
consistently use effective contraception while on HIV treatment (www.fda.gov).  
 
2.2 
Rationale  
 
Rationale for the study: The risk of PK drug interactions between BDQ and DLM is 
anticipated to be low. However, these drugs are likely to be used together commonly, 
and, importantly, both drugs have metabolites (M2 for BDQ and DM6705 for DLM) that 
have preliminary associations (in vitro or in vivo) with specific toxicities (phospholipidosis, 
QT prolongation) that may be of clinical concern. Most importantly, there is a potential for 
pharmacodynamic interaction, as both drugs prolong the QT interval (individually by 
around 12-15 ms). It is unknown if the combination will show less than additive, additive, 
or synergistic QTc prolongation and if QT prolongation when the drugs are 
coadministered will be of sufficient frequency and magnitude to be of clinical importance. 
It is therefore necessary to evaluate for potential interactions before proceeding to large 
clinical trials using the combination of BDQ and DLM. 
 
The combination of BDQ and DLM is not FDA-approved. There are several reasons 
why the combination of BDQ and DLM should be tested in participants with TB rather 
than healthy participants: the safety profiles of the drugs, the fact that QTc prolongation 
may increase with accumulation of the drugs/metabolites necessitating observations 
during extended dosing, and the need for multiple dosing to assess PK interaction 
effects because of the long half-lives of BDQ and the DLM metabolite (DM-6705); 
finally, the disease state and concomitant drugs may influence safety and PK. 
 
Rationale for the long period of follow-up. The later time points in the study are primarily 
to detect safety signals following the 24-week course of BDQ, as there was higher 
mortality in participants randomized to BDQ than placebo in the phase II study, resulting 
in a black box warning by the FDA on the label. These deaths generally occurred late, 
after BDQ discontinuation, and this mortality imbalance, thus, remains unexplained. 
 
Rationale for offering DTG for HIV treatment to participants with HIV/MDR-TB co-
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Among patients with MDR-TB in South Africa where this study will be conducted, about 
30-50% are coinfected with HIV and will require concurrent MDR-TB and HIV treatment. 
However, ART options are limited. Specifically, because BDQ is metabolized by CYP3A 
and its therapeutic window is not well-defined, it cannot be used with EFV or 
pharmacoenhancers like ritonavir or cobicistat because these medications may reduce 
or increase BDQ and M2 exposures substantially. Triple or quadruple NRTI regimens 
are available, but are therapeutically inferior to first-line ART regimens. Nevirapine can 
be used with BDQ, but patients with moderate to high CD4 counts cannot safely receive 
this drug, and it is associated with important liver and skin toxicities. DTG does not 
induce or inhibit CYP3A and its metabolism is not expected to be affected by BDQ or 
DLM. Further, it is under review by the Medicines Control Council in South Africa for 
registration and may be available locally in the near future. This study provides an 
opportunity to use DTG-based ART together with the newest, most promising anti-TB 
drugs for patients with MDR-TB and HIV coinfection, thus addressing an important  
unmet medical need. We will be able to assess HIV virologic suppression and safety 
among coinfected participants taking DTG-based ART and MDR-TB treatment. DTG will 
be offered to participants with HIV infection and will be continued throughout their study 
participation, even after study TB drugs have been discontinued. 
 
Rationale for longitudinal characterization of drug resistance. Molecular characterization 
of TB resistance to BDQ and DLM is both challenging and important. Both drugs 
possess potentially large numbers of unique mutations conferring resistance (within any 
one of ﬁve coenzyme F420 genes, a 7.5kb region, for nitroimidazoles, and within the atpE 
[37] and Rv0678 [38] genes for BDQ) not currently amenable to standard molecular TB 
diagnostic platforms due to target size and poorly characterized resistance-conferring 
“hot spots.” Both agents possess unique susceptibilities that may increase the likelihood 
of resistance development. While DLM has a relatively high stochastic spontaneous 
mutation rate of 6.44×10-6 to 4.19×10-5 [39], BDQ and its M2 metabolite have an average 
terminal elimination half-life of 132 and 112 days, respectively. This prolonged half-life 
may generate potentially long durations of sub-therapeutic drug concentrations with 
variable amounts of companion drug “protection,” depending on how the drug is 
incorporated into future MDR-TB [35] or MDR-latent TB infection (LTBI) [36] regimens. 
This is concerning given the frequency of TB resistance in the setting of monotherapy 
[40-42], the association of low drug concentrations with acquired drug resistance [43-47], 
and the clinical settings of salvage treatment in which these drugs are likely to be used.  
 
Drug resistance amplification during treatment is an important driver of the drug-resistant 
TB epidemic [48, 49], and we hypothesize that selection of initially hetero-resistant 
populations proceed to fully resistant ones through periodic exposure to sub-therapeutic 
companion drug levels. Thus, early detection of small drug-resistant populations may 
allow interventions to avert development of full drug resistance. Existing drug-
susceptibility tests have limited resolution (Xpert MTB/RIF, ≥65% [43]; pyrosequencing, 
≥10% [44]; line probe assay, ≥5% [50]); and mycobacteria growth indicator tube, ≥1% of 
a mixed population) for hetero-resistance, and none accurately quantify the proportion of 
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Next-generation sequencing provides rapid, accurate, efficient (through highly 
streamlined target enrichment prior to sequencing) [51], and quantitative (i.e., high 
resolution for hetero-resistance) detection of resistance-conferring mutations [52, 53]. 
TDS approaches, such as single molecule-overlapping reads (SMOR) [54], are able to 
rapidly and inexpensively identify resistant microbes representing ≥0.1% of a microbial 
community. As benchtop (and even handheld) [55] sequencers, along with cloud-based 
tools, become more available, this method has promise for rapid comprehensive 
detection and quantification of drug resistance in clinical samples—in particular, for 
patients at elevated risk for adverse treatment outcome. 
 
 
3.0 
STUDY DESIGN 
 
This is a randomized, open-label, three-arm trial evaluating the safety and drug-drug 
interactions of co-administered BDQ and DLM. It is anticipated that study participants will 
be hospitalized per standard of care for initiation of MDR-TB or RR-TB treatment for at 
least the first 2 weeks after randomization. Participants may also be hospitalized for 
longer than 2 weeks if they are too ill for discharge.  
 
To evaluate QT prolongations and examine the observed precision of estimates 
around the primary outcome (QT prolongation), an interim analysis will be 
conducted when week 24 QT data is available for at least 12 participants on the 
BDQ+DLM arm.  
 
An optional LP will be performed at weeks 8 or 24 in up to 16 participants who 
agree to this procedure for measuring concentrations of delamanid and/or 
bedaquiline in CSF. 
 
Multidrug Background Treatment (MBT)   
In addition to study TB drugs, all participants will receive a multidrug background 
treatment (MBT) for MDR-TB or RR-TB that includes at least three drugs to which the 
organism is thought or known to be susceptible (See section 5.4). In many participants, 
this will be a standardized, locally available regimen, but individualization of regimens 
based on available cultural and susceptibility data, or treatment history may be needed. 
Participants will need to take or have been taking MBT for at least 7 days and no more 
than 60 days prior to entry. 
 
Study TB Drugs 
Participants will be randomized to one of three arms. Arm 1 participants will receive BDQ 
at a dose of 400 mg once daily for 2 weeks followed by 200 mg thrice weekly (TIW) for 
22 weeks. Arm 2 participants will receive DLM at a dose of 100 mg BID for 24 weeks.  
Arm 3 participants will receive both BDQ and DLM (same doses and duration as in Arms 
1 and 2).     
 
 
 


 
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Treatment 
Schema: 
STUDY TREATMENT 
FOLLOW-UP TREATMENT 
Arm 
Weeks 1-2 
Weeks 3-24 
Weeks 25+ 
1 
BDQ400QD+ 
MBT 
BDQ200TIW+MBT 
MBT* 
2 
DLM100BID+
MBT 
DLM100BID+MBT 
MBT* 
3  
BDQ400QD+  
DLM100BID + 
MBT 
BDQ200TIW +  
DLM100BID + MBT 
MBT* 
*Note: After week 24, participants will continue to receive multidrug treatment provided 
by local TB programs.  
 
Bedaquiline (BDQ400QD): 
400 mg once daily (7/7) 
Bedaquiline (BDQ200TIW): 
200 mg thrice weekly 
Delamanid (DLM100BID): 
100 mg twice daily (7/7) 
 
Study ART 
Patients with HIV infection can participate provided they are taking an acceptable ART 
regimen (See section 5.4.4). For those participants without contraindications, study DTG 
at a dose of 50 mg once daily will be offered, to be used in combination with two NRTIs 
until study completion. 
 
Pharmacokinetic sampling 
Assays will be performed for DLM and its DM-6705 metabolite, and for BDQ and its M2 
metabolite. Intensive and sparse PK sampling will be performed per section 6.1.  
 
Hair sampling 
Hair collection will be performed for measurement of DLM, BDQ, and MBT drugs 
(levofloxacin, kanamycin, etc.) over the course of the study to assess long-term drug 
exposures.  
 
ECG monitoring 
ECGs will be performed at baseline and then every 2 weeks during administration of TB 
study drugs and then post-study TB drug discontinuation at week 28. 
 
Follow-up  
Participants will be followed for a total of 128 weeks (24 weeks on study TB drugs, then 
104 weeks after study TB drug completion for most participants), including quarterly 
visits beginning at the 36-week visit until the 96-week visit. 
 
Infection Control 
Strict infection control practices will be followed, including the wearing of N95 masks 
where appropriate and in facilities that adhere to WHO infection control principles (≥ 12 
air exchanges per hour, air cleaning with UV light, and administrative controls).  
 


 
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4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Men and women age 18 years of age. 
 
4.1.2 Documented pulmonary infection due to strains of MTB with (a) resistance to INH 
and RIF (MDR-TB) or (b) resistance to RIF but not INH (RR-TB) from a sputum 
sample collected within 60 days prior to entry. Must be lab confirmed by either 
genotypic (e.g., Hain GenoType MTBDRplus) or phenotypic (susceptibility testing 
on liquid or solid culture) methods. 
 
NOTE: MDR- or RR-TB diagnosis for purposes of meeting the inclusion criterion 
can be from a study testing laboratory or from an outside laboratory, as long as it 
is from a sputum sample collected within 60 days prior to entry. 
 
4.1.3 Laboratory confirmation of infection with an MTB strain that is susceptible to 
fluoroquinolones and aminoglycosides by either genotypic testing (such as Hain 
GenoType MTBDRsl) or phenotypic testing (susceptibility testing on liquid or 
solid culture) within 60 days prior to entry. 
NOTE: Fluoroquinolone and aminoglycoside susceptibility testing for purposes 
of meeting the inclusion criterion can be from a study testing laboratory or from 
an outside laboratory, as long as it is from a sputum sample collected within 60 
days prior to entry. 
4.1.4 HIV-1 infection status must be documented as either absent or present, as 
defined below: 
 
Absence of HIV-1 infection, as documented by any licensed rapid HIV test or 
HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit, within 60 
days prior to entry. 
OR 
HIV-1 infection, documented by any licensed rapid HIV test or HIV-1 E/CIA test 
kit at any time prior to entry and confirmed by a licensed Western blot or a 
second antibody test by a method other than the initial rapid HIV and/or E/CIA, 
or by HIV-1 antigen or plasma HIV-1 RNA viral load.  
NOTE: The term “licensed” refers to a US FDA-approved kit, which is 
recommended. For sites that are unable to obtain an FDA-approved kit, a kit that 
has been certified or licensed by an oversight body within the country and 
validated internally is acceptable.  
WHO and Centers for Disease Control and Prevention (CDC) guidelines 
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from the one used for the initial assessment. A reactive initial rapid test should 
be confirmed by either another type of rapid assay or an E/CIA that is based on 
a different antigen preparation and/or different test principle (e.g., indirect versus 
competitive), or a Western blot or a plasma HIV-1 RNA viral load. 
4.1.5 For HIV-positive participants only: CD4+ count greater than or equal to 100 
cells/mm3 within 60 days prior to entry. CD4+ count must be obtained from a 
laboratory certified for protocol testing by the DAIDS Immunology Quality 
Assurance (IQA) Program. 
 
4.1.6 For HIV-positive participants only: for those who have been on ART for ≥6 
months and have an HIV-1 viral load >500 copies/mL within 60 days prior to 
entry, an HIV-1 genotype within 60 days prior to entry must show that at least 
one fully active NRTI is available to the participant within the country program. 
 
4.1.7 For females of reproductive potential, negative serum pregnancy test within 48 
hours prior to entry.  
 
4.1.8 Female and male participants of reproductive potential who are participating in 
sexual activity that could lead to pregnancy must agree to use one of the 
following forms of birth control while receiving TB study medications and for 6 
months after stopping TB study medications: 
 
• 
Male or female condoms  
• 
Diaphragm or cervical cap with spermicide, if available 
• 
Intrauterine device (IUD) 
• 
Oral contraceptives or Depo-Provera  
 
NOTE A: Female participants who are not of reproductive potential are eligible 
without requiring the use of contraceptives. Participant-reported history is 
acceptable documentation of menopause (i.e., at least 1 year amenorrheic), 
hysterectomy, or bilateral oophorectomy or bilateral tubal ligation; these 
participants are all considered not of reproductive potential.  
 
NOTE B: Male participants who are not of reproductive potential (i.e., 
documented azoospermia) or whose female partner/s are not of reproductive 
potential (as defined above) are eligible without requiring the use of 
contraceptives.  
 
NOTE C: For HIV-positive female participants of reproductive potential, the 
use of contraceptives is required for the full duration of time the participant 
is taking dolutegravir (ie, through study completion at week 128). 
Contraceptive options for women of reproductive potential while taking 
dolutegravir include the following:  
 
• 
Contraceptive subdermal implant 
• 
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• 
Combined estrogen and progestogen oral contraceptive  
• 
Injectable progestogen  
• 
Contraceptive vaginal ring  
• 
Percutaneous contraceptive patches 
 
4.1.9 Chest x-ray performed within 60 days prior to entry to classify participant as 
having cavitary or non-cavitary disease.  
 
4.1.10 Documentation of Karnofsky performance score 50 within 14 days prior to study 
entry. 
 
4.1.11 Ability and willingness of participant or legally authorized representative to 
provide informed consent. 
 
4.1.12 Willingness to be hospitalized for the required inpatient component of the study. 
 
4.1.13 Taking MBT for a minimum of 7 days within the 10 days prior to entry. 
 
4.2 
Exclusion Criteria 
 
4.2.1 History of clinically relevant, currently active or underlying gastrointestinal, 
hepatic, cardiovascular, nervous system, psychiatric, metabolic (e.g., untreated 
hypothyroidism), renal, respiratory (other than due to TB), inflammatory, 
neoplastic, skin, immunological or infectious disease, which is not stable and 
controlled, that in the opinion of the investigator would preclude safe participation 
in the trial.  
 
4.2.2 Current clinically relevant extrapulmonary TB, in the opinion of the site 
investigator, including but not limited to CNS TB or TB osteoarthritis. 
 
4.2.3 Previous treatment for MDR- or RR-TB, other than for the qualifying episode, at 
any time in the past. 
 
4.2.4 Receipt of BDQ or DLM at any time in the past. 
 
4.2.5 Breast-feeding. 
 
4.2.6 QTcF interval >450 ms within 72 hours prior to entry. 
 
4.2.7 Clinically significant ECG abnormality in the opinion of the site investigator within 
60 days prior to entry, including but not limited to second 
or third degree atrioventricular (AV) block, prolongation of the QRS complex over 
120 ms (in both male and female participants), or clinically important arrhythmia. 
  
4.2.8 Current clinically relevant cardiovascular disorder in the opinion of the site 
investigator, including but not limited to heart failure, coronary heart disease, 
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4.2.9 Known family history of Long QT Syndrome in a first-degree relative (i.e., parent, 
offspring, or sibling). 
 
4.2.10 Requirement or expected requirement for protease inhibitors (PIs), EFV, or any 
other medication that is a moderate to strong inhibitor or inducer of CYP3A and 
CYP3A4 over the 24 weeks of study treatment. Drug information may be found on 
the ACTG Drug Interactions Database, located at: 
http://tprc.pharm.buffalo.edu/home/di_search/ 
 
NOTE: Participants taking a PI or EFV can be switched to a treatment that is 
allowed in the study, but the PI must be stopped at least 2 days prior to starting 
study MDR- or RR-TB drugs and EFV must be stopped at least 7 days prior to 
starting study MDR- or RR-TB drugs.  
 
4.2.11 Requirement or expected requirement for a medication that significantly prolongs 
QTc, including but not limited to moxifloxacin (levofloxacin is acceptable), from 72 
hours prior to study entry through 4 weeks after discontinuation of study treatment 
(week 28).  
 
4.2.12 Requirement or expected requirement of clofazimine, a drug that might cause QT 
prolongation at current treatment doses on its own and can potentiate QT 
prolongation when given together with BDQ for prolonged periods, from 7 days 
prior to study entry through week 24 (discontinuation of study treatment).  
 
4.2.13 For individuals receiving the WHO short course regimen that contains clofazimine, 
receipt of more than 21 cumulative days of clofazimine at any time prior to, or at 
the time of, study entry. 
 
4.2.14 Known allergy/sensitivity or any hypersensitivity to components of study TB drugs 
or their formulation or to the nitroimidazole class of antibiotics. 
 
4.2.15 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.16 Any of the following laboratory abnormalities within 14 days prior to entry at any 
network-approved non-US laboratory that operates in accordance with Good 
Clinical Laboratory Practices (GCLP) and participates in appropriate external 
quality assurance programs.  
 
a. Serum creatinine >1.4 x ULN 
b. Lipase >1.6 x ULN 
c. ALT >2.5 x ULN  
d. Total bilirubin >1.6 x ULN 
e. Potassium <3.4 or >5.6 mmol/L; magnesium <0.59 mmol/L; calcium <1.75 
mmol/L 
 


 
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4.2.17 Known current hepatitis B or C infection, current treatment for hepatitis B or 
hepatitis C infection, or positive for hepatitis B surface antigen or hepatitis C 
antibodies within 60 days prior to entry. 
 
4.2.18 Among participants with HIV infection, in whom use of DTG is anticipated, any of 
the following: 
 
a. Unstable liver disease (as defined by the presence of ascites, 
encephalopathy, coagulopathy, esophageal varices, or persistent jaundice), 
known biliary abnormalities (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones) 
b. History or presence of allergy to DTG or its components 
c. Severe hepatic impairment (Class C) as determined by Child-Pugh 
classification 
d. Previous use of raltegravir 
 
4.2.19 Documentation of any new and/or unstable AIDS-defining illness (other than TB) 
as defined by the CDC within 60 days prior to entry. 
 
4.2.20 Acute or serious illness (other than TB) requiring systemic treatment and/or 
hospitalization within 60 days prior to entry. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received.  
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. Site-specific ICF(s) will not be reviewed and approved by the DAIDS PRO 
and sites will receive an Amendment Registration Notification when the DAIDS 
PRO receives a complete registration packet. A copy of the final amendment 
Registration Notification issued by the DAIDS PRO should be retained in the 
site's regulatory files. 


 
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For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the parent or 
legal representative if the participant is under guardianship) will be asked to read 
and sign the approved protocol consent form.  
 
For participants from whom a signed informed consent has been obtained, an 
ACTG Screening Checklist must be entered through the Data Management 
Center (DMC) Participant Enrollment System.  
 
4.3.2 Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the protocol, an ACTG Screening 
Failure Results form must be completed and keyed into the database.  
 
4.4 
Co-enrollment Guidelines  
 
• 
Co-enrollment in other trials of investigational agents is not allowed. 
• 
Sites are encouraged to co-enroll participants in A5243, “Plan for Obtaining Human 
Biological Samples at Non-US Clinical Research Sites for Currently Unspecified 
Genetic Analyses.” Co-enrollment in A5243 does not require permission from the 
A5343 protocol chairs. 
• 
For specific questions and approval for co-enrollment in other studies, sites must 
contact the protocol chairs via e-mail as described in the Study Management section. 
 
 
5.0 
STUDY TREATMENT  
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens 
 
Participants currently receiving MBT for MDR- or RR-TB will be randomized with 
equal probability to one of three arms: 
 
Arm 1: Bedaquiline 400 mg orally (PO) once daily (QD) for 2 weeks followed by  
Bedaquiline 200 mg PO three times weekly (TIW) for 22 weeks 
 
Arm 2: Delamanid 100 mg PO twice daily (BID) for 24 weeks   
 
Arm 3: Bedaquiline 400 mg PO QD + 
Delamanid 100 mg PO BID for 2 weeks followed by 


 
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Bedaquiline 200 mg PO TIW +  
Delamanid 100 mg PO BID for 22 weeks 
 
*Note: HIV-1 positive participants will be offered dolutegravir through study 
completion (128 weeks), which should be given with two NRTIs. 
 
*Note: After week 24, participants will continue to take MBT provided by local TB 
programs.  
 
5.1.2 Administration 
 
5.1.2.1 Bedaquiline Administration 
 
Bedaquiline will be administered as four 100 mg tablets (400 mg) by 
mouth QD for 2 weeks, followed by two 100 mg tablets (200 mg) by 
mouth TIW for 22 weeks, for all study arms involving the use of this drug.  
 
Bedaquiline should be given one hour after a meal or food intake. 
 
5.1.2.2 Delamanid Administration 
 
Delamanid will be administered with food as two 50 mg tablets (100 mg) 
by mouth BID for 24 weeks, for all study arms involving the use of this 
drug. Delamanid dosing should be separated in time from other drugs by 
at least one hour. 
 
5.1.2.3 Dolutegravir Administration 
 
Dolutegravir will be administered at a dose of one 50 mg tablet once daily, 
to be used in combination with two NRTIs until study completion.  
 
*Note: NRTIs will not be provided by the study. 
 
5.1.3 Treatment Duration 
 
Participants in all study arms will remain on study TB treatment, with Bedaquiline, 
Delamanid or a combination of the two drugs, for a total of 24 weeks. 
 
Participants will have 185 days from enrollment to complete 168 days (24 weeks) 
of TB study drug.   
 
5.2 
Study Product Formulation and Preparation 
 
5.2.1 Bedaquiline: Bedaquiline will be supplied as tablets for oral administration. Store 
at 25°C (77°F); excursions permitted at 15-30°C (59-86°F) [See USP Controlled 
Room Temperature]. Dispense in original container. 
 


 
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5.2.2 Delamanid: Delamanid will be supplied as film-coated tablets, in blister packs, for 
oral administration. Delamanid is stable for 6 months at 25°C/60% relative 
humidity (RH), for 6 months at 40°C/75%. Store at 25°C (77°F); excursions 
permitted at 15-30°C (59-86°F). The Clinical Research Products Management 
Center (CRPMC) should be contacted if excursions occur outside of the 
permitted range of 15-30°C (59-86°F). Dispense in original container. 
 
5.2.3 Dolutegravir: Dolutegravir will be supplied as tablets for oral administration. Store 
at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled 
Room Temperature]. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Delamanid will be provided by Otsuka Pharmaceutical Company, Ltd. 
 
Bedaquiline will be provided by Janssen Scientific Affairs, LLC. 
 
 
Dolutegravir will be provided by ViiV Healthcare, Ltd. 
 
Study products will be available through the NIAID CRPMC. The site pharmacist 
should obtain the study product(s) for this protocol by following the instructions in 
the manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks.  
 
Any study product not provided by the study must comply with the NIAID 
(DAIDS) policy that outlines the process for authorizing the use of study products 
not marketed in the US in NIAID (DAIDS)-supported and/or –sponsored clinical 
trials. This policy is available on the NIAID (DAIDS) website at:  
https://www.niaid.nih.gov/sites/default/files/NonFDAapprovedProducts.pdf. 
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
products must be returned to the NIAID CRPMC (or as otherwise directed by the 
sponsor) after the study is completed or terminated. The procedures to be 
followed are provided in the manual Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks in the section Study Product Management 
Responsibilities. At non-US CRSs, the site pharmacist must follow the 
instructions in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks for the destruction of unused study products. 
 
5.4 
Concomitant Medications 
 
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investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the updated ACTG Drug Interactions 
Database located at: http://tprc.pharm.buffalo.edu/home/di_search/.   
 
5.4.1 Required Medications 
 
Multidrug background treatment (MBT):   
In general, participants will receive a standardized MBT regimen for MDR- or 
RR-TB except in cases where the participant has known resistance to one of the 
components of local standard treatment. MBT will be provided by the local 
program. In South Africa, for example, the current initial standard-duration MBT 
regimen is high dose INH (15 mg/kg), ethambutol, ethionamide, pyrazinamide, 
moxifloxacin, terizidone and kanamycin, which is modified according to 
susceptibility testing with the Hain MTBdr line probe and/or phenotypical INH 
susceptibility testing as this becomes available (e.g., for RR-TB, a lower dose of 
INH may be used). Levofloxacin will be used instead of moxifloxacin in the MBT 
in this study (through week 28) as it has much less potential to prolong the QT 
interval. Levofloxacin will be obtained locally. 
 
In some countries, the WHO shorter-duration MDR-TB regimen is now available. 
The components of the regimen are high-dose INH, prothionamide or 
ethionamide, kanamycin or amikacin, moxifloxacin, ethambutol, pyrazinamide, 
and clofazimine (given for 4-6 months, the ‘intensive phase’) followed by 
moxifloxacin, clofazimine, pyrazinamide, and ethambutol (given for 5-7 months, 
the ‘continuation phase’). In this trial, levofloxacin will be used instead of 
moxifloxacin during the period of co-administration with bedaquiline or delamanid 
and for 4 weeks after (through week 28). In addition, bedaquiline or delamanid or 
both will be substituted for clofazimine during the period of study TB drug 
treatment (after which time clofazimine will be added back to the regimen). This 
substitution is reasonable given that bedaquiline or delamanid are each potent 
sterilizing agents and the evidence for their individual contributions to 
microbiologic activity of multidrug regimens is similar to that of clofazimine [10, 
56-64].  
 
5.4.2 Prohibited Medications 
 
A list of prohibited medications is posted on the A5343 PSWP. It should be noted 
specifically that moxifloxacin is not allowed from 72 hours before study entry 
through 4 weeks after discontinuation of study treatment (week 28). Clofazimine 
is not allowed from 7 days before study entry through discontinuation of study 
treatment (week 24). (Note that moxifloxacin’s effects on QT are immediate 
whereas clofazimine’s effects take some time to develop or resolve given this 
drug’s large volume of distribution and long half-life.) In addition, dofetilide (or 
pilsicainide) is prohibited as DTG may inhibit its renal tubular secretion resulting 


 
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in increased dofetilide concentrations and potential for toxicity.  
 
5.4.3 Precautionary Medications 
 
A list of precautionary medications is posted on the A5343 PSWP. 
 
5.4.4 Medications for Treatment of HIV Co-Infection 
 
Only the following ART regimens are allowed during study TB treatment: (1) 
study-provided DTG plus two NRTIs or (2) nevirapine plus two NRTIs. NRTIs will 
be provided by the local program. Protease inhibitors (PI) and EFV are absolutely 
contraindicated because they significantly inhibit or induce CYP3A4, respectively. 
Participants taking a PI or EFV can be switched to a treatment that is allowed in 
the study, but the PI must be stopped at least 2 days prior to starting study MDR- 
or RR-TB drugs and EFV must be stopped at least 7 days prior to starting study 
MDR or RR-TB drugs. 
 
For those participants who are HIV treatment-naïve, it is recommended that DTG 
(study ART) plus two NRTI be started approximately 2 weeks following initiation 
of study TB drugs. For those participants already on ART with EFV or a boosted 
PI at the time of screening or who require a switch from their previous ART for 
another reason, it is recommended that DTG-based ART be started the day 
following discontinuation of their previous regimen.  DTG must be given together 
with two NRTIs. 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
6.1a 
Schedule of Evaluations (SOE): Screening through Treatment 
 
Evaluation 
Screening 
(-60 days) 
Entry 
(days   -
7 to 0)  
Start of TB 
Study Drugs 
(day 0) 
Treatment 
(weeks 1-8 ±3 days and weeks 10-24 ±7 days) 
1 
2 
3 
4 
5 
6 
7 
8 
10 
12 
14 
16 
18 
20 
22 
24 
Documentation of HIV status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signs/Symptoms, Diagnoses, Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Examination1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical Examination1 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Hematology 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Liver Function Tests 
X2 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry 
X2 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B Surface Antigen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C Antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Stimulating Hormone 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Pregnancy Testing3 
X 
 
 
As clinically indicated 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Viral Load (if HIV+) 
X4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X5 
HIV-1 Genotype (if HIV+) 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+ (if HIV+) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Sputum AFB Smear and Culture In Liquid 
Media7 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Drug Susceptibility Testing (DST) 
X 
 
 
 
 
 
 
 
 
 
X8 
 
X8 
 
 
 
 
 
X9 
Chest X-Ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
X10 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Sampling (intensive)11 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PK Sampling (sparse)11 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Pre-assessments for Optional LP 12 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Optional LP for Protocol-related Research13 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Hair Sampling 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 


 
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Evaluation 
Screening 
(-60 days) 
Entry 
(days   -
7 to 0)  
Start of TB 
Study Drugs 
(day 0) 
Treatment 
(weeks 1-8 ±3 days and weeks 10-24 ±7 days) 
1 
2 
3 
4 
5 
6 
7 
8 
10 
12 
14 
16 
18 
20 
22 
24 
Stored Whole Blood 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adherence Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 A visual acuity test will be done at entry and weeks 4, 8, 12, 16, 20, and 24 for those participants on ethambutol. 
2 Screening liver function tests and chemistry must be performed within 14 days prior to entry.  
3  Women of reproductive potential who are taking dolutegravir will be required to have pregnancy testing every two weeks during the first 24 weeks (i.e., weeks 2-24). 
4 Required only for HIV-positive participants who have been on ART for ≥ 6 months. 
5For HIV-1 RNA quantification in participants who initiated DTG while on study: If the 24 ±6-week window around DTG initiation does not fall within 24 weeks ± 3 days of study entry (initiation of BDQ 
and/or DLM), an additional visit may be scheduled for collection of plasma for the HIV-1 RNA quantification. 
6 Required only for HIV-positive participants on ART for ≥ 6 months who have a screening HIV-1 viral load >500 copies/mL. 
7Two sputum samples should be collected at the screening visit, at entry, and weeks 2 and 4; three sputum samples should be collected at the week 8 and week 24 visits. 
8Sputum specimens will be stored for possible DST should subsequent treatment failure or culture reversion occur.  
9 Isolates of MTB from positive cultures will be stored for TDS and DST should subsequent treatment failure or culture reversion occur. 
10 This ECG may be done at day -1 or day 0. These ECG results must be obtained prior to initiation of study TB drug(s). For participants who discontinued moxifloxacin and/or clofazimine prior to study 
entry, these ECG results must be obtained at least 72 hours after the last dose of moxifloxacin and 7 days after the last dose of clofazimine, and prior to initiation of study TB drug(s). 
11 See section 10.0 for instructions. Note that extra plasma will be stored for possible measurement of companion drugs in the future. Samples will not be collected for the intensive and sparse PK testing 
for participants who prematurely discontinue study treatment.  
12Participants undergoing a LP must have safety bloods (CBC/INR [international normalized ratio]) performed and medical history reviewed at least the prior visit to their LP. See section 
6.3.10 and Appendix I for instructions. 
13Not all participants will undergo the optional LP procedure. The LP will be performed at either week 8 or week 24, not both. Participants must have safety bloods performed and medical 
history reviewed at least one week prior to their LP. See section 6.3.11 and Appendix I for instructions.   
 
 


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6.1b 
SOE: Follow-up and Premature Discontinuation 
 
Evaluation 
Follow-up  
(weeks 28-128 ±2 weeks) 
Premature  
Study Discontinuation 
Evaluations 
28 
36 
48 
60 
72 
84 
96 
128 
Signs and Symptoms, Diagnoses, Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Examination  
 
 
 
 
 
 
 
 
X 
Targeted Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV Viral Load (if HIV+) 
 
 
X1 
 
 
 
 
 
 
CD4+(if HIV+) 
 
 
X 
 
 
 
 
 
 
Liver Function Tests 
X 
 
 
 
 
 
 
 
 
Chemistry 
X 
 
 
 
 
 
 
 
 
Pregnancy Testing2 
As clinically indicated 
Sputum AFB Smear and Culture in Liquid Media  
X 
X 
X 
 
 
X 
X 
X 
X 
Drug Susceptibility Testing (DST)3 
 
X 
X 
 
 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
X4 
PK Sampling (sparse)5 
X 
 
 
 
 
 
 
 
 
Hair Sampling 
 
 
X 
 
X 
 
X 
X 
 
Adherence Assessment 
X6 
 
 
 
 
 
 
 
X 
 
1 For HIV-1 RNA quantification in participants who initiated DTG while on study: If the 48 ±6-week window around DTG initiation does not fall within 48 ± 2 weeks of study entry, 
an additional visit may be scheduled for collection of plasma for the HIV-1 RNA quantification. 
2 Women of reproductive potential who continue taking dolutegravir after week 24 will be required to have pregnancy testing at all subsequent study visits (i.e., 
weeks 28-128).  
3DST may be performed if sputum smear or culture is positive. Two sputum samples should be collected at the week 48 and week 128 (or premature discontinuation) visits; TDS 
will be performed at these visits.  
4ECG is not required at this visit if the participant discontinued after week 28. 
5Samples will not be collected for sparse PK testing for participants who prematurely discontinue study treatment. 
 
6 For participants who do not complete TB study drugs by week 24.  


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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant starting any study 
medications, treatments, or interventions.  
 
Screening 
Screening evaluations to determine eligibility must be completed within 60 days 
prior to study entry, unless otherwise specified. In addition to data being collected 
on participants who enroll into the study, demographic, clinical, and laboratory 
data on screening failures will be captured in a Screening Failure Results form 
and entered into the ACTG database. Of note, participants who present for 
screening who have not started MBT can start MBT via the local TB program and 
must have received at least 7 days of MBT prior to entry. 
 
6.2.2 Entry Evaluations 
 
Participants must begin study TB treatment as soon as possible within 7 days 
after randomization (entry). For participants with HIV infection switching from 
EFV to study DTG at the time of enrollment, DTG should be started on the day of 
entry following blood collection for HIV viral load. For participants who 
discontinued moxifloxacin and/or clofazimine prior to study entry, the entry  (day -
1 or 0) ECG must be performed at least 72 hours after the last dose of 
moxifloxacin and 7 days after the last dose of clofazimine and prior to initiation of 
study TB drug(s). (Sites may find it more convenient to switch participants from 
moxifloxacin to levofloxacin during screening.) 
 
6.2.3 Post-Entry Evaluations  
 
Start of TB Study Drug 
Start of TB study drug may occur at entry or within 7 days after entry (i.e., 
randomization). Start of TB study drug is considered day 0. The timing of on-
study evaluations is based on the start of TB study drug.  
 
On-Treatment Evaluations  
During weeks 1-8, visits should be conducted within ±3 days. During weeks 10-
24, visits should be conducted within ±7 days. All participants are expected to be 
hospitalized for 2 weeks starting at entry. Participants may also be hospitalized 
for longer than 2 weeks if they are too ill for discharge. In certain circumstances 
(e.g., family or personal urgent issues), it may be allowable for participants to be 
discharged from the hospital early. Those participants who are discharged early 
will be allowed to remain on study and continue to receive the study drug. 
 
Post-Treatment Evaluations  
During weeks 28-128, visits should be conducted within ±2 weeks.  
 


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6.2.4 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment 
All case report forms (CRFs) must be completed and keyed for the period up to 
and including week 0. 
 
Premature Treatment Discontinuation Evaluations  
Participants who prematurely permanently discontinue study TB treatment will be 
referred to the National Tuberculosis Program (NTP) for treatment of his or her 
MDR or RR-TB according to local standard of care. The participant will continue 
to be followed on study, off study drugs for the duration of the study and undergo 
all evaluations (except intensive and sparse PK sampling) according to the 
schedule in sections 6.1a and 6.1b. The participant will be followed until the end 
of the study, through the last study visit at week 128.  
 
Premature Study Discontinuation Evaluations  
Participants who prematurely permanently discontinue the study will have 
discontinuation evaluations performed as noted in the SOE. 
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
Web site for information about what must be included in the source document:  
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 
 
All stated evaluations are to be recorded on the CRF and keyed into the database 
unless otherwise specified. This includes events that meet the International Council for 
Harmonisation (ICH) definitions for a serious adverse event (SAE): 
• 
Results in death 
• 
Life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Congenital anomaly/birth defect 
• 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the events listed above.   
 
NOTE: Adverse events that require expedited reporting via the DAIDS Adverse 
Experience Reporting System (DAERS) are listed in section 11.4.2.  
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.0, November 2014, which can be found on the DAIDS RSC Web site: http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables. Please also see 
section 7.1 for study-specific grading criteria.  
 


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6.3.1 Documentation of HIV-1 Status 
HIV-1 infection must be documented as indicated in section 4.1.4. HIV status will 
not be reported on a CRF. 
 
6.3.2 Medical/Medication History 
Medical History 
The medical history must include all diagnoses that occurred within the past 30 
days and meet the ACTG criteria for clinical events and other diagnoses. 
 
In addition to reporting the diagnoses that meet the above criteria, the following 
diagnoses should be reported regardless of when the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
• 
Cardiac history including history of arrhythmias, coronary artery disease, and 
heart failure 
• 
Hypothyroidism 
 
Smoking history (ever/never/current) must be recorded 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
Medication History 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history (HIV-related items 
are for HIV-1 positive participants only).  
 
Medication Category 
Complete History or 
Timeframe 
TB treatment 
Complete 
Antiretroviral therapy 
Complete 
Prescription drugs for treatment 
of opportunistic infections 
Within past 60 days 
Prescription drugs for 
prophylaxis of opportunistic 
infections 
Within past 60 days 
Prescription and non-
prescription drugs (other) 
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Medication Category 
Complete History or 
Timeframe 
Alternative or complementary 
medications (Record as yes/no 
on CRF; if yes, record details in 
source document.) 
Within past 60 days 
 
6.3.3 Clinical Assessments 
 
Complete Physical Exam 
A complete physical examination is to include an examination of the skin, head, 
mouth, and neck; auscultation of the chest; cardiac exam; abdominal exam; 
examination of the lower extremities for edema; and Karnofsky performance test. 
The complete physical exam will also include signs and symptoms, diagnoses, 
and vital signs (temperature, pulse, respiration rate, and blood pressure). Height 
and weight to be measured and recorded. A visual acuity test will be done at 
entry for those participants on ethambutol. The results of this test will be reported 
in the source documents only.  
 
Targeted Physical Exam 
A targeted physical examination is to include vital signs (temperature, pulse, 
respiration rate, and blood pressure) and is to be driven by any previously 
identified or new signs or symptoms including diagnoses that the participant has 
experienced since the last visit. Weight to be measured and recorded. A visual 
acuity test will be done at weeks 4, 8, 12, 16, 20, and 24 for those participants on 
ethambutol. The results of this test will be reported in the source documents only. 
 
Signs and Symptoms 
At entry, all grades that occurred within 14 days prior to entry must be recorded; 
post-entry, all signs and symptoms Grade ≥3 must be recorded. For QTcF 
prolongation, the grade is to be determined using the Quintiles ECG reads (not 
the site’s reads) and the supplemental toxicity table in section 7.1.1. Record all 
signs and symptoms that led to a change in BDQ, DLM, and/or DTG, regardless 
of grade. Further evaluation will be required for those events that meet Expedited 
Adverse Event (EAE) or ICH reporting requirements. 
 
Diagnoses 
Record specific diagnoses identified by the ACTG criteria for clinical events and 
other diseases. During the course of the trial, audiometry testing will be 
performed as per routine National TB Program guidelines.  
 
Post entry, see section 7.3 for collection requirements for pregnancy. 
 
Refer to section 7.1 for AE collection requirements. 
 


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TB Medications 
• 
Study TB Treatment (BDQ and/or DLM) Modifications: Record all study TB 
drug modifications, including start/stop dates, initial doses, participant-
initiated and/or protocol-mandated modifications, inadvertent and deliberate 
interruptions of more than 2 days for drugs given daily and 5 days for drugs 
given thrice weekly, at each visit. Record any permanent discontinuation of 
treatment. Report the initiation of study TB drug within 2 days of the first 
dose. 
• 
MBT Drugs: MBT drugs started or stopped since the last study visit must be 
recorded on the CRF, including actual or estimated start dates and stop 
dates, initial doses, participant-initiated and/or protocol-mandated 
modifications, inadvertent and deliberate interruptions of more than 2 days for 
drugs given daily and 5 days for drugs given thrice weekly, at each visit. 
Record any permanent discontinuation of any TB drugs. 
 
ART Medications 
• 
Study ART (DTG) Modifications: Record all DTG modifications, including 
start/stop dates, initial doses, participant-initiated and/or protocol-mandated 
modifications, inadvertent and deliberate interruptions of more than 2 days, at 
each visit. Record any permanent discontinuation of treatment. 
• 
Other ART Drugs: All modifications to ART including start/stop dates, initial 
doses, participant-initiated and/or protocol-mandated interruptions, 
modifications, and permanent discontinuation of ART will be recorded at each 
visit. Participant-initiated interruptions include both inadvertent and deliberate 
interruptions of any ART. Treatment interruption is failure for any cause to 
take ART for more than 72 hours. 
 
Concomitant Medications 
Medications started or stopped since the last study visit must be recorded on the 
CRF, including actual or estimated start dates and stop dates. Alternative and 
complementary medications will be recorded as yes/no on the CRF. 
 
6.3.4 
Laboratory Evaluations 
 
At screening and entry, all laboratory values that occurred within 60 day of entry, 
unless otherwise specified, must be recorded. Laboratories must be a network-
approved non-US laboratory that operates in accordance with GCLP and 
participates in appropriate external quality assurance programs. For post-entry 
assessments, report all Grade 3 laboratory values, unless otherwise specified. 
All laboratory toxicities that led to a change in BDQ, DLM, and/or DTG, 
regardless of grade, must be recorded. Further evaluation will be required for 
those events that meet EAE or ICH reporting requirements. Record abnormal 
laboratory findings as per section 7.1. 
 
Hematology  
Complete blood count (CBC), to include hemoglobin, platelets, white count, and 
neutrophil count will be performed. If INR is tested, record Grade ≥2. 


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Liver Function Tests 
AST, ALT, albumin, total bilirubin, and ALP.  
 
Blood Chemistry 
The following will be tested in the chemistry evaluation: lipase, creatinine kinase, 
glucose, electrolytes (potassium, magnesium, calcium), and creatinine.  
 
Hepatitis B Surface Antigen 
This test will be performed at screening. 
 
Hepatitis C Antibodies 
This test will be performed at screening. 
 
Thyroid stimulating hormone (TSH) 
This test will be performed at entry and week 12. 
 
Pregnancy Test 
For women with reproductive potential: Screening test must be serum. For later 
time points, serum or urine -HCG may be used; urine test must have a 
sensitivity of 15-25 mIU/mL. For HIV-infected women of reproductive 
potential receiving dolutegravir, pregnancy testing will be performed at 
screening and every two weeks during the first 24 weeks (weeks 2-24). At 
the end of study TB drug treatment (bedaquiline and/or delamanid, week 
24), women of reproductive potential may elect to remain on dolutegravir, 
provided they agree to adhere to protocol contraception requirements as 
described in Note C of section 4.1.8. In this case, pregnancy testing will be 
performed at all subsequent study visits. Participants may also choose to 
switch to efavirenz-based antiretroviral therapy, in which case pregnancy 
testing frequency will be unchanged, i.e., performed as clinically indicated. 
For pregnancy on study, refer to section 7.3. Note that women who become 
pregnant will be discontinued from study medications and will be followed 
through the end of the study period. Pregnancy outcome will be recorded 
per section 7.3, and pregnancies will be reported to the Antiretroviral 
Pregnancy Registry. Referral to obstetrical care will be made by the study 
team for any on-study pregnancies that occur. 
 
Urinalysis 
A dipstick urinalysis will be performed to assess proteinuria and hematuria. 
 
6.3.5 Virologic Studies 
 
HIV-1 Viral Load (HIV-positive participants) 
This test is required only at screening for participants who have been on ART for 
≥6 months. For these participants, if the screening test is done within 14 days 
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and/or time points, refer to the SOE. Quantitations must be performed at a 
DAIDS-approved laboratory in real time using a licensed assay. 
 
HIV-1 Genotype (HIV-positive participants) 
Genotypic-resistance testing will be performed at screening for participants who 
have been on ART for ≥6 months and have a screening HIV-1 viral load >500 
copies/mL. The test must be performed at an ACTG regional genotyping 
laboratory.  
 
6.3.6 Immunologic Studies 
 
CD4+ (HIV-positive participants) 
Obtain absolute CD4+ count within 60 days prior to entry and as per section 
6.1a. CD4s should be performed by a laboratory certified for protocol testing by 
the DAIDS Immunology Quality Assurance (IQA) Program. Screening CD4+ 
count does not need to be reported on a CRF. 
 
6.3.7 TB Diagnostics and Microbiology 
 
Sputum Acid-Fast Bacilli (AFB) Smear and Culture 
At screening, entry, and weeks 2 and 4 during the intervention phase, and at 
week 48 and week 128 (or premature discontinuation), two sputum samples will 
be collected for sputum AFB smear and culture in liquid medium. At weeks 8 and 
24, three sputum samples will be collected for sputum AFB smear and culture; at 
all other visits indicated in the SOE, one sputum sample will be collected for AFB 
smear and culture. For all cultures demonstrating growth of AFB, species will be 
identified to at least the level of MTB complex versus non-tuberculous 
mycobacteria. One sputum sample will be collected and stored for TDS (see 
below) at each of the following eight visits: screening; entry; weeks 2, 4, 8, 24, 
48, and 128 (or premature discontinuation). Isolates of MTB from positive 
cultures will be stored. Refer to the A5343 Manual of Procedures (MOPS) for 
sputum collection and laboratory procedure details.  
 
Drug Susceptibility Testing (DST)  
For each participant, the first study isolate of M. tuberculosis will have culture-
based phenotypic DST performed at the study site-designated laboratory for INH, 
RIF, fluoroquinolone, and aminoglycoside resistance. In addition, phenotypic 
DST should be performed for any MTB isolates obtained at or after the week 16 
study visit. For each participant, all isolates cultured from sputum should be 
stored frozen; in the event of participant relapse, DST will be performed for the 
last isolate collected prior to culture conversion. Refer to the A5343 MOPS for 
laboratory procedure details. 
 
Note that MDR or RR-TB diagnosis for purposes of meeting inclusion criterion at 
time of screening can be from a study testing laboratory or from an outside 
laboratory, as long as it is from a sputum sample collected within 60 days prior to 
entry (see sections 4.1.2 and 4.1.3). 


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Chest X-Ray  
The chest x-ray will be posterior-anterior. Extent of disease and cavitation status 
will be documented. 
 
TDS 
We will use SMOR analysis, a novel TDS approach, to identify microbes resistant 
to DLM, BDQ, and all background regimen drugs representing ≥0.1% of a 
microbial community in longitudinal fashion [54].  
 
Given storage and batched analysis (i.e., quarterly), and the unknown nature and 
significance of small microbial-resistant subpopulations, SMOR results will not be 
used for clinical management in real time. TDS will be accompanied (preceded) 
by culture techniques enriched with resuscitation promoting factors at sites able 
to perform these cultures within 2 days of collection. One sputum sample at each 
of these eight visits (i.e., screening, entry, weeks 2, 4, 8, 24, 48, and 128 [or 
premature discontinuation] will be collected and stored for TDS). TDS will be 
done on the sputum specimen itself without a culture step; if a culture isolate is 
available (i.e., from the prior specimens sent for culture), deep sequencing will be 
done on the culture isolate as well for comparison. 
 
The final sputum specimen at each time point will be collected for TDS. For 
example, if there are three sputum collections, one sample will be stored for deep 
sequencing and the other two samples will be stored for culture. If a participant 
cannot produce more than one or two samples at later time points in the study, a 
sputum specimen will not be collected for TDS so as to not interfere with the 
secondary endpoints (involving culture conversion) of the trial.   
 
6.3.8 ECG 
 
 Resting ECGs will be conducted at the site. Because of the diurnal variation of 
QT interval, ECGs for each participant should be done at approximately the same 
time of day throughout the study, before lunch approximately 4-6 hours post-dose 
(approximate time of maximal concentration, or Tmax, of study TB drugs).  
 
A screening ECG must be performed within 72 hours prior to entry. At all visits 
beginning at entry (performed at day -1 or day 0), ECG will be performed in 
triplicate (collection of three ECGs 5-10 minutes apart). Specific instructions 
related to ECG procedures are outlined in the MOPs available on the protocol-
specific website. On days where ECG testing and PK testing are scheduled, the 
participant should have ECGs performed followed immediately by PK sampling.  
 
(To minimize the variability in QT intervals, ECG trace data are also automatically 
transmitted to the central or core ECG laboratory for determination of QT interval. 
Statistical analyses to address study objectives will use ECG data as determined 
at the core ECG laboratory.) 
 


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For participants who discontinue moxifloxacin and/or clofazimine prior to study 
entry, the entry (performed at day -1 or day 0) ECG results must be obtained at 
least 72 hours after the last dose of moxifloxacin and 7 days after the last dose of 
clofazimine, and prior to initiation of study TB drug(s). 
 
6.3.9 Pharmacokinetic Studies 
 
See section 10.0, Pharmacology Plan. Details for intensive PK and sparse PK 
sampling are in section 10.2.2. For participants on Arms 1 and 3, intensive and 
sparse PK visits should be scheduled for a day when a BDQ dose is due to be 
taken. Blood samples for study TB drug concentrations may be collected from an 
indwelling catheter; if a catheter cannot be placed or maintained successfully or if 
a single sample is being collected for sparse PK, direct venipuncture will be 
used. 
 
On the days there is intensive PK sampling, a standardized meal will be provided 
(see MOPs for details.)  
 
Plasma PK samples from PK sampling days will also be stored for measurement 
of companion drugs should this be of future scientific interest. 
 
6.3.10 Pre-assessments for Optional LP 
 
Participants who agree to an LP will first undergo assessments to ensure 
that the procedure will be appropriate for them. The assessment visit 
should be done at the week 7 visit (for the week 8 LP), and/or at the week 
22 visit (for the week 24 LP). The assessments will include the following: 
• 
Medical history (including for history of bleeding diathesis, known 
presence of cerebral lesion) 
• 
CBC/INR  
 
Evaluation of the Assessments 
Participants with any of the following will not be considered for the LP:  
• 
Platelet count <100/mm3 
• 
INR >1.4 times the ULN 
• 
History of any allergies to anesthetics  
• 
Suspected raised intracranial pressure 
• 
Current diagnosis of multiple sclerosis 
• 
Current diagnosis of active CNS infection such as fungal meningitis or 
progressive multifocal leukoencephalopathy (PML), which could alter 
CNS/CSF inflammatory measures 
• 
Known presence of intracerebral mass lesion that is judged by the site 
investigator to affect the safety of a LP 
• 
History of bleeding diathesis 
• 
Current use of anticoagulant medications (e.g., anticoagulation dose 
warfarin, enoxaparin [Lovenox], heparin, dabigatran [Pradaxa], 


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apixaban [Eliquis], rivaroxaban [Xarelto], and edoxaban. Use of aspirin 
or clopidogrel [Plavix] is acceptable. Low-dose lovenox or heparin for 
deep venous thrombosis prophylaxis is also acceptable.) 
• 
Any other known contraindication to LP that, in the opinion of the 
investigator, would preclude safe participation in this nested study. 
 
NOTE: If the participant is unable to participate given the results of the pre-
LP assessments conducted at week 7, then the above assessments will 
need to be repeated at the week 22 visit, and the LP must be done at week 
24 if the participant qualifies. 
 
6.3.11 Optional LP for Protocol-related Research 
 
An LP will be performed at weeks 8 or 24 in up to 16 participants who agree 
to this procedure for measuring concentrations of delamanid and/or 
bedaquiline in CSF as outlined in Appendix I.  
 
 
The A5343 Laboratory Processing Chart (LPC), located on the A5343 
PSWP, describes the specific procedures for the collection and storage of 
these specimens.  
 
NOTE A: Participants currently enrolled under Version 3.0 who have not yet 
completed week 22, and new participants enrolling into Version 4.0 can opt 
to have the LP done. Participants currently enrolled under Version 3.0 will 
need to re-consent to Version 4.0 in order to be approached regarding the 
LP. Reconsent for participants currently enrolled under Version 3.0, as well 
as the additional consent for the optional LP, may be performed at any visit 
prior to and including week 22. Participants currently enrolled under 
Version 3.0 who have completed week 22 will not be approached to 
participant in the nested study and will not undergo reconsent for version 
4.0 of the protocol. 
 
NOTE B: If a participant consents to undergo the optional LP but does not 
meet requirements of the pre-LP assessments, or withdraws consent prior 
to the LP, the participant will not be included in this nested study and will 
be replaced within this nested study. 
 
6.3.12 Hair Sampling 
 
Hair collection will be performed for measurement of DLM, BDQ, and/or MBT 
drugs (levofloxacin, kanamycin, etc.) over the course of the study to assess 
long-term drug exposures (see section 10.2.3). 
 
6.3.13 Stored Whole Blood 
 
A whole blood sample will be collected and stored for future pharmacogenomics 
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6.3.14 Adherence Assessment/ Directly Observed Therapy (DOT)  
 
Study staff or others approved by the study staff will provide DOT for the morning 
study drug doses as follows: 
 
Arm 1: BDQ 7 days per week for 2 weeks, followed by 3 days per week for 22 
weeks. 
 
Arms 2 and 3: DLM 7 days per week for 2 weeks, followed by 5 days per week 
for 22 weeks  
 
Note that only the doses listed above must be given via DOT during the first 24 
weeks of the study. All other doses do not require DOT.  
 
During weeks 25–96, study DOT supporters or others approved by the study staff 
will provide twice-weekly support to participants to ensure they continue with 
background MDR-TB, RR-TB and, where appropriate, HIV treatment and remain 
engaged with the study. In addition, participants will receive extensive 
counseling, pill boxes, and adherence cards for study TB drugs. Pill count for 
study TB drugs (BDQ and DLM only) will be recorded on a CRF. 
 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
Except for QTcF interval, A5343 will use the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Version 2.0, November 2014, as a guideline for 
grading toxicities. 
 
This section provides guidelines for management of specific toxicities related to study TB 
drugs (BDQ and DLM) as well as TB drugs that are likely to be part of MBT, such as 
ethionamide (or prothionamide), levofloxacin, terizidone, high-dose INH, pyrazinamide, 
and/or kanamycin (or amikacin or capreomycin). It also provides guidelines for 
management of potential toxicities related to DTG. It also provides guidelines for the 
management of pregnancy. For any other AEs not discussed in section 7.1, follow 
toxicity management instructions in section 7.2.  
 
Every attempt should be made to continue to follow participants who discontinue study 
drugs because of a Grade 3 or 4 AE until resolution of AE can be documented and 
through week 128 of the study.  
 
The A5343 Clinical Management Committee (CMC) is available to discuss toxicity 
management of study drugs with investigators. The A5343 CMC consists of the A5343 
protocol chairs, statisticians, DAIDS medical officers, DAIDS pharmacist, data 
managers, clinical trials specialist, and other protocol team members selected by the 
A5343 protocol chairs. 
 


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7.1 
Specific Management of Toxicities Related to Study-Provided Drugs or MBT  
 
7.1.1 QTcF Prolongation 
 
Participants in this trial will be receiving at least one agent (BDQ, DLM, or both) 
that has the potential to prolong the QTcF interval. Grading will be based on the 
average of triplicate ECGs at each visit. Grading will be as follows: 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
(1) Absolute 
QTcF >480 and 
≤500 ms and 
QTcF change 
from baseline >0 
ms and ≤30 ms; 
or 
(1) Absolute 
QTcF >480 ms 
and ≤500 ms and 
QTcF change 
from baseline 
>30 ms and ≤ 60 
ms; or  
1) Absolute 
QTcF >500 ms; 
or 
Life-threatening 
consequence, e.g., 
torsades de 
pointes or other 
associated serious 
ventricular 
dysrhythmia. 
(2) absolute 
QTcF ≤480 ms 
and QTcF 
change from 
baseline >30 and 
≤60 ms 
(2) absolute 
QTcF ≤480 and 
QTcF change 
from baseline 
>60 ms. 
(2) absolute 
QTcF >480 and 
QTcF change 
from baseline 
>60 ms. 
 
 
 
If Grade 2 QTc prolongation develops during the course of study treatment, the 
participant will be monitored more closely, with once weekly ECG testing, and 
correction of electrolytes where necessary. If Grade 3 QTc prolongation occurs, 
study TB drugs and levofloxacin will be discontinued and the participant will be 
hospitalized for monitoring until the abnormality returns to Grade 2 or lower. 
Electrolytes will be checked and repleted where necessary. Repeat ECG 
following repletion of electrolytes should be performed, and if QTcF reading is a 
Grade <2, study TB drugs may be restarted, at the discretion of the investigator. 
If Grade 3 finding remains, study TB drugs will be permanently discontinued.  
 
For a Grade 4 event, the participant will be hospitalized and discontinued 
permanently from study TB medications. The participant will be referred to the 
NTP for treatment of his or her MDR or RR-TB according to local standards of 
care. The participant will continue to be followed on study, off study drugs. 
 
The immediate clinical management of participants should be based on the site’s 
interpretation of the ECG, unless a report from Quintiles is available. Sites should 
report the following events to the study team and to DAIDS  immediately: (1) 
Grade 4 QT prolongations, (2) deaths, and (3) results of repeated ECGs after 
holding study TB drug for a Grade 3. 
 


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7.1.2 ALT or Bilirubin Elevation 
  
Many anti-TB drugs including the study TB drugs and components of MBT can 
cause alterations in liver function tests. Participants entering this trial will have 
active TB. Elevation in liver function tests is not unexpected. Concomitant 
illnesses, including HIV infection, and other medications, such as ART, including 
DTG, may also alter these laboratory parameters. Therefore, changes in liver 
function enzymes or ALT should be evaluated within the clinical context of the 
abnormalities. LFTs will be checked regularly for all study participants, as per the 
SOE. All participants who have new Grade ≥3 elevation of ALT should be 
evaluated for hepatitis B and C virus infection and have an INR checked.  
 
For participants with normal or Grade 1 LFTs at entry who develop asymptomatic 
or symptomatic Grade 3 elevations during study treatment, study TB drugs and 
MBT (and DTG, where applicable) should be discontinued for up to a week and 
held until levels and symptoms are Grade ≤2, at which time therapy may be 
reintroduced. For participants entering the study with a Grade 2 elevation, they 
will be allowed to continue on study drugs unless they are symptomatic or the 
investigators feel it is unsafe for the participant to continue the medication.  If 
Grade 3 toxicity develops after re-introduction of the study medications or if the 
Grade 3 toxicity does not resolve within 14 days, then the participant will be 
discontinued from study medications and referred to the National TB Program 
(NTP) for treatment of their MDR or RR-TB according to local standards of care 
and, where applicable, to the local HIV clinic. The participant will continue to be 
followed on study, off study drugs. All medications may be restarted if the 
laboratory abnormalities were thought secondary to a concomitant illness. Study 
TB drugs (but not DTG) can be restarted if there has been documented acute 
viral hepatitis and the ALT or bilirubin take longer than 14 days to reach Grade 
≤2 toxicity. 
 
Study TB drugs and study ART will be permanently discontinued if any of the 
following liver chemistry criteria are met:  (1) ALT 3 × ULN and bilirubin 2 × 
ULN (>35% direct bilirubin; bilirubin fractionation required) (2) ALT 3 × ULN with 
symptoms of acute hepatitis or hypersensitivity such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia, 
OR (3) Grade 4 elevation of ALT or direct bilirubin. 
 
Participants permanently discontinued from study TB drugs will be referred to the 
NTP for treatment of his or her MDR or RR-TB according to local standards of 
care. The participant will continue to be followed on study, off study drugs for the 
duration of the study treatment (24 weeks). Similarly, participants permanently 
discontinued from DTG will be referred to the HIV clinic for HIV treatment 
according to local standards of care. 
 
In consultation with the core team, careful assessments should be done to rule 
out the use of alcohol, non-study medication-related toxicity, or viral hepatitis 
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syndrome) as the cause for any liver toxicity that warrants permanent study drug 
discontinuation based on the liver stopping criteria specified above. Evaluations 
to be considered (but are not required) include:  
• 
Viral hepatitis serology including: Hepatitis A IgM antibody; Hepatitis B 
Surface Antigen (HBsAg) and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Hepatitis E IgM antibody; 
• 
Cytomegalovirus IgM antibody; 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); 
• 
Syphilis screening; 
• 
Drugs of abuse screen including alcohol; 
• 
Serum acetaminophen test (APAP adduct test); 
• 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver 
kidney microsomal antibodies; 
• 
Liver imaging to evaluate liver disease. 
 
7.1.3 Allergic reaction 
 
Participants may continue study drugs for Grade 1 or 2 allergic reactions at the 
discretion of the study investigator. The participant should be advised to contact 
the study team immediately if there is any worsening of symptoms or if further 
systemic signs or symptoms develop. Antihistamines, topical corticosteroids, or 
antipruritic agents may be prescribed. 
 
Participants with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to a study drug should permanently discontinue that study drug. 
Participants should be treated as clinically appropriate and followed until 
resolution of the AE. These participants will remain on-study until the completion 
of study follow-up. 
 
7.1.4  Hearing loss  
 
Hearing tests are to be done according to local National Program guidelines to 
assess for harmful effects of injectable anti-TB medications.  
 
Ototoxicity hearing loss occurs if there is:  
• 
20dB decrease at any one frequency 
• 
10dB decrease at any two adjacent frequencies 
• 
Loss of response at three consecutive test frequencies where responses 
were previously obtained 
 
If there is any hearing loss prior to treatment and worsening of the grade of 
hearing by one grade, the injectable (kanamycin, capreomycin, or amikacin) 
should be stopped. If hearing was normal at the time of treatment initiation and 
Grade ≥2 hearing loss develops on-study, the injectable should be stopped. 


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7.1.5 Neutropenia 
 
Participants entering this trial will have active TB and some will have HIV 
infection. Neutropenia is common. Zidovudine has also been associated with 
bone marrow suppression and may cause neutropenia. 
 
If a participant develops Grade 3 or Grade 4 neutropenia and is on zidovudine, 
he or she will have his or her zidovudine discontinued and another effective NRTI 
will be added to the ART regimen, in collaboration with the participant’s HIV care 
provider. If the Grade 3 or 4 abnormality continues after 2 weeks off of 
zidovudine, the study treatment plus MBT should be discontinued and held for up 
to 14 days until levels and symptoms are Grade  2, at which time therapy may 
be reintroduced. If Grade 3 toxicity develops after re-introduction of the study 
medication or if the Grade 3 toxicity does not resolve within 14 days, then the 
participant will be discontinued from study medications and referred to the NTP 
for treatment of their MDR or RR-TB according to local standards of care. 
 
If a participant enters the study with Grade 2 neutropenia, he or she will be 
allowed to continue on the study regimen if he or she develops a Grade 3 
neutropenia, unless he or she is symptomatic or the investigators feel it is unsafe 
for the participant to continue the medication. 
 
If a participant not taking zidovudine develops Grade 4 neutropenia, he or she 
will be permanently discontinued from the study medications and referred to the 
National Tuberculosis Program (NTP) for treatment of his or her MDR or RR-TB 
according to local standards of care. The participant will continue to be followed 
on study, off study drugs. 
 
All participants experiencing any grade of neutropenia will have their CBC with 
differential counts checked weekly. 
 
7.1.6 Thrombocytopenia 
 
Participants entering this trial will potentially have active TB and some will have 
HIV infection. Thrombocytopenia is expected. Zidovudine and linezolid have also 
been associated with bone marrow suppression and may cause 
thrombocytopenia; a minority of participants in this trial may be receiving one of 
these medications. 
 
If a participant who is not taking zidovudine or linezolid develops Grade 3 or 
Grade 4 thrombocytopenia and is on zidovudine or linezolid, he or she will have 
his or her zidovudine or linezolid discontinued. Another effective NRTI will be 
added to the ART regimen to replace zidovudine. If the Grade 3 or 4 elevation 
continues after 2 weeks off of zidovudine or linezolid, the study regimen should 
be held for up to 14 days until levels and symptoms are Grade 2, at which time 
therapy may be reintroduced. If Grade 3 toxicity develops after re-introduction of 


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the study medication or if the Grade 3 toxicity does not resolve within 14 days, 
then the participant will be discontinued from study medications and referred to 
the NTP for treatment of their MDR or RR-TB according to local standards of 
care. For participants entering the study with a Grade 2 thrombocytopenia, they 
will be allowed to continue on study drug if they develop a Grade 3 abnormality 
unless they are symptomatic or the investigators feel it is unsafe for the patient to 
continue the medication. 
 
If a participant enters the study with Grade 2 thrombocytopenia, he or she will be 
allowed to continue on the study regimen if he or she develops a Grade 3 
thrombocytopenia, as long as the local investigators deem it is safe for the 
participant to continue. 
 
If a participant develops Grade 4 thrombocytopenia, he or she will be 
discontinued from the study medications and referred to the NTP for treatment of 
his or her MDR or RR-TB according to local standards of care. The participant 
will continue to be followed on study, off study drugs. 
 
All participants experiencing any grade of thrombocytopenia will have their CBC 
checked weekly. 
 
7.1.7 Anemia 
 
If any participants develop Grade 3 or Grade 4 low hemoglobin value and is on 
zidovudine or linezolid, they will have their zidovudine or linezolid discontinued 
and another effective NRTI will be added to the ART regimen.  If the Grade 3 or 4 
elevation continues after 2 weeks off of zidovudine or linezolid, the study regimen 
should be held for up to 14 days until levels and symptoms are Grade 2, at 
which time therapy may be reintroduced. If Grade 3 toxicity develops after re-
introduction of the study medication or if the Grade 3 toxicity does not resolve 
within 14 days, then the participants will continue to be followed on study, but will 
be discontinued from study medications and referred to the NTP for treatment of 
their MDR or RR-TB according to local standards of care. 
 
For participants entering the study with a Grade 2 low hemoglobin, they will be 
allowed to continue on study drug if they develop a Grade 3 abnormality unless 
they are symptomatic or the investigators feel it is unsafe for the participant to 
continue the medication. 
 
7.1.8 Severe Rash/Cutaneous Reaction 
 
Moderate to severe rash potentially related to drug hypersensitivity may occur 
with any of the study provided TB drugs as well as other drugs the participants 
may be taking. In addition, mild to moderate rash is an expected adverse 
reaction for DTG; rash episodes related to DTG generally occur within the first 
ten weeks of treatment, rarely require interruptions or discontinuations of therapy, 
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with DTG involved a profuse, purpuric and coalescing leukocytoclastic vasculitis 
as well as clinically significant liver chemistry elevations. Other than this case, no 
other instances of serious skin reaction, including Stevens-Johnson syndrome, 
toxic epidermal necrolysis, and erythema multiforme have been reported for DTG 
in clinical trials. It may not be possible to determine which, if any, of the study 
drugs is the cause.  
 
Participants with a Grade 1 rash may continue study drugs at the study 
investigator’s discretion. Participants should be advised to contact the study team 
immediately if there is any worsening of the rash, if any systemic signs or 
symptoms worsen, or if mucosal involvement develops.  
 
Participants may continue study drugs for an isolated Grade 2 rash. However, 
study drugs (and all other concurrent medications suspected in the investigator’s 
causality assessment) should be permanently discontinued for any Grade ≥3 
rash or for any Grade ≥2 rash that is associated with any of the following: 
increase in ALT, Stevens-Johnson syndrome, toxic epidermal necrolysis, or 
severe hypersensitivity: fever, generalized malaise or fatigue, muscle or joint 
aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the 
eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver 
abnormalities (e.g., jaundice, dark or tea colored urine, pale colored stools/bowel 
movements, nausea, vomiting, loss of appetite, or right upper quadrant 
abdominal pain). If the etiology of the rash can be definitely diagnosed as being 
unrelated to study drugs and due to a specific medical event or a concomitant 
non-study medication, routine management should be performed and 
documentation of the diagnosis provided.  
 
Participants taken off study drug for rash will be referred to the NTP and the local 
HIV clinic for MDR or RR-TB and HIV treatment, according to local standards of 
care. The participant will continue to be followed on study, off study drugs. 
 
7.1.9 Nausea and/or Vomiting 
 
Although common, nausea and/or vomiting following initiation of therapy with the 
study medications and/or ARV medications usually subsides or resolves during 
the first few weeks of treatment. For some patients, nausea can persist for a long 
period of time, largely owing to ethionamide or prothionamide. 
 
Steps in the management of nausea include taking the medication with food and 
administration of antiemetic or splitting the ethionamide dose. Antiemetics can 
only be used if they do not have drug-drug interactions with the study drugs and 
if they do not have overlapping toxicities with study drugs. Participants with 
vomiting should have their hydration status assessed daily and given volume 
resuscitation if clinically indicated depending on site-specific standard practices. 
 
Participants with Grade 3 or 4 nausea and/or vomiting can have their study 
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Grade ≤2 within 14 days or if Grade 3 or 4 nausea and/or vomiting occur after 
reintroduction, then the participant will be discontinued from study medications 
and referred to the NTP for treatment of their MDR or RR-TB and the local HIV 
clinic for treatment of their HIV infection according to local standards of care. The 
participant will continue to be followed on study, off study drugs. 
 
7.1.10 Diarrhea 
 
Diarrhea is a common side effect of infection and medication toxicity. If no 
infectious cause of diarrhea is found and onset is temporally related to new 
medication, symptomatic management with antidiarrheal agents is appropriate. 
Antidiarrheals (e.g., loperamide) can only be used if they do not have clinically 
significant drug-drug interactions with the study drugs and if they do not have 
overlapping toxicities with study drugs. Participants with diarrhea should have 
their hydration status assessed daily and given volume resuscitation if clinically 
indicated depending on site-specific standard practices. 
 
Participants with Grade 3 or 4 diarrhea can have their study medications held for 
up to 14 days until they are at Grade ≤2. If they do not reach Grade ≤2 within 14 
days or if Grade 3 or 4 diarrhea occur after reintroduction, then the participant will 
be discontinued from study medications and referred to the NTP for treatment of 
their MDR or RR-TB and to the local HIV clinic for HIV treatment according to 
local standards of care. He or she will be followed on study but off study drugs. 
 
7.1.11 Peripheral Neuropathy 
 
INH and ethionamide have both been associated with the development of 
peripheral neuropathy. If any participants develop new or worsening Grade 1 or 2 
neuropathy during the course of the study, they will continue on 
INH/ethionamide, undergo investigation for treatable causes of the impairment 
(e.g., glucose, vitamin B12 levels), be treated symptomatically according to local 
standards, and given pyridoxine 100 mg daily. If the participants develop new or 
worsening Grade 3 or 4 peripheral neuropathy, INH/ethionamide will be 
temporarily discontinued, while receiving symptomatic treatment and pyridoxine 
100 mg daily. If they do not have stabilization or improvement of symptoms after 
14 days, then INH/ethionamide will not be restarted. 
 
7.1.12 Arthritis/Arthralgia 
 
Arthritis and arthralgias are common symptoms experienced by patients on 
pyrazinamide. Since continuation on pyrazinamide is not an essential part of the 
study regimen, this is the one instance where it may be acceptable to temporarily 
or permanently discontinue pyrazinamide, if this agent is felt to be the likely 
cause of the symptoms. If the symptoms resolve within 14 days when 
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in the regimen may be continued and the participant will not be classified as 
having been intolerant of the regimen.  
 
If any participants develop Grade 1, 2 or 3 arthritis or arthralgia during the course 
of the study, they will continue on study drugs and treated symptomatically 
according to local standards. If they develop Grade 4 arthritis or arthralgia, they 
will be discontinued from pyrazinamide for up to 14 days until they are at Grade 
≤2. If they do not reach Grade <2 within 14 days, then these participants will be 
discontinued from study medications and referred to the NTP for treatment of 
their MDR or RR-TB according to local standards of care and followed on study 
but off study drugs. If they reach Grade <2 within 14 days but Grade 4 arthritis or 
arthralgia occur after reintroduction of pyrazinamide, then pyrazinamide will be 
permanently stopped but the participants may remain on study drugs. 
 
7.1.13 Neuropsychiatric Symptoms  
 
Terizidone or cycloserine have been commonly associated with development of 
neuropsychiatric side effects. Fluoroquinolones and high-dose INH are less 
commonly associated with neuropsychiatric side effects.  
 
If any participants develop Grade ≥2 neuropsychiatric side effects during the 
course of the study, consideration may be given to holding or stopping terizidone 
or cycloserine for 2 weeks. Should symptoms worsen or fail to resolve, 
consideration could be given to discontinuation or substitution of fluoroquinolones 
or INH. If Grade 4 symptoms fail to resolve after discontinuation for 
fluoroquinolones, then study drugs should be discontinued until symptoms 
resolve.  
 
7.1.14 Serum creatinine 
 
All participants experiencing Grade ≥1 serum creatinine elevation will have their 
creatinine checked weekly. These participants will have their injectable 
medication interrupted until creatinine normalizes.  
 
7.1.15 Suicidal Ideation  
 
Participants with HIV infection may occasionally present with symptoms of 
depression and/or suicidality (suicidal ideation or behavior). In addition, there 
have been some reports of depression, suicidal ideation and behavior 
(particularly in participants with a pre-existing history of depression or psychiatric 
illness) in some patients being treated with integrase inhibitors, including DTG. 
Therefore, it is appropriate to monitor participants for suicidality before and 
during treatment.  
 
Participants should be monitored appropriately and observed closely for suicidal 
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recommended that the investigator consider mental health consultation or referral 
for participants who experience signs of suicidal ideation or behavior. 
 
If the participant expresses suicidal ideations or intents, the data will be captured 
as AEs. Any suicide thought or attempt that qualifies as an EAE will be reported 
using the standard EAE mechanism. 
 
 
7.1.16 Ophthalmologic toxicity 
 
Ophthalmologic toxicity can occur with ethambutol treatment. Participants who 
develop new visual symptoms or decreased visual acuity will have ethambutol 
stopped and be referred for ophthalmological examination. 
 
7.2 
Toxicity Management – Other 
 
This section describes the toxicity management plan for toxicities not described in 7.1, 
using DAIDS grading. 
 
Grade 1 or 2  
Participants who develop a Grade 1 or 2 AE or toxicity may continue study drugs without 
dose adjustment. Participants experiencing Grade 1 or 2 toxicities will be managed at 
the discretion of the site investigator. Electrolyte abnormalities (hypokalemia, 
hypomagnesemia, hypocalcemia) should be corrected and rechecked. 
 
Grade 3 
If there is compelling evidence that the AE has NOT been caused by the study drugs, 
dosing may continue at the discretion of the site investigator/clinician. Except as stated 
in the above sections, participants who develop a Grade 3 AE or toxicity thought to be 
secondary to study drugs or of unknown etiology will have study drugs withheld. MBT 
drugs may also need to be held. Investigators will discuss toxicity management with the 
A5343 CMC and study drugs and/or MBT may be restarted, depending on the clinical 
situation; such decisions will be made on a case-by-case basis after consultation with 
the CMC. The participant should be reevaluated weekly if at all possible until the AE 
returns to Grade 2 or until stabilized and no longer in need of such frequent monitoring. 
Participants developing Grade 3 toxicity felt to be due to study drugs that does not 
resolve within 14 days will be discontinued from the study medications and referred to 
the NTP for treatment of MDR or RR-TB according to local standards of care. They will 
continue to be followed on-study, off study drugs. 
 
Grade 4 
Participants who develop a Grade 4 AE or toxicity, not specifically addressed above, will 
have all medications withheld and should be reevaluated weekly if at all possible until 
the AE returns to Grade 2 or until stabilized and no longer in need of such frequent 
monitoring, as determined by the site investigator. If the AE resolves and the site 
investigator has compelling evidence that the toxicity is NOT related to the study 
medications, they may be restarted. 
 


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If study drugs are permanently discontinued due to a toxicity, then the participant should 
continue to be followed on study and referred to the NTP for management of their MDR 
or RR-TB according to local standards of care. 
 
7.3 
Pregnancy 
 
If a participant becomes pregnant during the study, she will be discontinued from study 
medications and referred to the NTP for treatment of her MDR or RR-TB according to 
local standards of care and to a prenatal care program for management of her 
pregnancy according to local standards of care. HIV-positive women be referred to their 
local HIV clinic for appropriate care. She will be followed through the end of the study 
period. At the end of the pregnancy, the outcome and AEs for the participant and the 
infant will be recorded on an outcome CRF.  
 
If a female participant has completed the study or chooses to discontinue from the study 
before the end of the pregnancy, then site staff should request permission to contact her 
regarding pregnancy outcomes at the end of pregnancy. If the information is obtained, 
pregnancy outcomes will be submitted on a CRF at the end of the pregnancy.  
 
Pregnancies that occur on study among women taking ART should be reported 
prospectively to The Antiretroviral Pregnancy Registry. More information is available at 
www.apregistry.com. Fax: 44-1628-789-666 or 910-246-0637; Phone: 910-679-1598.   
 
7.4  
Expected Toxicities of MBT Drugs  
 
Drug AEs can range from minor side effects, toxic reactions, hypersensitivity reactions or 
idiosyncratic reactions. Since patients with MDR or RR-TB receive combination 
chemotherapy, it is often difficult to determine which drug is the source of the undesired 
effect. Some AEs present soon after treatment is initiated while others tend to manifest 
later. Some of the AEs to second-line anti-TB drugs are described below. 
 
Table: Common Adverse Effects of Second-line Drugs 
 
Drug 
Adverse effects 
Ethionamide or prothionamide 
Gastrointestinal disturbance, hepatitis. 
Hypothyroidism: tends to be a late effect  and 
symptoms can be subtle 
Rarely causes peripheral neuropathy 
Terizidone or cycloserine 
Neurological and psychiatric disturbances:  headache, 
irritability, depression, psychosis, seizures, suicidal 
ideation 
Peripheral neuropathy: presents as paraesthesia such 
as tingling and numbness, starting at the feet and 
spreads proximally. May be accompanied by myalgia, 
weakness and ataxia. 
Kanamycin, amikacin, capreomycin 
Pain at injection site 


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Drug 
Adverse effects 
Electrolyte wasting is often asymptomatic, patients 
may complain of cramps or palpitations; hypokalaemia 
and hypomagnesaemia, may occur early or late in 
treatment 
Nephrotoxicity - this adverse effect is common, occult 
in onset and can be fatal 
Ototoxicity: impaired hearing or impaired balance is 
almost always due to the injectable agents.  May be 
dose-dependent. 
Peripheral neuropathy 
Levofloxacin 
Generally well tolerated, occasional gastrointestinal 
disturbance, joint pain. 
Prolongation of the QT interval, minimal if any. 
Infrequently causes seizures and psychosis. 
High-dose isoniazid 
Gastrointestinal intolerance 
Moderate rises in serum transaminase concentrations 
are common. 
Severe hepatotoxicity is rare. 
Peripheral neuropathy 
Clofazimine 
Skin discoloration 
Ichthyosis 
Ethambutol 
Ophthalmologic toxicity 
Pyrazinamide 
Arthralgia 
Gastrointestinal intolerance. 
Hypersensitivity reactions are rare, but some patients 
complain of pruritus and slight flushing of the skin. 
Moderate rises in serum transaminase concentrations 
are common during the early phases of treatment. 
Severe hepatotoxicity is rare. 
As a result of inhibition of renal tubular secretion, a 
degree of hyperuricaemia usually occurs, but this is 
often asymptomatic.  
All drugs 
Skin rashes - ranging from pruritus  to Steven Johnson 
Syndrome 
Source: Adapted from World Health Organisation, 2008 Guidelines. 
 
 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Failure by the participant to attend three consecutive study visits. 
• 
Protocol-defined drug-related toxicity (see section 7.0 Toxicity). 
• 
Requirement for prohibited concomitant medications (see section 5.4.2). 
• 
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• 
Request by participant to terminate treatment. 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity section of the protocol. 
 
8.2 
Premature Study Discontinuation 
 
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if she or he thinks the study is no longer in the 
best interest of the participant. 
• 
At the discretion of the IRB/Ethics Committee, Food and Drug Administration (FDA), 
NIAID, Office for Human Research Protections (OHRP), other government agencies 
as part of their duties, investigator, or industry supporter.  
 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
General Design Issues 
 
ACTG A5343 is a randomized, open-label, three-arm trial of the safety of and drug-drug 
interactions between co-administered bedaquiline (BDQ) and delamanid (DLM), when 
added to multidrug background treatment (MBT) for infection with drug-resistant TB 
(DR-TB). The study is 128 weeks in duration (24 weeks of treatment with BDQ and/or 
DLM, then 104 weeks of follow-up). Protocol versions 1.0-3.0 required that 
participants be hospitalized for at least the first 2 months of DR-TB 
treatment. Following an interim review conducted in October 2017, the SMC 
determined that 2 weeks of hospitalization was sufficient. 
 
Participants will be randomized to one of three arms. Arm 1 participants will receive BDQ 
400 mg QD for two weeks followed by 200 mg thrice weekly for 22 weeks. Arm 2 
participants will receive DLM 100 mg BID for 24 weeks. Arm 3 participants will receive 
both BDQ and DLM (same dose amounts and duration as in Arms 1 and 2). Participants 
with HIV-1 infection may enter the study provided their CD4 count is ≥100 cells/mm3. 
Randomization will be stratified by HIV status, with balancing by institution. The total 
accrual target is 84, or 28 participants per arm, which is anticipated to yield 25 
participants per arm who are evaluable for the primary endpoints. An interim analysis 
will be conducted when week 24 QT data is available for at least 12 participants on 
the BDQ+DLM arm, to assess QT prolongations and to evaluate the observed 
precision on primary outcome estimates. 
 
Among anti-TB drugs, BDQ and DLM exhibit novel and distinct mechanisms of action; 
thus their combined use holds promise for the treatment of DR-TB. There is hope that, in 
the treatment of DR-TB, they may displace older drugs associated with significant 
toxicities. However, independently BDQ and DLM have each been associated with 
prolongations in Fridericia-adjusted QT intervals (QTcF) of 12-15 ms.  The study team 
seeks: (a) to estimate the combined effects of these two drugs (with MBT) on QT 
prolongation (QTcF increases from baseline; Arm 3 participants), and (b) to compare the 
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participants to QT prolongations seen with BDQ or DLM alone (also with MBT; Arms 1 
and 2, respectively).   
 
The rationale for the choice of QT prolongation (change from baseline in QTcF duration) 
as the outcome measure (in contrast to a categorical or binary outcome, e.g., absolute 
QTc >500 ms) is two-fold: (1) the ICH guidance document identifies analyses of central 
tendency in QTc duration changes from baseline as the primary analysis to be used in 
assessing the proarrhythmic potential for non-antiarrhythmic drugs (with occurrence of 
absolute QTc intervals above specific thresholds to be used as a secondary measure, 
and to be used in drug discontinuation criteria for the safety of participants in the study) 
[62], and (2) the continuous measure is more sensitive and provides greater power than 
a categorical/binary outcome. The power consideration is especially important given the 
relatively small sample size (which reflects the urgency of identifying treatment options 
for patients infected with MDR or RR-TB). 
 
QTc prolongation will be measured by changes from baseline in QT intervals (durations) 
adjusted for heart rate using Fridericia’s correction, QTcF. The rationale for using the 
Fridericia correction is as follows. The duration of the (uncorrected) QT interval typically 
exhibits an inverse relationship to heart rate (i.e., the duration of the QT interval is 
proportional to the duration of inter-beat interval). For this reason, when assessing 
prolongation relative to baseline, the measured QT interval is generally corrected for 
heart rate. In adults, Bazett’s correction (QTcB = QT/RR0.5, where RR represents the 
interbeat interval) tends to overcorrect at elevated heart rates and undercorrect at heart 
rates below 60 beats per minute. Fridericia’s correction (QTcF = QT/RR0.33) is thought to 
be more accurate than Bazett’s correction in participants with such altered heart rates. 
 
Primary objectives 1 and 2 will be addressed via estimation of arm-specific QTcF values 
at baseline (week 0) and on-treatment (weeks 8-24) and estimation of changes from 
baseline; a mixed-effects analysis of variance (ANOVA) model will be used for this 
estimation.  
 
Secondary objectives include: (a) estimation of  arm-specific proportions of participants 
who exhibit QTcF above 500 ms at any time during administration of study TB drug(s) 
when not present at baseline, (b) estimation of arm-specific proportions of participants 
with a QTcF increase from baseline of more than 60 ms at any time during 
administration of study TB drug(s), (c) description of visit- (week-) specific QTcF 
changes by study arm, (d) assessment of drug-drug interactions, and (e) description of 
arm-specific safety and tolerability.  
 
Exploratory objectives include PK/PD modeling that incorporates concurrent: (a) 
concentrations of BDQ, DLM and their metabolites and (b) QTcF. Models may include 
external data. PK/PD modeling can provide additional sensitivity to address these 
objectives, and can provide results with greater clinical applicability (e.g., by providing 
thresholds for PK parameters above which clinically significant QT prolongations are 
likely). Another exploratory objective is to estimate arm-specific proportions of 
participants exhibiting TB culture conversion at 8 and 24 weeks, and to estimate time-to-
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each arm, treatment efficacy estimates will be imprecise and used for description 
purposes. Systemic exposure to BDQ, DLM and other TB drugs, as measured via PK 
assay of hair samples, will be described. Among participants with concurrent HIV 
infection who initiate DTG as part of their ART regimen within ±4 weeks of study entry, 
the following proportions will be estimated: (1) with suppressed HIV-1 viral load below 50 
c/mL at weeks 24 (±6) and 48 (±6) (after study entry), (2) discontinuing DTG prior to 
week 24, and (3) exhibiting grade 3 or higher signs/symptoms, diagnoses or laboratory 
values. The proportion of participants with favorable TB outcome at week 128 will be 
reported, by arm. Relationships between drug concentrations (parent drug and 
metabolites of BDQ and DLM in plasma and hair) and emergence of drug-resistant 
subpopulations (at several time points, as characterized by TDS) will be examined. 
 
9.2 
Outcome Measures 
 
9.2.1 Primary Outcome Measures 
 
9.2.1.1 Mean baseline QTcF, on-treatment QTcF, and change from baseline in 
QTcF among participants on each arm, as estimated from a mixed-
effects ANOVA model, where participant-specific QTcF measurements 
from the week 0 visit contribute to estimation of baseline QTcF, and 
participant-specific QTcF measurements from weeks 8 through 24 
contribute to estimation of the on-treatment QTcF. 
 
The rationale for mean QTcF (averaged over visits) as the primary 
outcome measure is that, given the small sample size, such averaging 
will improve statistical power.  The rationale for choosing weeks 8-24 to 
contribute to the primary outcome measure is that a long half-life is 
observed for both study TB drugs.  For DLM, both the maximum 
concentration of DM-6705 (DLM active metabolite) in plasma and the 
maximum QT effect were observed at week 8. With loading doses, 
plasma concentrations of BDQ are highest at 2 weeks (2 weeks after the 
loading dose).  Concentrations then drop through about week 4, then 
exhibit a gradual increase and level off around week 16.  For BDQ, the 
largest mean increase in QT duration was observed at 18 weeks, and 
differences from baseline of about this magnitude persisted to week 24 
(likely due to the long terminal half-lives of BDQ and its active M2 
metabolite).  It is expected that any additive or larger than additive effect 
on QT duration of the two drugs combined would be seen after week 8. 
 
If a participant discontinues study TB drug permanently prior to week 24 
due to Grade 3 or higher prolongation in QT interval (as defined in 
Section 7.1), the QTcF value from the participant’s last visit will be 
carried forward to subsequent weeks, under the assumption that if the 
participant had continued study TB drug(s), the QT prolongation would 
likely have persisted (if not increased). 
 


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If a participant discontinues study drug permanently prior to week 24 for 
a reason other than Grade 3 or higher prolongation in QT interval, 
available QTcF values obtained while taking study TB drug will be 
included but will not be carried forward.  (The participant will be 
considered unevaluable as of the date after the last dose of (either) 
study TB drug(s).) 
 
For temporary discontinuations of study TB drug: (a) If the 
discontinuation lasts for 7 or fewer days, the ECG at the next scheduled 
visit will be performed and the QTcF value from that visit will be used in 
the analysis. (b) If the discontinuation lasts for 8-14 days, the ECG at 
the next scheduled visit will be performed and the QTcF value from that 
visit will be treated as missing.   
 
Visit-specific QTcF values are the average of QTcF values calculated 
from three separate complexes 5-10 minutes apart, as measured during 
the study visit.  If fewer than three are available, the one or two available 
QTcF values are used. The rationale for multiple ECGs at a given visit is 
as follows. Compared to a single QTcF measurement, clinically relevant 
decreases in ECG variability are seen when the outcome measure is an 
average of more than one ECG. The most common numbers of QTcF 
values used in clinical trials are one (no replicates), 3, and 6, and thus 
reviewers have experience interpreting such. The rationale for 
measuring QTcF at a single time of day (rather than multiple times of 
day and averaging hour-specific differences between on-treatment and 
baseline visits) is as follows: unlike with some drugs that prolong QT, 
after multiple BDQ and DLM doses, QT readings do not vary 
appreciably over the dosing interval. For a given participant, we will 
attempt to measure around the same time of day to control for diurnal 
variability; however, there is no need to exclude or reschedule ECGs 
when they are collected at different time of day from a previous visit. 
 
9.2.1.2 Arm-specific mean change from baseline in QTcF among participants on 
all arms, as estimated from a mixed-effects ANOVA model, where 
participant-specific QTcF measurements from the week 0 visit contribute 
to estimation of baseline QTcF, and participant-specific QTcF 
measurements from the week 8 through week 24 visits contribute to 
estimation of the on-treatment QTcF, and details of data handling are as 
given above in 9.2.1.1. 
 
9.2.2 Secondary Outcome Measures 
 
9.2.2.1 Occurrence of absolute QTcF above 500 ms at any time during study 
treatment when not present at baseline. 
 
9.2.2.2 Occurrence of QTcF change from baseline of more than 60 ms at any 
time during study treatment. 


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9.2.2.3 Visit-specific QTcF changes from baseline during study treatment, and 
at week 28 (4 weeks after discontinuation of study TB drug, in 
participants who complete 24 weeks of study treatment). 
 
9.2.2.4 Occurrence of each of the following, at any time during study treatment: 
(a) absolute QTcF >480 and ≤500 ms and (b) QTcF increase from 
baseline of >30 and ≤60 ms. 
 
9.2.2.5 In Arms 1 and 3, participant-specific PK parameters for BDQ and its 
metabolite, estimated using noncompartmental methods applied to 
concentrations from intensive PK sampling visits (weeks 2, 8, and 24). 
Week 2, 8, and 24 PK parameters will be summarized separately. 
 
9.2.2.6 In Arms 2 and 3, participant-specific PK parameters for DLM and its 
metabolite, estimated using noncompartmental methods applied to 
concentrations from intensive PK sampling visits (weeks 2, 8, and 24).  
Week 2, 8, and 24 PK parameters will be summarized separately. 
 
9.2.2.7 Among participants who take at least one dose of study TB treatment: 
occurrence of Grade 3 or higher adverse events of any type at any time 
while on study TB drug (safety); and discontinuation of study TB drug(s) 
for any reason (tolerability). 
 
9.2.2.8 Among participants who take at least one dose of study TB treatment: 
occurrence of death at any time while on study TB drug (safety). 
 
9.2.3 Exploratory Outcome Measures 
 
9.2.3.1 Participant-specific on-treatment (medians of visit-specific QTcF 
measurements from visits at weeks 8-24) and post-treatment (week 28) 
QTcF changes from baseline and concurrent concentrations of BDQ, its 
M2 metabolite, DLM and its DM-6705 metabolite. 
 
9.2.3.2 Single early-morning sputum samples collected weekly (after initiation of 
study treatment) through week 8, every other week through week 12 
and every 4 weeks through week 24. (Two samples will be collected at 
weeks 8 and 24.) These samples will be cultured on liquid medium. 
Culture conversion at weeks 8 and 24 is declared if both samples for the 
week have a time-to positivity of ≥ 42 days. (If one of the two specimens 
is contaminated, the single sample will be used to determine culture 
conversion.)  Time-to-positivity results at all weeks will be used in 
nonlinear mixed effects modeling as described in 9.6.3.2. 
 
9.2.3.3 Participant-specific hair concentrations for BDQ, DLM and their 
metabolites, as well as other components of the MBT regimen. 
 


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9.2.3.4 Among participants with MDR or RR-TB and HIV co-infection who 
initiated DTG within ±4 weeks of study entry (as part of their ART 
regimen), proportion of participants with HIV-1 RNA ≤50 copies/mL at 
24 (±6) weeks and 48 (±6) weeks after start of co-treatment. 
 
9.2.3.5 Among participants who receive concurrent dolutegravir-based ART and 
at least one dose of study treatment, occurrence of Grade 3 or higher 
AEs of any type at any time while taking dolutegravir-based ART and 
MDR or RR-TB treatment. Discontinuation of dolutegravir for any 
reason. 
 
9.2.3.6 Favorable TB outcome at week 128 [65]. A participant is classified as 
having a favorable outcome if she or he (1) has negative sputum culture 
via liquid medium from samples collected on at least two of weeks 84, 
96, and 128, provided none of these are positive, and (2) has not been 
classified as having an unfavorable outcome on/before week 128. A 
participant is classified as having an unfavorable outcome if any of the 
following occurs: (1) death (from any cause, from the time of first dose of 
study drug through week 128), (2) treatment failure (the presence of a 
positive mycobacterial culture from at least one specimen of weeks 84, 
96, or 128), (3) treatment discontinuation (discontinuation of study TB 
drug, for any reason, during weeks 0–24), or (4) recurrence (diagnosis 
of MDR-, RR-, or XDR-TB  on or before week 128 after exhibiting 
negative cultures via liquid medium on two or more prior occasions, 
weeks 0–72). 
 
9.2.3.7 Participant- and visit-specific plasma AUCs and hair concentrations of 
DLM, its DM-6705 metabolite, BDQ, its M2 metabolite, and participant- 
and visit-specific emergence of drug-resistant subpopulations 
characterized by TDS. 
 
9.3 
Randomization and Stratification 
 
Participants will be randomized, using permuted blocks, with equal probability to Arms 1, 
2 and 3.  Randomization will be stratified by HIV-1 status, with balancing by institution. 
 
9.4 
Sample Size and Accrual 
 
Sample size 
Co-primary objectives are to estimate QT prolongation (i.e., changes from baseline in 
QTcF) for participants taking both BDQ and DLM (Arm 3), and to compare such changes 
seen for participants in Arm 3 to changes seen on Arms 1 and 2 (BDQ alone and DLM 
alone, respectively [with MBR]). These objectives will be addressed by fitting a single 
mixed-effects ANOVA model to baseline and on-treatment QTcF measurements 
collected from participants on all 3 arms, as described in 9.6.1.1 and 9.6.1.2. Changes 


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from baseline and differences between arms therein will be represented by estimated 
contrasts and associated 95% CIs. 
 
The sample size calculations below, however, are based on non-model-based 
calculations of means and t-based inference.  It is recognized that within-participant 
correlation may increase the variability around estimates of primary outcome measures.  
Power for the mixed-model contrasts were calculated for several scenarios (not shown).  
For all scenarios studied, assuming 20 evaluable participants per arm, the resulting 
power was good (above 95%) to detect a 10 ms difference between QTcF changes on 
Arm 3 compared (separately) to Arms 1 and 2.   
 
The standard deviations (SDs) of differences (sdiff) in QTcF, post-baseline (BL, where 
baseline refers to measurements taken at entry prior to administration of study TB 
drug(s); (single week, mean of 3 ECGs measured 5-10 minutes apart) minus BL (single 
week, mean of 3 ECGs measured 5-10 minutes apart), are 7-10 ms when measured by 
the core ECG laboratory ERT (personal communication. Dr. Joel Morganroth).  (a) Using 
the formula for the variance of differences, sdiff2 = sBL2 + sPBL2 – 2**s3BL*s3PBL (where s3BL 
and s3PBL represent the standard deviations of the BL and post-BL QTcF measurements, 
respectively, when the analysis [outcome] measure is the average of 3 separately 
reported intervals measured 5-10 minutes apart during a single ECG procedure), and (b) 
assuming that s3BL = s3PBL, and (c) for a range of sdiff values and within-subject 
correlations (“historical rho”), Table 9.1 gives corresponding SDs of QTcF values from a 
single visit when each QTcF value is based on 3 (s3BL), 2 (s2BL) and 1 (s1BL) QTcF 
intervals (hereafter, “reads”) reported by a central reader. (s1BL is calculated as 
sqrt(3)*s3BL, and s2BL is calculated as s1BL/sqrt(2), where sqrt denotes square root.)   
 
For example, if the SD of within-subject changes from baseline in QTcF (based on three 
reads at each visit) is 7 ms, and the true within-subject correlation is 0.4, the SD of QTcF 
at a single visit is 6.4 ms when the QTcF is based on three reads, and 11.1 ms when the 
QTcF is based on a single read.  If the SD of within-subject changes from baseline in 
QTcF (based on 3 reads at each visit) is 10 ms, and the true within-subject correlation is 
0.7, then back-calculation to estimate the SD of QTcF at a single visit is 12.9 ms when 
the QTcF is based on 3 reads, and 22.4 ms when the QTcF is based on a single read.  
In subsequent tables, to be conservative, values for s1BL of 10 and 20 ms are examined.  
Values for sdiff in the literature are typically in the 9-11 ms range, while a value of 7 ms is 
likely only for carefully controlled studies.  For this reason, in subsequent tables, a value 
of 20 ms is assumed for s1BL (slightly smaller than 22.4 ms in the last row of Table 9.1).  
 
Table 9.1: Standard Deviations (s1BL) in Milliseconds (ms) of a Single QTcF 
Measurement, as a Function of Assumed SD of Differences (sdiff) and Within-
Subject Correlations. 
sdiff, ms Historical 
rho 
SD (in ms) of QTcF measured at a single visit, 
when number of separately reported intervals (separate “reads,”) 
(measured 5-10 minutes apart during a single ECG procedure) is… 
…3 (s3BL) 
…1 (s1BL) 
7 
0.4 
6.4 
11.1 


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0.5 
7.0 
12.1 
 
0.6 
7.8 
13.6 
 
0.7 
9.0 
15.7 
10 
0.4 
9.1 
15.8 
 
0.5 
10.0 
17.3 
 
0.6 
11.2 
19.4 
 
0.7 
12.9 
22.4 
 
For several sample sizes, Table 9.2 gives the anticipated precision, i.e., the half-widths 
of 95% CIs around estimates of: (a) QT change from baseline on Arm 3, (b) the 
difference in QT change from baseline between Arm 3 and each of Arms 1 and 2, and 
(c) the percent of participants exhibiting QTcF increase from baseline of >60 ms (at any 
time while taking study TB drug(s). Precisions given in the table are calculated based on 
the following assumptions: (a) The SD of QTcF from single on-treatment read is 20 ms. 
(b) Within-participant correlation between baseline and on-treatment means is 0.4. (c) 
For each visit, 3 ECGs will be read/reported, and will be averaged to determine the visit-
specific QTcF. (d) For the primary outcome, the participant-specific on-study-TB-drug 
mean QT duration is the average of 9 visit-specific averages (weeks 8, 10, 12, 14, 16, 
18, 20, 22 and 24), with a standard deviation of 3.8 ms (ignoring correlation within-
participant of on-treatment QTcF values; note that other assumptions are very 
conservative). (For the last column, an event rate of 30% is assumed (high and therefore 
conservative), and the larger ‘half’ of the asymmetric CI is reported as the half-width.)   
 
The total sample size (accrual target) is 84 participants. Table 9.2 indicates that accruing 
28 participants per arm, anticipated to yield 25 evaluable participants per arm with 
complete ECG data (participant has 3 ECGs conducted at each of the 9 on-study-TB-
drug visits and a single baseline visit (with 3 ECGs read/reported), CIs around Arm 3 QT 
prolongation are expected to be about ±4.5 ms, for good precision. For the estimates of 
differences in QT prolongation between Arm 3 and each of Arms 1 and 2, CIs are 
expected to give a precision of about ±6.0 ms. It is anticipated that no more than 10% of 
participants will discontinue study TB drug(s) before week 24, and that the majority of 
participants will have 3 QTcF values reported from each visit. (Anticipating loss to follow-
up of about 10%, setting accrual targets of 28 per arm should provide 25 evaluable 
participants per arm. The anticipated precision in Table 9.2 assumes that all 25 
evaluable participants will have QT values from each of the 3 ECGs conducted at each 
of the 9 visits contributing to the primary endpoint. Precision will be somewhat smaller if 
more than the anticipated 3 participants provide incomplete ECG data.) In the event that 
only 20 participants per arm are evaluable, CIs around estimates of Arm 3 QT 
prolongation would have a precision of about ±5.1 ms, and CIs around estimates of 
differences in QT prolongation between Arm 3 and each of Arms 1 and 2 would have a 
precision of about ±6.8 ms, which would still provide meaningful data.  
 
Table 9.2: Anticipated Precision (half-width of 95% CIs) for Estimating: (a) QT 
prolongations on Arm 3, (b) the difference in QT-prolongation between Arm 3 
and each of Arms 1 and 2, and (c) the percent of participants exhibiting 
QTcF increase from baseline of >60 ms (at any time while taking study TB 


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drug(s)). 
Number of 
evaluable 
participants per 
arm 
PRECISION 
(CI half-width) in ms for estimating… 
Within-
participant 
QTcF changes 
from baseline 
on Arm 3 
Between arm differences 
in within-participant QTcF 
changes from baseline 
(Arm 3 vs. Arm 1, and 
Arm 3 vs. Arm 2) 
Percent of participants 
exhibiting QTcF 
increase from BL of 
>60 ms 
20 
5.1 
6.8 
31% 
25 
4.5 
6.0 
25% 
30 
4.0 
5.5 
20% 
 
Accrual 
The total accrual target is 84 participants. Across at least 2 ACTG sites enrolling to this 
study, we expect to enroll about 8-10 participants per month (all sites combined), in 
which case the accrual target would be met in less than 12 months after all sites have 
begun enrolling.   
 
9.5 
Monitoring 
 
During the study, the safety and tolerability of the study medication will be monitored by 
means of adverse event reports (AER) and toxicity reports, reviewed by the study team, 
that present laboratory and clinical data, including QTcF prolongation events. All Grade 
3 or higher adverse events and all adverse events leading to discontinuation of BDQ 
and/or DLM will be included in these reports. It is the responsibility of the study team to 
interpret the toxicity data and make any decisions needed to protect participants from 
undue risk. Concerns will be presented to the DAIDS Clinical Representative. 
 
In these once monthly toxicity reports, the statisticians will also calculate and provide 
arm-specific proportions of participants exhibiting Grade 3 or higher QT prolongations 
(targeted AE), along with 95% CIs around the proportions, and will report these to the 
core team. (For the first 3 months after the first participant is randomized, and if the 
accrual rate is eight or more per month in the past month, this report will be generated 
and reviewed twice monthly.) Provided 10 or more Arm 3 participants have evaluable AE 
data through week 12 (available ECG data from 3 of the 9 visits at which ECGs 
contributing to the primary objective), if the upper bound of a 95% confidence interval 
(CI) around the proportion of Arm 3 participants exhibiting Grade 3 or higher QT 
prolongations exceed a threshold of 70%, the team will evaluate the events carefully in 
conjunction with the DAIDS Representative and the Study Monitoring Committee (SMC, 
appointed by the chair of the ACTG Tuberculosis Transformative Science Group [TB 
TSG]) to consider whether there should be study modifications. Table 9.3 gives the 
probabilities of this level of concern, for several true rates of Grade 3 or higher QT 
prolongations, for several observed numbers of participants, and for several threshold 
values. 
 
Ideal characteristics of the trigger for DAIDS Representative and TB TSG SMC 
evaluation are that the trigger is: (1) unlikely to occur for low probabilities of the targeted 


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AE (under 10-20%, say) and (2) likely to occur for high probabilities of the AE (30% and 
above). Table 9.3 shows the probabilities of the trigger occurring for various true 
probabilities of the targeted AE, for numbers of participants observed and for particular 
choices for threshold. For example, if the true probability of the targeted AE is 5%, 
applying the trigger rule with data available from only seven participants, there is a 30% 
probability of triggering evaluation for a threshold of 50%. If the true AE probability is 
30%, there is a high probability (>50%) of triggering evaluation with available data from 
7, 10, 15 or 20 participants, when the threshold is set to 50%. The threshold of 50% is 
applied once there is ECG data from at least 10 participants on Arm 3. This trigger gives 
a high probability of evaluation (≥85%) if the true AE rate is ≥30%, and a low probability 
of evaluation (≤26%) if the true AE rate is ≤10%. 
 
Balanced against the need for effective treatment against multidrug-resistant TB, an 
incidence of 50% for Grade 3 or higher QT intervals may be acceptable in practice. The 
higher threshold of 70% is chosen as a trigger for SMC review so that the SMC will only 
review in the case of a strong signal. 
 
Sites should report the following events to the study team and to DAIDS immediately:  
(1) Grade 4 QT prolongations, (2) deaths and (3) results of repeated ECGs after holding 
study TB drug for a Grade 3. 
 
Approximately 6 months after the first participant enrolls, an interim review for safety will 
occur.  A Study Monitoring Committee (appointed by the chair of the ACTG Tuberculosis 
Scientific Committee) will review adverse event summaries, as well as accrual, off-
treatment and off-study rates by study arm. Adverse event summaries will include the 
arm-specific proportions of Grade 3 or higher QT prolongations (with 95% CIs), rates of 
all Grade 3 or higher and all Grade 4 or higher signs/symptoms and laboratory values, 
and plots of arm- and visit-specific QT interval changes from baseline. 
 
The study team will also monitor accrual, to ensure accrual targets are met, and will 
review data availability reports prepared by study statisticians and/or the lab data 
manager regularly to ensure that samples for primary and secondary endpoints are 
collected as expected. 
 
Table 9.3. For Selected Numbers of Observed Participants and True Rates of Adverse 
Event (AE, Grade 3 or higher QT prolongation), this table gives probabilities that the 
upper bound of an 95% exact, Clopper-Pearson CI (around the estimated probability AE) 
is above several thresholds (data are deemed consistent with an AE rate this high). 
 
Number of 
Participants 
Observed 
True 
Probability 
of AE 
Threshold… 
0.50 
0.70 
0.80 
0.90 
7 
0.05 
0.30 
0.04 
0.00 
0.00 
 
0.10 
0.52 
0.15 
0.03 
0.00 
 
0.20 
0.79 
0.42 
0.15 
0.03 
 
0.30 
0.92 
0.67 
0.35 
0.13 


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0.50 
0.99 
0.94 
0.77 
0.50 
10 
0.05 
0.09 
0.00 
0.00 
0.00 
 
0.10 
0.26 
0.01 
0.00 
0.00 
 
0.20 
0.62 
0.12 
0.03 
0.00 
 
0.30 
0.85 
0.35 
0.15 
0.01 
 
0.50 
0.99 
0.83 
0.62 
0.17 
15 
0.05 
0.01 
0.00 
0.00 
0.00 
 
0.10 
0.06 
0.00 
0.00 
0.00 
 
0.20 
0.35 
0.02 
0.00 
0.00 
 
0.30 
0.70 
0.13 
0.02 
0.00 
 
0.50 
0.98 
0.70 
0.30 
0.06 
20 
0.05 
0.00 
0.00 
0.00 
0.00 
 
0.10 
0.01 
0.00 
0.00 
0.00 
 
0.20 
0.20 
0.00 
0.00 
0.00 
 
0.30 
0.58 
0.05 
0.01 
0.00 
 
0.50 
0.98 
0.59 
0.25 
0.02 
 
 
9.5.1  Interim review to assess the need for an initial hospitalization of 2 months 
 
Based on comments from the March 2017 SMC review, to increase the rate of 
accrual and to reduce the burden of study participation on participants, the team 
wanted to shorten the duration of the initial hospitalization that was required 
when the participant begins taking TB study drug(s), provided it is safe to do so. 
An interim analysis was to be conducted when QTcF data through week 8 are 
available for at least 12 participants on the BDQ+DLM regimen. For participants 
on the BDQ+DLM arm, the mean of participant-specific mean QTcF changes 
from baseline at week 8 was to be calculated, along with the corresponding 95% 
CI. This summary was to be provided to the SMC.  
 
The interim review occurred in October 2017 and supports the hypothesis that 
the observed QTcF intervals are consistent with a true QT prolongation of no 
higher than 40 ms. Therefore, the SMC recommended that the duration of 
hospitalization for participants initiating TB study drug(s) be reduced from 2 
months to 2 weeks. (Note that those participants who would require inpatient stay 
based on local practice or severity of illness would stay for longer than 2 weeks, 
as necessary.)  
 
Table 9.4 below shows that with an interim review sample size of 12, if the true 
population QT prolongation is 30 ms, there is only a 1 in 3 chance of retaining the 
original 2-month hospitalization, and if the true population QT prolongation is 40 
ms, the original 2-month duration is retained with high probability (98%). 
 
Table 9.4.  For several hypothesized true QT prolongations and several interim 
review sample sizes, this table shows the probability (expressed as percent) that 
the 95% CI around within-participant change from baseline in QTcF fails to 


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exclude a value as high as 40 ms (95% CI upper bound is above 40 ms). 
True QT 
prolongation 
Number of participants with Week 8 QT data available 
6 
7 
8 
9 
10 
11 
12 
10 
1% 
<1% 
<1% 
<1% 
<1% 
<1% 
<1% 
20 
20% 
10% 
6% 
3% 
1% 
1% 
<1% 
30 
69% 
64% 
57% 
48% 
46% 
37% 
34% 
40 
98% 
98% 
97% 
98% 
98% 
97% 
98% 
50 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
60 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
70 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
>99% 
 
 
9.5.2 
Interim analysis to assess QT prolongations and the observed 
precision to date of estimates of QT prolongations 
 
Because this trial has been slow to accrue, and given the urgent need for 
information on the safety of co-administration of bedaquiline and delamanid 
for patients with highly resistant forms of TB, an interim analysis will be 
performed when week 24 QT data is available for at least 12 participants on the 
BDQ+DLM arm.  Results will be shared with the SMC.   
 
The interim analysis will present:   
(1) Arm-specific averages of week 24 QTcF changes from baseline,  
(2) Arm-specific averages of week 8 QTcF changes from baseline, 
(3) The estimated difference between (a) the average week 24 QTcF change 
from baseline on the BDQ+DLM arm and (b) the sum of the week 24 
averages seen on the BDQ-alone and the DLM-alone arms,  
(4) The difference between the average week 24 QTcF change from baseline 
on the BDQ+DLM arm and (b) (separately) on the BDQ-alone and the DLM-
alone arms,  
(5) Corresponding confidence intervals (CIs) around each of these point 
estimates, and 
(6) The precision (half-widths of CIs) for each estimate. 
 
Point estimates. Arm-specific week 24 QTcF changes from baseline are 
defined as the average of participant-specific changes, where participant-
specific change is calculated as the average of changes from baseline at 
weeks 8 through 24; all participants with week 24 data are included. Arm-
specific week 8 QTcF changes from baseline are defined as the averages of 
change from baseline at week 8 only. 
 
Confidence intervals for measures (1), (2) and (3). Based on the method of 
Repeated Confidence Intervals, 99.9% CIs will be constructed. To maintain at 
least 95% simultaneous coverage for both the interim and final analysis CIs, a 
95.1% confidence level will be used for CIs in the final analysis.   
 
Precision for measure (4). To allow comparison of observed precision to the 
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point estimates for measure (4) will be calculated. The CIs themselves will not 
be reported, but the precision will be. Table 9.5 below is an extension of Table 
9.2 above: a row for 12 evaluable participants per arm has been added. 
 
Table 9.5-1: Anticipated precision (half-width of 95% CIs) for estimating: (a) 
arm-specific QT prolongations at week 24, and (b) the difference in QT-
prolongation between Arm 3 and each of Arms 1 and 2. Precision estimates are 
based on the original protocol assumptions. 
Number of 
evaluable 
participants per 
arm 
PRECISION 
(CI half-width) in ms for estimating… 
Arm-specific 
average of week 24 
within-participant 
QTcF changes from 
baseline 
Between arm differences 
in week 24 QTcF 
changes from baseline 
(Arm 3 vs. Arm 1, and 
Arm 3 vs. Arm 2) 
12 
7.0 
9.0 
20 
5.1 
6.8 
25 
4.5 
6.0 
30 
4.0 
5.5 
 
9.6 
Analyses 
 
9.6.1 Primary analyses 
 
9.6.1.1 A mixed-effects ANOVA model (with fixed effects for treatment arm and 
“period” (baseline vs. on-treatment), and random effects for participant) 
will be fit to data from participants on all arms. The QTc prolongation on 
Arm 3 will be represented as the estimated contrast (difference between 
QTc duration during weeks 8-24 and QTc duration at week 0) along with 
the corresponding model-based 95% CI.  (See 9.2.1.1 for definitions of 
handling of data from participants who discontinue study treatment 
before week 24 and of missing data.) QTc prolongations on Arms 1 and 
2 will be similarly estimated. 
 
9.6.1.2 A mixed-effects ANOVA model (with fixed effects for treatment arm and 
“period” (baseline vs. on-treatment), and random effects for participant) 
will be fit to data from participants on all arms. The difference between 
QTc prolongations on Arms 3 and 1 will be estimated as the 
corresponding contrast (Arm 3 change from baseline minus Arm 1 
change from baseline) along with the corresponding model-based 95% 
CI.  No adjustments will be made for multiple comparisons.  Arms 2 and 
3 will be similarly compared. (See 9.2.1.1 for definitions of handling of 
data from participants who discontinue study treatment before week 24 
and of missing data.) 
 


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9.6.2 Secondary analyses 
 
9.6.2.1 Arm-specific proportions of participants exhibiting new QTcF >500 ms 
will be reported, along with the associated 95% exact, Clopper-Pearson 
binomial CI. (Because the study TB drugs have a long half-life, 
participants will be included in the proportion whether or not they took 
study TB drug(s) through Week 24.) Between-arm comparisons will not 
be conducted. 
 
9.6.2.2 Arm-specific proportions of participants exhibiting QTcF change from 
baseline >60 ms at any visit after the first dose of study TB drug through 
week 24 will be reported, along with the associated 95% exact, Clopper-
Pearson binomial CI. (Because the study TB drugs have a long half-life, 
participants will be included in the proportion whether or not they took 
study TB drug(s) through week 24.) Between-arm comparisons will not 
be conducted. 
 
9.6.2.3 Arm- and visit-specific medians, ranges and interquartile ranges of 
within-participant QTcF changes from baseline will be reported, 
beginning with the first on-treatment ECG in the SOE, and continuing 
through the last ECG measured after scheduled discontinuation of study 
TB drug(s) at week 28. For participants who discontinue study TB 
drug(s) prematurely, QTcF changes will be excluded from analysis; 
however, in a sensitivity analysis, QTcF changes from such participants 
will be carried forward as described in 9.2.1.1. (Statistical summaries of 
QTcF changes from baseline measured after scheduled discontinuation 
of study TB drug(s) allow characterization of the resolution of QT 
changes.)  
 
On a single graph but with separate lines (colors, symbols) for each 
arm, week-specific mean changes and associated 95% CIs will be 
plotted against week, to allow a visual comparison of arms with respect 
to time effects. The arm- and week-specific summaries will also be 
tabulated. Between-arm comparisons will not be conducted. 
 
9.6.2.4 Arm-specific proportions of participants exhibiting each of the following 
(at any time during study treatment) will be reported, along with the 
associated 95% exact, Clopper-Pearson binomial CI: (a) QTcF >480 
and ≤500 ms and (b) QTcF change from baseline >30 and ≤60 ms. 
Between-arm comparisons will not be conducted. 
 
9.6.2.5 Participant-specific PK parameters for BDQ and its M2 metabolite will be 
summarized by week (weeks 2, 8, and 24). Effects of DLM co-
administration on BDQ PK parameters will be estimated by (week-
specific) geometric mean ratios (GMRs; BDQ/metabolite PK parameter 
with DLM divided by BDQ/metabolite PK parameter without DLM), and 
the associated 90% CI around the GMR.  


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9.6.2.6 Participant-specific PK parameters for DLM and its DM-6705 metabolite 
will be summarized by week (Weeks 2, 8, and 24). Effects of BDQ co-
administration on DLM PK parameters will be estimated by (week-
specific) geometric mean ratios (GMRs; DLM/metabolite PK parameter 
with BDQ divided by DLM metabolite PK parameter without BDQ), and 
the associated 90% CI around the GMR.  
 
9.6.2.7 Arm-specific proportions of participants exhibiting each of the following 
will be reported, along with the associated 95% exact, Clopper-Pearson 
binomial CI: (a) Grade 3 or higher clinical or laboratory adverse event of 
any type, and (b) early discontinuation of study TB drug for any reason. 
 
9.6.3 Exploratory analyses 
 
9.6.3.1 PK/PD modeling will be used to characterize relationships between (a) 
QTcF changes from baseline and (b) concurrently-collected plasma 
concentrations of BDQ, DLM and their metabolites. 
 
9.6.3.2 Arm-specific proportions of participants exhibiting culture conversion will 
be estimated for weeks 8 and 24 using a modified intention-to-treat 
(MITT) analysis wherein participants without confirmed MDR or RR-TB 
or Mycobacterium tuberculosis growth at baseline and participants who 
did not take at least one dose of study TB drugs are excluded from 
analysis. So that the 24-week culture conversion rates will not be 
overestimated, participants who experience dose limiting adverse 
events or die (from any cause) will be included in the analysis by 
retaining them in the risk group through Week 24. Description of change 
in time-to-detection over time on MGIT (liquid) culture (decline over time 
in viable mycobacteria in the sputum) will also be explored, using a 
nonlinear mixed-effects, repeated time-to-event model [66]. 
 
9.6.3.3 Drug concentrations in hair will be reported using descriptive statistics. 
 
9.6.3.4 Among participants with MDR or RR-TB and HIV co-infection who 
initiated DTG within ± 4 weeks of study entry (as part of their ART 
regimen), proportions of participants exhibiting each of the following will 
be reported, along with the associated 95% exact, Clopper-Pearson 
binomial CI: (a) HIV-1 RNA ≤50 copies/mL 24 (±6) and 48 (±6) weeks 
after initiating DTG, (b) Grade ≥3 clinical or laboratory adverse event of 
any type at any time while taking DTG and (c) early discontinuation of 
DTG for any reason. Overall proportions will be presented as well as 
proportions in the following subgroups: ART-naïve at study entry (or 
having initiated ART within 4 weeks of study entry), on ARV with HIV-1 
RNA >50 copies/mL at time of study entry and on ARV with HIV-1 RNA 
≤50 at study entry. 
 


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9.6.3.5 Arm-specific proportions of participants exhibiting favorable outcomes at 
week 128 will be estimated using a modified intention-to-treat (MITT) 
analysis, wherein participants without confirmed MDR or RR-TB or MTB 
growth at baseline and participants who did not take at least one dose of 
study TB drugs are excluded from analysis. Kaplan-Meier survival 
analysis will be used to estimate the proportion of participants exhibiting 
favorable week 128 outcomes. 
 
9.6.3.6 
Exploratory plots will be examined, the details of which will be given in 
the Statistical Analysis Plan. For example, for each DLM, its DM-6705 
metabolite, BDQ and its M2 metabolite, and for the plasma-based drug-
exposure metric AUC and the hair-based metric (time-averaged) 
concentration, the distribution of drug-resistance phenotypes will be 
tabulated for two to four drug-exposure “bins” created by splitting the 
continuous exposure metric into halves, thirds, or fourths. 
 
9.6.3.7 
Concentrations of BDQ and DLM in CSF, and CSF to plasma ratios 
of BDQ and DLM, will be summarized by week and hour, and by 
hour (both weeks combined). Pharmacologists will conduct 
nonlinear mixed-effects modeling to estimate partition coefficient 
and half-life of the distribution between plasma to CSF. 
 
 
10.0 
PHARMACOLOGY PLAN 
 
10.1 
Pharmacology Objectives 
 
See Sections 1.3.5, 1.3.6, and 1.4.1. 
 
10.2 
Pharmacology Study Design   
 
10.2.1 
Overview 
 
The overall aims of the PK investigation are: 1) To evaluate the relationship 
between BDQ and DLM PK and QT interval changes in participants on MBT 
with DLM, BDQ or the 2 drugs in combination; 2) To identify any important PK 
drug-drug interactions between the two study TB drugs.  
 
An initial noncompartmental analysis (9.2.2.5 and 9.2.2.6) will be used to 
evaluate differences in measures of exposure of the respective drugs and 
metabolites at 2 weeks, 8 weeks, and 24 weeks between the treatment arms, 
using the intensive PK data. 
 
An integrated population PK model for each drug with or without its major 
metabolite (M2 and DM6705, respectively), which will characterize the PK 
during the 24-week treatment and during the post-study drug period will be 
developed. The model will be supported by:  


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1) intensive PK sampling over a 24-hour dosing interval (for 24 hours 
immediately after the morning doses of BDQ and/or DLM) at week 2 
(corresponding to the end of the loading dose phase for BDQ), during week 8 
(at which time the maintenance doses of both drugs are established) and during 
week 24 (corresponding to the end of treatment when maximal accumulation 
may be seen); 2) sparse sampling corresponding to ECG times; and 3) post-
study drug samples at 28 weeks.  
 
Population PK modelling will be used to identify important covariate effects and 
to evaluate the effect of concomitant BDQ on DLM PK and the effect of 
concomitant DLM on BDQ PK, as well as estimation of drug exposures at the 
time of ECG assessments.     
 
A PK-PD model will be developed to examine the relationship between QTcF 
measurements and BDQ, DLM and their respective metabolites.    
 
10.2.2 Methods and Timing for Assessing, Recording, and Analyzing PK Outcome 
Measures 
 
Intensive PK sampling: Blood samples will be taken over a 24-hour period at 
weeks 2, 8, and 24 (see section 6.1 and table below). Every effort should be 
made to ensure that the week 2 intensive PK sampling for BDQ is collected on 
day 12, 13, or 14 to allow for PK assessment following an observed dose of 400 
mg of BDQ. On PK sampling days, a standardized meal will be provided, as 
described in the MOPS. The date and time of the meal should be recorded on 
the CRF. DLM will be dosed immediately after the standardized meal, while BDQ 
and the other TB medicines will be dosed one hour after the meal. PK sampling 
will be performed immediately after the meal but prior to drug dosing (predose), 
and at 4 (±0.5) h, 6 (±0.5) h, 8 (±0.5) h, 11 (±1) h and 23 (±1) h, as outlined in the 
table below, where time is set to 0 hour at the time of the DLM dose or 1 hour 
before the BDQ dose: 
EVENT 
ARM 1 (BDQ) 
ARM 2 (DLM) 
ARM 3 (BDQ+DLM) 
Standard meal 
- 0.5 h 
- 0.5 h 
- 0.5 h 
Pre-dose PK sample 
- 0.25 to 0 h 
- 0.25 to 0 h 
- 0.25 to 0 h 
DLM dose 
- 
0 h 
0 h 
BDQ dose 
1 h 
- 
1 h 
Other TB drug doses 
1 h 
1 h 
1 h 
ECG 
(±3.5 to 4 h) 
(±3.5 to 4 h) 
(±3.5 to 4 h) 
PK sample* 
-   
4 (±0.5) h  
4 (±0.5) h 
PK sample** 
6 (±0.5) h 
- 
6 (±0.5) h 
PK sample 
8 (±05) h 
8 (±05) h 
8 (±05) h 
PK sample 
11 (±1) h 
11 (±1) h 
11 (±1) h 
PK sample 
23 (±1) h 
23 (±1) h 
23 (±1) h 
* For analysis of DLM and its metabolite only. 
** For analysis of BDQ and its metabolite only. 
All other PK samples to be analyzed for both drugs and their respective metabolites. 
 


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Sparse PK sampling: Sparse sampling will be conducted at weeks 4, 6, 10, 12, 
14, 16, 18, 20, 22, and 28. PK sampling days are scheduled for days when 
ECGs are also collected. ECGs are performed in triplicate, and ECG evaluation 
should be followed immediately by PK sampling. The exact time of the dose 
preceding the PK sampling and the exact time of the PK sample collection 
should be noted. 
 
The actual (24-hour clock) times of BDQ, DLM, and MBT doses and samples 
will be recorded in the CRF, as well as the time of the 2 prior doses for BDQ 
and DLM. If the required specimen is not obtained or sent to the lab, 
information about why should be included on the CRF. On days when PK 
samples are collected for intensive PK analysis, ECG should precede the PK 
collection. 
 
10.2.3 
PK: Blood and Hair Collection and Processing 
Detailed blood and hair collection, processing, handling, and storage 
procedures can be found in the A5343 LPC and MOPS. Plasma PK samples 
from PK sampling days will also be stored for measurement of MBT drugs 
should this be of future scientific interest. 
 
10.2.4 
Pharmacogenomics: Host Genetic Analysis 
 
A whole blood sample will be collected and stored to evaluate for 
pharmacogenomics should relationships between genetics and PK variability be 
discovered in the future as these could potentially serve as explanatory 
variables in PK analyses.  
 
10.2.5 
Laboratory Performing the Assays 
 
Plasma BDQ, M2, DLM, and DL6705 concentrations, and CSF BDQ and DLM 
concentrations, will be determined by a validated procedure performed 
according to written standard operating procedures. The intraday accuracy and 
intraday precision will be obtained with quality control samples, which will be 
analyzed concurrently with each set of volunteer samples. Quality control 
procedures will be in place to ensure stability of sample materials. Hair assays 
for MBT, BDQ, M2, DLM and DL6705 are being developed in the analytical 
laboratory at University of California at San Francisco (UCSF) and hair 
concentrations will be determined by a validated procedure performed 
according to written analytic validation reports and standard operating 
procedures.  
 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
See Sections 9.6.2.5 and 9.6.2.6 for descriptions of noncompartmental analyses to be 
performed using intensive PK sampling data.  
 
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be analyzed using nonlinear mixed-effects (NLME) modeling using the software 
NONMEM. A stepwise procedure will identify the structural model best describing the data 
for each drug and its metabolite. Various structural models will be evaluated varying the 
number of compartments and testing different absorption models. Allometric scaling will 
be tested in the model to account for the effect of body size on the PK parameters, using 
total body weight or fat-free mass. Other covariate effects (such as those of race, sex, HIV 
co-infection status, time on treatment, albumin) will be evaluated and retained if they result 
in statistically important improvement in model fit. The effect of drug-drug interactions will 
be investigated on clearance, bioavailability, and other primary parameters of importance. 
Graphical and statistical diagnostic tools will be used during model development for model 
selection and data tracking.  
 
PK/PD models will be developed to explore the relationship between drug and metabolite 
concentrations and QTcF. Details are provided in the Statistical Analysis Plan.  
 
10.4 
Anticipated Outcomes 
 
See Hypothesis 1.1.2.2. 
 
QTcF will correlate with DM6705 concentrations but not with DLM, BDQ, or M2 
concentrations. 
 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Case report forms (CRF) will be provided for each participant. Participants must not be 
identified by name on any CRFs. Participants will be identified by the patient 
identification number (PID) and study identification number (SID) provided by the ACTG 
DMC upon randomization. 
 
11.2 
Role of Data Management 
 
11.2.1 Instructions concerning the recording of study data on CRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
11.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
11.3 
Clinical Site Monitoring and Record Availability 
 
11.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, CRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 


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of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
11.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily available 
for inspection by the local IRB, the site monitors, the FDA, the NIAID, the OHRP, 
the industry supporter(s) or designee, other local, US, and international 
regulatory entities for confirmation of the study data. 
 
11.4 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
11.4.1 
Adverse Event Reporting to DAIDS 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/manual. 
 
The DAERS, an internet-based reporting system, must be used for expedited 
AE reporting to DAIDS. In the event of system outages or technical difficulties, 
expedited AEs may be submitted via the DAIDS EAE Form. For questions 
about DAERS, please contact DAIDS-ES (now part of the NIAID Clinical 
Research Management System) at CRMSsupport@niaid.nih.gov. Site queries 
may also be sent from within the DAERS application itself.  
 
For questions about expedited reporting, please contact the DAIDS RSC 
Safety Office at (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2 
Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study through the week 48 visit. Thereafter, the 
SUSAR Reporting category will be used. 
• 
The study agents for which expedited reporting are required are: 
bedaquiline and delamanid and dolutegravir. 
• 
In addition to the EAE Reporting Category identified above, other AEs that 
must be reported in an expedited manner are as follows: 
 
▪ 
Any liver toxicity that warrants permanent study drug discontinuation 
based on liver stopping criteria in 7.1.2. 
▪ 
If any participant experiences a possible suicidality-related adverse 
event (PSRAE) ≥Grade 3 while participating in this study that is 
considered by the investigator to meet ICH-E2A definitions for 
seriousness, the investigator will collect information using a PSRAE 
CRF in addition to reporting the event on a SAE CRF. A PSRAE may 
include, but is not limited to, an event that involves suicidal ideation, a 


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preparatory act toward imminent suicidal behavior, a suicide attempt, 
or a completed suicide. The investigator will exercise his or her 
medical and scientific judgment in deciding whether an event is 
possibly suicide-related. 
▪ 
Episodes of ventricular tachycardia or fibrillation, syncope, and 
seizure. 
▪ 
Grade 3 QTcF prolongation, as defined in section 7.1.1.   
▪ 
Grade 3 pancreatitis.  
▪ 
Grade 3 myalgias or creatine kinase.  
▪ 
Grade 3 rash. 
▪ 
Any Grade 4 event, including laboratory values. 
 
Any AE leading to permanent study drug discontinuation will be reported as an 
EAE at the time it is decided that the study drug will be permanently 
discontinued. 
 
11.4.3 
Grading Severity of Events 
 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 2.0, November 2014, must be used and is 
available on the DAIDS RSC Web site at http://rsc.tech-res.com/clinical-
research-sites/safety-reporting/daids-grading-tables. One exception is QT 
grading (see Section 7.1 above).   
 
11.4.4 
Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is as per the EAE manual.   
• 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
 
12.0 
HUMAN PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix II) and any subsequent 
modifications will be reviewed and approved by the IRB or ethics committee responsible 
for oversight of the study. A signed consent form will be obtained from the participant (or 
legal guardian, or person with power of attorney for participants who cannot consent for 
themselves). The consent form will describe the purpose of the study, the procedures to 
be followed, and the risks and benefits of participation. A copy of the consent form will 
be given to the participant, or legal guardian, and this fact will be documented in the 
participant’s record. 
 


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12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, US, and international regulatory entities as part of their duties, or 
the industry supporters or designee. 
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
or the industry supporters, or other government agencies as part of their duties to ensure 
that research participants are protected.  
 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies.  Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporters prior to submission.  
 
 
14.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention and the National Institutes of Health. As TB is a 
respiratory infection, appropriate infection control procedures will be employed, as 
described in section 3.0. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  
 


 
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15.0 
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52. Blakemore R, Story E, Helb D, et al. Evaluation of the analytical performance of the 
Xpert MTB/RIF assay. J Clin Microbiol 2010;48:2495-501. 
53. Lin SY, Rodwell TC, Victor TC, et al. Pyrosequencing for rapid detection of extensively 
drug-resistant Mycobacterium tuberculosis in clinical isolates and clinical specimens. J 
Clin Microbiol 2014;52:475-82. 
54. Folkvardsen DB, Svensson E, Thomsen VO, et al. Can molecular methods detect 1% 
isoniazid resistance in Mycobacterium tuberculosis? J Clin Microbiol 2013;51:1596-9. 
55. Mardis ER. Next-generation DNA sequencing methods. Annu Rev Genomics Hum 
Genet 2008;9:387-402. 
56. Daum LT, Fourie PB, Bhattacharyya S, et al. Next-generation sequencing for identifying 
pyrazinamide resistance in Mycobacterium tuberculosis. Clin Infect Dis 2014;58:903-4. 


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57. Eilertson B, Maruri F, Blackman A, Herrera M, Samuels DC, Sterling TR. High proportion 
of heteroresistance in gyrA and gyrB in fluoroquinolone-resistant Mycobacterium 
tuberculosis clinical isolates. Antimicrob Agents Chemother 2014;58:3270-5. 
58. Colman RE, Schupp JM, Hicks ND, et al. Detection of low-level mixed-population drug 
resistance in Mycobacterium tuberculosis using high fidelity amplicon sequencing. PLoS 
One 2015;10:e0126626.  
59. Oxford Nanopore Technologies. The MinION™ device: a miniaturised sensing system. 
Accessed on February 21, 2015, at: https://nanoporetech.com/technology/the-minion-
device-a-miniaturised-sensing-system/the-minion-device-a-miniaturised-sensing-system. 
60. Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic Drugs. US Department of Health and Human Services Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics 
Evaluation and Research (CBER). [E14. International Conference on Harmonisation. 
October 2005.] 
61. Fox GJ, Benedetti A, Cox H, et al. Group 5 drugs for multidrug-resistant tuberculosis: 
individual patient data meta-analysis. Eur Respir J 2017; 49. pii: 1600993. doi: 
10.1183/13993003.00993-2016. 
62. Tang S, Yao L, Hao X, et al. Clofazimine for the treatment of multidrug-resistant 
tuberculosis: prospective, multicenter, randomized controlled study in China. Clin Infect 
Dis 2015;60:1361-7. doi: 10.1093/cid/civ027. 
63. Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture 
conversion with bedaquiline. N Engl J Med 2014;371:723-32. doi: 
10.1056/NEJMoa1313865. 
64. Ndjeka N, Conradie F, Schnippel K, et al. Treatment of drug-resistant tuberculosis with 
bedaquiline in a high HIV prevalence setting: an interim cohort analysis. Int J Tuberc 
Lung Dis 2015;19:979-85. doi: 10.5588/ijtld.14.0944. 
65. Furin J, Alirol E, Allen E et al. Drug-resistant tuberculosis clinical trials:  proposed core 
research definitions in adults. Int J Tuberc Lung Dis 2016;20:290-4.   
66. Chigutsa E, Patel K, Denti P, et al. A time-to-event pharmacodynamic model describing 
treatment response in patients with pulmonary tuberculosis using days to positivity in 
automated liquid mycobacterial culture. Antimicrob Agents Chemother 2013;57;789-95. 
67. Chiang SS, Khan FA, Milstein MB, et al. Treatment outcomes of childhood 
tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 
2014;14:947-57. doi: 10.1016/S1473-3099(14)70852-7 [doi].  
68. Seddon JA, Visser DH, Bartens M, et al.. Impact of drug resistance on clinical 
outcome in children with tuberculous meningitis. Pediatr Infect Dis J 2012;31:711-
16. doi: 10.1097/INF.0b013e318253acf8 [doi].  
69. Akkerman OW, Odish OF, Bolhuis MS, et al. . Pharmacokinetics of bedaquiline in 
cerebrospinal fluid and serum in multidrug-resistant tuberculous meningitis. Clin 
Infect Dis 2016;62:523-4. doi: 10.1093/cid/civ921 [doi].  


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70. Wager TT, Hou X, Verhoest PR, Villalobos A. Moving beyond rules: the 
development of a central nervous system multiparameter optimization (CNS MPO) 
approach to enable alignment of druglike properties. ACS Chem Neurosci 
2010;1:435-49. doi: 10.1021/cn100008c [doi]. 
71. Blennow K, Fredman P, Wallin A, et al. Protein analysis in cerebrospinal fluid. II. 
Reference values derived from healthy individuals 18-88 years of age. Eur Neurol. 
1993;33:129-33. 


 
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APPENDIX I: ASSESSMENT OF CEREBROSPINAL FLUID (CSF) CONCENTRATIONS OF 
DELAMANID AND BEDAQUILINE AMONG PARTICIPANTS WITH MDR-TB 
 
1.0 
OBJECTIVE 
 
1.1 
To measure plasma and lumbar (cerebrospinal fluid) CSF concentrations of 
delamanid (DLM) and/or bedaquiline (BDQ) (total and unbound) in up to 16 
participants (within the A5343 study) who are receiving one or both drugs 
for treatment of MDR-TB or RR-TB. 
 
2.0 
BACKGROUND 
 
Tuberculous Meningitis (TBM)  
TBM is a devastating illness, killing and disabling more patients than any other 
form of TB; particularly young children under 5 years of age [1-4]. In endemic 
regions, TBM is often the leading cause of bacterial meningitis [5]. TBM is 
characterized by a progressive granulomatous inflammation of the basal 
meninges resulting in hydrocephalus, brain infarction, and death if left untreated 
[6]. Among treated patients, outcomes are uniformly poor with mortality of 30-50% 
in adults and 20% in children; among those who survive, serious neurologic 
sequelae are common [7]. 
 
Multidrug resistant (MDR) TBM  
Drug-resistant TBM, specifically multidrug-resistant (MDR) TBM, caused by M. 
tuberculosis that is resistant to at least rifampicin and isoniazid, has especially 
poor outcomes. MDR-TBM confers a 12-fold higher risk of death in children [8]. In 
adults, infection with isoniazid monoresistant TBM results in slower clearance of 
mycobacteria from CSF but no difference in clinical response or outcomes; 
however, infection with an MDR-TB isolate results in a 12-fold higher risk of death 
[9]. In patients co-infected with MDR-TB and HIV, outcomes are especially 
frightful, with nearly 100% mortality [10, 11]. 
 
Penetration of drugs with activity against MDR-TB into central nervous system 
(CNS) and CSF 
To construct an MDR-TBM treatment regimen, a drug combination must be 
selected that has the following properties: (1) adequate penetration into CNS and 
CSF both early and late in the disease at doses that are clinically safe; (2) activity 
against most DR strains; (3) sterilizing activity (e.g., inclusion of a drug that can 
kill metabolically less-active bacilli that must be eradicated to effect cure); and (4) 
low risk of clinically relevant acquired resistance (that is, the drugs must protect 
each other from emergence of resistance). Drugs must be present at adequate 
concentrations in the CSF and CNS both early in treatment, when there is typically 
significant inflammation and the blood-CSN and blood-CSF barriers are leaky, and 
later when inflammation is reduced by treatment with steroids and antimicrobial 
therapy. 
 


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Current treatment for MDR TB and its CNS/CSF penetration 
Standard World Health Organization (WHO) recommended treatment of MDR-TB 
typically includes a fluoroquinolone, an aminoglycoside, cycloserine (or 
terizidone), and ethionamide or isoniazid plus one or both of the following: 
pyrazinamide, ethambutol. BDQ, DLM, clofazimine and/or linezolid are commonly 
used for MDR-TB with additional resistance or drug intolerance requiring a 
substitution. Fluoroquinolones, ethionamide, and cycloserine (or terizidone) have 
good-to-excellent CSF penetration. Aminoglycosides enter the CSF well but only 
when there is inflammation, thereafter penetration is poor. Linezolid achieves a 
CSF:plasma area under the concentration-time curve (AUC) ratio of 0.77 [12]. 
Patients with TBM receiving linezolid at a dose of 600 mg twice daily had quicker 
Glasgow coma scale recovery in a small clinical study of 33 patients with severe 
TBM [13]. However, linezolid dose and duration are limited by toxicities and high 
inter-patient variability. Clofazimine in CSF has not been measured.  
 
Bedaquiline and/or delamanid for CNS-TB? 
When looking at predictors of good CNS and CSF penetration, bedaquiline has 
features suggesting poor uptake including a hydrogen bond donor, large 
molecular weight, high protein binding, and a high distribution co-efficient. Animal 
studies found low CNS tissue uptake of the drug (Janssen IB). BDQ CSF 
concentrations have only been measured in one patient with MDR-TBM. Drug 
concentrations collected via a lumbar drainage system after 5 weeks of dosing 
were undetectable at all time points following an observed dose [12].  
 
DLM has never been measured in human CNS or CSF, but there are 
characteristics of its structure that would suggest it has a reasonably high 
likelihood of achieving satisfactory concentrations in these matrices. DLM is a 
large polar molecule, it has no hydrogen bond donors, and it has some molecular 
characteristics in common with antipsychotics, which suggest good penetration 
[13]. Negative features for CSF and CNS penetration include high protein binding 
(97-99% in man) and a distribution coefficient of 4.4 at pH of 7.4 (<2 is most 
desirable). Animal studies showed penetration into the brain following 
administration of 14C-delamanid. In in vitro experiments, DLM was not a substrate 
of P-glycoprotein (P-gp; also known as MDR1), but its metabolite (which does not 
contribute meaningfully to activity but has a modest association with QT 
prolongation) is a P-gp substrate (Otsuka IB); DLM is, thus, not likely to be 
actively pumped out of CSF via P-gp.  
 
Therefore, DLM has characteristics that make us think it is quite likely to cross the 
blood-CNS and blood-CSF barriers and be active in those compartments. If so, 
DLM could be an anchor drug for MDR-TBM and potentially a companion drug for 
drug-sensitive TBM, given rifampicin’s poor CNS and CSF penetration and DLM’s 
sterilizing activity. BDQ may not penetrate meaningfully into CSF, but this 
requires confirmation. 
 


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3.0 
RATIONALE 
 
A5343 participants will not have meningitis with inflamed and thus more 
penetrable blood-CNS and blood-CSF barriers. Therefore, CSF concentrations will 
most meaningfully reflect those achieved later in MDR-TBM treatment when 
antibiotics and steroid treatment have largely restored the integrity of these 
barriers. This is a time in treatment when TB drugs must continue to penetrate the 
CSF/CNS in adequate concentrations to kill M. tuberculosis and cure the patient. 
Therefore, these values will be clinically relevant. Further, in the future, this data 
can be paired with early CSF data from patients with MDR-TBM (or from relevant 
alternative models) in other studies. MDR-TBM is relatively rare (so challenging to 
recruit), therefore clinicians are unlikely to prescribe BDQ or DLM to patients with 
MDR-TBM without some evidence that it penetrates into CSF/CNS, thus late PK 
assessments in MDR-TBM may not occur because of the tragically high early 
mortality in this population. This nested study will maximize the contribution of 
the PK-data accumulated in A5343 to advance what is known about BDQ and DLM 
in MDR-TB.  
 
 
4.0 
HYPOTHESES AND ANALYSES 
 
4.1 
Exploratory Hypotheses 
 
4.1.1 Administration of BDQ and/or DLM for a minimum of 8 weeks in 
patients with RR or MDR pulmonary TB, without TB meningitis, will 
result in measurable drug concentrations (total and unbound) in the 
CSF. 
 
4.1.2 BDQ and/or DLM CSF levels will follow a similar concentration curve 
to that found in plasma. 
 
4.2 
Primary Analyses 
 
4.2.1 Total concentration of BDQ and/or DLM will be measured in plasma 
and CSF by mass spectrometry. If total concentration in CSF is 
measurable, unbound concentration in plasma will be measured 
where possible to evaluate differences in measures of exposure of 
the respective drugs.   
 
4.3 
Secondary Analyses 
 
4.3.1 Nonlinear mixed-effects modeling will be used to describe the 
partition coefficient and half-life of the distribution between plasma 
to CSF. Thereafter CSF area under the curve (AUC) will be estimated 
for each individual and this information may be used for further 


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analysis in comparison with plasma parameters. 
 
5.0 
EVALUATIONS 
 
This optional procedure is open to participants currently enrolled under Version 
3.0 who have not yet completed week 22 and new participants enrolling into 
Version 4.0. Participants currently enrolled under Version 3.0 will need to be re-
consented to Version 4.0 in order to be approached regarding the optional LP. 
 
The intent is to have between 8-16 participants consent into Version 4.0 and 
participate in the optional LP procedure. Participant selection of the optional LP 
evaluation will be captured on a tracking CRF. Because the form is not available in 
real time, such accounting is approximate. The sites and the Protocol Data 
Manager will be in close contact to determine when 16 participants have had the 
LP evaluation. Once determined, additional participants will no longer be 
approached to consent for the LP. The intent is to have a total of eight participants 
contribute CSF PK data for BDQ (Arms 1 and 3) and eight participants contribute 
PK data for DLM (Arms 2 and 3), where Arm 1 = BDQ plus multidrug background 
therapy (MBT), Arm 2 = DLM plus MBT, and Arm 3 = BDQ and DLM plus MBT. At 
either the week 8 or week 24 visit, when the participants have an already-
scheduled intensive plasma PK, a LP will be performed so that BDQ and/or DLM 
(total and unbound) concentrations can be measured in CSF. LP timing post-dose 
will be different for each participant. LP timing will occur in close proximity to a 
plasma PK sampling time so that CSF:plasma ratios can be determined at 
different time points over the dosing interval.  
 
If a participant consents to undergo the optional LP but does not meet the 
requirements of the pre-LP assessments, or withdraws consent prior to LP, the 
participant will not be included in this nested study and will be replaced within 
this nested study. 
 
For BDQ, CSF samples will be collected at either 6, 8, or 11-hour plasma PK. The 
BDQ concentration is expected to be low and therefore the 23-hour plasma PK 
sample will not have a corresponding CSF sample. For DLM, CSF samples will be 
collected at either 4, 8, or 11 hours post-dose. The 11-hour plasma concentration 
for DLM is expected to be the same as the 23-hour plasma concentration as DLM 
is dosed 12 hourly and therefore the 23-hour plasma sample will not have a 
corresponding CSF sample. Participants will be spread evenly across sampling 
times until an estimated two to three participants per drug per time point to a total 
of eight samples per drug has been achieved. 
 
Participants will be evaluated for contraindications to LP. Safety bloods, including 
a complete blood count (CBC) and international normalized ratio (INR), will be 
performed through an ACTG-approved laboratory at the assessment visit prior to 
the LP either at week 7 or week 22. Participants who have a coagulopathy defined 
as platelets <100/mm3 and/or INR >1.4 times the ULN, or other known 
contraindications to LP, in the opinion of the investigator, will not be considered 


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for the LP. The week 8 visit will be preferable for the LP. If the participant has 
already passed week 8 or is not able to undergo an LP at week 8, the participant 
will be reassessed for inclusion for the week 24 visit. If the participant is unable to 
participate given the pre-LP assessments (see section 6.3.10) conducted at week 
7, then these assessments will need to be repeated at the week 22 visit. 
Otherwise, safety bloods will only be done at one time point. 
 
PK modeling will be performed to describe drug penetration into CSF and drug 
exposures over time with oral dosing. Approximately 5-10 mL of CSF will be 
collected from each participant, the sample will be used for PK analysis, and the 
remaining CSF will be stored, in case measurement of companion drugs should 
be of scientific interest in the future. While no meningeal inflammation is expected 
in this population, CSF albumin will be quantified and the CSF/serum albumin 
ratio calculated as a marker of inflammation, which may affect the penetration of 
the drugs [14]. 
 
LABORATORY CONTACT INFORMATION FOR THE ABOVE TESTING 
 
UCT SHIPPING ADDRESS FOR PK SAMPLES 
Jennifer Norman/Shameema Witbooi 
K50 Division of Clinical Pharmacology 
Old Main Building, Groote Schuur Hospital 
Observatory, 7925 
Cape Town, South Africa 
Phone (021) 404 7695 
Fax (086) 669 1348 
Email: Jennifer.Norman@uct.ac.za/Shameema.witbooi@uct.ac.za  
LDMS lab code: 499 
 
6.0 
REFERENCES 
 
1. Arnold F, Parasuranman S, Arokiasamy P, Kothari M. Nutrition in India. National 
Family Health Survey (NFHS-3), India, 2005-06. Mumbai: International Institute for 
Population Sciences; Calverton, Maryland, USA, 2009.  
2. Berenguer J, Moreno S, Laguna F, et al. Tuberculous meningitis in patients 
infected with the human immunodeficiency virus. N Engl J Med 1992;326:668-72. 
doi: 10.1056/NEJM199203053261004.  
3. Cegielski JP, McMurray DN. The relationship between malnutrition and 
tuberculosis: evidence from studies in humans and experimental animals. Int J 
Tuberc Lung Dis 2004;8:286-98.  
4.  Thwaites G, Chau TT, Mai NT, Drobniewski F, McAdam K, Farrar J. Tuberculous 
meningitis. J Neurol Neurosurg Psychiatry 2000;68:289-99.  
5.  Chiang SS, Khan FA, Milstein MB, et al. Treatment outcomes of childhood 
tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 
2014;14:947-57. doi: 10.1016/S1473-3099(14)70852-7 [doi].  
6. Seddon JA, Visser DH, Bartens M, et al.. Impact of drug resistance on clinical 
outcome in children with tuberculous meningitis. Pediatr Infect Dis J 2012;31:711-


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16. doi: 10.1097/INF.0b013e318253acf8 [doi].  
7. Thwaites GE, Lan NT, Dung NH, et al. Effect of antituberculosis drug resistance on 
response to treatment and outcome in adults with tuberculous meningitis. J Infect 
Dis 2005;192:79-88. doi: 10.1086/430616.  
8.  Tho DQ, Torok ME, Yen NT, et al. Influence of antituberculosis drug resistance and 
Mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous 
meningitis. Antimicrob Agents Chemother 2012;56:3074-9. doi: 
10.1128/AAC.00319-12 [doi].  
9. Daikos GL, Cleary T, Rodriguez A, Fischl MA. Multidrug-resistant tuberculous 
meningitis in patients with AIDS. Int J Tuberc Lung Dis 2003;7:394-8.  
10. Luque S, Grau S, Alvarez-Lerma F, et al. Plasma and cerebrospinal fluid 
concentrations of linezolid in neurosurgical critically ill patients with proven or 
suspected central nervous system infections. Int J Antimicrob Agents 
2014;44:409-15. doi: 10.1016/j.ijantimicag.2014.07.001 [doi]. 
11. Sun F, Ruan Q, Wang J, et al. Linezolid manifests a rapid and dramatic therapeutic 
effect for patients with life-threatening tuberculous meningitis. Antimicrob Agents 
Chemother 2014;58:6297-301. doi: 10.1128/AAC.02784-14 [doi].  
12. Akkerman OW, Odish OF, Bolhuis MS, et al. . Pharmacokinetics of bedaquiline in 
cerebrospinal fluid and serum in multidrug-resistant tuberculous meningitis. Clin 
Infect Dis 2016;62:523-4. doi: 10.1093/cid/civ921 [doi].  
13. Wager TT, Hou X, Verhoest PR, Villalobos A. Moving beyond rules: the 
development of a central nervous system multiparameter optimization (CNS MPO) 
approach to enable alignment of druglike properties. ACS Chem Neurosci 
2010;1:435-49. doi: 10.1021/cn100008c [doi]. 
14. Blennow K, Fredman P, Wallin A, et al. Protein analysis in cerebrospinal fluid. II. 
Reference values derived from healthy individuals 18-88 years of age. Eur Neurol. 
1993;33:129-33. 
 
 


 
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APPENDIX II: SAMPLE INFORMED CONSENT 
 
Division of AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
For protocol A5343 
 
 A Trial of the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone 
and in Combination, among Participants Taking Multidrug Treatment for Drug-Resistant 
Pulmonary Tuberculosis 
 
SHORT TITLE FOR THE STUDY: Bedaquiline and Delamanid for Multidrug-Resistant 
Tuberculosis 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you have tuberculosis that is 
resistant to some of the drugs generally used to treat it (which is known as multidrug resistant 
tuberculosis or MDR-TB) or you have tuberculosis that is resistant to an anti-tuberculosis drug 
call rifampin (which is known as rifampin monoresistant tuberculosis or RR-TB). This study is 
sponsored by the National Institutes of Health (NIH).  The doctor in charge of this study at this 
site is: (insert name of Principal Investigator). Before you decide if you want to be a part of this 
study, we want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
Current drug treatments for MDR-TB and RR-TB are not well tolerated and patients on these 
drugs often have a lot of side effects. Bedaquiline and delamanid are newly approved anti-TB 
drugs and are both well tolerated. However, the combined effects of these two drugs have not 
been studied. The main purpose of this study is to determine if these two anti-TB drugs can be 
safely used together. This study will specifically look at the effect of the drugs on your heart, 
since both of these drugs have an effect on the electrical activity of the heart. The study will also 
look at the levels of these drugs in your blood and whether taking them together affects these 
levels. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to join this study, you will be expected to be in the hospital for at least the first 2 
weeks of the study, so that you may be monitored closely. You would be hospitalized longer 
than 2 weeks if you are too ill to leave the hospital. 
 


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During the study, you will have screening and entry visits, weekly visits for 8 weeks after you 
enter the study, visits every other week until week 24, and eight additional visits between weeks 
25 and 128. The schedule of visits and study procedures are explained in Appendix II-A. 
 
If you do not join the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of this screening visit, some demographic (for 
example, age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory 
(for example, CD4 cell count if you are HIV-positive) information is being collected from you so 
that ACTG researchers may help determine whether there are patterns or common reasons why 
people do not join a study. 
 
If you enter the study 
At the study entry visit, you will be assigned to one of three treatment groups. Participants in 
groups A, B, and C will receive bedaquiline, delamanid, or both drugs in combination (group C), 
for 24 weeks together with your non-study medications prescribed to treat your TB (multidrug 
background treatment [MBT]): 
 
 
Because your assignment is random, like the flip of a coin, you will have an equal chance of 
being in one of the three groups. You will not be able to choose your group, but you and the 
study doctor, as well as the study staff, will know which group you are in.  
 
The MBT will include at least 3 drugs to which your tuberculosis infection is thought or known to 
be sensitive. You will need to take or have been taking these drugs for at least 7 days within the 
10 days before your study entry visit. There are two possible options for the MBT. In some 
countries, a longer course of treatment for MDR-TB or RR-TB is given that lasts for up to 24 
months. In other countries, a shorter course lasting for 9-12 months may be given. In the shorter 
course, a medicine called clofazimine is used. This medicine can cause the same side effects 
as bedaquiline and delamanid. This side effect is an increase in the QT interval (a measure of 
the heart’s electrical cycle). As we want to measure accurately the effect of bedaquiline and 
delamanid on your heart, you will not be given clofazimine until you have finished your 
bedaquiline and/or delamanid. While we cannot be sure, we think that bedaquiline and 
delamanid are as good as clofazimine in killing TB. 
 
If you are infected with HIV (the virus that causes AIDS), your doctor will talk with you about the 
best options for treating your HIV if you join the study. If you are taking anti-HIV drugs that are 
Group A: 
Bedaquiline + MBT 
Group C: 
Bedaquiline + 
Delamanid + MBT 
Study Entry 
Group B: 
Delamanid + MBT 


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not recommended to be used with the TB drugs used in this study, the doctor may advise you to 
change your HIV drug treatment and may advise you to use an anti-HIV drug called 
dolutegravir. If so, this drug will be provided to you by the study. 
 
In addition, you will be asked to have a small sample of hair (about 50-100 strands) cut from 
your head so that we can measure levels of the TB drugs in this small hair sample.  Levels in 
hair may give us a better idea of long-term exposure to a drug. Of note, humans lose about 100 
hairs from their head every day naturally, so this amount of hair removal should not be 
noticeable. Results of this testing will not be available to you. 
 
At any visit prior to and including week 22, you may be asked to take part of a CSF 
(cerebrospinal fluid) sampling study (within A5343). CSF is the fluid that surrounds your 
brain and spinal cord. If you agree to take part of this CSF sampling study, you will have 
optional lumbar puncture done at weeks 8 or 24. You will be asked to sign a separate 
consent form for this optional procedure.  
 
Other 
If you agree, some of your blood that is left over after all required study testing is done may be 
stored (with usual protections of your identity) and used for future ACTG-approved research that 
is separate from this study. Genetic testing will not be done on these blood samples. Samples 
collected from you will be stored in the US. These samples may be stored for an indefinite 
period of time. Results of testing performed on these samples will not be given to you. You may 
withdraw your consent for research on stored specimens at any time and the specimens will be 
discarded. No matter what you decide, it will not affect your participation in the study. 
 
________ YES, I agree to have my leftover blood stored.  
 
________ NO, I do not agree. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 84 people will take part in this study 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 2 years.   
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early if: 
• 
You request to be taken off the study. 
• 
The study is stopped or cancelled.  
• 
Your primary care provider thinks the study is no longer good for you. 
 


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The study doctor may also need to take you off the study drug(s) without your permission if: 
• 
You fail to attend 3 consecutive study visits. 
• 
Continuing the study drug(s) may be harmful to you. 
• 
You need a treatment that you may not take while on the study. 
• 
You are a woman who becomes pregnant or is breast-feeding. 
• 
You are not able to take the study drug(s) as required by the study. 
 
If you must stop taking the study drug(s) before the study is over, the study doctor may ask you 
to continue to be part of the study and return for some study visits and procedures. 
 
 
IF I HAVE TO PERMANENTLY STOP TAKING STUDY-PROVIDED BEDAQUILINE, 
DELAMANID AND/OR DOLUTEGRAVIR, OR ONCE I LEAVE THE STUDY, HOW WOULD 
THESE STUDY DRUGS BE PROVIDED? 
 
During the study: 
If you must permanently stop taking study-provided bedaquiline, delamanid, and/or dolutegravir 
before your study participation is over, the study staff will discuss other options that may be of 
benefit to you.  
 
After the study: 
After you have completed your study participation, the study will not be able to continue to 
provide you with bedaquiline, delamanid, and/or dolutegravir that you received on the study. If 
continuing to take these or similar drugs/agents would be of benefit to you, the study staff will 
discuss how you may be able to obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. Many of the side 
effects of the study TB drugs have similar side effects as other treatments you would receive for 
your TB infection. If you have questions concerning the additional study drug side effects, 
please ask the medical staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Risks of Anti-TB Medications 
Some medications used to treat TB may be associated with diarrhea/loose or watery bowels, 
including bloody diarrhea, which may be serious. 
 


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Bedaquiline 
The most common side effects of bedaquiline are: 
• 
headache  
• 
dizziness with change in position 
• 
diarrhea 
• 
nausea 
• 
joint pain 
• 
increase of a chemical called uric acid in the blood, which may be associated with an 
increased risk of joint pain or gout, a type of arthritis.   
• 
vomiting 
• 
increase in the QT interval (a measure of the heart’s electrical cycle). A prolonged QT 
interval may increase the risk of heart rhythm disturbances, which in rare cases, may be 
fatal. You should tell your doctor if you have had heart problems, including a slow heart rate, 
or had low thyroid hormone levels. You will have periodic ECGs (electrocardiograms) to 
monitor the electrical activity of your heart including QT interval.  
• 
elevations in some liver tests called transaminases. You should not drink alcohol while you 
are taking study medication or other TB drugs as alcohol may also cause elevation of liver 
tests.   
• 
inflammation of the nose and/or throat 
 
An increased risk of death was seen in the bedaquiline treatment group (9 out of 79 participants, 
11.4%) compared to the placebo treatment group (2 out of 81 participants, 2.5%) in one 
placebo-controlled study. The participants taking bedaquiline died from many different causes 
and it is unclear if the events were related to bedaquiline. No participant died because of a large 
increase in the QT interval. 
 
In another later study, there was an increased risk of kidney damage because of vomiting and 
dehydration from bedaquiline.  
 
As of 30 April 2014, bedaquiline, when taken together with other TB drugs, has been approved 
to treat difficult adult cases of MDR-TB in the United States, Europe, and South Africa and all 
adult cases of MDR-TB in Russia and South Korea. 
 
Delamanid 
The most common side effects of delamanid are: 
• 
nausea or vomiting 
• 
abdominal discomfort 
• 
headache 
• 
tiredness 
• 
anxiety or depression 
• 
rash 
• 
joint pain 
• 
decreased blood counts 
• 
increase in the QT interval  
• 
liver disease 
• 
fever 


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• 
chest pain 
• 
jaundice (yellowing of the skin or whites of the eyes) 
 
These adverse events could have been due to delamanid, the disease TB itself, other 
medications, or the development of other illnesses.  
 
As of December 2014, delamanid, when taken together with other TB drugs, has been approved 
to treat MDR-TB in Europe, Japan, and South Korea. 
 
For your safety, you will have blood tests and an ECG performed before you are allowed to 
participate in the study and receive study treatment with bedaquiline or delamanid or both, and 
you will have regular ECGs during the trial to watch for any important changes. If important 
changes in QT interval are found in your ECG, study TB drugs will be stopped immediately. You 
may be hospitalized for monitoring. Although cases of lengthened QT interval have happened 
before, no patients experienced any harm from it.  
 
Risks of Combination Antiretroviral Drugs Used to Treat HIV Infection 
 
Immune Reconstitution Syndrome:  
In some people with advanced HIV infection, symptoms from other infections or certain 
diseases may occur soon after starting combination anti-HIV treatment but can also occur later. 
Some of these symptoms may be life threatening. If you start having new symptoms, or notice 
that existing symptoms are getting worse after starting your antiretroviral therapy, tell your 
healthcare provider right away. 
 
The use of potent antiretroviral drug combinations may be associated with an abnormal 
placement of body fat and wasting. Some of the body changes include: 
• 
increase in fat around the waist and stomach area 
• 
increase in fat on the back of the neck 
• 
thinning of the face, legs, and arms 
• 
breast enlargement 
 
Dolutegravir 
Recently, some new information about DTG from another study being done in Botswana 
was reported. This study found that women taking DTG when they became pregnant 
appeared to be more likely to have babies with an abnormality called a neural tube defect 
than women who were taking other HIV medicines when they became pregnant. A neural 
tube defect is an abnormality of the spine or brain that can be severe. This abnormality 
can cause babies to die. Neural tube defects usually happen in about 1 out of every 1000 
babies. In the Botswana study, neural tube defects were found in about 1 out of 100 
babies born to women who were taking DTG when they became pregnant. A baby’s 
neural tube is formed in the first 4 weeks after pregnancy. In the Botswana study, no 
neural tube defects were found in babies born to women who started taking DTG in 
pregnancy, after the neural tube had formed. The drug company and regulatory 
authorities and different researchers are looking into this issue to see if DTG really does 
cause neural tube defects. In the meantime, the US FDA and other groups have 
recommended that women who are going to start DTG have a pregnancy test first. They 


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also recommend that women use birth control to prevent pregnancy while taking DTG. 
HIV-infected women who are able to become pregnant are allowed to participate in this 
study, but they must use a method of birth control in order to not become pregnant while 
taking DTG from the following list: 
• 
Contraceptive subdermal implant 
• 
Intrauterine device (IUD) or intrauterine system 
• 
Combined estrogen and progestogen oral contraceptive  
• 
Injectable progestogen (Depo-Provera) 
• 
Contraceptive vaginal ring  
• 
Percutaneous contraceptive patches 
 
If you do become pregnant while on study and taking DTG, you must call the study 
doctor right away. 
 
Side Effects 
The following serious side effects have been associated with the use of dolutegravir.  
These include allergic reactions and liver problems, which may be life-threatening.  
 
Contact your health care provider right away if you develop a rash while taking 
dolutegravir, especially if it’s associated with any of the following symptoms: 
 
• 
Fever 
• 
General ill feeling 
• 
Extreme tiredness 
• 
Muscle or joint aches 
• 
Blisters or sores in your mouth 
• 
Blisters or peeling skin 
• 
Redness or swelling of your eyes 
• 
Swelling of your mouth, face, lips, or tongue 
• 
Trouble breathing 
• 
Common cold (nasopharyngitis) 
• 
Diarrhea 
 
Contact your health care provider right away if you have any of the following symptoms 
that could be signs of liver problems: 
 
• 
Yellowing of your skin or whites of your eyes (jaundice) 
• 
Dark or tea-colored urine 
• 
Pale-colored bowel movements 
• 
Nausea or vomiting 
• 
Loss of appetite 
• 
Pain, aching, or tenderness on your right side below your ribs 
 
People with pre-existing history of depression or other mental health illness may be at 
greater risk for suicidal thoughts, or attempts, which may lead to death.  If your mental 
health illness worsens, or if you develop suicidal thoughts, call your healthcare provider 


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right away. 
 
Other side effects include: 
• 
Changes in liver test results, more common in people with hepatitis B or C 
• 
Trouble sleeping 
• 
Tiredness 
• 
Headache 
 
Tell your study doctor about any side effect that bothers you or that does not go away. 
 
Risks of Non-Study Medications 
There is a risk of side effects when non-study medications are taken with bedaquiline, 
delamanid, and dolutegravir. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. In addition, you must tell the study doctor or nurse before 
enrolling in any other research studies while on this study. 
 
Risks of Drawing Blood  
Taking blood may cause some discomfort, bleeding, bruising, and/or swelling where the needle 
enters the body, lightheadedness, and in rare cases, fainting or infection.  
 
Risks of ECG 
You may experience mild irritation, slight redness and itching on your skin where the electrodes 
from the electrocardiogram machine are placed. 
 
Risks of Hair Collection 
There is a small risk of cutting or nicking the scalp during the hair collection, although this is 
extremely rare. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV or TB 
status secret from people close to you. This may lead to unwelcome discussions about or 
reactions to your HIV or TB status. Please talk with the study staff if you have any concerns in 
this regard. 
 
Risks to Stored Samples  
There is a risk that your stored samples and/or health information may be misused. There are 
laws against this kind of misuse, but they may not fully protect you. The chance that this will 
happen is considered small because of the security taken with your samples and information.  
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
Bedaquiline and delamanid may be unsafe for unborn babies. If you are having sex that could 
lead to pregnancy, you must agree not to become pregnant or to impregnate your partner while 


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you are taking bedaquiline and/or delamanid and for 6 months after stopping the study drug(s). 
You must use one of the following methods of birth control that you discuss with the study staff: 
• male or female condoms  
• diaphragm or cervical cap with a cream or gel that kills sperm 
• intrauterine device (IUD) 
• oral contraceptives or Depo-Provera  
 
If you become pregnant while taking part in this study, you will continue to be followed on the 
study and your pregnancy outcome will be recorded. If you are taking antiretroviral therapy 
(ART) for treatment of Human Immunodeficiency Virus (HIV), your pregnancy will be reported to 
the Antiretroviral Pregnancy Registry. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made. It is also possible that you may receive no benefit from being in this study. Information 
learned from this study may help others who have tuberculosis. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
treatment with prescription drugs available to you 
• 
treatment with experimental drugs, if you qualify  
• 
no treatment 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the ACTG, OHRP, FDA, (insert name of site) Institutional 
Review Board (IRB) or Ethics Committee (EC), National Institutes of Health (NIH), other local, 
US, and international regulatory entities, study staff, study monitors, and drug companies 
supporting this study. An IRB or EC is a committee that watches over the safety and rights of 
research participants. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. 
law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.  
 


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WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study.   
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You may be reimbursed for your time and travel expenses as part of your participation in this 
study. (Insert site-specific information about payment.)  
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the National Institutes of 
Health. You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
• 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
telephone number of above 
 


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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
_______________________________         __________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
_______________________________         ___________________________________ 
Participant’s Legal Representative (print) 
Legal Representative’s Signature and Date 
(As appropriate) 
 
 
______________________________ 
___________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
______________________________ 
___________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 


 
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APPENDIX II-A: A5343 STUDY VISITS 
 
The study staff can answer any questions you have about individual study visits, how long they 
will last, or about the tests that will occur. The table below can be used as a quick reference for 
you, along with the explanations that follow. 
 
I. 
Study Schedule 
 
Evaluation or 
Procedure 
Screening1 
Entry2 
 
Start of 
TB Study 
Drug3 
Visits in 
First 24 
Weeks4 
Follow-up 
Visits5 
Early 
Treatment 
or Study  
Discontin-
uation6 
Consent & 
contact 
information 
collected 
√ 
 
 
 
 
 
HIV status 
checked 
√ 
 
 
 
 
 
Physical exam 
√ 
√ 
√ 
√ 
√ 
√ 
Blood 
collected (see 
blood tests 
below) 
√ 
√ 
 
√ 
√ 
 
Pregnancy 
test7 
√ 
 
 
If needed 
If needed 
If needed 
Pre-lumbar 
puncture (LP) 
assessments 
and optional 
LP8 
 
 
 
√ 
 
 
Urinalysis 
 
√ 
 
 
 
 
Sputum 
collected 
√ 
√ 
 
√ 
√ 
√ 
Hair collected 
 
√ 
 
√ 
√ 
 
Chest x-ray 
√ 
 
 
 
 
 
ECG 
√ 
√ 
 
√ 
√ 
√ 
Adherence 
questions 
 
 
 
√ 
 
√ 
1Screening Visit: After you have read and signed the consent form, you will have several tests 
done to make sure that you meet the requirements for joining the study. 
2Entry Visit: If you are able to join the study, you will enter the study and receive your treatment 
assignment. At this visit, you will find out if you receive bedaquiline, delamanid, or both drugs in 
combination. 
3Start of TB Study Drug: This visit may occur at entry or within 7 days after entry. You will start 
your TB study drug at this visit.  
4Visits in First 24 Weeks: You will have a visit every week for 8 weeks after you start TB study 
drug and then every other week until 24 weeks after the entry visit. This is the treatment period, 
during which you will receive study drugs. You will be hospitalized for at least the first 2 weeks of 
the treatment period. 
5Follow-up Visits: After the first 24 weeks, you will have visits at weeks 28 and 36, every 12 
weeks until week 96, and at week 128. 
6Early Treatment or Study Discontinuation: If you stop the study drug early, you will be asked to 


 
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come in for an early treatment discontinuation visit. 
7Women of reproductive potential who are taking dolutegravir will be required to have 
pregnancy testing every two weeks during the first 24 weeks (i.e., weeks 2-24) and during 
follow-up study visits at weeks 28, 36, 48, 60, 72, 84, 96, and 128. 
8Not all participants will have an LP to collect cerebrospinal fluid (CSF) done at week 8 or 
24. Only participants who are asked and wish to participate in the LP for CSF collection, 
and complete a separate consent form (see Appendix III), will have an LP done. Pre-LP 
assessments are required prior to the optional LP for participants who consent to have the 
LP done. 
 
II. 
Explanation of Evaluations  
 
Below are descriptions of the evaluations. You will be told the results of all tests performed 
with the exception of those tests to look at the levels of study drugs in your body and for 
future ACTG-approved testing. 
 
Consent and contact information collected  
After you read the consent and have had a chance to ask questions about the study, you 
will sign the consent form if you want to continue and join the study. You will also be asked 
how to be contacted in case you miss a visit or there are problems with your tests, and 
whether you give the study team permission to contact you. 
 
HIV-1 infection status checked 
If there is no record available, another HIV-1 test will be done. If an HIV-1 test has to be 
done, you may have to sign a separate consent form before this is done. You will be told 
the results of the HIV-1 test as soon as it is available.   
 
Physical examination 
You will have a physical exam and will be asked questions about your health and about 
any medicines you have taken or are taking now. At entry and weeks 4, 8, 12, 16, 20, and 
24, your vision will also be checked if you are taking the anti-TB drug ethambutol. 
 
Blood collected  
Between 5 and 60 mL (1 teaspoon to 4 tablespoons) of blood may be collected at any one 
visit. Blood will be collected from you for various tests during the study including:  
 
Hematology, chemistry and liver function tests 
These are routine blood tests for safety. You will have blood for some or all of these 
routine tests drawn at every visit through week 28.  
 
Hepatitis B surface antigen  
This test shows if you are infected with hepatitis B. You will have blood drawn for this test 
at screening.  
 
Hepatitis C antibodies 
This test shows if you have been infected with hepatitis C. You will have blood drawn for 
this test at screening. 
 
Thyroid Stimulating Hormone 
This test shows how well your thyroid gland is working. You will have blood drawn for this 


 
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test at entry and week 12.  
 
HIV-1 viral load 
This is a test that shows how much HIV is in your blood. If you are infected with HIV-1, you 
will have blood drawn for this test at entry, week 24, and week 48. If you have been on  
anti-HIV drugs for 6 months or longer, you will also have this test at screening and 
possibly also at entry.  
 
HIV-1 genotype 
This test is used to determine if the HIV in your blood has genetic mutations that are 
known to cause resistance to certain anti-HIV drugs. You will have this test at screening if 
you have been on anti-HIV for 6 months or longer and have an HIV-1 viral load at 
screening that shows the level of HIV in your blood is high enough for the genotype to be 
done.  
 
CD4+ count 
This is a test that shows how many infection-fighting cells you have in your blood. If you 
are infected with HIV-1, you will have blood drawn for this test at screening and weeks 24 
and 48. 
 
Pharmacokinetic sampling 
These tests look at the levels of the anti-TB drugs in your body. You will have blood drawn 
for these tests at weeks 4, 6, 10, 12, 14, 16, 18, 20, 22, and 28. In addition, you will have 
blood drawn for intensive pharmacokinetic (PK) testing at weeks 2, 8, and 24. During 
these visits, five  
or six PK blood samples will be taken over a 24-hour period. These blood samples will be 
collected from an indwelling catheter in your arm, if one can be placed and maintained 
successfully. 
 
Pharmacogenomic analyses 
Some blood will be collected and stored to look at how a person’s genes affect their 
response to drugs. 
 
Pregnancy test  
Women who are able to become pregnant, you will be asked to give a small urine or blood 
sample (about 5 mL or 1 teaspoon) for a pregnancy test at screening and at other times 
during the study, if you think you might be pregnant. Women receiving dolutegravir for 
treatment of HIV infection will have more regular testing for pregnancy (at every 
scheduled study visit).   
 
Pre-Lumbar Puncture (LP) Assessments and Optional LP 
You may be asked to participate in an optional LP to collect your CSF. If you agree, 
you will have safety bloods done approximately one week prior to the LP. The LP 
will be done as described in Appendix III.  
 
Urinalysis 
You will be asked to provide a sample of urine at entry. 
 
Sputum collected  


 
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You will be asked to provide sputum samples at screening, weeks 0-12, 16, 20, 24, 28, 36, 
48, 84, 96, and 128. To provide this sample, you will be asked to cough deeply and then 
spit into a cup. If you need help to cough deeply, the clinic staff may ask you to briefly 
breathe a mist of saltwater through a tube or a mask. At some visits, these samples will be 
used for TB drug susceptibility tests, to see if your tuberculosis infection responds to TB 
drugs. Some of your sputum may be stored.   
 
Hair Collected 
You will have a small sample of hair (about 50-100 strands) cut from your head to 
measure levels of the TB drugs in this small hair sample. You will have a hair sample 
taken at entry and weeks 8, 16, 24, 48, 72, 96, and 128. 
 
Chest x-ray  
You will have a chest x-ray at screening.  
 
ECG 
You will have electrocardiograms to look at the electrical activity of your heart. These tests 
will be done at screening, at entry one day prior to TB study treatment or on the day you 
start TB study treatment, every 2 weeks for 24 weeks during TB study treatment, at week 
28, and if you discontinue study treatment or the study early. If you discontinue the study 
treatment after week 28, an ECG is not required at the early treatment or study 
discontinuation visit.  
 
Adherence questions 
While you are taking study drugs, you will be asked questions about how well you 
remember to take the study drugs every week between weeks 1-8, every 2 weeks 
between weeks 10 and 24, and if you stop the study drugs or the study early. You will also 
be given pill boxes for your study drugs. Study staff or others approved by the study staff 
will watch you take one of your study drugs for some of your doses. This is called directly 
observed therapy or DOT. If you are on bedaquiline, this DOT will be done once a day in 
the morning 7 days per week for 2 weeks and then 3 days per week for 22 weeks. If you 
are on delamanid or both bedaquiline and delamanid, DOT will be done once a day in the 
morning on your delamanid dose 7 days per week for 2 weeks and then 5 days a week for 
22 weeks. After week 24, study DOT supporters or others approved by the study staff will 
watch you take one of your study drugs twice each week.  


 
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APPENDIX III: CONSENT FOR OPTIONAL LUMBAR PUNCTURE (LP) AT WEEK 8 OR 24 
 
At any visit prior to and including week 22, you may be asked and consented to take part 
in an optional LP that will be done at week 8 or 24. This optional procedure (as described 
below) will advance the scientific goals of this study but will offer no direct benefit to 
participants. Up to 16 participants will take part in the optional LP. If you are one of the 
16 participants who agrees to have this procedure, neither you nor your doctor will 
receive any results from the procedures because the tests are for research purposes 
only. If you are asked and choose not to participate in the optional procedures, it will not 
affect your ability to take part in this study (A5343).   
 
NOTE: If you are pregnant, the LP will not be done.  
 
A. 
Explanation of LP 
 
Participants undergoing a LP must have safety bloods (CBC/INR) performed, 
along with an assessment of medical history approximately one week prior to 
your LP. The LP will be done at your week 8 or 24 visit. A LP is a medical 
procedure that involves removing a small amount of cerebrospinal fluid (CSF) 
from your spine. You should drink plenty of fluids the day before the LP 
procedure. The procedure will be performed at [insert site-specific details]. You 
will be asked to lie down on your side or to sit “backwards” in a chair (so that you 
are facing the back of the chair). An area of skin on your lower back will be 
sterilized with fluid. You will get an injection to numb the skin in the sterilized 
area. You may feel a burning sensation from the fluid that is injected. When the 
area is numb, the doctor will insert a thin needle between two of the bones in your 
spine. Approximately 5-10mL of CSF will be collected through the needle. The 
entire LP procedure will take about 30 minutes.  
 
After the CSF collection, you may be asked to lie flat for up to 30 minutes to 
reduce the chance that you will get a headache. You should limit your physical 
activity for the remainder of the day. The study or clinic staff will call you the day 
after the procedure to check on how you are feeling. 
 
B. 
Risks Associated with LP 
 
The risks of LP include local soreness at the site of needle entry, and pain and 
possible allergic reaction associated with local anesthesia. There is a small risk of 
headache or decreased blood pressure from removing the small amount of fluid 
or leaking of CSF after the procedure. There is a small risk of infection and a very 
small risk of damage to nerves in the lumbar spinal roots after the procedure, 
which could cause pain, numbness, or loss of sensation to the legs. Before the 
procedure, the area where the needle will be inserted will be cleaned with an 
antiseptic (such as betadine or rubbing alcohol) in order to reduce the risk of 
infection. A bandage will be placed on the skin where the needle went in, and the 
participants will be asked to remove the bandage the next day and tell the study 
doctor right away if any redness or tenderness is present. Participants will be 
asked to remain lying flat for up to 30 minutes after the procedure, and will be 
given fluid to drink after the procedure. The site staff will ask the participants 


 
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about history of any allergies to anesthetics and will not perform a LP in any 
participant with such a history. The site staff will perform safety blood tests a few 
days before the LP, and will not perform the LP if the blood results indicate it is 
not safe to do so. 
 
C. Storage of CSF Specimens 
CSF specimens may be stored and used in future study-related and/or unspecified 
future research. Your CSF specimens will be shipped and/or stored outside of the 
country where they were collected. 
 
Please indicate below if you agree to have the LP done. No matter what you decide, it will 
not affect your participation in the study (A5343).  
 
________ (initials) YES, I agree to have the LP done. 
 
________ (initials) NO, I do not agree to have the LP done.  
 
 
If you agree to have the LP done, please indicate below if you agree to have some of your 
CSF specimens stored.  
 
________ (initials) YES, I agree to have CSF stored. 
 
________ (initials) NO, I do not agree to have CSF stored. 
 


 
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SIGNATURE PAGE: A5343 INFORMED CONSENT FOR OPTIONAL LUMBAR PUNCTURE 
PROCEDURE 
 
If you have read this consent form (or had it explained to you), all your questions have 
been answered, and you agree to take part in the optional LP procedure that will be done 
at weeks 8 or 24, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 

SAP_000.pdf: 
Filename: S:\A5343\documentation\Analysis\SAP\A5343_primarySAP_v1.0.for.ct.gov.submission.2019-12-
05.docx 
Directory mapping: X:\ maps to \home\actg 
Printed on: December 5, 2019 
 
ACTG A5343 
A Trial of the Safety, Tolerability, and Pharmacokinetics of 
Bedaquiline and Delamanid, Alone and in Combination, among 
Participants Taking Multidrug Treatment for Drug-Resistant 
Pulmonary Tuberculosis 
ClinicalTrials.gov Identifier: NCT02583048 
 
Primary Statistical Analysis Plan 
Version 1.0 
July 11, 2018 
 
This is ACTG A5343 SAP Version 1.0 with names of authors, names of publication 
writing team members and analysis timeline redacted.  
 
 
 
 


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Table of Contents 
1 
Introduction ............................................................................................................................................. 3 
1.1 
Purpose ......................................................................................................................................... 3 
1.2 
Key updates to the SAP ................................................................................................................ 3 
2 
Protocol Overview................................................................................................................................... 3 
2.1 
Study design .................................................................................................................................. 3 
2.1.1 
Study treatment:  Study TB drugs ..................................................................................... 4 
2.1.2 
Study treatment:  Study Antiretroviral Therapy (ART): ...................................................... 5 
2.1.3 
Multidrug Background Treatment (MBT): .......................................................................... 5 
2.1.4 
Evaluations ........................................................................................................................ 5 
2.1.5 
Replacements .................................................................................................................... 6 
2.1.6 
Permanent and Premature Treatment Discontinuation Criteria (protocol section 8.1)...... 6 
2.1.7 
Premature Study Discontinuation Criteria (protocol section 8.2) ....................................... 6 
2.1.8 
Duration of study and anticipated time to meet accrual target .......................................... 6 
2.1.9 
Sample size considerations ............................................................................................... 6 
2.2 
Protocol History ............................................................................................................................. 7 
2.3 
Hypotheses .................................................................................................................................... 8 
2.3.1 
Primary hypothesis ............................................................................................................ 8 
2.3.2 
Secondary Hypotheses ...................................................................................................... 8 
2.4 
Study objectives and outcome measures...................................................................................... 9 
2.4.1 
Primary Objectives ............................................................................................................. 9 
2.4.2 
Secondary Objectives ........................................................................................................ 9 
3 
Definitions ............................................................................................................................................. 11 
3.1 
Baseline ....................................................................................................................................... 11 
3.2 
Analysis population ...................................................................................................................... 11 
3.3 
Safety population ......................................................................................................................... 11 
3.4 
QT intervals ................................................................................................................................. 11 
4 
Statistical methods................................................................................................................................ 12 
4.1 
General considerations................................................................................................................ 12 
4.2 
Visit schedule and analysis windows .......................................................................................... 12 
4.3 
Analyses of outcomes measures ................................................................................................ 12 
4.3.1 
Primary QT prolongation outcomes ................................................................................. 12 
4.3.2 
Secondary QT prolongation outcomes ............................................................................ 13 
4.3.3 
Secondary safety and tolerability outcomes .................................................................... 13 
4.3.4 
PK outcomes ................................................................................................................... 13 
5 
Report components .............................................................................................................................. 13 
 
 


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1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcomes measures of 
ACTG A5343 that will be included in the primary manuscript, and which address the primary and key 
secondary objectives of the study; the pharmacology objectives will be addressed separately.  The 
Primary SAP outlines the general statistical approaches that will be used in the analysis.  It has been 
developed to facilitate discussion of the statistical analysis components among the study team, and to 
provide agreement between the study team and statisticians regarding the statistical analyses to be 
performed and presented in the primary statistical analysis report.  It also describes the results for the 
primary and secondary outcome measures that will be posted on ClinicalTrials.gov.  Detailed outlines of 
tables, figures, and coding descriptions that will be included in the Primary Statistical Analysis Report are 
included in the Analysis Implementation Plan (AIP).   
A separate Statistical Analysis Plan for Other Objectives and Outcome Measures will be developed once 
results for the Primary and key Secondary Objectives are known, and analyses will be presented in a 
separate report.  These analyses may include nonlinear mixed-effects modeling of drug concentrations. 
Data for the Primary Analysis Report will be downloaded when Week 24 ECG data are available for the 
last enrolled participant, all queries have been resolved, and the database is frozen for analysis.   
The Primary Analysis Report will be used for submission of results to ClinicalTrials.gov. Results for 
primary outcomes are required to be submitted within one year of the primary completion date (PCD), 
which is the date the last participant is examined for the purposes of data collection for the primary 
outcome measure.  For this study, the PCD is based on ECG data collected at the week 24 visit.  Results 
for secondary outcome measures are due one year after the last participant reaches Week 28.   
1.2 
Key updates to the SAP 
Version 
Date 
Content/changes 
1.0 
July 11, 2018 
Original version of SAP. 
 
2 
Protocol Overview 
2.1 
Study design 
ACTG A5343 is a phase II, randomized, open-label, three-arm pharmacokinetic (PK) and safety trial of 
the anti-tuberculosis drugs bedaquiline (BDQ) and delamanid (DLM) in participants with pulmonary 
infection with multidrug-resistant M. tuberculosis (MDR-TB).  Participants will be randomized to one of 
three arms.  Participants in arms 1, 2, and 3 will receive BDQ, DLM, or both drugs in combination, 
respectively, for 24 weeks together with multidrug background treatment (MBT) for MDR-TB.   


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The study will enroll a total of 84 evaluable men and women age 18 or older (28 per arm), with pulmonary 
MDR-TB, with or without HIV co-infection.  Randomization will be stratified by HIV status, with institutional 
balancing.   Participants will be followed for a total of 128 weeks: 24 weeks on study treatment, followed 
by 104 weeks of follow-up.   
To be eligible to enroll in the study, participants must have documented pulmonary infection due to strains 
of M. tuberculosis from a sputum sample collected within 60 days prior to entry with resistance to 
isoniazid (INH) and rifampin (RIF) and susceptibility to fluoroquinolones and aminoglycosides; resistance 
and susceptibility may be determined by either genotypic or phenotypic testing.  Participants with HIV-1 
infection may enter the study provided their CD4+ count is ≥100 cells/mm3 within 60 days prior to entry.  
In addition to study TB drugs, participants will need to take MBT for MDR-TB for a minimum of 7 days 
within the 10 days prior to entry.  Previous treatment for MDR-TB (other than for the qualifying episode) or 
receipt of BDQ or DLM at any time in the past is exclusionary.  In addition, QTcF interval greater than 450 
ms within 72 hours prior to entry, clinically significant ECG abnormalities, current clinically relevant 
cardiovascular disorder, known family history of Long QT Syndrome,  and several other cardiovascular-
related criteria are exclusionary (see Protocol section 4.2).   
Version 1.0 of the protocol stated that study participants were to be hospitalized per standard of care for 
initiation of MDR-TB treatment for at least the first two months after randomization and possibly longer 
than two months if they were too ill for discharge. 
Based on an interim monitoring review added to version 3.0 of the protocol, to potentially allow the 
duration of the initial hospitalization to be shortened, the Tuberculosis Transformative Science Group (TB 
TSG) Study Monitoring Committee (SMC) recommended that participants be offered a 2-week 
hospitalization period and that 8 weeks of hospitalization was no longer required.  LOA #1 to Protocol 
version 3.0 clarified and codified this protocol change.  (See Protocol History, below). 
This is a limited-site study open to 3 non-US sites: TASK (Bellville, South Africa), SATVI (Capetown, 
South Africa) and Barranco (Lima, Peru).    
2.1.1 
Study treatment:  Study TB drugs 
Participants will be randomized to one of three arms: 
• 
Arm 1: BDQ 400 mg PO QD for 2 weeks followed by 200 mg PO TIW for 22 weeks 
• 
Arm 2: DLM 100 mg PO BID for 24 weeks 
• 
Arm 3: Both BDQ and DLM (same doses and durations as in Arms 1 and 2, respectively) 
Participants will have 185 days from enrollment to complete 168 days (24 weeks) of TB study drug.  (The 
extra seventeen days are allowed for the possibility of missed TB study drug during the 24 week period.) 


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2.1.2 
Study treatment:  Study Antiretroviral Therapy (ART): 
Participants with HIV infection can participate provided they are taking an acceptable ART regimen.  For 
those participants without contraindications, study dolutegravir (DTG) at a dose of 50 mg once daily will 
be offered, to be used in combination with two NRTIs until study completion (week 128).  The other 
acceptable ART regimen is nevirapine (NVP) plus two NRTIs.  NRTIs are provided by the local program.  
PIs and EFV are contraindicated though switching from a regimen containing these to an acceptable 
study ART regimen prior to starting study TB drugs is allowed (as per protocol section 5.4). 
For participants who are HIV treatment naïve, it is recommended that DTG (study ART) plus two NRTIs 
be started approximately 2 weeks following initiation of study TB drugs.  For participants already on ART 
with EFV or a boosted PI at the time of screening, or who require a switch from the previous ART for 
another reason, it is recommended that DTG-based ART be started the day following discontinuation of 
their previous regimen.  Per Letter of Amendment #2 for protocol version 3.0, HIV-positive female 
participants of reproductive potential, are required to use contraceptive for the full duration of time the 
participant is taking DTG (ie, through study completion at week 128).  (See Protocol History below.) 
2.1.3 
Multidrug Background Treatment (MBT): 
While receiving study TB drugs, participants will also receive MBT for MDR-TB that includes at least 3 
drugs to which the organism is thought or known  to be susceptible (as per protocol section 5.4).  In many 
participants this will be a standardized, locally-available regimen, but individualization of regimens based 
on available culture and susceptibility data, or treatment history, may be needed.  Participants should 
take MBT for all 128 weeks on study.   
2.1.4 
Evaluations 
ECGs will be performed (in triplicate, 5-10 minutes apart) at entry; every two weeks during administration 
of BDQ and/or DLM (even-numbered weeks 2-24); and at week 28 (4 weeks after TB study drug(s) have 
been discontinued).  To minimize variability in QT intervals, ECG trace data are automatically transmitted 
to the central ECG laboratory (Quintiles) for determination of QT interval and other ECG measures.  
Intensive PK sampling will be performed at weeks 2, 8, and 24.  Sparse PK sampling will be performed 
during study treatment at weeks 4, 6, 10, 12, 14, 16, 18, 20 and 22, and at week 28 (4 weeks after study 
TB drugs have been discontinued).  Assays will be performed for DLM and its DM-6705 metabolite, and 
for BDQ and its M2 metabolite.   
Hair collection will be performed for measurement of DLM, BDQ, and MBT drugs over the course of the 
study to assess long-term drug exposures. 
In HIV-1 positive participants, viral load will be measured at the time points indicated in protocol section 
6.0. 


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Other clinical and laboratory evaluations (e.g. signs/symptoms, diagnoses, chemistry, hematology, 
sputum smears, adherence) will also take place on a regular basis through week 28 and then 
approximately quarterly through week 128 as defined in protocol section 6.0. 
2.1.5 
Replacements 
Because BDQ and DLM are known to have long half-lives, there is no plan to replace participants or 
reschedule PK visits for participants who miss the prior two doses of BDQ or DLM or who do not eat the 
standardized meals on the intensive PK days.   
2.1.6 
Permanent and Premature Treatment Discontinuation Criteria (protocol section 8.1) 
• 
Failure by the participant to attend 3 consecutive study visits. 
• 
Protocol-defined drug-related toxicity (see protocol section 7.0 Toxicity). 
• 
Requirement for prohibited concomitant medications (see protocol section 5.4.2) 
• 
Pregnancy or breastfeeding. 
• 
Request by participant to terminate treatment. 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in the toxicity 
section of the protocol. 
2.1.7 
Premature Study Discontinuation Criteria (protocol section 8.2) 
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if s/he thinks the study is no longer in the best interest of the 
participant. 
• 
Participant judged by the investigator to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the validity of the 
study results. 
• 
At the discretion of the IRB/Ethics Committee, Food and Drug Administration (FDA), NIAID, Office 
for Human Research Protections (OHRP), other government agencies as part of their duties, 
investigator, or industry supporter. 
These participants will not be replaced. 
2.1.8 
Duration of study and anticipated time to meet accrual target 
The duration of the study is 128 weeks from entry through the final clinic visit.   
Originally the study was expected to enroll about 8-10 participants per month across at least two ACTG 
sites, and to meet the accrual target of 84 participants in less than 12 months.   
2.1.9 
Sample size considerations 
Sample size calculations were chosen to provide specific precision of 95% confidence intervals (CIs 
around (1) arm-specific QTcF interval changes from baseline, and (2) between-arm differences in 


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changes from baseline (BDQ+DLM arm vs. BDQ-alone arm, and BDQ+DLM arm vs. DLM-alone arm). 
With 25 evaluable participants per arm with complete ECG data, the anticipated precision these CIs are 
(1) ± 4.5 milliseconds (ms) and (2) ± 6.0 (ms), respectively.   
Letter of Amendment #2 to Protocol version 3.0 was released on 06/04/2018, called for interim calculation 
of 99.9% CIs for the primary outcome measures.  To account for the interim CIs, the LoA specified that 
coverage probabilities of CIs in the final analysis will be adjusted to 95.1%.  (A participant who is in the 
analysis population is consider evaluable.)    
2.2 
Protocol History 
The study opened under version 1.0 of the protocol, dated 07/13/2015. 
Clarification Memo #1, dated 08/25/2015:  Corrected an inconsistency in the recommended time frame for 
switching ART treatment from EFV-based treatment to DTG-based treatment among participants with HIV 
co-infection.  The 3-day window between starting DTG and starting study TB drugs was modified to a 7-
day window to allow the needed days for EFV to wash out. 
Letter of Amendment #1, dated 06/20/2016:  Updated the Expedited Adverse Event (EAE) Reporting 
Requirements for A5343 adding several additional AEs that must be reported in an expedited manner. 
Protocol version 2.0 was released on 12/23/2016:  Its main purpose was to add two exploratory 
objectives to the study, add screening viral load testing and genotyping for HIV-infected participants who 
have been on ART for 6 months or longer, and clarify the management of participants who prematurely 
discontinue study treatment.  This version incorporates all prior changes from Letter of Amendment #1 
and Clarification Memo #1.  In addition, minor changes were made in the protocol document for 
clarification purposes.   
A Letter of Amendment #1 to Protocol version 2.0, dated 03/14/2017, clarified the directly observed 
therapy requirements for those on the BDQ arm and added Grade 4 events to the list of adverse events 
that must be reported in an expedited manner. 
A5343 protocol version 3.0 was released on 07/18/2017.  The main amendments were:  (1) a change to 
inclusion criteria to allow individuals with rifampin mono-resistant TB (RR-TB) to enter the study, and (2) 
introduction of a new interim monitoring trigger and review, to potentially allow the duration of the initial 
hospitalization to be shortened. 
A Letter of Amendment #1 to Protocol version 3.0 was released on 11/20/2017.  Per A5343, Version 3.0, 
an interim review was planned after QTcF data through week 8 were available for at least 12 participants 
on the BDQ+DLM regimen (study arm 3), to help determine if it is safe to decrease the duration of 
hospitalization from 8 weeks to 2 weeks. The TB TSG SMC reviewed the interim report on these data. 
Based on the report, they recommended that participants be offered a 2-week hospitalization period, and 
that the 8 weeks of hospitalization no longer be required.  The main purpose of LOA #1 to Protocol 


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version 3.0 was to clarify that the required hospitalization stay had been reduced from 8 weeks to 2 
weeks. 
A Letter of Amendment #2 to Protocol version 3.0 was released on 06/04/2018 in response to the release 
of a safety announcement on 05/18/2018 by The World Health Organization (WHO), the U.S. Food and 
Drug Administration (FDA), and the European Medicines Agency (EMA) regarding an unplanned analysis 
of an ongoing study in Botswana of pregnant HIV-positive women on antiretroviral therapy. In that 
analysis, investigators noted an increase in neural tube defects in infants born to women who conceived 
while on DTG.   This prompted regulatory agencies and the WHO to issue advice to health care 
professionals and HIV-positive patients that include avoiding DTG in HIV-positive women who are 
contemplating pregnancy, testing for pregnancy prior to starting DTG, and ensuring adequate birth control 
use among women taking DTG.   Based on discussions within the US Division of AIDS (DAIDS) and 
regulatory groups, changes to the A5343 study were needed to revise the pregnancy/contraception 
language for HIV-infected women of reproductive potential who receive DTG.  
The main purpose of this LOA was thus to update the pregnancy/contraception requirements and DTG 
risk information in the protocol and the sample informed consent form, and to add this interim analysis to 
evaluate precision on primary outcome estimates and to conduct an early look at safety and QT intervals 
in the setting of slow enrollment given the global need for such information.   
A5343 protocol version 4.0 was released on 06/26/2018.  The main purpose of this amendment was to 
add an assessment of cerebrospinal fluid (CSF) concentrations of DLM and BDQ for up to 16 participants 
with MDR-TB or RR-TB enrolled in A5343, via an optional lumbar puncture to be performed at week 8 or 
week 24. The amendment also incorporates all prior changes from the version 3.0 Letter of Amendment 
(LOA) #1 (11/20/17) and LOA #2 (06/04/18). 
2.3 
Hypotheses 
2.3.1 
Primary hypothesis 
Co-administration of delamanid (DLM) and bedaquiline (BDQ) (with multidrug background treatment 
[MBT] for multidrug resistant TB infection [MDR-TB] or rifampin-monoresistant TB [RR-TB]) will increase 
the duration of the QT interval (QTcF, as measured on electrocardiogram (ECG), adjusted for heart rate 
using the Fridericia correction formula) compared to administration of either drug alone (with MBT), but 
the combined effects on the QT interval will be no greater than additive. 
2.3.2 
Secondary Hypotheses 
2.3.2.1 When DLM and BDQ are co-administered with MBT for TB infection, clinically 
significant QTcF prolongation (see section 7.1.1 for definition) will be uncommon.   
 


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2.3.2.2 Co-administration of BDQ and DLM (in the context of MBT) for MDR-TB or RR-TB will 
not significantly affect concentrations (area under the concentration-time curve, or AUC) 
of either drug (or their main metabolites, M2 and DM-6705, respectively). 
2.4 
Study objectives and outcome measures 
2.4.1 
Primary Objectives 
2.4.1.1 To estimate the mean changes from baseline (averaged over weeks 8-24) in QTcF when 
DLM and BDQ are co-administered (along with MBT; Arm 3), when BDQ is administered 
without DLM (along with MBT; Arm 1) and when DLM is administered without BDQ 
(along with MBT; Arm 2). 
2.4.1.2 To compare the mean change from baseline (averaged over weeks 8-24) in QTcF when 
BDQ and DLM are co-administered (with MBT) to the mean change observed when 
each drug is administered alone (with MBT) (separate comparisons of Arm 3 to Arm 1 
and Arm 3 to Arm 2). 
Outcome measure.  For both primary objectives, the outcome measure is participant-specific 
changes from baseline in QTcF among the participants on each arm.  QTcF measurements 
from the week 0 visit contribute to estimation of baseline QTcF, and QTcF measurements from 
weeks 8 through 24 contribute to estimation of the on-treatment QTcF.  QTcF replicates arise 
from 3 separate complexes, ideally measured 5-10 minutes apart during the study visit.  If fewer 
than 3 values are available, the 1 or 2 available QTcF values are used.  See Analysis 
Population below for details of which QT intervals will be used in the primary and secondary 
analyses of QT intervals. 
2.4.2 
Secondary Objectives 
2.4.2.1 To estimate the proportion of participants who exhibit QTcF >500 ms at any time during 
study treatment, by arm. 
Outcome measure:  The participant-specific outcome measure is the visit-specific average of 
the 1-3 available QTcF values.  
2.4.2.2 To estimate the proportion of participants who exhibit an increase from baseline in QTcF 
of greater than 60 ms at any time during study treatment, by arm. 
Outcome measure:  The participant-specific outcome measure is the visit-specific average of 
the 1-3 available QTcF values. 
2.4.2.3 To describe visit-specific QTcF changes from baseline while on study drug treatment 
and following completion of study treatment (at week 28), for participants in Arm 1 
(BDQ), Arm 2 (DLM), and Arm 3 (BDQ and DLM). 
Outcome measure:  The participant-specific outcome measure is the average of the 1-3 QTcF 
values available from the week 28 visit.   


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2.4.2.4 To estimate, by arm, the proportion of participants for whom the following occurs: (a) 
absolute QTcF >480 and ≤500 ms and (b) (separate measure) QTcF increase from 
baseline of >30 and ≤60 ms. 
Outcome measure:  The participant-specific outcome measure is the visit-specific average of the 
1-3 available QTcF values.  
2.4.2.5 To compare the pharmacokinetics (PK) of BDQ when given together with DLM with MBT 
for MDR-TB or RR-TB (Arm 3) versus when given alone with MBR for MDR-TB or RR-
TB (Arm 1). 
Outcome measure:  Outcome measures are participant-specific PK parameters for BDQ and its 
M2 metabolite, estimated using noncompartmental methods applied to concentrations from 
intensive PK sampling visits (weeks 2, 8, and 24).  PK parameters consist of Cmin; Cmax; and 
area under the concentration time curve pre-dose to 22 hours (AUC0-22h)1.  Weeks 2, 8, and 24 
PK parameters will be summarized separately. This outcome measure is limited to the analysis 
population in arms 1 and 3.  If PK sampling occurs on days when BDQ dose is not taken (ie, if 
reltive time post dose is >25 hours), non-model-based PK parameters will not be calculated, 
although model-based secondary/exploratory model-based analyses will include the 
concentrations. 
2.4.2.6 To compare the PK of DLM when given together with BDQ with MBT for MDR-TB or RR-
TB (Arm 3) versus when given alone (Arm 2). 
Outcome measure:  Outcome measures are participant-specific PK parameters for DLM and its 
DM6705 metabolite, estimated using noncompartmental methods applied to concentrations 
from intensive PK sampling visits (weeks 2, 8, and 24).  PK parameters consist of Cmin; Cmax; 
and area under the concentration time curve from pre-dose to 11 hours (AUC0-11h)2.  Week 2, 8, 
and 24 PK parameters will be summarized separately.  This outcome measure is limited to the 
analysis population in arms 2 and 3. 
2.4.2.7 To describe the safety and tolerability of study treatment, by arm. 
Outcome measure:  Outcome measures are:  (1) occurrence of Grade 3 or higher adverse 
event of any type at any time through week 24 (safety), (2) occurrence of death at any time 
while on study TB drug (safety), (3) discontinuation of study TB drug(s) for any reason prior to 
week 24.  Analysis is conducted on the safety population. 
 
                                                     
1 The necessity of separating BDQ and DLM dosing by one hour leads to the last sample for BDQ assay 
being collected at 22h rather than the more standard 24h.  
2 The necessity of separating BDQ and DLM dosing by one hour leads to the last sample for DLM assay 
being collected at 11h rather than the more standard 12h. 


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3 
Definitions 
3.1 
Baseline 
Baseline (study entry, week 0) is defined as the date on which the participant initiated study TB drug(s).  
Values used for baseline (Week 0) will be the latest evaluation on or before this date. 
3.2 
Analysis population 
A participant is considered to have complete ECG data if 3 ECGs were collected at single baseline visit 
and at each of the 9 on-study-TB-drug visits, provided the participant is still taking study TB drug(s) at the 
time of the visit; see details below. 
A participant is in the analysis population through the week 24 visit provided there were no interruptions in 
dosing of study TB drug(s).  Details: 
• 
If a participant discontinues study TB drug permanently prior to week 24 due to Grade 3 or higher 
prolongation in QT interval (as defined in Section 7.1 of the protocol), the QTcF value from the 
participant’s last visit will be carried forward to subsequent weeks (under the assumption that if the 
participant had continued study TB drug(s), the QT prolongation would likely have persisted or 
increased). 
• 
If a participant discontinues study drug permanently prior to week 24 for a reason other than Grade 3 
or higher prolongation in QT interval, available QTcF values obtained while taking study TB drug will 
be included but will not be carried forward.  (The participant is removed from the analysis population 
as of the date after the last dose of study TB drug(s).) 
• 
For temporary discontinuations of study TB drug: (a) If the discontinuation lasts for 7 or fewer days, 
the ECG at the next scheduled visit will be performed and the QTcF value from that visit will be used 
in the analysis. (b) If the discontinuation lasts for 8-14 days, the ECG at the next scheduled visit will 
be performed and the QTcF value from that visit will be treated as missing.   The preceding text is 
taken directly from the protocol, but is difficult to interpret.  As a clarification:  For temporary 
discontinuations of study TB drug:   At any one visit at which ECG is measured during a temporary 
period of without doses, if the participant has taken a dose within 7 days of the visit, the QTcF value 
will be used in analysis.  If it has been more than 7 days since the last dose, the QTcF value will not 
be used in analysis. 
3.3 
Safety population  
The safety population consists of participants who take at least one dose of study TB drug(s).  
3.4 
QT intervals 
The QT interval is the duration of time (in milliseconds, ms) between the Q and T waves in the heart's 
electrical cycle.  The outcome measure, QTcF, is the duration of the QT interval corrected for heart rate 
using the Fridericia correction formula. 


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4 
Statistical methods  
4.1 
General considerations 
Baseline characteristics will be summarized by arm, but there will be no statistical comparisons 
comparing arms because of the randomized study design.   
Inference consists of point estimates and confidence intervals (CIs).  With the exception of an adjustment 
described in the Letter of Amendment #2 to Protocol version 3.0, CI coverage will not be adjusted for 
multiple intervals.  For the interim analysis described in CIs in the Letter of Amendment #2 to Protocol 
version 3.0, CIs will be constructed to have 99.9% coverage.  To maintain no less than 95% simultaneous 
coverage for both the interim and final analysis, CIs reported in the final analyses will have95.1% 
coverage.   
Categorical data will be summarized using N (%), and continuous data using N, min, Q1, median, Q3, 
max, and mean (standard deviation [SD]) (when appropriate).  Any modifications to outcome measures 
after the team has seen data that were collected after entry will be identified as such in the analysis 
report. 
4.2 
Visit schedule and analysis windows 
ECGs for determination of QT interval duration are conducted at study entry and at weeks 2, 4, 6, 8, 10, 
12, 14, 16, 18, 20, 22, 24 and 28. Intensive PK sampling I plasma for BDQ and DLM is conducted on at 
weeks 2, 8 and 24.  For weeks 2-8, the visit window is ±3 days; for weeks 10-24, the visit window is ±7 
days; for week 28, the visit window is ±2 week. 
For the purposes of analysis, visit windows will be formed around each study visit using the midpoints 
between adjacent weeks as cutoffs, and potentially including assessments collected outside the 
recommended visit windows described above.  If there are multiple evaluations within the analysis 
window for a given visit, the evaluation closest to the scheduled study week will be used, and the earlier 
measurement will be used if there are two measurements which are equally distant from the scheduled 
week.   
4.3 
Analyses of outcomes measures 
4.3.1 
Primary QT prolongation outcomes 
A mixed-effects ANOVA model, with fixed effects for arm and period (baseline vs. on-treatment) and 
random effects for participant, will be fit to data from participants on all arms, with handling of QTcF 
values as described in Section 3.2.  
Objective 2.4.1.1.  For the primary analysis, the QT prolongation (change from baseline) on Arm 3 will be 
represented as the estimated contrast between periods, along with the corresponding model-based 
95.1% CI.  QT prolongations on Arms 1 and 2 will be similarly estimated.  (CIs with 99.9% coverage are 
used in the July 2018 interim analysis.) 


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Objective 2.4.1.2.  For the primary analysis, the difference between QT prolongations on Arms 3 and 1 
will be estimated as the corresponding contrast (Arm 3 change from baseline minus Arm 1 change from 
baseline) along with the corresponding model-based 95.1% CI.  Arms 2 and 3 will be similarly compared.  
(CIs with 99.9% coverage are used in the July 2018 interim analysis.) 
4.3.2 
Secondary QT prolongation outcomes 
Objectives 2.4.2.1, 2.4.2.2, and 2.4.2.4.  The analysis will be conducted in the safety population.  
(Because the study TB drugs have a long half-life, participants will be included in the proportion whether 
or not they took study TB drug(s) through the corresponding visit week.)  For each binary outcome listed 
under Objectives 2.4.2.1, 2.4.2.2, and 2.4.2.4, numbers and proportions of participants experiencing one 
or more such event will be summarized by arm, along with 95% exact Clopper-Pearson binomial CIs.  
Between-arm comparisons will not be conducted. 
Objective 2.4.2.3.  Arm- and visit-specific within-participant changes from baseline in QTcF will be 
described, beginning with the first on-treatment ECG in the Schedule of Events, and continuing through 
the last ECG measured after scheduled discontinuation of study TB drug(s) at week 28.  Descriptions will 
include N, minimum, Q1, median, Q3, maximum, mean and standard deviation (SD).  For participants 
who discontinue study TB drug(s) prematurely, QTcF changes will be excluded from analysis; however, in 
a sensitivity analysis, QTcF changes from such participants will be carried forward as described in 
Section 3.2.  To allow a visual comparison of arms with respect to time effects, medians and IQRs in 
changes from baseline will be plotted against week on a single graph but with separate lines (colors, 
symbols) for each arm.  In a separate graph, week-specific mean changes and associated 95% CIs will 
be plotted against week.  Between-arm comparisons will not be conducted. 
4.3.3 
Secondary safety and tolerability outcomes 
Objective 2.4.2.7.  The analysis will be conducted in the safety population.  For the binary outcomes 
listed under Objective 2.4.2.7, numbers and proportions of participants experiencing one or more such 
event will be summarized by arm, along with 95% exact Clopper-Pearson binomial CIs. 
4.3.4 
PK outcomes 
Objectives 2.4.2.5 and 2.4.2.6.  For BDQ and its M2 metabolite, and for DLM and its DM-6705 
metabolite:  Participant-specific PK parameters Cmin, Cmax and AUC will be summarized by arm and week 
(weeks 2, 8, and 24).  Effects of DLM co-administration on BDQ PK parameters will be summarized by 
estimation of (week-specific) geometric mean ratios (GMRs), BDQ PK parameter with relative to without 
DLM co-administration.  Effects of BDQ co-administration on DLM PK parameters will be summarized by 
estimation of GMRs, DLM PK parameter with relative to without BDQ coadministration.  CIs around the 
GMRs will be constructed to have 90% coverage.  (Nonlinear mixed-effects modeling of the PK of BDQ 
and DLM will be conducted; this analysis is outside the scope of this SAP.) 
5 
Report components 
Detailed descriptions of the content of each of the following sections are given in the AIP.   


ACTG A5343 Primary Statistical Analysis Plan, version 1.0 
 
 
 
July 11, 2018 
 
 
14 of 14 
1. Study entry 
a. Screening 
b. Enrollment 
c. Eligibility errors 
2. Baseline characteristics 
3. Protocol deviations 
4. Study status 
5. Study treatment status (study TB drug(s)) 
6. Changes/interruptions to study TB drug(s) during study follow-up 
7. QT prolongation 
8. Other safety: 
a. ECG findings other than QT intervals 
b. Signs/symptoms, labs, diagnoses 
c. Pregnancies 
d. Deaths 
9. BDQ and DLM PK parameters