Clinical trial NCT04311502
Conditions: HIV Tuberculosis
Keywords: rifapentine clofazimine drug-susceptible tuberculosis tuberculosis treatment shortening
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2021-11-05; Completion date: 2025-06-24
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to compare a 3-month rifapentine (RPT)/clofazimine (CFZ)-containing regimen with a CFZ loading dose with the 6-month standard of care (SOC) regimen for drug-susceptible (DS) tuberculosis (TB).

Detailed description:
This study compared a 3-month rifapentine (RPT)/clofazimine (CFZ)-containing regimen with a CFZ loading dose with the 6-month standard of care (SOC) for drug-susceptible (DS) tuberculosis (TB).

Randomization was stratified based on HIV status and the presence of advanced disease as determined by chest X-ray.

Participants were randomized to one of three arms:

* Arm 1 (Experimental): rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + CFZ 300 mg once daily for 2 weeks; then PHZE + CFZ 100 mg once daily for 6 weeks; then rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 100 mg once daily for 5 weeks
* Arm 2 (SOC): rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) for 8 weeks; then rifampicin/isoniazid (RH) for 18 weeks
* Arm C (PK-only subgroup): PHZE + CFZ 100 mg once daily for 4 weeks; then remain on study, off study medications and treated according to SOC (RHZE for 4 weeks; then RH for 18 weeks)

All participants received pyridoxine (vitamin B6) with each dose of isoniazid (INH) based on current local, national or international dosing guidelines.

Arm 1 participants were treated for 13 weeks (including a 2-week CFZ loading dose of 300 mg daily). Arm 2 participants were treated for 26 weeks, and Arm C participants were treated for 4 weeks.

All participants in Arms 1, 2, and C were followed from randomization to Week 65.

On June 1, 2023, the Data and Safety Monitoring Board (DSMB) recommended that the study permanently close to accrual because of the high rate of treatment failure and TB recurrence. The A5362 team, NIAID and DAIDS leadership, and ACTG leadership concurred with the DSMB's recommendation and the study was closed to accrual on June 2, 2023. A letter of amendment was created that extended follow-up to 117 weeks for some participants in Arm 1.

Due to the early close to accrual, a primary analysis report forming the basis of the primary trial manuscript used data collected at study visits up to and including the date when the last enrolled participant completed the week 26 study visit (September 25. 2023). Another final analysis was performed using data collected at study visits up to the date when the last enrolled participant completed the week 65 assessment.

Study visits included physical examinations; blood, urine, and/or sputum collection; chest X-rays; and electrocardiograms (ECG).

Arms: arm 1: Participants received rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 300 mg once daily for 2 weeks; then PHZE + CFZ 100 mg once daily for 6 weeks; then rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 100 mg once daily for 5 weeks. arm 2: Participants received rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) for 8 weeks; then rifampicin/isoniazid (RH) for 18 weeks. arm 3: Participants received PHZE + CFZ 100 mg once daily for 4 weeks; then remained on study, and were treated with off study medications according to local SOC (RHZE for 4 weeks; then RH for 18 weeks).
Interventions: intervention 1: Rifapentine intervention 2: Rifampicin intervention 3: Isoniazid intervention 4: Pyrazinamide intervention 5: Ethambutol intervention 6: Clofazimine loading dose intervention 7: Clofazimine 100 MG
Intervention descriptions: intervention 1: 1200 mg once daily intervention 2: 600 mg once daily intervention 3: 300 mg once daily intervention 4: 1000mg once daily if weight is 40 to \<55kg; 1500mg once daily if weight is 55 to \<71kg; 2000mg once if weight is ≥71kg intervention 5: 800 mg once daily if weight is 40 to \<55kg; 1200 mg once daily if weight is 55 to \<71kg; 1600mg once if weight is ≥71kg intervention 6: 300 mg once daily for 2 weeks (loading dose), then 100 mg once daily intervention 7: 100 mg once daily

Protocol documents:
Prot_ICF_000.pdf: 
 
 
 
A5362 
 
A Phase IIc Trial of Clofazimine- and Rifapentine-Containing Treatment 
Shortening Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST Study 
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
IND # 147535 
 
 
 
 
The ACTG Tuberculosis  
Transformative Science Group Chair: 
Kelly Dooley, MD, PhD  
 
Protocol Chair:   
John Metcalfe, MD, PhD, MPH 
 
 
Protocol Co-Vice Chairs:  
Samuel Pierre, MD 
 
Kimberly Scarsi, PharmD, MS  
 
DAIDS Clinical Representatives: 
Richard Hafner, MD 
 
Melanie Michele Goth, MD FAAP 
 
 
Clinical Trials Specialist: 
Austin Leah Van Grack, MPH 
 
 
 
 
 
 
 
 
FINAL Version 2.0 
July 8, 2022 
 


A5362 
 
 
FINAL Version 2.0 
 
 
08Jul2022 
 
A Phase IIc Trial of Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens 
in Drug-Susceptible Tuberculosis: The CLO-FAST Study 
 
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 US 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 (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
 
 
 
 


A5362 
 
 
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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.................................................................. 16 
1.1 
Hypotheses ........................................................................................................ 16 
1.2 
Primary Objectives ............................................................................................. 16 
1.3 
Secondary Objectives ........................................................................................ 16 
1.4 
Exploratory Objectives ....................................................................................... 17 
2.0 
INTRODUCTION ........................................................................................................... 18 
2.1 
Background ........................................................................................................ 18 
2.2 
Clinical and Preclinical Evidence for CFZ Efficacy ............................................. 18 
2.3 
Rationale ........................................................................................................... 32 
3.0 
STUDY DESIGN ........................................................................................................... 32 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 33 
4.1 
Inclusion Criteria ................................................................................................ 33 
4.2 
Exclusion Criteria ............................................................................................... 36 
4.3 
Study Enrollment Procedures............................................................................. 37 
4.4 
Co-enrollment Guidelines ................................................................................... 38 
5.0 
STUDY REGIMEN......................................................................................................... 39 
5.1 
Regimens, Administration and Duration ............................................................. 39 
5.2 
Formulations and Preparation ............................................................................ 42 
5.4 
Concomitant Medications ................................................................................... 42 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 43 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 43 
6.1 
Schedule of Evaluations..................................................................................... 43 
6.2 
Timing of Evaluations ......................................................................................... 49 
6.3 
Instructions for Evaluations ................................................................................ 52 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 61 
7.1 
Definition of Adverse Events .............................................................................. 61 
7.2 
Adverse Event Collection Requirements for this Study....................................... 61 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 62 
7.4 
Study Monitoring ................................................................................................ 63 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 64 
8.1 
Toxicity .............................................................................................................. 64 


A5362 
 
 
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CONTENTS (Cont’d) 
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Page 
 
 
8.2 
Specific Conditions ............................................................................................ 65 
8.3  
Pregnancy.......................................................................................................... 70 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 70 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 70 
9.2 
Premature Study Discontinuation ....................................................................... 71 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 71 
10.1 
General Design Issues ....................................................................................... 71 
10.2 
Outcome Measures ............................................................................................ 71 
10.3 
Randomization and Stratification ........................................................................ 76 
10.4 
Sample Size and Accrual ................................................................................... 77 
10.5 
Data and Safety Event Monitoring ..................................................................... 80 
10.6 
Analysis Sets .................................................................................................... 83 
10.7 
Analyses ........................................................................................................... 83 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 86 
11.1 
Pharmacology Objectives .................................................................................. 86 
11.2 
Pharmacology Study Design .............................................................................. 87 
11.3 
Primary and Secondary Data, Modeling and Data Analysis ............................... 88 
11.4 
Anticipated Outcomes ........................................................................................ 90 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 90 
12.1 
Records to Be Kept ............................................................................................ 90 
12.2 
Role of Data Management ................................................................................. 90 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 90 
13.0 
PARTICIPANTS ............................................................................................................ 91 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 91 
13.2 
Participant Confidentiality ................................................................................... 91 
13.3 
Study Discontinuation ........................................................................................ 92 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 92 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 92 
16.0 
REFERENCES .............................................................................................................. 93 
APPENDIX A: A5362 PROHIBITED AND PRECAUTIONARY MEDICATIONS ...................... 101 
APPENDIX B: A5362 PERMITTED ANTIRETROVIRALS MEDICATIONS ............................. 103 
APPENDIX I: SAMPLE INFORMED CONSENT ..................................................................... 104 
APPENDIX I-A: A5362 STUDY VISITS ................................................................................... 117 
APPENDIX I-B: SAMPLE CONSENT FORM FOR USE OF SAMPLES AND 
INFORMATION IN OTHER STUDIES ......................................................................... 124 


 
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SITES PARTICIPATING IN THE STUDY 
 
A5362 is open to non-US AIDS Clinical Trials Group (ACTG) clinical research sites (CRSs) in 
countries with reported cases of drug-susceptible tuberculosis (DS-TB). Refer to the Site tab on 
the protocol’s webpage on the ACTG Member website for the list of eligible sites. 
 


 
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PROTOCOL TEAM ROSTER 
 
Chair 
John Metcalfe, MD, PhD, MPH 
University of California, San Francisco 
Division of Pulmonary/Critical Care Med 
San Francisco General Hospital 
1001 Potrero Avenue, Room 5K1 
San Francisco, CA 94110 
Phone: 415-206-4679 or 415-596-9348 
E-mail: john.metcalfe@ucsf.edu 
 
Co-Vice Chairs 
Samuel Pierre, MD 
Les Centres Gheskio CRS 
33 Boulevard Harry Truman 
Port-au-Prince, HT-6110 
HAITI 
Phone: 509-3740-7711 
E-mail: pierresamuel1@yahoo.fr 
 
Kimberly Scarsi, PharmD, MS 
University of Nebraska Medical Center  
Department of Pharmacy Practice, Rm 3021 
986145 Nebraska Medical Center 
Omaha, NE 68198-6145 
Phone: 402-559-9916 
E-mail: kim.scarsi@unmc.edu  
 
DAIDS Clinical Representatives  
Richard Hafner, MD 
Chief, TB Clinical Research Branch 
DAIDS/NIAID/NIH/TBCB 
5601 Fishers Lane, Room 9E30 
Rockville, MD 20852 
Phone: 301-435-3766 
E-mail: rhafner@niaid.nih.gov  
 
Melanie Michele Goth, MD, FAAP 
TB Clinical Research Branch 
TRP/DAIDS/NIAID 
5601 Fishers Lane 
Room 9E36  
MSC 9829 
Rockville, MD 20892-9829 
Phone: 301-761-7490 
E-mail: melanie.goth@nih.gov 
 
 
Clinical Trials Specialist 
Austin Leah Van Grack, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3033  
E-mail: austin.vangrack@dlhcorp.com 
 
Statisticians 
Jorge Tomas Leon-Cruz 
Statistical & Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 549 
Boston, MA 02115 
Phone: 617-432-7469 
E-mail: jleoncru@sdac.harvard.edu  
 
Isabelle R. Weir, PhD, MA 
Statistical & Data Analysis Center 
Harvard School of Public Health 
651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-2998  
E-mail: iweir@sdac.harvard.edu 
 
Data Managers 
Scott Anderson, MS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900  
E-mail: sanders@frontierscience.org  
 
Jenna Meldrum, BA 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900  
E-mail: meldrum@frontierscience.org 
 


 
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Data Managers (Cont’d) 
Brooke Altman  
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 
E-mail: altman@frontierscience.org  
 
DAIDS Pharmacist 
Justine Beck, PharmD, BCPS, RPh  
Pharmaceutical Affairs Branch 
OCSO/DAIDS/NIAID/NIH/DHHS 
5601 Fishers Lane, 9D39, MSC 9829 
Rockville, MD 20852 
Phone: 301-761-5288 
E-mail: justine.beck@nih.gov  
 
Pharmacologist  
Gary Maartens, MBChB, MMed  
University of Cape Town 
Division of Clinical Pharmacology 
Anzio Road, Cape Town 7925 
SOUTH AFRICA 
Phone: 27-21-4066286  
E-mail: gary.maartens@uct.ac.za 
 
Pharmacometrician 
Elin Svensson, PhD 
Radboud University Medical Center 
Department of Pharmacy 
P.O. Box 9101, 62 HB Nijmegen 
THE NETHERLANDS 
Phone: 31-623217888 
E-mail: elin.svensson@radboudumc.nl  
 
Dermatologist 
Maria Wei, MD, PhD 
Department of Dermatology 
VA 190, 4150 Clement Street 
San Francisco, CA 94121 
E-mail: maria.wei@ucsf.edu 
 
Investigators 
Richard E. Chaisson, MD  
Division of Infectious Diseases  
Johns Hopkins University 
1503 E. Jefferson Street  
Baltimore, MD 21231  
Phone: 410-955-1755  
E-mail: rchaiss@jhmi.edu  
 
Jennifer Furin, MD, PhD 
Case CRS,  
2120 Circle Drive, Room E-202 
Cleveland, OH 44106 
Phone: 216-368-6727  
E-mail: jjf38@case.edu 
 
Jacques Grosset, MD 
Johns Hopkins University CRS 
CRB2, Room 105 
1550 Orleans Street 
Baltimore, MD 21231-1044 
Phone: 410-502-8234 
E-mail: jgrosse4@gmail.com  
 
David W. Haas, MD 
Vanderbilt Therapeutics CRS 
One Hundred Oaks 
719 Thompson Lane, Suite 47183 
Nashville, TN 37204 
Phone: 615-936-8594  
E-mail: david.haas@vanderbilt.edu 
 
Natthapol Kosashunhanan, MD 
Chiang Mai University HIV Treatment CRS 
Chiang Mai University Research Institute for 
Health Sciences 
110 Intavaroros Road 
Chiang Mai 50200 
THAILAND 
Phone: 66-53-3945055 Ext. 354  
E-mail: natapolk@yahoo.com  
 


 
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Investigators (Cont’d) 
Rahul Lokande, MD 
Byramjee Jeejeebhoy Medical College 
(BJMC) CRS (31441) 
Pulmonary Medicine Department OPD 
NO. 34, Sassoon General Hospital 
Jai Prakash Narayan Road 
Pune 411001 
INDIA 
Phone: 91-98-22894972 
E-mail: drrahul_2007@yahoo.com  
 
Alberto Mendoza-Ticona MD,  
Socios en Salud Sucursal Peru CRS 
(31985) Jr. Puno 279, Cercado de Lima 
Lima 15001 
PERU 
Phone: 51 953982909 
E-mail: amendoza_ses@pih.org 
 
Gus Rosania, PhD 
Department of Pharmaceutical Sciences 
University of Michigan College of Pharmacy 
428 Church Street 
Ann Arbor, MI 48109 
Phone: 734-358-5661 
E-mail: grosania@med.umich.edu 
 
Wadzanai Samaneka MBChB, MSc 
Parirenyatwa CRS, P.O. Box A5178 
Corner Josiah Tongogara and Mazowe  
Harare 263 
ZIMBABWE 
Phone: 263-242-705986 
E-mail: wsamaneka@uzchs-ctrc.org  
 
International Program Specialist 
Akbar Shahkolahi, PhD 
ACTG Network Coordinating Center 
Social and Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3318  
E-mail: akbar.shahkolahi@dlhcorp.com 
Field Representative 
Joan Coetzee, CPN, PN  
Tygerberg Hospital 
Ward J8/ Francie van Zijl Drive  
Parow Valley, 7505 
Cape Town 7505 
SOUTH AFRICA 
Phone: 27-21-9384157 
E-mail: joan@sun.ac.za  
 
Community Scientific Subcommittee (CSS) 
Representative 
Anne Wambui Njoroge 
Moi University Clinical Research Center 
(MUCRC) CRS (12601) 
Chandaria Cancer and Chronic Diseases 
Centre at Moi Teaching and Referral Hospital 
Nandi Road, P.O. Box: 4606 
Eldoret 30100 
KENYA 
Phone: 254-728934777 
E-mail: anbartilol@yahoo.com 
 
Laboratory Data Managers 
Brooke Altman 
Frontier Science & Technology Research Foundation 
4033 Maple Road 
Amherst, NY  14226 
Phone: 716-834-0900 
E-mail: altman@frontierscience.org 
 
Laura Hovind, BS, MS 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7468 
E-mail: hovind@fstrf.org 
 
Kevin Knowles  
Frontier Science & Technology Research Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7238 
E-mail: knowles@frontierscience.org 
 


 
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Laboratory Technologists 
Brian Clagett, BA 
Case CRS 
BRB, Room 1048B 
2109 Adelbert Road  
Cleveland, OH 44106 
Phone: 216-368-4853  
E-mail: bmc@case.edu 
 
Neeta N. Pradhan, MSC 
Byramjee Jeejeebhoy Government 
Medical College CRS (31441) 
Jaiprakash Narayan Road 
P.O. Box 411001 
Pune 411001 
INDIA 
Phone: 985-0044897 
E-mail: neetapradhanpune@gmail.com 
 
Laboratory Specialists 
Afton Dorasamy, BS 
ACTG Laboratory Center 
University of California Los Angeles 
11075 Santa Monica Blvd. Suite #200 
Los Angeles, CA 90025 
Phone : 443-972-0685 
E-mail : adorasamy@milabcentral.org 
 
Cherisse Heirs, BA 
ACTG Laboratory Center 
University of California Los Angeles 
11075 Santa Monica Blvd. Suite #200 
Los Angeles, CA 90025 
Phone: 585-397-4730 
Email: cheirs@milabcentral.org 
 
 
Source Document Specialist 
Josie Marshall, BS 
ACTG Network Coordinating Center 
Social and Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 303-724-0803 
E-mail: josie.marshall@dlhcorp.com 
 


 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teama5362@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teama5362@fstrf.org. A 
response should generally be received within 24 hours (Monday-Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.prota5362 e-mail group. 
Include the protocol number in the email subject line. 
• 
Send an e-mail message to actg.user.support@fstrf.org. 
 
Clinical Management:  
For questions concerning entry criteria, toxicity management, concomitant medications, co-
enrollment, and all decisions regarding change, restart, or extension of TB treatment, 
contact the Clinical Management Committee (CMC).  
• 
Send an e-mail message to actg.cmcA5362@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to pharmacology laboratory tests, contact the protocol 
pharmacologist. 
• 
Send an e-mail message to actg.teama5362@fstrf.org (ATTENTION: Gary Maartens/Elin 
Svensson). 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the data 
manager. Completion guidelines for eCRFs and participant-completed eCRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Brooke 
Altman, Scott Anderson, and Jenna Meldrum directly.  
• 
For other questions, send an e-mail message to actg.teama5362@fstrf.org (ATTENTION: 
Brooke Altman/Scott Anderson/Jenna Meldrum). 
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration  
For randomization/participant registration 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 extension 7301. 
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support: 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 


 
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Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist.  
• 
Send an e-mail to actg.teama5362@fstrf.org (ATTENTION: Austin Van Grack). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website (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 at non-US sites contact the ACTG Site Coordination 
Group.  
• 
Send an email message to actgsitecoordination@dlhcorp.com. 
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Justine Beck, protocol pharmacist, at 301-761-5288.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
The IND number will be available on the PSWP within 30 days of the submission to the FDA. 
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.  
 
Telephone Calls 
Sites are responsible for documenting any phone calls made to A5362 team members. 
• 
Send an e-mail to actg.teama5362@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 
 
AE 
adverse event 
AMEZ 
amikacin/moxifloxacin/ethambutol/pyrazinamide  
AMEZC 
amikacin/moxifloxacin/ethambutol/pyrazinamide/clofazimine 
ART 
antiretroviral therapy 
ATP 
adenosine triphosphate 
AUC 
area under the concentration-time curve 
BDQ 
bedaquiline 
CES-D 
Center for Epidemiologic Studies Depression Scale 
CFU 
colony-forming unit 
CFZ (or C) 
clofazimine 
CI 
confidence interval 
Cmax 
maximum concentration 
CYP 
cytochrome P450 
DOT 
directly observed therapy 
DS-TB 
drug susceptible tuberculosis 
DST 
drug susceptibility testing 
DTG 
dolutegravir 
EAE 
expedited adverse event 
EBA 
early bactericidal activity 
ECG 
electrocardiogram 
EFV 
efavirenz 
EMB (or E) 
ethambutol 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
HR 
hazard ratio 
INH (or H) 
isoniazid 
ITT 
intent-to-treat  
LPA 
line probe assay (Hain GenoType MTBDRplus v2.0 or greater) 
MDR-TB 
multidrug-resistant tuberculosis 
MGIT 
mycobacteria growth indicator tube 
MIC 
minimum inhibitory concentration 
mITT 
modified intent-to-treat 
MOPS 
Manual of Procedures 
ms 
milliseconds 


 
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GLOSSARY (Cont’d) 
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Mtb 
Mycobacterium tuberculosis 
NTM 
nontuberculous mycobacteria 
NTP 
National Tuberculosis Program 
PD 
pharmacodynamic 
PHZ 
rifapentine/isoniazid/pyrazinamide 
PHZE 
rifapentine/isoniazid/pyrazinamide/ethambutol 
PK 
pharmacokinetics 
PZA (or Z) 
pyrazinamide 
QTcF 
corrected QT based on the Fridericia correction method 
RAL 
raltegravir 
RH 
rifampicin/isoniazid 
RHZE 
rifampicin/isoniazid/pyrazinamide/ethambutol 
RIF (or R) 
rifampicin (also referred to as rifampin) 
RPT (or P) 
rifapentine 
RS ratio  
ribosomal RNA synthesis ratio 
SAE 
serious adverse event 
SOC 
standard of care 
TB 
tuberculosis 
WHOQOL-BREF 
World Health Organization Quality of Life-BREF  
XDR-TB 
extensively drug-resistant tuberculosis 
Xpert 
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SCHEMA 
 
A Phase IIc Trial of Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens 
in Drug-Susceptible Tuberculosis: The CLO-FAST Study 
 
DESIGN 
A5362 is a Phase IIc, randomized, open-label comparison of a 3-month 
rifapentine (RPT)/clofazimine (CFZ)-containing regimen with CFZ loading 
dose (Arm 1, experimental) versus 6-month standard of care (SOC; Arm 
2) for drug-susceptible (DS) tuberculosis (TB). Early bacteriologic 
efficacy, early relapse, safety, and tolerability of the 3-month experimental 
arm versus standard of care will be evaluated. A 65-week composite 
efficacy outcome including treatment failure, relapse, and death will be a 
key secondary outcome. A PK-only subgroup to study the effect of the 
CFZ loading dose will be concurrently randomized to a RPT/CFZ-
containing regimen without CFZ loading dose (Arm C, PK only subgroup) 
but will not be included in efficacy analyses. 
 
DURATION 
65 weeks  
 
SAMPLE SIZE 
The total sample size will be 185. 
Arm 1 (Experimental): 110 
Arm 2 (Standard of Care): 55 
Arm C (PK only subgroup): 20 
 
POPULATION 
Participants aged ≥18 years living with and without HIV co-infection, and 
with pulmonary TB without demonstrated isoniazid or rifampicin 
resistance. Participants living with HIV with CD4+ T-cell count ≥100 
cells/mm3 are eligible to enroll, and co-administration of antiretroviral 
therapy is required. 
 
STRATIFICATION 
Participants will be stratified based on HIV status, and presence of 
advanced disease based on chest X-ray conducted at screening. 
 
REGIMEN 
Participants will be randomized to Arm 1, 2, or C: 
 
Arm 1 (Experimental 3-month, with CFZ loading dose): 
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine 
(CFZ) 300 mg once daily for 2 weeks; then PHZE + CFZ 100 mg once 
daily for 6 weeks; then rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 
100 mg once daily for 5 weeks, for a total of 13 weeks of study treatment. 
 
Arm 2 (Standard of Care): rifampicin/isoniazid/pyrazinamide/ethambutol 
(RHZE) for 8 weeks; then rifampicin/isoniazid (RH) for 18 weeks, for a 
total of 26 weeks of study treatment. 
 


 
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Arm C (PK only subgroup): PHZE + CFZ 100 mg for 4 weeks; then 
remain on study, off study medications and be treated per SOC 
(completing RHZE for 4 weeks; then RH for 18 weeks). 
 
CFZ and RPT are investigational agents. Rifampicin (RIF or R), isoniazid 
(INH or H), pyrazinamide (PZA or Z), and ethambutol (EMB or E) are 
study-supplied standard TB drugs. 
 
Schema Figure 1 
 
 
Arm 1 
(Experimental) 
N=110 
Weeks 
0-2 
3-4 
5-8 
9-13 
14-26 
27-65 
PHZE + 
CFZ 300 mg 
PHZE + 
CFZ 100 mg 
PHZE + 
CFZ 100 mg 
PHZ + 
CFZ 100 
mg 
Follow-up 
Follow-up 
Arm 2 
(Standard of 
Care) 
N=55 
RHZE 
 
RH 
Follow-up 
Arm C 
(PK only 
subgroup) 
N=20 
PHZE + 
CFZ 100 mg 
PHZE + 
CFZ 100 mg 
RHZE: On 
SOC treatment 
and study 
follow-up 
 
RH: On SOC treatment 
and study follow-up 
Follow-up 
 


 
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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
Primary Hypothesis 
 
A 3-month regimen of rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) with 
clofazimine (CFZ) dosed as 100 mg daily with a 2-week 300 mg daily loading dose (Arm 
1) will demonstrate early efficacy (time to 12-week liquid culture conversion) relative to 
standard of care (SOC) (RHZE; Arm 2), and will have acceptable safety and tolerability. 
 
1.2 
Primary Objectives  
 
1.2.1 To compare time to 12-week liquid culture conversion between Arm 1 and Arm 2 
participants 
 
1.2.2 To compare adverse events (safety) over 65 weeks between Arm 1 and Arm 2 
participants 
 
1.3 
Secondary Objectives  
 
1.3.1 To compare proportion of participants who experience a favorable composite 
efficacy outcome at 65 weeks between Arm 1 and Arm 2 participants (see 
Table 10.4-1 and section 10.2.4B) 
 
1.3.2 To compare premature regimen discontinuation (tolerability) between Arm 1 and 
Arm 2 participants 
 
1.3.3 To estimate and compare CFZ-associated increases in QT interval (QTcF, using 
the Fridericia correction)  
 
1.3.4 To estimate and compare time to stable liquid and solid mycobacterial culture 
conversion  
 
1.3.5  To compare proportion of participants with liquid and solid culture conversion at 
weeks 8 and 12 between Arm 1 and Arm 2 
 
1.3.6  To compare days to positivity in liquid culture over treatment time 
 
1.3.7  To compare chest radiographic score (with specific attention to resolution of 
cavitary disease) from baseline to end of treatment (Arm 1, week 13; Arm 2, 
week 26) between Arm 1 and Arm 2 participants 
 
1.3.8 To compare proportion of participants who experience a favorable 
clinical/bacteriologic treatment outcome at 65 weeks between Arm 1 and Arm 2 
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1.3.9 To estimate cumulative relapse and recurrence proportions up to week 65 for 
participants on Arm 1 and Arm 2 
 
1.3.10 To determine CFZ pharmacokinetic (PK) parameters in plasma in Arm 1 
 
1.3.11 To compare PK parameters when CFZ is given with a loading dose in Arm 1 and 
without a loading dose in Arm C 
 
1.3.12 To objectively and subjectively assess CFZ-associated skin hyperpigmentation 
between Arm 1 and Arm 2 participants 
 
1.4 
Exploratory Objectives 
 
1.4.1 To examine the association of plasma concentrations of CFZ with: 
 
1.4.1.1 QTcF changes from baseline, on treatment and post-treatment, using a 
population pharmacokinetic-pharmacodynamic (PK-PD) model 
 
1.4.1.2 Time to stable (liquid and solid) culture conversion 
 
1.4.1.3 Time (days) to positivity in liquid culture (MGIT) over time after start of 
treatment 
 
1.4.1.4 CFZ-associated adverse events 
 
1.4.1.5 Emergence of CFZ drug resistance (and cross-resistance with 
bedaquiline) as determined by phenotypic and genotypic methods 
 
1.4.2  To describe RPT PK parameters when combined with CFZ  
 
1.4.3 To explore whether efficacy, safety and/or PK of CFZ are associated with 
polymorphisms in human genes that may affect metabolism, disposition, and 
toxicity of study drugs as well as concomitant medications (e.g., NAT2 and 
CYP2B6)  
 
1.4.4 To assess social stigma and the impact of perceived skin changes on quality of 
life in a subset of Arm 1 and Arm 2 participants using an open-ended qualitative 
interview 
 
1.4.5 To estimate and compare changes in quality of life at weeks 8, 13, 26, and 65 
 
1.4.6 To estimate and compare changes in symptoms of depression at weeks 8, 13, 
26, and 65 
 


 
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1.4.7 To evaluate the sputum ribosomal synthesis (RS) ratio, an exploratory 
molecular pharmacodynamic (PD) marker, as follows: 
 
1.4.7.1 Compare the sputum RS ratio between Arm 1 and Arm 2 (weeks 2 
and 4) and between the intensive PK groups in Arm 1 and Arm C 
(weeks 1, 2, 3, and 4) 
 
1.4.7.2 Examine association of the sputum RS ratio at weeks 2 and 4 with 
time to 12-week liquid culture conversion 
 
1.4.7.3 Examine association of the sputum RS ratio at weeks 2 and 4 with 
65-week composite efficacy outcome 
 
1.4.7.4 Characterize the sputum RS ratio at the time of Possible Poor 
Treatment Response (as defined in section 6.2.3) 
 
1.4.7.5 Determine the longitudinal association of the sputum RS ratio with 
clinical, radiographic, and PK measures 
 
2.0 
INTRODUCTION 
 
2.1 
Background  
 
CFZ is a fat-soluble riminophenazine dye first synthesized in 1954 by Barry et al. as an 
anti-TB drug [1-3]. CFZ became an established antileprosy drug following demonstration 
of efficacy against Mycobacterium leprae in 1955 [4]. Since the 1990s, the growing 
global burden of drug resistant TB rekindled interest in CFZ as a key repurposed 
constituent of newer TB regimens. 
 
2.2 
Clinical and Preclinical Evidence for CFZ Efficacy 
 
In 2010, an unblinded, single-site, sequential observational cohort study of the Bangladesh 
regimen, a cocktail of seven agents given for 4 months followed by four drugs for 5 months, 
with CFZ throughout, demonstrated a 15% increase in cure (with no increase in patient default) 
in treatment of fluoroquinolone-sensitive multi-drug resistant TB (MDR-TB) [5]. A subsequent 
follow-up study of over 500 patients treated with the Bangladesh regimen demonstrated 
84.5% bacteriologically favorable treatment outcomes, with >80% of patients completing 24-
month post-treatment follow-up [6]. The Bangladesh regimen was later evaluated in the study, 
“The Evaluation of a Standardized Treatment Regimen of Anti-tuberculosis Drugs for Patients 
with Multi-drug Resistant Tuberculosis” (STREAM I, with STREAM II ongoing) [7]. STREAM I 
demonstrated noninferior efficacy (long-term successful outcome in more than 78% of 
participants) and similar safety relative to conventional 20-month regimens, though more 
deaths were reported in the short-regimen group (8.5% vs. 6.4%) [8]. A randomized trial 
evaluating CFZ (100 mg daily for 21 months versus placebo) within an optimized MDR-TB 
background regimen found significantly faster time to culture conversion and healing of 
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p=0.035) in patients randomized to CFZ; relapse was not assessed [9]. A second small 
randomized clinical trial evaluating CFZ as part of individualized XDR-TB regimens over 36 
months found no difference in time to sputum culture conversion on solid medium [10]. Of 
note, no patient discontinued therapy because of adverse events in the CFZ arm of either trial. 
Finally, additional observational clinical data in MDR-TB and extensively drug-resistant TB 
(XDR-TB) from multiple settings are supportive of CFZ efficacy [11-15]. 
 
While a recent human early bactericidal activity (EBA) study showed no antimicrobial effect of 
CFZ during 14 days of therapy [16], CFZ has demonstrated significant Mycobacterium 
tuberculosis (Mtb) killing activity and treatment-shortening potential in murine models. In a study 
of second-line anti-TB drugs [17], the addition of CFZ 25mg/kg/day (dose approximating 200 
mg/day in humans) to a 2-month regimen of amikacin/moxifloxacin/ethambutol/pyrazinamide 
(AMEZ) followed by 7 months of AMEZ alone dramatically increased clearance of isoniazid 
(INH)-resistant Mtb (H37Rv) from the lungs of BALB/c mice, with most being culture-negative 
after 5 months of treatment, compared with none at 9 months of AMEZ alone (average 
log10CFU of 4). Relapse rates between the two groups were unable to be compared, as mice 
treated with the CFZ-free regimen were still heavily culture positive at treatment cessation. 
Among mice treated with AMEZC, relapses occurred similarly with treatment durations of 5 
months (3/15) and 9 months (1/15), suggesting that a plateau in sterilization capability of CFZ had 
been reached long before treatment cessation [17].  
 
These findings led to a subsequent mouse model of drug-susceptible TB (DS-TB) 
demonstrating that substitution of CFZ (25 mg/kg/day) for ethambutol (EMB) in the standard 
DS-TB regimen of isoniazid (H; 10 mg/kg), E (100 mg/kg), rifampicin (RIF; 10 mg/kg), and 
pyrazinamide (PZA; 150 mg/kg) (2HRZE/4HR) in BALB/c mice resulted in significantly faster 
clearance of organisms from the lungs, curing 100% of mice in just 3 months (15/15 culture-
negative 6 months after discontinuation of therapy) (Figure 2.2-1) [18]. 
 
 
Figure 2.2-1: Antimicrobial effect of replacing ethambutol with clofazimine in standard 
TB therapy (RHZC) in BALB/c mice. 
 


 
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Further, among BALB/c mice (n = 307) aerosol-infected with Mtb H37Rv, replacement of 
RIF with rifapentine (RPT; 20 mg/kg) exhibited an additive effect with CFZ (12.5 mg/kg/day, 
approximating a human dose of 100 mg/d) within a DS-TB regimen (Figure 2.2-2), achieving 
no detectable 6-month relapse following 12 weeks of treatment (Table 2.2-1) [19].  
 
 
 
Figure 2.2-2: Additive effect of high-dose RIF within a clofazimine-based DS-TB 
regimen over 12 weeks [19]. 
 
 
Table 2.2-1:  Sterilizing Activity of Rifapentine-clofazimine-containing DS-TB Regimen, 
BALB/c Mice [19] 
 
The majority of mice under stand-of-care treatment relapsed after 12 weeks of treatment; 
addition of clofazimine alone (RHZEC) resulted in about a 2-month treatment shortening; 
addition of RIF alone (PHZE) did better than clofazimine alone; addition of both RIF and 
clofazimine (PHZEC) resulted in a further relative 25% treatment shortening. 
 
0
-2
4
6
8
10
12
0
1
2
3
4
5
6
7
8
9
Weeks of treatment
Log10 CFU per lung
RHZE
RHZEC
PHZE
PHZEC
Treatment initiation
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Reassuringly, sterilizing activity was similar among C3HeB/FeJ (“Kramnik”) mice  
(Table 2.2-2), though mice with the most caseation seemed to benefit least from CFZ [19]. 
Thus, in both BALB/c and C3HeB/FeJ mice, high-dose RPT and CFZ have additive 
treatment-shortening effects, with a rank-order of PHZEC > PHZE > RHZEC > RHZE. 
Although head-to-head studies have not been performed, BALB/c experiments further 
suggest that (1) high-dose RPT (20 mg/kg) would be more effective than high-dose RIF, 
given that RIF 40 mg/kg appears to be dose-equivalent with RPT 10 mg/kg [20]; and (2) a 
PHZEC regimen has similar efficacy as a registered-PA-824-moxifloxacin-pyrazinamide 
regimen, and is likely marginally better than registered-PA-824-pyrazinamide and 
registered-moxifloxacin-pyrazinamide [21, 22]. 
 
Table 2.2-2: Sterilizing Activity of Rifapentine-clofazimine-containing DS-TB Regimen, 
C3HeB/FeJ (“Kramnik”) Mice [19] 
 
Prior C3HeB/FeJ mouse experiments had demonstrated poor efficacy [23], hypothesized 
to be due to ineffective killing of extracellular Mtb residing within the caseous necrotic 
centers of granulomata, a finding potentially supported by matrix-assisted laser 
desorption/ionization mass spectrometry imaging studies [24]. However, PZA likewise 
performs poorly in C3HeB/FeJ mice (due to pH dependence) [25], despite substantial 
sterilizing activity in clinical trials [26]. 
 
As murine studies indicate a dose-dependent additive effect of CFZ during intensive phase 
DS-TB treatment, they also suggest dose-dependent antagonism in the absence of 
pyrazinamide/ethambutol (i.e., low-dose CFZ (between 1-3 mg/kg) resulted in higher CFU at 
3-4 months) during the continuation phase (Figure 2.2-3, Table 2.2-3) [19]. The mechanism of 
antagonism is poorly understood, but may be due to induction of RIF clearance (e.g., through 
effects on major ABC transporters [27], such as P-glycoprotein). It is not known whether such 
antagonism would also occur during co-administration with RPT, rather than RIF. 
 
These results collectively suggest a potent antimicrobial effect for CFZ. We hypothesize 
that use of CFZ in combination with other drugs with potent sterilizing activity, such as  
RPT and PZA, may powerfully synergize in a way not seen with second-line 
companion drugs to effect substantial treatment shortening for DS-TB. 
 
 


 
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Figure 2.2-3: Decline in lung CFUs in mice treated with clofazimine plus RHZE for 12 
weeks [19]. 
 
 
Table 2.2-3: Dose-dependent Effects of Clofazimine on DS-TB Regimens 
 
 
0
1
2
3
4
5
6
0
1
2
3
4
5
6
7
M o n th s o f tre a tm e n t
L o g 1 0 C F U  p e r lu n g
2 R H ZE /4 R H
2 R H ZE C 1 .5/2 R H C 1 .5
2 R H ZE C 3 .1/2 R H C 3 .1
2 R H ZE C 6 .2 5/2 R H C 6 .2 5
2 R H ZE C 1 2 .5/2 R H C 1 2 .5
2 R H ZE C 2 5/2 R H C 2 5
T re a tm e n t in itia tio n
N o  d ru g
D is c o n tin u e
Z  a n d  E


 
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2.2.1 Clofazimine Resistance and Potential Cross-resistance with Bedaquiline 
 
Despite extensive use, development of CFZ resistance is conspicuously rare in 
leprosy [28-31]. Further, in vivo Mtb CFZ resistant strains have been described 
rarely, and the prevalence of various molecular mechanisms of resistance is 
largely unknown. To our knowledge, no CFZ-resistant clinical isolates have been 
reported; however, clinical strains resistant to BDQ have recently demonstrated 
cross-resistance to CFZ [32]. Reduced susceptibility to both CFZ and BDQ, due to 
de-repression of the MmpS5-MmpL5 efflux pump (non-target based mutations in 
Rv0678) or loss-of-function mutations in pepQ (encoding a cytoplasmic proline-
specific aminopeptidase), has been demonstrated in mouse models, in patient 
cohorts treated with BDQ, and generated in vitro [32-36]. 
 
2.2.2 Clofazimine Pharmacology 
 
CFZ’s proposed antimicrobial mechanism of action includes redox cycling and 
toxic production of reactive oxygen species superoxide and H2O2. In addition, 
there is increased lysophospholipid production resulting in inhibition of cellular 
uptake of K+. These mechanisms interfere with adenosine triphosphate (ATP) 
production, resulting in bacterial cell wall dysfunction and death [37]. In addition, 
CFZ has anti-inflammatory effects thought to be due to decreased activation and 
proliferation of T-lymphocytes [37-39]. 
 
Minimal modern PK data exist to describe the disposition of, or important drug-
drug interactions with CFZ. CFZ bioavailability after oral administration is variable 
(45-60%) and enhanced by co-administration with food [40, 41]. A single 200 mg 
dose of CFZ results in a mean plasma concentration of 0.41 mg/L in healthy 
volunteers [40]; daily dosing of 100, 300, and 400 mg in leprosy patients results in 
average plasma concentrations of 0.7, 1.0, and 1.41 mg/L, respectively [42]. 
 
The metabolism of CFZ is not well characterized but is known to involve 
glucuronidation [42]. CFZ is primarily eliminated as unchanged drug in the feces, 
due to both biliary excretion and unabsorbed orally administered drug. A smaller 
fraction is eliminated in the urine as both unchanged drug and metabolites [43]. 
CFZ is >99% protein bound, primarily to beta-lipoproteins but also alpha-
lipoproteins in serum (Clofazimine Investigator’s Brochure, Edition 2, August 31, 
2016). CFZ distributes extensively to the reticuloendothelial system and adipose 
tissue. In mice, this accumulating drug in the tissues results in the serum half-life 
extending from 1.45 to 8.19 weeks when CFZ administration is extended from 4 to 
20 weeks [44]. In humans, the half-life of CFZ is not well characterized. After 8 
days of dosing, CFZ plasma half-life was estimated to be 10.5 days [41]. 
However, it should be noted that this is not based on steady-state (which can take 
up to 110 days to achieve) [45]. Another early report estimated the elimination 
half-life of CFZ based on spectrographic analysis of urine from a small number of 
leprosy patients receiving high-dose CFZ as at least 69 days [46]. 
 


 
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Intriguingly, CFZ has been characterized as a cytochrome P450 (CYP) 3A4 
inhibitor in two in vitro studies [47, 48], and by Novartis probe drug-drug 
interaction studies (Clofazimine Investigator’s Brochure, Edition 2, August 31, 
2016); a single study has also suggested that it may be a weak inducer of 
CYP3A4 at low concentrations [36]. CFZ is also an inhibitor of CYP2C8 and 
CYP2D6, but not CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP2E1 
(Clofazimine Investigator’s Brochure, Edition 2, August 31, 2016). Despite this, 
very few drug-drug interaction studies have been conducted. A recent 
population pharmacokinetic model elaborated by members of our protocol team 
did not find a statistically significant PK drug-drug interaction between CFZ and 
BDQ, a substrate of CYP3A4 [49]. One study of six subjects suggested that RIF 
Tmax was delayed and half-life was increased by CFZ co-administration [50] but 
there was no resultant change in Cmax or area under the curve (AUC); this 
suggests a likely minimal clinical impact, and CFZ and RIF are routinely used in 
combination for leprosy. Though CFZ and RPT have not been studied in 
combination, these data support the proposed combination. 
 
Recently, CFZ pharmacokinetics was characterized after 14 days in an EBA 
study in combination with BDQ, PZA, and pretomanid [16]. CFZ was 
administered as 300 mg orally for 3 days, followed by 100 mg orally daily 
through day 14, with a resulting median Cmax ranging from 229-268 ng/mL and 
AUC0-24 range 3742-4459 ng*h/mL. Notably, these parameters were lower than 
previously described after a single dose [40], highlighting the uncertainties 
related to the optimal CFZ dosing and resulting pharmacokinetic exposure in 
humans. Using intensive and sparse PK sampling, A5362 will contribute 
significantly to the understanding of CFZ over a treatment course for DS-TB. 
 
Potential for CFZ-ART Drug-Drug Interaction 
 
In drug-drug interaction studies conducted by Novartis, CFZ was a moderate 
inhibitor of EFV, RAL, and dolutegravir (DTG) metabolism, resulting in 2.12- to 
3.26-fold higher antiretroviral therapy (ART) AUC (Clofazimine Investigator’s 
Brochure, Edition 2, August 31, 2016). Notably, these increases in exposure 
would not typically prevent co-administration based on FDA regulatory 
guidelines; therefore, there are no contraindications to combining these ART 
regimens with CFZ. Importantly, this observation was in the absence of RIF or 
rifampicin, which are known inducers of these same medications, potentially 
mitigating the impact of CFZ inhibition. CFZ exposure in A5362 will be 
evaluated in participants receiving concomitant ART via population PK 
modeling using intensive and sparse samples of CFZ, though sample sizes will 
preclude specific study of ART PK in A5362. 
 
Despite in vitro data indicating that CFZ is a CYP3A4 inhibitor, summarized in 
the preceding paragraph, the only in vivo data is a population PK study [49] 
showing no effect of CFZ on bedaquiline (BDQ) concentrations (BDQ is a 
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EFV dosed once daily and DTG dosed twice daily. EFV is a CYP2B6 and a 
minor CYP2A6 substrate; CFZ does not inhibit either of these enzymes, so no 
interaction is expected. DTG is primarily metabolized by UGT1A1, with only a  
minor contribution from CYP3A4. It is possible that CFZ could increase DTG 
concentrations modestly, but this is unlikely, as boosted protease inhibitors 
(which strongly inhibit CYP3A4) do not significantly alter DTG exposure. 
Therefore, there is no evidence of a drug-drug interaction that could reduce 
antiretroviral concentrations and result in ART failure. 
 
2.2.3 Clofazimine Dosing 
 
CFZ is available as 50 mg and 100 mg oral capsules. Despite longstanding use in 
leprosy, CFZ remains classified by the Food and Drug Administration (FDA) as an 
investigational drug without an indication for TB. Adult dosing for multi-bacillary 
leprosy is 50 mg daily for 12 months (21.6g total dose, WHO), or 24 months (36g 
total dose, National Hansen’s Disease Program) in combination with RIF and 
dapsone. Severe type II lepra reactions unresponsive to corticosteroids can be 
treated with CFZ 300 mg daily, potentially for months; the anti-inflammatory 
activity of CFZ in these cases is thought to be paramount. 
 
As described above, murine models provide evidence of CFZ efficacy at doses 
similar to 100 mg and 200 mg per day in humans. In these models, loading doses 
of CFZ result in serum concentrations above the minimum inhibitory concentration 
(MIC) more quickly, but no increase in speed of mycobacterial killing. Novartis has 
described a desirable CFZ dosing interval to achieve the MDR-TB CFZ MIC99 of 
1.18 mcg/mL as early as possible (approximately week 8) and to sustain it for the 
remainder of the 24-week intensive phase. Because of its extremely long half-life, 
the previously proposed dosing of CFZ in Novartis MDR-TB studies is 200 mg 
once daily for 18 weeks, followed by 100 mg once daily for the remaining 6 weeks 
of intensive therapy [45].  
 
In internal studies, Novartis has determined CFZ’s MIC99 against drug-sensitive, 
clinical TB isolates to be 0.18 to 0.84 mcg/mL, much lower than those desired 
for MDR-TB, which was 0.3 to 1.18 mcg/mL [51]. However, prior studies have 
demonstrated a lower MIC for CFZ in treating drug-susceptible and drug-
resistant Mtb (MIC90 ranging from 0.06-1.0 mcg/mL, with most tested strains 
between 0.12-0.25 mcg/mL) [15, 52-56, 57]. However, the surrogacy of plasma 
drug concentrations in representing the active compartment of interest is 
unclear, given high intracellular concentrations and prolonged redistribution due 
to a large volume of distribution estimated at 1470 liters. Although loading doses 
did not effect decline in lung Mtb CFU in BALB/c mice treated with CFZ 
monotherapy [44] (Figure 2.2.3-1), extant pharmacokinetic data in humans 
(Figure 2.2.3-2) and a murine human translational model [Rada Savic, personal 
communication] are supportive of loading doses, similar to other anti-TB drugs 
with long elimination half-lives (e.g., bedaquiline [Sirturo (Bedaquiline) 
Investigator’s Brochure, January 2017]). Based on population PK modeling, 


 
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loading doses of 300 mg daily for 2 weeks will reach a desired concentration of 
250 ng/mL by the end of the loading period, while 100 mg daily throughout 
therapy will reach the same concentration approximately 7 weeks into therapy 
[Rada Savic, personal communication]. Given the pharmacologic properties of 
clofazimine, and the desire to reach target concentrations as soon as possible 
for a treatment shortening strategy, we will administer a 2-week 300 mg per day 
load, followed by 100 mg daily. This dosing regimen was futher investigated 
through simulations with a population PK model developed on data from the 
ProBex study (MDR-TB patients [58]) and an EBA study (DS-TB patients [59]. 
The simulations confirmed that expected active concentrations will be reached 
substantially faster with the loading dose. The peak concentrations at the end of 
the loading phase may be higher than at steady state with CFZ dosed at 100 mg 
daily, but lower than what is seen at long-term dosing with 200 mg daily [Elin 
Svensson, personal communication]. 
 
 
Figure 2.2.3-1: Decline in lung Mtb colony-forming units in mice treated with 
CFZ monotherapy with and without loading doses [44]. Dose-dependent 
concentrations of clofazimine in the blood and tissues did not translate into 
dose-dependent antimicrobial activity. Doses: A, 25 mg/kg daily; B, 12.5 mg/kg 
daily; C, 6.25 mg/kg daily; D (load), d1, 200 mg/kg; d2, 100 mg/kg; d3–14, 75 
mg/kg daily; wk 2–12, 25 mg/kg; E (load), d1, 100 mg/kg; d2, 75 mg/kg; d3–14, 
50 mg/kg daily; wk 2–12, 25 mg/kg; F (load), d1, 50 mg/kg; d2–14, 25 mg/kg 
daily; wk 2–12, 25 mg/kg. 
 
 


 
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Figure 2.2.3-2: Simulated typical plasma concentration-time profiles of CFZ 
following multiple dosing of 100 mg daily in TB patients with and without loading 
phase (2 weeks 300 mg daily). Dashed lines represent (black) the suggested 
MIC target (0.25 mg/L) and (red) Cmax at steady for 100 mg QD in standard 
MDR treatment (9 months) [MT Abdelwahab et al., in manuscript].  
 
Although existing evidence is supportive of the need for CFZ loading doses, the 
data are not definitive, and equipoise exists; this is evidenced by the multiple 
dosing strategies currently in practice and under evaluation (i.e., 100 mg daily 
with 300 mg daily 2-week loading dose in A5362; 200 mg daily in the 
TRUNCATE-TB trial [60]; 100 mg daily without load as WHO-recommended 
dosing for DR-TB [61]. In our trial, we propose a secondary objective to 
compare Arm C, a group of participants who receive the guideline- 
recommended dose of CFZ 100 mg daily, without a loading dose, to inform our 
understanding of the impact of the 2-week loading dose used in Arm 1. The 
impact of a loading dose on CFZ pharmacokinetics has not been evaluated 
outside of a modeled simulation, and this Arm will allow us, for the first time, to 
definitively reference the influence of time versus dose effect on how quickly 
CFZ achieves steady state and enable characterization of the suggested 
nonlinearity in bioavailability. Currently, it is unclear if this is caused by 
saturation of absorption at higher doses or by an induction phenomenon 
changing absorption over time. This will improve our ability to translate the 
findings of A5362 to other ongoing trials using different CFZ dosing.  
 
2.2.4 Clofazimine Safety 
 
CFZ is well tolerated and has been used in over 14 million patients with 
lepromatous leprosy over the past 40 years, usually at a dose of 50 mg daily for 
12 to 24 months in conjunction with RIF and dapsone, as well as in thousands of 
patients with nontuberculous mycobacteria (NTM) disease within the United 
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The most common toxicities are non-melanotic hyperpigmentation (due to 
partitioning of the circulating, free base form of the drug into subcutaneous fat) 
and phototoxicity, ichthyosis, and gastrointestinal distress [62]. CFZ is a 
phenazine dye and causes a reddish-black discoloration of the skin which is 
slowly reversible after stopping treatment. In a recent clinical trial enrolling 2,912 
participants with leprosy from India and China, CFZ-related pigmentation of the 
skin during 6 months of treatment was usually short-lived and acceptable to 
patients [63]. 
 
The prevalence of CFZ-associated skin discoloration demonstrates 
geographical variability. In studies from Bangladesh, Cameroon, and Niger, 
skin discoloration was unreported or reported in only 3.1% of the cases. [6, 13, 
64]. In other settings, hyperpigmentation has been much more commonly 
reported. In Peru, 93% of 27 MDR-TB cases treated with CFZ developed 
hyperpigmentation [65]. In China, hyperpigmentation reached 94.3% in one 
prospective clinical trial, [9] 23% in another [10], and 79% in a retrospective 
cohort [66]. Even in studies reporting high rates of discoloration, no participants 
in these settings discontinued CFZ. 
 
A meta-analysis of cohort studies including 602 MDR-TB cases treated with 
CFZ reported a pooled proportion of adverse drug reactions requiring 
discontinuation of CFZ in 0.1% of the cases, comparable to that of first-line TB 
treatment. The two most reported adverse events were skin discoloration and 
gastrointestinal reactions. Cardiotoxicity was not systematically evaluated in the 
primary studies [67]. 
 
CFZ has the potential to prolong the QTc interval and may exacerbate QTc 
prolongation when given with other anti-TB agents such as fluoroquinolones or 
BDQ. In a recent study by Diacon [16], mean QTcF prolongation (~13ms) was 
reported among patients treated with CFZ alone; however, QTc interval 
prolongations remained within specified safety limits. No additive or synergistic 
QTc prolongation was seen when CFZ was combined with BDQ or PA824 after 
2 weeks of exposure [16]. In a 24-week study, synergistic QTc prolongation of 
BDQ and CFZ was reported, but not associated with clinically relevant 
arrhythmia [68]. 
 
Studies of CFZ in patients with AIDS-related Mycobacterium avium complex 
found increased mortality when CFZ was added to clarithromycin. The QTc 
interval was not assessed, and individuals assigned to the CFZ arm had higher 
baseline mycobacterial load, implying that there may have been residual 
confounding despite randomization [69]. Increased mortality has not been 
replicated in animal models or in human studies of leprosy or MDR-TB. 
 


 
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2.2.5 
Rifapentine Pharmacology 
 
RPT is a semisynthetic rifamycin derivative used in combination with other anti-
TB agents for latent TB therapy and treatment of drug susceptible active 
pulmonary TB. RPT is bactericidal and binds the β-subunit of DNA-dependent 
RNA polymerase in Mtb, inhibiting synthesis of bacterial RNA. RPT has a 
microbiologic profile similar to that of RIF. Its structure differs from that of RIF by 
the presence of a cyclopentyl ring instead of a methyl group at the piperazinyl 
moiety. TBTC Study 29 demonstrated similar sputum culture conversion rates 
during substitution of RPT five times a week for rifampicin in standard intensive 
phase TB treatment regimens [70]. 
 
Absolute bioavailability of RPT has not been studied. RPT is well absorbed from 
the gastrointestinal tract, and relative bioavailability of 70% is achieved among 
individuals with TB compared to healthy volunteers. Food significantly increases 
absorption of RPT (bioavailability increased by 86% with high-fat meal. 
Administration with a high-fat meal increases the AUC and Cmax of RPT (both 40 
to 50%) compared to fasting conditions, and RPT should be administered with 
meals [Priftin package insert, 2018]. Maximum plasma concentrations occur 
within 5 to 6 hours following oral administration. RPT and its active 25-desacetyl 
metabolite are highly protein-bound (97 – 99% and 93%, respectively), primarily 
to albumin [71]. The apparent volume of distribution is 70.2 ± 9.1 L in 
tuberculosis patients [Priftin package insert, 2018]. RPT is hydrolyzed by 
arylacetamine deacetylase in the liver and blood to 25-desacetyl-rifapentine. This 
active metabolite contributes about 40% of the drug’s overall activity. RPT and its 
active metabolite have half-lives from 13 to 17 hours. This is approximately four 
times longer than the half-life of RIF (4 hours), permitting intermittent dosing of 
RPT. RPT is primarily excreted in bile and eliminated in feces (70%). Less than 
10% of RPT is excreted in the urine as unchanged drug. 
 
The MIC for of RPT for activity against Mtb is 0.01 to 0.06 μg/ml [71]. RPT 
accumulates intracellularly and achieves intracellular concentrations that up to 
five times higher than RIF [71]. 
 
RPT, like other rifamycins, induces CYP3A4, 2C8, and 2C9, which can lead to 
more rapid metabolism and clearance of many drugs. Rifamycins are also known 
to induce the activity of phase II enzymes such as as glucuronosyl- and 
sulphotransferase and may reduce levels of drugs metabolized by those 
pathways.  
 
2.2.5.1 Rifapentine Dosing 
 
RPT is available as 150 mg tablets. For active pulmonary TB, RPT is 
used in combination with other anti-TB agents and dosed intermittently 
as 600 mg twice weekly during the intensive phase of therapy (2 
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continuation phase of treatment (4 months) [Priftin package insert, 
2018]. TBTC Study 29X (n=334) was a RPT dose-ranging extension 
(∼10, 15, or 20 mg/kg) of TBTC Study 29 [72]. RPT was administered 
once daily for 7 days per week in combination with other anti-TB agents 
during intensive phase treatment compared to standard dose RIF. The 
study found 8-week culture conversion in the RPT arm (92.5%, 89.4%, 
and 94.7% in 10, 15, and 20 mg/kg RPT groups, respectively) than the 
RIF arm (81.3%). 
 
2.2.5.2 Potential for Rifapentine-ART Drug-Drug Interaction 
 
Interactions between RPT and EFV and DTG [73] have been studied 
with weekly RPT used in prevention [74]. There was no significant effect 
on EFV concentrations but, as expected, DTG trough concentrations 
were reduced by about 50%. Despite this, all participants maintained 
virologic suppression. It is expected that twice-daily DTG will overcome 
the induction by RPT, as is the case with RIF. 
 
2.2.5.3 Rifapentine Safety 
 
RPT, like other rifamycins, causes red-orange discoloration of body 
fluids and can stain contact lenses. In clinical trials in which RPT was 
combined with INH and other anti-TB drugs and administered once or 
twice weekly, rates of adverse reactions were similar with RIF and RPT, 
with increased liver aminotransferase activity in about 5% of patients. 
The only adverse effect that has occurred more often with RPT than with 
RIF has been hyperuricemia when the drug was given twice weekly; of 
note, hyperuricemia was attributed to PZA that was administered 
concomitantly. Other adverse reactions reported in 1-5% of patients 
included the following: hemoptysis, dizziness, hypertension, headache, 
gastrointestinal upset, rash, cytopenias, hematuria, pyuria, and 
proteinuria [Priftin package insert, 2018]. 
 
Adverse events are similar between RPT and RIF, including hepatotoxicity 
and rifamycin hypersensitivity syndrome [71]. In TBTC Study 29, 1.5% of 
participants in the RPT arm (n=275) discontinued RPT due to toxicities 
[70]. Three participants had either Grade 3 or 4 hepatitis in the RPT arm 
(1.1%), and similar proportions of participants in either the RIF or RPT 
group experienced hepatitis: 7 of 254 (2.8%) in the RIF group and 11 of 
275 (4.0%, P = .48) in the RPT group. Frequencies of other side effects 
were similar between RPT and RIF arms. These included anemia (0.4%), 
neutropenia (1.5%), nausea or vomiting (0.7%), rash (2.2%). Increased 
dose RPT (n=81, 20 mg/kg) found similar adverse events rates as 
compared to RIF and RPT arms dosed at 10 or 15 mg/kg, including 
hepatitis (2.5%), neutropenia (3.7%), and pruritis/rash (1.2%) [72]. 
 


 
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2.2.6 
Pharmacogenetics of TB Medications  
 
It is important to consider the impact of human genetic polymorphisms when 
studying efficacy, safety and PK of TB drugs. Among TB drugs, the 
pharmacogenetics of INH has most extensively been studied. Frequent 
polymorphisms in NAT2 (which encodes N-acetyltransferase 2) predict increased 
plasma INH exposure [75-78], and have been associated with increased risk for 
INH hepatotoxicity [79, 80]. Risk for INH-induced neuropathy may also increase 
with NAT2 slow acetylator alleles [81, 82]. Regarding other TB drugs, RIF is a 
substrate for organic anion-transporting polypeptide 1B1 (coded by SLCO1B1) 
[83], and one study associated an SLCO1B1 polymorphism with RIF bioavailability 
in South Africans [84]. Parenteral aminoglycosides such as streptomycin can 
cause sensorineural hearing loss [85-89], and mitochondrial DNA mutations in the 
gene that encodes 12S ribosomal RNA confer increased risk [85, 88, 90, 91]. CFZ 
is metabolized by glucuronidation. Although there is no information regarding the 
pharmacogenetics of CFZ, other drugs with glucuronidation (UGT) metabolism or 
associated adverse events do have known pharmacogenetic associations. 
Frequent polymorphisms in the gene UGT1A1 are associated with premature 
atazanavir discontinuation due to hyperbilirubinemia [92-94] and with 
approximately 50% increased plasma DTG exposure [95].  
 
In addition, pharmacogenetics results in drug-drug interaction between INH and 
EFV. Rifampicin induces hepatic CYP 450 2B6, so should decrease plasma EFV 
exposure [96], but in patients with slow metabolizer genotypes in CYP2B6 and 
NAT2 prescribed RIF with INH, plasma EFV exposure increases [97-99]. This 
may be because high INH concentrations in NAT2 slow acetylators inhibit 
CYP2A6, which is a necessary pathway for EFV clearance in CYP2B6 slow 
metabolizers [98-100]. Given the above considerations, it is important to evaluate 
the potential impact of genetic polymorphisms on CFZ PK, efficacy and toxicity, 
as well as on potential drug-drug interactions involving CFZ. 
 
2.2.7 
Sputum Ribosomal RNA Synthesis (RS) Ratio  
 
There is a need for new PD markers that maximize information gained from 
early-phase human clinical trials. More accurate PD markers would enable 
selection of the most efficacious regimens for testing in definitive Phase III trials 
[101, 102]. The RS ratio is a novel class of PD marker. Unlike culture-based 
measures, which evaluate mycobacterial load, the RS ratio may evaluate a 
physiologic state of Mtb potentially reflective of treatment regimen or other 
factors. Specifically, the RS ratio quantifies the abundance of Mtb precursor 
ribosomal RNA (rRNA) relative to total structural rRNA. The RS ratio provides a 
measure of ongoing Mtb synthesis of rRNA, a process fundamental to all 
bacteria. 
 
Studies in vitro and in mice suggest that drug regimens that cure TB faster 
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than regimens with lesser sterilizing activity. Additionally, human and mouse 
studies demonstrate a dose-response relationship between concentrations 
of sterilizing drugs administered and suppression of the RS ratio [103] 
[Walter ND, et al. Unpublished observations on Mycobacterium tuberculosis 
precursor rRNA indicates treatment-shortening activity of drugs; 2020].  
 
The RS ratio is currently being investigated as a candidate PD marker in 
A5349 [(TBTC S31) ClinicalTrials.gov Identifier: NCT02410772]. A5349 tests 
two experimental regimens including high-dose RPT (1200 mg daily) versus 
the standard of care regimen. A5362 will extend the findings from A5349 by 
determining the effect of adding CFZ to a high-dose RPT regimen. By 
including the RS ratio as an exploratory biomarker, A5362 will generate 
additional molecular information about the effect of CFZ in humans and will 
advance a practical PD marker that will enhance the design of future trials. 
 
2.3 
Rationale 
 
The anti-leprosy drug CFZ contributes substantially to the sterilizing activity of TB 
regimens in mice and to the relapse-free cure of MDR-TB regimens in humans, but 
significant gaps in our knowledge concerning optimal dosing, PK-PD, safety and 
tolerability, and treatment duration remain. Anti-inflammatory, as well as anti-
mycobacterial properties, rare drug resistance, abundant and reassuring safety data, and 
high intracellular accumulation within macrophages have maintained interest in the 
chemotherapeutic role of CFZ in light of a weak pipeline of alternative anti-mycobacterial 
agents. Reversible but potentially stigmatizing skin discoloration and known QTc 
prolongation continue to temper enthusiasm and delay conclusive drug trials. Release of 
the WHO Update to MDR-TB Treatment Guidelines in 2018 recommending treatment 
regimens with CFZ as a Category B drug reinforces the need for fundamental research 
related to the disposition, drug-drug interactions, and adverse effects related to CFZ. 
Although a 3-month treatment duration is unprecedented in modern TB trials, strong 
preclinical data, allowance to extend treatment in the absence of clinical resolution, and 
the close follow-up afforded by significant trial infrastructure reassure us that adverse 
patient outcomes will be minimal and not dissimilar from contemporaneous drug-
susceptible TB treatment trials. 
 
3.0 
STUDY DESIGN  
 
A5362 is a Phase IIc, open-label, randomized trial to study the impact of adding CFZ and 
substituting RPT for RIF compared with SOC combination TB therapy for participants 
with DS-TB. Participants will be stratified based on HIV status and the presence of 
advanced disease as determined by chest X-ray [104].  
 
Participants will be randomized to Arm 1 and treated for 13 weeks (including a 2-week 
CFZ loading dose of 300 mg daily; Arm 2 and treated for 26 weeks; or Arm C and 
treated for 4 weeks (PK only subgroup). 
 


 
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• 
Arm 1 (Experimental): PHZE + CFZ 300 mg once daily for 2 weeks, PHZE + CFZ 
100 mg once daily for 6 weeks; then PHZ + CFZ 100 mg once daily for 5 weeks 
• 
Arm 2 (SOC): RHZE for 8 weeks; then RH for 18 weeks 
• 
Arm C (PK only subgroup): PHZE + CFZ 100 mg once daily for 4 weeks; then on 
study, off study medications and treated according to SOC (RHZE for 4 weeks; RH 
for 18 weeks)  
 
For participants who consent to intensive PK sampling, they will be randomized 
using a 2:1:1 randomization ratio (Arm 1:Arm 2:Arm C). For participants who do 
not consent to intensive PK sampling, they will be randomized using a 2:1 
randomization ratio (Arm 1:Arm 2). The first 20 participants randomized to Arm 1 
who also consent to intensive PK sampling will be registered to be in the Intensive 
PK Sampling subgroup. The first 20 participants randomized to each of Arm 1 and 
Arm 2 who also consent to answering an open-ended qualitative interview at the 
end of treatment will be registered to be in the Qualitative Interview subgroup. 
Participants in Arm 1 may consent to either or both intensive PK sampling and 
qualitative interviews, or they can decline both. 
 
CFZ and RPT are investigational agents. Rifampicin (RIF or R), isoniazid (INH or H), 
pyrazinamide (PZA or Z), and ethambutol (EMB or E) are study-supplied standard TB 
drugs. 
All participants in Arms 1, 2, and C will be followed from randomization to week 65.  
 
The primary analysis will be a superiority comparison of time to 12-week liquid culture 
conversion in Arm 1 compared with Arm 2. Important secondary analyses include 65-
week favorable composite efficacy outcome, including cumulative relapse proportion 
versus 6-month SOC controls; and safety and tolerability (regimen discontinuation) in 
Arms 1 and 2. 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS  
 
4.1 
Inclusion Criteria  
 
4.1.1 Pulmonary TB (among participants with or without history of prior TB treatment) 
identified within 5 days prior to entry by: 
 
At least one sputum specimen positive for M. tuberculosis by molecular TB assay 
(Xpert) or line probe assay [LPA]) 
 
OR 
At least one sputum specimen positive (1+ or greater) for acid-fast bacilli (AFB) 
on smear microscopy 
 
Note: TB diagnosis for purposes of meeting 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 5 days prior to entry. 


 
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4.1.2  Pulmonary TB diagnosed without known INH resistance (e.g., by LPA or Xpert 
MTB/XDR) and without known RIF resistance (e.g., by either LPA or Xpert 
MTB/RIF or Ultra). 
 
Note: In cases later shown to be RIF or INH resistant post-enrollment by 
molecular test (if the LPA on direct sputum is initially invalid, it can later be 
followed up with LPA on the culture isolate), or in cases shown to be RIF and INH 
susceptible by molecular test but later confirmed to be INH or RIF resistant 
according to phenotypic DST, participants will discontinue study treatment. The 
documentation of INH and RIF susceptibility must be only from study testing 
laboratory. 
 
4.1.3 Aged ≥18 years. 
 
4.1.4 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 30 
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. Two or more HIV-1 RNA 
viral loads of >1,000 copies/mL are also acceptable as documentation of HIV-1 
infection. 
 
Note A:  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.  
 
Note B:  WHO and Centers for Disease Control and Prevention (CDC) 
guidelines mandate that confirmation of the initial test result must use a 
test that is different 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 participants living with HIV, CD4+ cell count ≥100 cells/mm3, obtained within 
30 days prior to study entry at any network-approved non-US laboratory that is 
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4.1.6 For participants living with HIV must be currently receiving or planning to initiate 
ART at or before study week 8.  
 
Note A: For a list of study-permitted ARV medications, refer to Appendix B.  
 
Note B: Dosing of study-permitted ART should be reflective of local standard of    
care based on WHO or national guidelines in combination with RIF- or RPT-
containing TB therapy. 
 
4.1.7 
A verifiable address or residence readily accessible to facilitate directly observed 
therapy (DOT), and willingness to inform the study team of any change of 
address during the treatment and follow-up period. 
 
4.1.8 
The following laboratory values obtained at or within 5 days prior to entry by any 
US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) 
certification or its equivalent, or at any network-approved non-US laboratory that 
operates in accordance with Good Clinical Laboratory Practice (GCLP) and 
participates in appropriate external quality assurance programs. 
• 
Serum or plasma alanine aminotransferase (ALT) ≤3 times the upper limit of 
normal (ULN) 
• 
Serum or plasma total bilirubin ≤2.5 times ULN 
• 
Serum or plasma creatinine ≤2 times ULN 
• 
Serum or plasma potassium ≥3.5 mEq/L and ≤5.5 mEq/L 
• 
Absolute neutrophil count (ANC) ≥650/mm3  
• 
Hemoglobin ≥7.0 g/dL 
• 
Platelet count ≥50,000/mm3 
 
4.1.9 For study candidates of child-bearing potential, negative serum or urine 
pregnancy test within 5 days prior to entry by any US clinic or laboratory that has 
a Clinical Laboratory Improvement Amendments (CLIA) certification or its 
equivalent, or is using a point of care (POC)/CLIA-waived test, or at any network-
approved non-US laboratory or clinic that operates in accordance with Good 
Clinical Laboratory Practice (GCLP) and participates in appropriate external 
quality assurance programs.  
 
4.1.10 Female participants of reproductive potential must agree not to participate in the 
conception process (i.e., active attempt to become pregnant, in vitro fertilization), 
and if participating in sexual activity that could lead to pregnancy, must agree to 
use at least one reliable nonhormonal method of contraception, as listed below, 
while on study treatment and for 30 days after stopping study medications. 
 
Acceptable forms of contraception include: 
• 
Condoms 
• 
Intrauterine device or intrauterine system 
• 
Cervical cap with spermicide 


 
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• 
Diaphragm with spermicide 
 
Note: Hormonal birth control alone is not acceptable, as it may not be sufficiently 
reliable in combination with RPT or RIF. 
 
4.1.11  Female participants who are not of reproductive potential must have 
documentation of menopause (i.e., at least 1 year amenorrheic), hysterectomy, 
or bilateral oophorectomy or bilateral tubal ligation. 
 
Note: Participant-reported history is acceptable documentation.  
 
4.1.12 Documentation of Karnofsky performance score 50 within 30 days prior to entry. 
 
4.1.13 Documentation of either the presence or absence of advanced disease as 
determined by chest X-ray within 5 days prior to entry. 
 
Note: Advanced disease will be defined as a total combined area of air-space 
disease, cicatricial atelectasis, and/or fibrosis across all lung fields equivalent to 
or greater than one entire lung, or one or more large cavitations (≥3cm). See 
section 6.3.11. 
 
4.1.14 Ability and willingness of participant to provide informed consent. 
4.2 
Exclusion Criteria  
 
4.2.1 More than 5 days of treatment directed against active TB for the current TB 
episode preceding study entry. 
 
4.2.2 Pregnant or breast-feeding. 
 
4.2.3 Unable to take oral medications. 
 
4.2.4 Current receipt of clofazimine or bedaquiline or known receipt of clofazamine or 
bedaquiline at any time in the past. 
 
4.2.5 QTcF interval >450 ms for men or >470 ms for women within 30 days prior to 
entry.  
 
4.2.6 Weight <40 kg. 
 
4.2.7 Current or planned use within 6 months following enrollment of one or more of 
the following medications: HIV protease inhibitors, HIV entry and fusion 
inhibitors, HIV non-nucleoside reverse transcriptase inhibitors (other than EFV), 
elvitegravir/cobicistat, bictegravir, quinidine, procainamide, amiodarone, sotalol, 
disopyramide, ziprasidone, or terfenadine. 
 
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4.2.9 Current or history of known personal or family long QT syndrome. 
 
Note: Family is considered a first-degree relative (i.e., parent, offspring, or 
sibling). 
 
4.2.10 Known allergy/sensitivity or any hypersensitivity to components of study TB 
drugs or their formulation. 
 
4.2.11 Active drug, alcohol use or dependence; or mental illness (e.g., major 
depression) that, in the opinion of the site investigator, would interfere with 
adherence to study requirements. 
 
4.2.12 Known history of acute intermittent porphyria. 
 
4.2.13 Other medical conditions (e.g., severe uncontrolled diabetes, liver or kidney 
disease, blood disorders, peripheral neuritis, chronic diarrhea) in which the 
current clinical condition of the participant is likely to prejudice the response to, or 
assessment of, treatment. 
 
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 
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 (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. Protocol activation 
may be required before each site can enroll any participants. 
 
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 approvals 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. The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all the required 
documents have been received. Site-specific ICFs will not be reviewed and approved 
by the DAIDS PRO. Sites will receive an Amendment Registration Notification when the 
DAIDS PRO receives a complete registration packet. A copy of the Amendment 
Registration Notification 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 will be asked to read and sign the 
approved protocol consent form. 
 
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the Data Management Center (DMC) Participant 
Enrollment System.  
 
For participants in Arm 1 and Arm 2 who agree to participate in the open-ended 
qualitative interview evaluations (Qualitative Interview subgroup), or for Arm 1 
participants who agree to participate in the intensive PK evaluations (Intensive 
PK Sampling subgroup), DM A5362 eligibility checklists are required through 
the DMC Participant Enrollment System. 
 
4.3.2  Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
 
4.3.3 Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database. 
Participants who meet the enrollment criteria will be randomized to the study 
according to standard ACTG DMC procedures.  
 
4.4 
Co-enrollment Guidelines  
• 
Non-US sites are encouraged to coenroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-U.S. Clinical Research Sites for Currently 
Unspecified Genetic Analyses.” Co-enrollment in A5243 does not require permission 
from the A5362 protocol chairs.  
• 
For specific questions and approval for co-enrollment in other studies, sites should 
first check the A5362 PSWP or contact the protocol team via e-mail as described in 
the Study Management section. 


 
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5.0 
STUDY REGIMEN 
 
5.1 
Regimens, Administration and Duration 
 
5.1.1 Regimens 
 
Participants will be randomized to Arm 1, 2, or C: 
 
Table 5.1.1-1: Regimens for Arms 1, 2, and C. All study products will be given once daily.  
Weeks 
Arm 1 (Experimental) 
Arm 2 (SOC) 
Arm C (PK only subgroup) 
0 – 2 
Rifapentine 1200 mg  
Isoniazid 300 mg  
Pyrazinamide weight-based dosing* 
Ethambutol weight-based dosing* 
Clofazimine 300 mg  
Rifampicin 600 mg 
Isoniazid 300 mg 
Pyrazinamide weight-based dosing* 
Ethambutol weight-based dosing* 
Rifapentine 1200 mg  
Isoniazid 300 mg 
Pyrazinamide weight-based dosing* 
Ethambutol weight-based dosing* 
Clofazimine 100 mg 
3 – 4 
Rifapentine 1200 mg  
Isoniazid 300 mg 
Pyrazinamide weight-based dosing*  
Ethambutol weight-based dosing* 
Clofazimine 100 mg  
Rifampicin 600 mg  
Isoniazid 300 mg 
Pyrazinamide weight-based dosing* 
Ethambutol weight-based dosing* 
 
Rifapentine 1200 mg  
Isoniazid 300 mg 
Pyrazinamide weight-based dosing* 
Ethambutol weight-based dosing* 
Clofazimine 100 mg  
5 – 8 
Rifapentine 1200 mg  
Isoniazid 300 mg 
Pyrazinamide weight-based dosing*  
Ethambutol weight-based dosing* 
Clofazimine 100 mg  
Rifampicin 600 mg  
Isoniazid 300 mg 
Pyrazinamide weight-based dosing* 
Ethambutol weight-based dosing* 
 
To remain on study, off study medications; will 
complete treatment per local SOC 
9 – 13 
Rifapentine 1200 mg  
Isoniazid 300 mg  
Pyrazinamide weight-based dosing* 
Clofazimine 100 mg  
Rifampicin 600 mg 
Isoniazid 300 mg  


 
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Weeks 
Arm 1 (Experimental) 
Arm 2 (SOC) 
Arm C (PK only subgroup) 
14 – 26 No treatment 
Rifampicin 600 mg 
Isoniazid 300 mg 
*Dosed based on weight, refer to Table 5.1.1-2.  
 
 
 
Table 5.1.1-2: Weight-based Dosing for Pyrazinamide and Ethambutol 
Weight Band 
Pyrazinamide 
Daily Dose 
Number of Pyrazinamide  
500 mg tablets per daily dose 
Ethambutol Daily 
Dose 
Number of Ethambutol 400 mg tablets 
per daily dose 
40 to <55 kg 
1000 mg 
2 
800 mg 
2 
55 to <71 kg 
1500 mg 
3 
1200 mg 
3 
≥71 kg 
2000 mg 
4 
1600 mg 
4 
 


 
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5.1.2 Administration  
 
CFZ 100 mg: will be administered as one capsule orally once daily with food. 
 
CFZ 300 mg: will be administered as three 100 mg capsules orally once daily with 
food.  
 
RPT 1200 mg: will be administered as eight 150 mg tablets orally once daily with food. 
Tablets may be crushed and added to semi-solid food. 
 
INH 300 mg: will be administered as one tablet orally once daily. All participants must 
receive pyridoxine (vitamin B6) with each dose of INH based on current local, national 
or international dosing guidelines. 
 
PZA: will be administered based on weight (Table 5.1.1-2) orally once daily. 
 
EMB: will be administered based on weight (Table 5.1.1-2) orally once daily. 
 
RIF 600 mg: will be administered as two 300 mg capsules orally once daily on an 
empty stomach, 1 hour before or 2 hours after eating. 
 
PHZE + CFZ may be administered at the same time, with food. 
 
PHZ + CFZ may be administered at the same time, with food. 
 
RHZE may be administered at the same time on an empty stomach, 1 hour before or 2 
hours after eating. 
 
RH may be administered at the same time on an empty stomach, 1 hour before or 2 
hours after eating.  
 
If a daily dose is missed, the participant will be instructed to administer the missed 
dose as soon as possible, unless the next dose is due within 6 hours. If the next dose 
is due within 6 hours, the missed dose will be skipped and the next dose will be 
administered as originally scheduled. Participants should not double the next dose of 
study drug in order to "make up" what had been missed.  
 
5.1.3 Duration  
 
Participants will be treated for 13 weeks (Arm 1), or 26 weeks (Arm 2), then followed 
post-treatment to week 65. Participants will be treated for 4 weeks in Arm C, then 
complete treatment according to SOC, and be followed to week 65. 
 


 
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5.2 
Formulations and Preparation 
 
5.2.1 Clofazimine (CFZ or C): 100 mg capsules. Do not store above 25ºC (77ºF). Protect 
from moisture. Dispense in a tight container. 
 
5.2.2 Rifapentine (RPT or P): 150 mg tablets. Store at 25°C (77°F) with excursions between 
15° and 30°C (59°-86°F) permitted (see USP Controlled Room Temperature). Protect 
from excessive heat and humidity. 
 
5.2.3 Isoniazid (INH or H): 300 mg tablets. Store below 30°C (86°F) and in the original 
container. 
 
5.2.4 Pyrazinamide (PZA or Z): 500 mg tablets. Store below 30°C (86°F). Protect from 
moisture. 
 
5.2.5 Ethambutol (EMB or E): 400 mg tablets. Store below 30°C (86°F) and in the original 
container. 
 
5.2.6 Rifampicin (RIF or R; also referred to as rifampin): 300 mg capsules. Store at a 
temperature not exceeding 25°C, in a dry place, protected from light. Store capsules in 
blisters in the provided carton. 
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study product is initiated, or a dose changed, 
investigators must review the concomitant medication’s and study product’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 Precautionary and Prohibited 
Medications Database located at: http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.4.1 Required Medications 
 
See section 4.1.6 and Appendix B for specifications about ART. Changes in ART must 
be discussed with the A5362 protocol team during the study product dosing period. 
 
While on INH, participants must receive pyridoxine (vitamin B6) with each dose of INH 
based on current local, national, or international dosing guidelines. 
 
5.4.2 Prohibited Medications 
 
For a list of prohibited medications, including those known to significantly prolong the 
QTc interval, see Appendix A. 
 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability  
 
5.3.1  Study Product Acquisition/Distribution  
 
Clofazimine (Lamprene®) will be manufactured by Novartis.  
 
Rifapentine (Priftin®) will be manufactured by Sanofi.  
 
Isonazid, pyrazinamide, ethambutol and rifampicin will be manufactured by Macleods Pharmaceuticals. 
 
Study products will be purchased through the ACTG Leadership and Operations and made available through the NIAID Clinical 
Research Products Management Center (CRPMC). The site pharmacist should obtain the study product(s) for this protocol by 
following the instructions in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 
 
Antiretroviral medications are NOT provided through the study and must be obtained locally by the site. Selection and dosing of ART 
in combination with RIF or RPT should adhere to local guidelines at each site.  
 
Pyridoxine (vitamin B6) will NOT be provided through the study and must be obtained locally by the site. 
 
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. The site pharmacist at non-US CRSs must follow the instructions in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks for the destruction of unused study products. 
 
6.1 
Schedule of Evaluations 
 
Table 6.1-1: Schedule of Evaluations for Arms 1 and 2 


 
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Evaluation 
Screening 
(-30 days) 
Entry (week 0) 
Day 3 (±1 day) 
Treatment Weeks (Visit Window ±3 days)14 
Follow-up 
(Visit Window is ±7 days) 
Time of 
Suspected 
Treatment Failure 
or Recurrence or 
Poor Treatment 
Response 
Premature 
Treatment /Study 
Discontinuation 
11 
2 
31 
4 
6 
8 
10 
12 
13 
17 
21 
26 
34 
42 
52 
65 
Documentation of 
HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Serum 
 
X 
 
 
 
 
 
 
 
 
 
X15 
 
 
X2 
 
 
 
X 
X 
X 
Targeted Physical 
Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hyperpigmentation 
Assessment 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X3 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Liver Function Tests 
X3 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Chemistry 
X3 
 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Diabetes Testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing 
X3 
Required at week 13 for Arm 1; otherwise as clinically indicated 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 RNA 
(if HIV+) 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
CD4+ (if HIV+) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Sputum AFB Smear 
and Culture4 
X3 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sputum RS Ratio5 
(optional) 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


 
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Evaluation 
Screening 
(-30 days) 
Entry (week 0) 
Day 3 (±1 day) 
Treatment Weeks (Visit Window ±3 days)14 
Follow-up 
(Visit Window is ±7 days) 
Time of 
Suspected 
Treatment Failure 
or Recurrence or 
Poor Treatment 
Response 
Premature 
Treatment /Study 
Discontinuation 
11 
2 
31 
4 
6 
8 
10 
12 
13 
17 
21 
26 
34 
42 
52 
65 
Molecular TB 
Diagnostic Assay (to 
detect Mtb) 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Molecular Assay to 
Detect Mtb INH- and 
RIF- Resistance 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Whole Genome6 
Sequencing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug-Susceptibility 
Testing7 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray 
X3 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X2 
 
 
 
 
X 
 
ECG 
X3 
 
X 
 
X8 
 
 
 
X 
 
 
X8 
 
 
 
 
 
 
 
 
X 
Intensive PK 
Sampling9 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Sparse PK 
Sampling10 
 
 
 
 
X11 
 
X 
 
X 
 
X 
X11 
X 
X 
X 
X 
 
 
 
X 
X 
Serum for 
Lipoprotein 
Measurement 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
Pharmacogenetics12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOT 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X2 
X2 
X2 
 
 
 
 
 
 
WHO Quality of Life 
Questionnaire 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
Depression Scale 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
Open-Ended 
Qualitative 
Interview13 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
1 Arm 1 intensive PK sampling group only: Week 1 and Week 3. 


 
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2 Arm 2 only.  
3 Must be obtained within 5 days prior to study entry. 
4 Two sputum samples for AFB smear microscopy and culture in liquid and solid media will be collected at each time point. Sputum specimens and culture 
isolates will be stored for targeted deep sequencing and phenotypic drug-susceptibility testing in the event of TB treatment failure or TB recurrence.  
5 For sites that have optionally completed the RS ratio training and material procurement, Arms 1 and 2, sputa sample will be collected at Entry, 
Weeks 2 and 4, and, if applicable, at Suspected Treatment Failure or Recurrence or Poor Treatment Response or Premature Treatment/Study 
Dicontinuation visits; for the intensive PK Sampling subgroup, sputa will also be collected at Week 1 and Week 3.  
6 For participants with suspected recurrence, whole genome sequencing performed on the baseline and recurrent isolate pair. 
7 See section 6.3.9. 
8 ECG should be performed 6-8 hours after CFZ dosing in Arm 1 during the week 2 and week 13 intensive PK visit. 
9 Arm 1 intensive PK sampling subgroup only. See section 11.2.1 for sampling time points. 
10 Arm 1 only. See section 11.2.2 for sampling time points. 
11 Sampling at these visits will occur only for those not assigned to complete intensive PK visit at the same study week. 
12 See section 6.3.14. 
13 Qualitative interview will be among a subset of participants in Arm 1 at week 13, and in Arm 2 at week 26.  
14 Visit windows cannot extend beyond last day of treatment. Visit must take place while participant is still on treatment. 
15 Arm 1 only. 
 
 
 
 


 
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Table 6.1-2: Schedule of Evaluations for Arm C 
Evaluation 
Screening 
(-30 days) 
Entry 
(week 
0) 
Day 
3 
(±1 
day) 
Treatment Weeks  
(Visit Window ±3 
days)10 
Follow-up 
(Visit Window is ±7 
days) 
Time of 
Suspected 
Treatment Failure 
or Recurrence or 
Poor Treatment 
Response 
Premature Treatment/ 
Study Discontinuation 
1 
2 
3 
4 
8 
26 
65 
Documentation of  
HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Stored Serum 
 
X 
 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X1 
 
 
 
 
 
X 
 
 
 
 
 
Liver Function Tests 
X1 
 
 
 
 
 
X 
 
 
 
 
 
Chemistry 
X1 
 
X 
X 
X 
 
X 
 
 
 
 
 
Diabetes Testing 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing 
X1 
Required at week 4; otherwise as clinically indicated 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 RNA (if 
HIV+) 
 
X 
 
 
 
 
 
X 
 
 
 
 
CD4+ (if HIV+) 
X 
 
 
 
 
 
 
 
 
 
 
 
Sputum AFB Smear and 
Culture2 
X1 
X 
 
X 
X 
X 
X 
 
 
 
X 
X 
Sputum RS Ratio3 
(optional) 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
X 
Molecular TB Diagnostic 
Assay (to detect Mtb) 
X 
 
 
 
 
 
 
 
 
 
 
 
Molecular Assay to Detect 
Mtb INH- AND RIF-
Resistance 
X 
 
 
 
 
 
 
 
 
 
X 
 


 
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Evaluation 
Screening 
(-30 days) 
Entry 
(week 
0) 
Day 
3 
(±1 
day) 
Treatment Weeks  
(Visit Window ±3 
days)10 
Follow-up 
(Visit Window is ±7 
days) 
Time of 
Suspected 
Treatment Failure 
or Recurrence or 
Poor Treatment 
Response 
Premature Treatment/ 
Study Discontinuation 
1 
2 
3 
4 
8 
26 
65 
Whole Genome4 
Sequencing 
 
X 
 
 
 
 
 
 
 
 
X 
 
Drug-Susceptibility 
Testing5 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Chest X-ray 
X1 
 
 
 
 
 
 
 
 
 
X 
 
ECG 
X1 
 
X 
 
X6 
 
 
 
 
 
 
Intensive PK Sampling7 
 
 
 
 
X 
 
 
 
 
 
 
 
Sparse PK Sampling8 
 
 
 
 
 
 
X 
 
 
 
 
 
Serum for Lipoprotein 
Measurement 
 
 
 
 
X 
 
X 
 
 
 
 
 
Pharmacogenetics9 
 
X 
 
 
 
 
 
 
 
 
 
 
DOT 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Depression Scale 
 
X 
 
 
 
 
 
X 
 
 
 
 
1  Must be obtained within 5 days prior to study entry. 
2 Two sputum samples for AFB smear microscopy and culture in liquid and solid media will be collected at each time point. Sputum specimens and culture 
isolates will be stored for targeted deep sequencing and phenotypic drug-susceptibility testing in the event of TB treatment failure or TB recurrence.  
3 For sites that have optionally completed the RS ratio training and material procurement, sputum sample at each indicated visit will be collected for 
determination of RS ratio. 
4   For participants with suspected recurrence, whole genome sequencing performed on the baseline and recurrent isolate pair. 
5 See section 6.3.9. 
6 ECG should be performed 6-8 hours after CFZ dosing during the week 2 intensive PK visit. 
7 Intensive PK sampling: See section 11.2.1 for sampling time points. 
8 Sparse PK sampling. See section 11.2.2 for sampling time points. 
9 See section 6.3.14. 
10 Visit windows cannot extend beyond last day of treatment. Visit must take place while participant is still on treatment. 


 
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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 30 days 
prior to study entry unless otherwise specified.  
 
Note: Screening evaluations for the identification of pulmonary TB and sputum 
samples collected for molecular and phenotypic drug susceptibility testing must 
be completed within 5 days prior to study entry.  
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures and participants 
who do not enroll will be captured in a Screening Failure Results form and 
entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
Entry evaluations can occur on the same day as screening evaluations if all 
screening criteria have been met prior to enrollment and prior to randomization. 
Participants must not have taken more than 5 days of total TB treatment prior to 
starting study medications. Participants must begin study medications within 72 
hours following randomization.  
 
6.2.3 Post-Entry Evaluations  
 
On-Treatment Evaluations  
Arm 1: 
The window for study visit at day 3 is ± 1 day. The window for study visits during 
weeks 1-13 is ± 3 days. Visit window cannot extend beyond last day of treatment. 
Week 13 visit must take place while participant is still on treatment.  
 
Arm 2: 
The window for study visit at day 3 is ± 1 day. The window for study visits during 
weeks 2-26 is ± 3 days. Visit window cannot extend beyond last day of treatment. 
Week 26 visit must take place while participant is still on treatment.  
 
Arm C: 
The window for study visit at day 3 is ± 1 day. The window for study visits during 
weeks 1-4 is ± 3 days. Visit window cannot extend beyond last day of treatment. 
Week 4 visit must take place while participant is still on treatment.  
 


 
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Post-Treatment Evaluations  
Arm 1: The window for study visits during weeks 17-26 is ± 3 days. The window 
for study visits during weeks 34-65 is ± 7 days.  
 
Arm 2: The window for study visits during weeks 34-65 is ± 7 days. 
 
Arm C: The window for study visits at weeks 8, 26 and 65 is ± 7 days. 
 
Event Driven Evaluations 
Participants whose screening, entry, and first post-entry visit sputum cultures all 
fail to grow Mtb complex, or whose molecular or drug susceptibility test results 
demonstrate resistance to INH or RIF after enrollment, must be discontinued 
from study treatment immediately and followed on study, off study drugs. 
Complete the Premature Treatment/Study Discontinuation Evaluations as 
indicated in section 6.1 at the time of discontinuing study treatment. 
 
Suspected TB Treatment Failure or TB Recurrence, or Poor Treatment 
Response 
For study purposes a possible poor treatment response evaluation is triggered by 
any one or more of the following, but not limited to: 
a. Worsening signs and/or symptoms consistent with TB at or after week 13 
(Arm 1) or week 17 (Arm 2, SOC)  
b. Radiographic worsening consistent with TB at or after week 13 (Arm 1) or 
week 17 (Arm 2, SOC)  
c. AFB sputum smear-positivity involving at least two separate sputa at or after 
week 13 (Arm 1) or week 17 (Arm 2, SOC)  
d. The site investigator is considering extension of TB treatment beyond that of 
the participant’s assigned regimen  
e. The site investigator is considering retreatment with any TB therapy after the 
participant has completed assigned study treatment  
f. For a participant on assigned study treatment, the site investigator is 
considering a change in treatment for efficacy reasons (this does not apply to 
changes in treatment for pregnancy, temporary drug challenge, or toxicity). 
 
Perform the evaluations according to section 6.1 as soon as feasible when a 
possible poor treatment response is suspected, and ideally prior to extension, 
change or re-start of TB medications (in consultation with the Steering 
Committee) if the participant’s clinical condition permits. Complete the Possible 
Poor Treatment Response case report form. For study purposes, those 
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outcome determination unless the participant withdraws consent. 
 
Persistent Clinical Disease and Extension of Treatment 
In the event of poor clinical response at week 13 among Arm 1 participants, 
treatment extension to a maximum of 17 weeks (119 doses) will occur if, at week 
13 (or after completion of 91 daily doses if treatment has been extended for 
missed doses), the participant has persistent symptoms consistent with ongoing 
active TB without alternative, more likely explanation for those symptoms, along 
with at least one of the following: (a) lack of radiographic improvement, or 
presence of radiographic worsening consistent with TB; (b) week 8 culture result 
is not negative; or (c) AFB sputum smear-positivity at week 13 involving at least 
two separate sputa.  
 
All decisions regarding treatment extension should be discussed with and 
approved by the A5362 Steering Committee before implementation. Perform the 
evaluations according to section 6.1, Time of Suspected Treatment Failure or 
Recurrence, as soon as feasible, and ideally before a restart or change in 
treatment regimen. 
 
The study regimen should not be extended beyond 17 weeks from randomization 
(or after completion of 119 daily doses if treatment has been extended for missed 
doses). If the participant continues to have persistent clinical disease at week 17, 
TB treatment may be further extended by switching to SOC, guided by DST and 
Xpert MTB/RIF results obtained at week 13. For study purposes, those 
participants should continue to be followed in the study per section 6.1 for 
outcomes determination unless the participant withdraws consent. 
 
If culture-positivity occurs at EOT (week 13 for Arm 1) in an otherwise well 
participant is not noted until week 19, approximately 6 weeks later, the participant 
will be retreated with local SOC anti-TB medications guided by DST and 
molecular DST results obtained at week 13. 
 
Follow-up of Arm C 
Although data are limited, what is known from drug-drug interaction studies (see 
section 2.2.2) suggest lack of adverse clinical impact related to combination of 
either CFZ-ART or CFZ-RIF. Further, murine studies suggest that PHZEC without 
CFZ loading doses is a more potent regimen than RHZE, therefore, the existing 
evidence supports the likelihood that Arm C participants will receive treatment 
enhanced beyond SOC, without known or expected drug-drug interactions that 
would influence the remaining SOC drugs. By extension, Arm C participants 
should be less likely to experience treatment failure than Arm 2 SOC participants. 
Nevertheless, monitoring of the trial will be comprehensive (detailed in section 
10.5), including Data Safety and Monitoring Board (DSMB) oversight. 
 
6.2.4 Discontinuation Evaluations 
 


 
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Evaluations for Randomized Participants Who Do Not Start Study Treatment 
All eCRFs must be completed and keyed for the period up to and including the 
entry visit. Participants who do not start study treatment will be taken off study 
with no further evaluations required. 
 
Premature Treatment Discontinuation Evaluations  
Participants who prematurely and permanently discontinue study drug will have 
the treatment discontinuation evaluations performed as noted in section 6.1 
within 4 weeks after discontinuation. Premature treatment discontinuation 
evaluations that overlap within 4 weeks of regularly scheduled evaluations do not 
have to be repeated. 
 
If the participant discontinues study drug prematurely, the participant will be 
encouraged to continue on study and receive all evaluations per section 6.1 
through week 65. 
  
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue from the study for any reason will have 
the study discontinuation evaluations performed as noted in section 6.1 prior to 
being taken off study. 
 
Evaluations for Participants Who Die 
All eCRFs must be completed and keyed for the period up to the week of death. 
 
6.3 
Instructions for Evaluations 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for Laboratories Performing Testing for DAIDS-Supported and/or Sponsored Clinical 
Trials, which is available at https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 
All clinical and laboratory information required by this protocol must be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website 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 eCRF unless otherwise specified. Refer 
to section 7.0 for information on the DAIDS AE Grading Table and AE reporting of 
adverse events requirements. 
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.4 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 
6.3.2 Medical History 


 
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The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days. In addition, the following 
diagnoses should be recorded regardless of when the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis A 
• 
Chronic hepatitis B 
• 
Acute hepatitis  
• 
Long QT syndrome 
• 
History of, or ongoing, inflammatory skin disorder such as leprosy, eczema, 
psoriasis, lichen planus, or other skin rash 
• 
History of intestinal obstruction 
• 
Major depression 
• 
SARS-CoV-2 infection 
 
Any allergies to any medications and their formulations must also be documented.  
 
6.3.3 Medication History 
 
A medication history must be present, including start and stop dates. Alternative 
therapies and dietary supplements should be recorded on source documents 
only. The table below lists the medications that must be included in the history:  
 
Table 6.3.3-1: Medication History 
Medication Category 
Complete History or Timeframe 
TB therapy for the current episode 
Complete History 
Prior TB treatment 
Complete History 
ART (for participants living with HIV only) 
Complete History 
Immune-based therapy 
Within 30 days prior to study entry 
Blinded study treatment 
Complete History 
Prescription drugs for all acute and chronic diseases, including 
for treatment and/or prophylaxis of opportunistic infections 
Within 30 days prior to study entry 
Alternative therapies 
Currently being taken 
Dietary supplements 
Currently being taken 
Sex-hormone medications or sex-hormone analogues or 
antagonists* 
Last 12 months  
*Hormone-releasing intrauterine devices (e.g., Mirena inserted in the last 5 years); oral, injectable, 
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testosterone therapy; leuprolide or other synthetic gonadotropin-releasing hormone; tamoxifen, raloxifene, 
aromatase inhibitors or any other androgen, estrogen, or progesterone analogue or antagonist therapy.  
 
6.3.4 Clinical Assessments 
 
Complete Physical Exam 
A complete physical examination will be performed at screening only and is to 
include, at a minimum, 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, height, weight 
and vital signs (temperature, pulse, respiration rate, and blood pressure). 
 
Targeted Physical Exam 
At and after entry, a targeted physical examination is to include weight and vital 
signs (temperature, pulse, respiration rate, and blood pressure), and is to be 
driven by any previously identified or new adverse event/targeted condition (as 
described in below bullets) that the participant has experienced since the 
previous study visit. 
 
Post-entry, see section 8.3 for collection requirements for pregnancy. 
 
Post-entry, record the following targeted event regardless of grade: 
• 
AIDS-defining conditions (refer to the CDC HIV Classification and the WHO 
Staging System for HIV Infection and Disease)  
• 
Coronary heart disease 
• 
Arrhythmia 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis Immune Reconstitution Inflammatory Syndrome (IRIS) 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
• 
Uterine pregnancy 
• 
Intestinal obstruction 
• 
Major depression  
• 
Inflammatory skin disorder such as leprosy, eczema, psoriasis, lichen planus, 
or other skin rash 
• 
SARS-CoV-2 infection 
 
Post-entry, refer to section 7.2 for AE reporting requirements. 
 
Hyperpigmentation Assessment 
A skin colorimeter will be used to take colorimetric images at four facial triangulated 
anatomic locations unobstructed by hair (forehead, left cheek, right cheek, chin) 
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points specified in section 6.1. Clinical images (standard photographs, used for 
quality assurance and as a visual record of outcomes) will be obtained at the same 
anatomic locations in sequence with the colorimeter under reproducible settings and 
lighting. Colorimetric measurements will be manually entered on an eCRF. Refer to 
the A5362 Manual of Procedures (MOPS) for details.  
 
Subjective: Participant-reported changes in skin pigment and distress specifically 
related to these changes will be assessed by verbal response to a 10-point 
numeric rating scale (NRS): 
  
• 
Skin pigment change: 0 (none) to 10 (most significant possible) 
• 
Distress related to skin pigment changes: 0 (none) to 10 (worst possible)  
 
Concomitant Medications 
Post-entry, the following new and discontinued concomitant medications must be 
recorded on the eCRFs: 
• 
Sex-hormone medications or sex-hormone analogues or antagonists (see 
section 6.3.3 for examples). 
• 
All prescription medications, excluding study-provided TB medications. 
o All study-provided TB medications for Arms 1 and 2 should not be 
recorded as Concomitant Medications. 
o All study-provided TB medications for Arm C weeks 0-4 should not 
be recorded as Concomitant Medications. 
o Site-provided standard of care TB medications for Arm C after week 
4 should be recorded as Concomitant Medications. 
 
The following concomitant medications must be present only in the source 
documents: 
• 
Nonprescription medications 
 
Study-provided TB Medication Modifications  
Record as study treatment all study-provided TB medication modifications, 
including initial doses, participant-initiated and/or protocol-mandated 
modifications, inadvertent and deliberate interruptions since the last visit. Record 
any permanent discontinuation of treatment. 
 
6.3.5 Laboratory Evaluations 
 
At screening and entry all laboratory values must be recorded on the eCRF. For 
post-entry assessments, record on the eCRF all laboratory values regardless of 
grade and refer to section 7.2 for AE reporting requirements for abnormal 
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Hematology 
Hemoglobin, white blood cell count (WBC), differential WBC (to include only 
neutrophils, lymphocytes, and monocytes), absolute neutrophil count (ANC), and 
platelet count will be performed in real time at the local laboratory. 
 
Liver Function Tests 
AST [SGOT], ALT [SGPT], total and direct bilirubin, and alkaline phosphatase will 
be performed in real time at the local laboratory. 
 
Blood Chemistry 
Lipase, creatine kinase, electrolytes (potassium, magnesium, calcium), and 
creatinine will be performed in real time at the local laboratory.  
 
Diabetes Mellitus Test 
Hemoglobin A1c (if unavailable, fasting blood glucose) will be performed at the 
local laboratory. If fasting blood glucose must be performed rather than 
Hemoglobin A1c, participants who are not fasting at the time of blood glucose 
ascertainment (e.g., at baseline) will be counseled to fast prior to their next (e.g., 
week 1 or week 2) visit. 
 
Pregnancy Test 
For women of reproductive potential: Serum or urine -HCG may be used (urine 
test must have a sensitivity of ≤25 mIU/mL). Record pregnancy and pregnancy 
outcome per section 8.3. 
 
Urinalysis 
A dipstick urinalysis will be performed at entry to assess proteinuria and 
hematuria. 
 
6.3.6 Virologic Studies 
 
Plasma HIV-1 RNA (if HIV positive) 
Obtain HIV-1 RNA from a laboratory that is VQA approved.  
 
6.3.7 Immunologic Studies 
 
CD4+ (if HIV positive) 
Obtain absolute CD4+ count within 30 days prior to study entry from a laboratory 
that possesses IQA certification. 
 
6.3.8 Stored Serum 
 
Stored serum will be collected at entry (all participants), at end of treatment 
(weeks 13 and 26 for Arms 1 and 2, respectively), and at end of follow-up 
(week 65, Arms 1 and 2 only) and may be analyzed for SARS-CoV-2 


 
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serology within a central laboratory at the end of the study if indicated to 
assess study outcomes. 
 
 
6.3.9 TB Laboratory Diagnostics and Microbiology 
 
Sputum AFB Smear and Mycobacterial Culture in Liquid/Solid Media  
Two sputum samples will be collected for smear and culture in liquid and solid 
medium within 5 days prior to study entry and at other time points noted in 
section 6.1. Sputum AFB smear must be reported per WHO criteria (i.e., 
negative, scanty, +, ++, +++). Bacterial load will be determined and recorded for 
all specimens using the time to positivity output automatically provided by the 
mycobacteria growth indicator tube (MGIT) system. For all cultures 
demonstrating growth of AFB, species will be identified to at least the level of Mtb 
complex versus non-TB mycobacteria. Sputum and isolates from positive 
cultures will be stored at the site laboratory or the local TB laboratory performing 
the TB testing (as appropriate to the site procedures) unless shipment to a 
central lab is requested. Refer to the A5362 MOPS for laboratory procedure 
details. 
 
Sputum Ribosomal RNA Synthesis (RS) Ratio (Optional) 
Sites and participants are not required to participate in this collection. 
Participant selection must be documented in the Sample Informed 
Consent. For sites that have completed the RS ratio training and material 
procurement, sputa will be collected for the RS ratio at the intervals 
identified in section 6.1 to test this exploratory candidate molecular 
biomarker. Because of its putative role as a PD marker, the frequency of 
sample collection is higher for participants in Arm 1 and Arm C undergoing 
intensive PK than for other participants. Participants in the intensive PK 
Sampling subgroups will have sputa for RS ratio collected at entry, weeks 
1, 2, 3, and 4, and, if applicable, at Suspected Treatment Failure or 
Recurrence or Poor Treatment Response or Premature Treatment/Study 
Discontinuation visits. All other participants not in the intensive PK 
Sampling subgroups will have sputa for RS ratio collected at entry, weeks 2 
and 4, and, if applicable, at Suspected Treatment Failure or Recurrence or 
Poor Treatment Response or Premature Treatment/Study Discontinuation 
visits.  
 
Molecular TB Diagnostic Assay (to detect Mtb) 
Where available, WHO-endorsed molecular diagnostic TB assays (Xpert, Hain 
GenoType MTBDRplus v2.0 or greater (LPA), performed within 5 days prior to 
study entry for initial identification of Mtb will be documented.  
 
Molecular Assay to Detect Mtb INH- and RIF- Resistance  
The detection of resistance to INH and RIF via LPA or Xpert MTB/XDR or Xpert 
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eligibility, and in the event of suspected TB treatment failure, TB recurrence, poor 
treatment response, or premature treatment or study discontinuation.  
 
Whole Genome Sequencing (WGS) 
All relapse isolates will undergo WGS according to internationally accepted 
protocols to determine molecular genotyping relative to baseline isolates.  
(https://support.illumina.com/sequencing/sequencing_kits/nextera-dna-flex-
kit.html) 
 
Drug-Susceptibility Testing (DST)  
For all participants, phenotypic (i.e., culture-based) DST for INH and RIF will 
be performed at entry on Mtb isolates collected using the MGIT system as 
indicated in section 6.1.  
 
For participants experiencing treatment failure or relapse, the following 
tests will be perfomed on positive Mtb sputum cultures (1) at time points of 
treatment failure or relapse (i.e., Mtb isolates at or after the week 12 study 
visit for Arm 1, and at or after week 17 for Arm 2 and Arm C) for INH, RIF, 
PZA, CFZ, and BDQ, and (2) on stored baseline (i.e., entry) Mtb isolates for 
PZA, CFZ, and BDQ: 
• 
Phenotypic DST 
• 
Minimal inhibitory concentrations (MICs) 
• 
Genotypic DST (i.e., whole genome and targeted deep sequencing 
[single molecule-overlapping reads {SMOR}], see paragraph below).  
 
Because of challenges in interpretation of MIC values for PZA, CFZ, and 
BDQ (due to a relative lack of data from susceptible controls for these 
drugs), two additional samples will be used as control determinations for 
PZA, CFZ, and BDQ MICs. Mtb isolates collected at entry from two 
consecutive prior participants not known to have experienced a poor 
clinical outcome will undergo MIC testing for PZA, CFZ, and BDQ; if two 
consecutive prior participants with favorable outcome are not available, up 
to two consecutive subsequent participants with favorable outcome may 
be substituted. 
 
Single molecule-overlapping reads (SMOR) analysis, a novel targeted deep 
sequencing approach, will be used to identify microbes resistant to CFZ, BDQ, 
and all SOC drugs representing ≥0.1% of a microbial community in longitudinal 
fashion [105]. Given storage and batched analysis, and the unknown nature and 
significance of small microbial-resistant subpopulations, SMOR results will not be 
used for clinical management in real-time.  
 
6.3.10  Possible Poor Treatment Response Evaluation 
 
At the time of suspected TB treatment failure, TB recurrence, poor treatment 
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treatment beyond that of the participant’s assigned regimen, participants will be 
evaluated for possible poor treatment response. Trigger for poor treatment 
response, type and date of poor response, treatment outcome, and confirmation 
of poor response will be documented. 
 
6.3.11 Chest X-ray  
 
The chest X-ray will be posterior-anterior at time points described in section 6.1. 
Extent of disease (limited to one lobe or region, unilateral, bilateral, or diffuse) 
and cavitation status (cavities present [location] or absent) will be documented by 
numerical score for grading chest X-ray in adult smear-positive pulmonary TB 
[106]. For purposes of randomization stratification, screening chest X-ray will be 
read, interpreted, and recorded at each site as advanced or non-advanced 
disease. Advanced disease will be defined as a total combined area of 
pulmonary opacity across all lung fields equivalent to or greater than one entire 
lung, or one or more large cavitations (≥3cm) [104]. Chest radiographs will be 
retrospectively reviewed in batched fashion centrally (in DICOM format by two 
Board Certified Chest Radiologists) for confirmation of advanced disease 
stratification and detailed findings. Refer to the A5362 MOPS for details. 
 
6.3.12 ECG 
 
Screening and longitudinal ECGs will be conducted at the study site according to 
section 6.1. At all visits, ECG will be performed in triplicate (collection of three 
ECGs 5-10 minutes apart). Specific instructions related to ECG procedures are 
described in the A5362 MOPS.  
 
After entry, the ECG should be performed 6-8 hours after CFZ dosing in Arm 1 
during intensive PK sampling at weeks 2 and 13, and in Arm C during intensive 
PK sampling at week 2. At all other visits, the ECG should be performed 4-8 
hours after CFZ dosing.  
 
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. 
 
6.3.13 Pharmacokinetic Studies: Arm 1 and Arm C only 
 
For visits occurring at week 13 or earlier, all PK sampling visits must be 
completed prior to discontinuation of study treatment. Sparse PK for CFZ will be 
collected after discontinuation of study treatment. 
 
Intensive PK Sampling  
Arm 1: 20 participants 
Arm C: 20 participants 
See sections 6.1 and 11.2.1 for designated PK visits and sampling time points. 
 


 
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Sparse PK Sampling 
Arm 1: Participants not assigned to intensive PK 
Arm C: 20 participants 
See sections 6.1 and 11.2.2 for designated PK visits and sampling time points. 
 
Serum for Lipoprotein Measurement  
A single serum sample will be collected and stored for assessment of alpha- and 
beta-lipoprotein at each intensive or sparse PK visit. 
 
6.3.14 Pharmacogenetics 
 
A single whole blood sample will be obtained at entry from all study participants 
for genotyping of polymorphisms in human genes that may affect metabolism, 
disposition, and toxicity of study drugs as well as concomitant medications (e.g., 
NAT2 and CYP2B6).  
 
6.3.15 Directly Observed Therapy (DOT)  
 
DOT will be performed throughout treatment. Each site must follow local TB 
guidelines about DOT. All drugs must be taken orally, 7 days per week. At least 
five doses per week must be administered as DOT by trained study outreach 
workers living close to the participant’s home. Doses taken on weekends and on 
holidays may be under DOT or self-administered, as permitted by local TB 
guidelines. 
 
6.3.16 Questionnaires 
 
Questionnaires are posted on the DMC Portal in the Forms Management Utility. 
 
WHO Quality of Life-BREF (WHOQOL-BREF): Arm 1 and Arm 2 only 
The WHOQOL-BREF will be administered to assess how participants feel about 
their quality of life, health and other areas of their life, and will be conducted 
according to section 6.1. 
 
Center for Epidemiologic Studies Depression Scale (CES-D) 
The CES-D will be administered to screen for depression in participants, and will 
be conducted according to section 6.1. 
 
6.3.17 Open-Ended Qualitative Interview: Arm 1 and Arm 2 only 
 
An open-ended interview will be conducted in 20 consenting participants in each 
arm balanced by site to obtain ethnographic data on the impact of perceived skin 
color changes on their quality of life. 
 


 
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7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant during the 
conduct of the study REGARDLESS of the attribution (i.e., relationship of event to 
medical treatment/study product/device or procedure/intervention). This includes any 
occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition. 
 
7.2 
Adverse Event Collection Requirements for this Study  
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met. 
• 
All AEs that led to a change in study treatment/intervention regardless of grade 
• 
All AEs meeting SAE definition or EAE reporting requirement 
• 
All Grade ≥3 AEs 
• 
All Grade ≥2 AEs for the following conditions: 
o Conduction abnormality/atrioventricular heart block 
o Hyperpigmentation 
o Dry skin 
o Photosensitivity 
o Pruritus/itching 
o Rash 
o Hair loss/alopecia 
o Suicidal ideation or attempt 
 
Note: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting 
system. 
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (DAIDS AE Grading Table), Corrected Version 2.1, July 2017, which can be 
found on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
 
Serious Adverse Events (SAEs) 
A SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
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• 
Is an important medical event that 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 other outcomes listed in the definition above). 
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events 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 https://rsc.niaid.nih.gov/clinical-research-sites/manual-
expedited-reporting-adverse-events-daids.  
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
system outages or technical difficulties, EAEs may be submitted using the DAIDS 
EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that 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). 
 
7.3.2  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 from the time of enrollment through week 
65 for all participants.  
 
• 
The study agents for which expedited reporting is required are: 
o Investigational agents: 
▪ Clofazimine 
▪ Rifapentine  
o Study-supplied standard TB drugs: 
▪ Isoniazid  
▪ Pyrazinamide  
▪ Ethambutol  
▪ Rifampicin 
 
7.3.3 Grading Severity of Events 
 
Except for QTcF prolongation (which will be graded according to Table 8.2.1-1), 
adverse events must be graded according to the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading 


 
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Table), Corrected Version 2.1, July 2017, available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables.  
 
7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is the entire study duration 
for an individual participant (from study enrollment until study completion or 
discontinuation of the participant from study participation for any reason). 
• 
After the protocol-defined EAE reporting period, unless otherwise noted, only 
suspected unexpected serious adverse reactions (SUSARs) as defined in 
Version 2.0 of the DAIDS EAE Manual will be reported to DAIDS if the study 
staff become aware of the events on a passive basis (e.g., from publicly 
available information). 
 
7.4 
Study Monitoring 
 
The protocol team will monitor the conduct and safety of the study via regular summaries 
of screening failures, accrual, deaths, SAEs, AEs, study discontinuation, and 
delinquency of forms, data, or specimens pooled across treatment arms. The A5362 
Clinical Management Committee (CMC) will be provided with and monitor QT 
prolongation, early recurrence, and unfavorable composite outcome in Arm 1 
participants. 
 
The DAIDS clinical representative will review and assess select EAE reports for potential 
impact on the study participant safety and protocol conduct as per DAIDS policies, 
guidance documents, and SOPs, as applicable. Additionally, the DAIDS clinical 
representative will review aggregated AEs pooled over treatment arms prepared 
quarterly by the Statistical and Data Analysis Center (SDAC).  
 
The study will be reviewed by the DSMB at least every 6 months or on another 
schedule requested by the DSMB. The first interim review will occur 4-6 months 
after the first enrollment. In addition, there are several triggers for unplanned 
reviews based on Arm 1 participants with prolonged QTcF interval, recurrences, 
and unfavorable composite outcomes during the course of the study. The primary 
outcome of 12-week time to culture conversion will be analyzed as soon as the 
complete data is available. Depending on the timing of the culture conversion 
analysis, the DSMB review schedule may need to be adjusted in order to review 
the final results for the primary outcome and make a recommendation as to 
whether the study should continue as planned. An ad hoc DSMB review of the 
data may be requested by the study team or the DAIDS clinical representative if 
there are serious concerns. See section 10.5 for additional considerations (e.g., 
triggers) related to interim monitoring. 
 
Detailed plans for study monitoring will be outlined in a Study Progress, Data, and 
Safety Monitoring Plan developed by the SDMC prior to enrollment of the first 
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8.0 
CLINICAL MANAGEMENT ISSUES  
 
Criteria for participant management, dose interruptions, modifications, and 
discontinuation of treatment are mandated only for toxicities attributable to study-
provided drugs. The protocol Clinical Management Committee (CMC) must be notified 
within 48 hours regarding toxicities that result in a change in study treatment (including 
transitory or permanent discontinuation) during the study-defined treatment period.  
 
8.1 
Toxicity  
 
8.1.1 Grade 1 or Grade 2 Toxicity 
 
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 
should be corrected and rechecked. 
 
8.1.2 Grade 3 Toxicity 
 
For any Grade 3 AE or toxicity thought to be secondary to study drugs or of 
unknown etiology, inclusive of those noted in section 8.2, site investigators must 
discuss toxicity management with the A5362 CMC. 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 
below, 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. 
Investigators will discuss toxicity management with the A5362 CMC and study 
drugs may be restarted sequentially, 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 until the AE returns to Grade 2 or 
until stabilized and clinically no longer in need of weekly 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 National Tuberculosis Program (NTP) for treatment according to local 
standards of care. They will continue to be followed on-study, off study drugs. In 
some cases, this will require discontinuation of the co-formulated drugs in place 
of individual components or alternate anti-TB medications. These cases should 
be managed individually in conjunction with the A5362 CMC. To the extent 
possible, such participants will continue to be followed on-study, off study drugs. 
 
8.1.3 Grade 4 Toxicity 
 
For any Grade 4 AE or toxicity thought to be secondary to study drugs or of unknown 
etiology, inclusive of those noted in section 8.2, site investigators will discuss toxicity 
management with the A5362 CMC. For a Grade 4 event thought to be secondary to 


 
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study drugs (decided in conjunction with the A5362 CMC), the participant will be 
hospitalized and discontinued permanently from study TB medications. The 
participant will be referred to the NTP for TB treatment according to local standards 
of care. The participant will continue to be followed on study, off study drugs. 
 
8.2 
Specific Conditions 
 
8.2.1 QTcF Prolongation 
 
Participants who receive CFZ (with some also receiving EFV) have the potential 
of prolongation of the QTcF interval. Grading is based on the average of triplicate 
ECGs at each visit. Grading is as follows: 
 
Table 8.2.1-1: QTcF Prolongation Grading 
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, 
CFZ will be discontinued and the participant will be hospitalized for monitoring 
until the abnormality returns to Grade ≤2. Electrolytes will be checked and 
repleted where necessary. Repeat ECG following repletion of electrolytes will be 
performed within 3 days, and if QTcF reading is a Grade ≤2, CFZ may be 
restarted, at the discretion of the investigator. If Grade 3 finding remains, CFZ 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 TB treatment according to local standards of care. The participant will 
continue to be followed on study, off study drugs. 
 
The following events should be reported to the A5362 CMC and to DAIDS 
immediately: 
• 
Grade 4 QT prolongations 


 
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• 
Deaths 
• 
Results of repeated ECGs after holding CFZ for Grade 3 events 
 
8.2.2 ALT or Total Bilirubin Elevation 
 
Many anti-TB drugs, including the study-provided drugs and components of SOC 
can cause alterations in liver chemistry tests. Participants entering this trial will 
have active TB. Elevation in liver function tests is expected. Concomitant 
illnesses, including HIV infection, and other medications, such as antiretrovirals, 
may also alter these laboratory parameters. Therefore, changes in liver chemistry 
tests (ALT, bilirubin) should be evaluated within the clinical context of the 
abnormalities. Liver chemistry tests will be checked regularly for all study 
participants, as per section 6.1. All participants who have new Grade ≥3 
elevation of ALT should be evaluated for hepatitis B and C virus infection. If there 
has been documented acute viral hepatitis, the A5362 CMC should be consulted 
regarding management of study medications. 
 
For participants who develop asymptomatic or symptomatic Grade 3 elevations 
during study treatment, and, after discussion with the study team), the elevations 
are not attributed to documented acute viral hepatitis, study-provided drugs and 
SOC (and ART, if applicable) should be discontinued for up to 2 weeks. Liver 
function and chemistry tests should be repeated weekly and study-provided 
drugs and SOC (and ART, if applicable) held until levels and symptoms are 
Grade ≤2, at which time therapy may be reintroduced. After consultation with the 
team, if there has been documented acute viral hepatitis and the ALT or total 
bilirubin takes longer than 14 days to reach Grade ≤2 toxicity, study-provided 
drugs may be restarted.  
 
If Grade 3 toxicity recurs after re-introduction of study-provided drugs and SOC 
(and ART, if applicable), or if Grade 3 toxicity does not resolve within 14 days, or 
if any Grade 4 toxicity develops, the participant will have study-provided drugs 
permanently discontinued and will be referred to the NTP for TB treatment 
according to local standards of care. Participants permanently discontinued from 
ART will be referred to their local HIV clinic or provider for HIV treatment 
according to local standards of care. The participant will continue to be followed 
on study, off study-provided drugs.  
 
8.2.3 Allergic Reaction 
 
Participants may continue study drugs for Grade 1 or Grade 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. 
 
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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. 
 
8.2.4 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 participants may 
be taking.  
 
Participants with a Grade 1 rash may continue study drugs at the study 
investigator’s discretion. Investigators are advised to contact the A5362 CMC 
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  
• 
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 
• 
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 TB and HIV treatment, according to local standards of care. The 
participant will continue to be followed on study, off study drugs. 
 


 
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8.2.5 Abdominal Pain, Nausea and/or Vomiting 
 
Although not uncommon, nausea following initiation of therapy with CFZ and/or 
antiretroviral medications is usually mild and subsides or resolves during 
treatment. Steps in the management of nausea include taking the medication 
with food and administration of antiemetic. Antiemetics can only be used if they 
do not have drug-drug interactions with the study-provided drugs and if they do 
not have overlapping toxicities with the study-provided drugs.  
 
Participants with Grade ≥3 vomiting or abdominal pain, in particular during the 
loading dose phase of CFZ, should have their hydration status assessed and be 
referred to appropriate local medical care for monitoring and volume resuscitation 
or nasogastric suction, respectively, if clinically indicated depending on site-
specific standard practices. If Grade 3 or Grade 4 abdominal pain, nausea and/or 
vomiting occurs, if there is compelling evidence that these have NOT been caused 
by study-provided drugs, dosing may continue and supportive care given. If, after 
discussion with the A5362 CMC, the site investigator determines that Grade 3 or 
Grade 4 abdominal pain, nausea and/or vomiting is possibly or probably related to 
study-provided drugs then study-provided drugs may be temporarily held for up to 
14 days until these symptoms return to Grade ≤2. If symptoms do not reach 
Grade ≤2 within 14 days or if Grade 3 or Grade 4 symptoms occur after 
reintroduction, then study-provided drugs should be permanently discontinued 
and the participant referred to his/her national TB program or local TB 
clinic/provider for treatment of his/her TB according to local SOC. These 
participants will continue to be followed on study, but off study-provided drugs. 
 
8.2.6 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. 
Anti-diarrheals (e.g., loperamide) can be used only 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 local standard practices. 
 
Participants with Grade 3 or Grade 4 diarrhea can have their study medications held 
for up to 14 days until toxicity resolves to Grade ≤2. If toxicity does not resolve to 
Grade ≤2 within 14 days, or if Grade 3 or Grade 4 diarrhea occurs after reintroduction, 
the participant will be discontinued from study medications and referred to the NTP for 
TB treatment and to the local HIV clinic for HIV treatment according to local standards 
of care. The participant will continue to be followed on study, off study drugs. 
 


 
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8.2.7 Peripheral Neuropathy 
 
Isoniazid has been associated with the development of peripheral neuropathy. If a 
participant develops new or worsening Grade 1 or Grade 2 peripheral neuropathy 
during the course of the study, the participant will continue on isoniazid, 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 a participant develops new or worsening Grade 3 or 
Grade 4 peripheral neuropathy, isoniazid will be temporarily discontinued and the 
participant will be provided pyridoxine 100 mg daily. If symptoms do not stabilize 
or improve after 14 days, isoniazid will not be restarted, and the participant will be 
discontinued from study medications and referred to the NTP for TB treatment 
according to local standards of care and followed on study, off study drugs. 
 
8.2.8 Arthritis/Arthralgia 
 
Arthritis and arthralgia are common symptoms experienced by participants on 
pyrazinamide.  
 
If a participant develops Grade ≤3 arthritis or arthralgia during the course of the 
study, the participant will continue on study drugs and be treated according to local 
standard practices. If the participant develops Grade 4 arthritis or arthralgia, 
pyrazinamide will be held for up to 14 days until toxicity resolves to Grade ≤2. If 
toxicity does not resolve to Grade ≤2 within 14 days, the participant will be 
discontinued from study medications and referred to the NTP for TB treatment 
according to local standards of care and followed on study, off study drugs. If 
toxicity resolves to Grade <2 within 14 days but Grade 4 arthritis or arthralgia occur 
after reintroduction of pyrazinamide, pyrazinamide will be permanently stopped. 
 
8.2.9 Depression  
 
Participants living with HIV may occasionally present with symptoms of 
depression and/or suicidality (suicidal ideation or behavior). In addition, there 
have been reports of depression, suicidal ideation and behavior (particularly in 
participants with a pre-existing history of depression or psychiatric illness) in 
participants treated with CFZ or integrase inhibitors. Therefore, it is appropriate 
to monitor participants for depression before and during treatment.  
 
If depression occurs, participants should be monitored and referred appropriately for 
unusual changes in behavior. It is recommended that the investigator consider mental 
health consultation or referral for participants who experience moderate (score 16-19 on 
CES-D) or severe (score >20 on CES-D) depression. In the case of severe depression, 
the investigator should arrange for escort of the participant to mental health services. 
 
If Grade 3 (severe mood alteration interfering with activities of daily living (CES-D 
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is compelling evidence that these have NOT been caused by study-provided drugs, 
dosing may continue, and supportive care given. If, after discussion with the study 
team, the site investigator determines that Grade 3 or Grade 4 mood alteration is 
possibly or probably related to study-provided drugs then study-provided drugs will 
be temporarily held for up to 14 days until symptoms return to Grade ≤2. If 
symptoms do not reach Grade ≤2 within 14 days or if Grade 3 or Grade 4 symptoms 
occur after reintroduction, then study-provided drugs should be permanently 
discontinued, and the participant referred to his/her national TB program or local TB 
clinic/provider for treatment of his/her TB according to local SOC. These 
participants will continue to be followed on study, but off study-provided drugs.  
 
If the participant expresses suicidal ideations or intents, the data will be captured 
as an AE. Any suicidal thought or suicide attempt that qualifies as an EAE will be 
reported using the standard EAE mechanism. 
 
8.3  
Pregnancy  
 
Pregnancy and pregnancy outcomes that occur on study among females taking ART will 
be recorded on the eCRFs. Pregnancies that occur on study should be reported 
prospectively to the Antiretroviral Pregnancy Registry. More information is available at 
www.apregistry.com. Telephone: 910-679-1598; Fax: 44-1628-789-666 or 910-256-0637.) 
 
Pregnancy Outcomes and Reporting 
If a participant becomes pregnant during the study, she will be discontinued from study 
medications and referred to the NTP for the treatment of TB according to local standards 
of care, and to a prenatal care program for management of her pregnancy according to 
local standards of care. Women living with HIV will be referred to their local HIV clinic for 
appropriate care. Women 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 the outcome eCRFs.  
 
If a female participant has completed the study or chooses to discontinue from the study 
before the end of the pregnancy, 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 the eCRFs at the end of the pregnancy.  
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Serious drug-related toxicity (see sections 8.1 and 8.2). 
• 
Requirement for prohibited concomitant medications (see section 5.4). 
• 
Completion of treatment as defined in the protocol. 
• 
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• 
Participants whose screening, entry, and first post-entry visit sputum cultures all fail 
to grow Mtb complex. 
• 
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. 
 
9.2 
Premature Study Discontinuation 
 
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if he or she thinks the study is no longer in the 
best interest of the participant. 
• 
At the discretion of the ACTG, IRB/EC, FDA, NIAID, Office for Human Research 
Protections (OHRP), and other US, local, and international regulatory entities as part 
of their duties to ensure that research participants are protected, or the industry 
supporter or its designee. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
General Design Issues 
 
This is an open-label, randomized phase IIc study to evaluate whether a 3-month 
regimen of PHZE + 100 mg CFZ with a 2-week loading dose is superior to the standard 
6-month regimen of RHZE for DS-TB with respect to early bacteriologic efficacy defined 
as time to culture conversion by 12 weeks post-randomization. Additionally, participants 
will be followed for up to 65 weeks in order to characterize and compare safety, relapse 
rates, and a composite long-term favorable outcome 1 year post-randomization as key 
secondary outcomes.  
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures below will be addressed in the study’s 
primary Statistical Analysis Plan, which will define the content of the Primary Analysis 
Report. This report will form the basis for the primary study manuscript and results 
reporting to ClinicalTrials.gov. Outcomes of interest for secondary and exploratory 
objectives intended for subsequent publication are listed under “Exploratory Outcome 
Measures.” 
 
10.2.1 Primary Outcomes 
 
10.2.1.1 Time to stable culture conversion in liquid media, defined as the first of 
two (consecutive or non-consecutive) negative sputum cultures without 
an intervening positive culture, and/or visits wherein the participant is 
unable to produce sputum and has no signs of active TB, up to 12 
weeks post-randomization. [Objective 1.2.1.1] 


 
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10.2.1.2 Safety: proportion across study arms experiencing any Grade 3 or 
higher AE that is at least a one grade increase from baseline over 65 
weeks. [Objective 1.2.1.2] 
 
10.2.2 Secondary Outcomes 
 
10.2.2.1   A. 
Efficacy: proportion with favorable clinical/bacteriologic outcome     
(definition 10.2.4.A) at 65 weeks post-randomization. [Objective 
1.3.8] 
 
B.  Efficacy: proportion with favorable composite outcome including 
treatment completion (definition 10.2.4.B) at 65 weeks post-
randomization.  
 
 
C. Efficacy: proportion with favorable composite outcome including 
treatment completion (definition 10.2.4.B) at 65 weeks post-
randomization. [Objective 1.3.1]  
 
10.2.2.2 Tolerability: proportion with premature treatment discontinuation 
through 65 weeks, defined as discontinuation other than due to violent 
death, natural disaster, or administrative censoring. [Objective 1.3.2] 
 
10.2.2.3   A.  Mean baseline QTcF and change from baseline in mean QTcF at 
weeks 2, 8, and end of treatment (EOT) (Arm 1, week 13; Arm 2, 
week 26).  
 
B. Occurrence of absolute QTcF ≥480 ms and ≤500 ms, and ≥500 
ms, at any time during study treatment. 
 
C. Occurrence of QTcF change from baseline of ≥30 ms and ≤60 ms,    
and ≥60 ms, at any time during study treatment. [Objectives 1.3.3 
and 1.4.1.1] 
 
10.2.2.4 Time to stable culture conversion in liquid and solid media through 
week 65 defined as the first of two (consecutive or non-consecutive) 
negative sputum cultures without an intervening positive culture, 
and/or visits wherein the participant is unable to produce sputum and 
has no signs of active TB. [Objectives 1.3.4, 1.4.1.2, and 1.4.7.2] 
 
10.2.2.5 Proportion of participants achieving culture conversion at weeks 8 and 12 
(liquid MGIT and solid media considered separately). [Objective 1.3.5] 
 
10.2.2.6 Time (days) to positivity in liquid culture (MGIT) after start of 
treatment through week 65. [Objectives 1.3.6 and 1.4.1.3] 
 


 
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10.2.2.7    Change in chest X-ray score from baseline to EOT. [Objective 1.3.7] 
 
10.2.2.8    Proportion of participants with one or more SAEs through week 65. 
[Objective 1.2.1.2] 
 
10.2.2.9 Proportion of participants who have a TB relapse, from EOT until week 
65. [Objective 1.3.9] 
10.2.2.10 Proportion of participants who have a TB recurrence, from EOT until 
week 65. [Objective 1.3.9] 
 
10.2.2.11 Plasma pharmacokinetic parameters for CFZ, estimated using 
noncompartmental methods applied to concentrations from intensive PK 
sampling visits at weeks 2 (Arm 1 and Arm C) and 13 (Arm 1). Minimum 
concentration (Cmin), maximum concentration (Cmax), time of Cmax (Tmax), and 
area under the concentration curve (AUC0-24h). Weeks 2 and 13 PK 
parameters will be summarized separately. [Objectives 1.3.10 and, 1.3.11] 
 
10.2.2.12 Change from baseline in skin pigmentation (colorimetric L*, a*, b* 
parameters) utilizing ambient light-independent reﬂectance 
mapping at weeks 8, 13, 26, and 65. [Objective 1.3.12] 
 
10.2.2.13 Change from baseline in participant-reported changes in skin 
pigment and distress related to perceived skin hyperpigmentation 
at weeks 8, 13, 26, and 65. [Objective 1.3.12] 
 
10.2.3 Exploratory Outcomes 
 
10.2.3.1 CFZ-associated adverse events through week 65. [Objective 1.4.1.4] 
 
10.2.3.2 Acquired drug resistance to CFZ through week 65. [Objective 1.4.1.5] 
 
10.2.3.3 Plasma pharmacokinetic parameters for rifapentine (RPT), estimated 
using noncompartmental methods applied to concentrations from 
intensive PK sampling visits for Arms 1 (Week 2 and Week 13) and C 
(Week 2) (Cmin, Cmax, Tmax, AUC0-24h). [Objective 1.4.2] 
 
10.2.3.4 Qualitative interview at EOT (Arm 1, week 13; Arm 2, week 26) to 
assess participant experiences with social stigma and impact of 
perceived skin changes on quality of life. [Objective 1.4.4] 
 
10.2.3.5 Change from baseline in participant-reported quality of life as 
measured by the WHOQOL-BREF at weeks 8, 13, 26, and 65. 
[Objectives 1.4.1 and 1.4.5] 
 
10.2.3.6 Change from baseline in CES-D score at weeks 8, 13, 26, and 65. 
[Objective 1.4.6] 


 
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10.2.3.7 Sputum RS ratio at weeks 1, 2, 3, 4 (Arm 1 and Arm C) or weeks 2 
and 4 (Arm 2) and at time of Possible Poor Treatment Response 
(Arm 1, Arm 2, and Arm C). [Objectives 1.4.7.1, 1.4.7.2, 1.4.7.3, 
1.4.7.4, and 1.4.7.5] 
 
10.2.3.8 Population PK model parameters of CFZ through week 65. 
[Objectives 1.3.10, 1.4.1.1, 1.4.1.2, 1.4.1.3, 1.4.1.4, and 1.4.1.5]  
 
10.2.4 Definitions of Secondary Composite Outcome Status 
 
For the key secondary analysis of favorable composite outcome, each participant 
will be classified into one of three outcome categories: Favorable, Unfavorable, 
or Unevaluable. If unevaluable, the participant will be censored at the time of 
their last visit from efficacy analyses.  
 
A. Clinical/bacteriologic efficacy outcome measure (refers to 10.2.2.1A) 
 
Favorable Outcome (any one of the following scenarios) 
• 
Participants with liquid culture negative status at week 65.  
• 
Participants without signs or symptoms of ongoing active TB and are unable 
to produce a sputum specimen at 65 weeks. 
• 
Participants who at the end of the follow-up period are clinically without 
symptoms/signs of ongoing active TB and produce a sputum specimen that is 
contaminated in two liquid cultures without evidence of TB. 
 
For any of the above to be considered favorable, participants must not already 
have been considered unfavorable, as defined below. 
 
Unfavorable Outcome 
• 
Absence of cure. A participant will be considered to have absence of 
bacteriological cure if a sputum sample obtained at or after end of treatment 
for Arm 1 (week 13), or at or after week 17 for Arm 2 is culture-positive in 
liquid or solid media for an Mtb strain genotypically matched with the initial 
isolate. A second sputum sample, obtained at least four hours following the 
first sputum collection (see section 6.2.3), is required to confirm absence of 
bacteriological cure.  
• 
Participants who die from any cause during study treatment or follow-up 
except from violent or accidental cause (e.g., road traffic accident). 
• 
Participants who had a positive culture for Mtb when last seen, whether 
confirmed by a second sample or not, unless determined to have been re-
infected. 
• 
Participants experiencing extension of treatment beyond the nominal level 
(week 13 for Arm 1 and week 26 for Arm 2) due to clinically inadequate 
response. These cases should be managed individually in conjunction with 


 
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and after having notified the A5362 CMC. Extension of treatment to make up 
missed doses will not count as unfavorable. 
 
Unevaluable Outcome 
• 
Participants lost to follow-up during treatment or post-treatment follow-up with 
their last culture being negative for Mtb.  
• 
Violent or accidental death.  
• 
Participants with recurrent TB due to a new strain of Mtb confirmed by 
conventional molecular genotyping (as defined by MIRU and IS6110 typing). 
• 
Women who become pregnant during their assigned active treatment and 
stop their assigned treatment. 
 
B. Composite efficacy outcome measure (refers to 10.2.2.1B) 
 
Favorable Outcome 
Same as in Outcome Measure 10.2.2.1A. 
 
Unfavorable Outcome 
Same as in Outcome Measure 10.2.2.1A, and: 
• 
Participants lost to follow-up during treatment phase of each Arm (i.e., 13 
weeks and 26 weeks for Arms 1 and 2, respectively). 
• 
Participants failing to complete treatment (see sections 10.2.5 and 10.2.6, 
Definitions of Adequate Treatment) and not assessable at the end of the 
follow-up period. 
• 
Participants receiving any one or more of the following: 
o Extension of treatment beyond the nominal level, except to make up 
missed doses 
o A re-start of treatment following ≥30 consecutive days lost to follow-up 
o A change in at least one drug in treatment regimen for any reason except 
re-infection, pregnancy, or temporary drug challenge. 
 
Unevaluable Outcome 
• 
Participants lost to follow-up after treatment phase, and not assessable at the 
end of follow-up, with their last culture being negative for Mtb.  
• 
Violent or accidental death. 
• 
Participants re-infected with a new strain of Mtb confirmed by conventional 
molecular genotyping (as defined by MIRU and IS6110 typing). 
• 
Women who become pregnant during their assigned active treatment and 
stop their assigned treatment. 
  
10.2.5 Definitions of Adequate Treatment Within 3-month Regimen (Arm 1) 
• 
Taken a total of at least 56 doses of allocated intensive phase treatment 
within 70 days of starting treatment 
• 
AND taken at least 28 doses of continuation phase treatment within 49 days 
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• 
AND missed no more than 21 doses of medication overall. 
 
10.2.6 Definitions of Adequate Treatment within 6-month Regimen (Arm 2) 
• 
Taken a total of at least 56 doses of allocated intensive phase treatment 
within 70 days of starting treatment 
• 
AND taken at least 100 doses of continuation phase treatment within 154 
days (22 weeks) of completion of the intensive phase 
• 
AND missed no more than 42 doses of medication overall. 
 
10.3 
Randomization and Stratification 
 
If willing to consent to random assignment in Arm C, participants will be randomized in a 
2:1:1 ratio between Arms 1, 2, or C, using permuted blocks, balanced by institution. If 
unwilling to consent to random assignment in Arm C, participants will be randomized in a 
2:1 ratio between Arms 1 or 2 only, using permuted blocks, balanced by institution. 
Participants will be stratified based on HIV status, and by presence of advanced disease 
on chest X-ray (see section 6.3.11) conducted at screening. 
 
The first 20 participants randomized to Arm 1 who also consent to intensive PK 
sampling will be registered to the Intensive PK Sampling subgroup. Participants 
who withdraw consent for participation in the Intensive PK sampling in Arm 1 or 
Arm C will be replaced.  In both Arm 1 and Arm C, accrual will be limited to 6 
participants per site with intensive PK sampling.  If fewer than 4 sites are able to 
carry out intensive PK sampling then the accrual limit per site will be increased in 
order to reach the target sample size of 20. 
 
The first 20 participants randomized to each of Arm 1 and Arm 2 who also consent 
to answering an open-ended qualitative interview at the end of treatment will be 
registered to the Qualitative Interview subgroup. We will use accrual limits to 
balance enrollment to the Qualitative Interview subgroup by site and by treatment 
arm. Participants who withdraw consent for participation in the Qualitative 
Interview subgroup will be replaced. 
 
NOTE: Participants in Arm 1 may consent to both intensive PK sampling and 
qualitative interview, one, or neither. 
 
Consent into Arm C predicated on participant willingness to undergo intensive PK 
studies, potentially indicating a relatively “healthier” group, raises the possibility of 
selection bias for a comparison of safety rates between Arm C (CFZ no loading dose) 
with Arm 1 (CFZ loading dose). However, (1) PK concentrations are the primary 
comparison of interest between these arms, and these should be unbiased (since the 
comparative groups are both willing to undergo intensive PK studies by nature of their 
inclusion); (2) we note the expectation that better safety will occur with Arm C vs. Arm 1, 
given the lack of loading dose; and (3) alternative randomization schemes, such as 
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of enrollment, risk considerable correlate problems with respect to external validity. 
 
10.4 
Sample Size and Accrual 
 
Primary Efficacy Outcome 
For the primary efficacy outcome, we plan to compare time to liquid culture conversion 
between Arm 1 (CFZ load) and Arm 2 (SOC) up to 12 weeks, a common surrogate 
endpoint for Phase II TB trials. For a treatment-shortening regimen to work effectively, it 
is reasonable to assume that it is necessary for culture conversion rates in the 
experimental arms to be faster than in SOC. Under a proportional hazards model, effect 
sizes that are inversely proportional to length of treatment would correspond to a 
necessary hazard ratio of 2.0 for the 3-month arm. The high-dose rifampicin trial 
conducted by the PanACEA [107] consortium assumed a true hazard ratio (HR) of 1.8 
would indicate potential for treatment shortening since it represented an increase over 
the HR 1.68 seen in the Phase II trial that led to the Phase III REMox trial (which was 
ultimately unable to demonstrate non-inferiority). We also propose that a true HR of at 
least 1.8 would be necessary for the 3-month arm to have potential as a shortened 
regimen comparable to SOC.  
 
Under a 70% 12-week culture conversion event proportion in the control arm (Table 
10.4-1), a true hazard ratio of 1.8 for Arm 1 vs. Arm 2, a one-sided alpha level of 0.05, 
and a 2:1 randomization allocation to Arm 1: Arm 2, we would need a total of 150 
evaluable participants to have 90% power to reject the null hypothesis that there is no 
difference in time to 12-week culture conversion between the experimental and control 
arms. Assuming approximately 10% are late exclusions, withdraw, or have several 
missing culture results, we propose to enroll 165 participants for efficacy analyses (110 
Arm 1, 55 Arm 2). 
 
Table 10.4-1: Comparative Historical SOC Efficacy Rates 
Trial 
12-week MGIT 
Culture 
Conversion in 
Control Arms 
(Primary 
Outcome) 
 52-week 
Bacteriologic/ 
Clinical Efficacy 
(Secondary 
Outcome; 
10.2.2.1A) 
52-week 
Composite 
Treatment 
Outcome 
(Secondary 
Outcome; 
10.2.2.1B) (mITT) 
52-week 
Composite 
Treatment 
Outcome 
(Secondary 
Outcome; 
10.2.2.1B) (Per 
Protocol) 
REMox [108]  
65-70% (12-week) 
89% 
89% 
91% 
OFLOTUB 
[109]  
-- 2 
88.4%
4
 
82.8% (104 
weeks);
1
 N=694 
88.7%
4
 
RIFAQUIN 
[110] 
81% (8-week)3 
91.2%
4
 
85.6% (78 weeks); 
N=188
4
 
95.1%
4
 


 
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Trial 
12-week MGIT 
Culture 
Conversion in 
Control Arms 
(Primary 
Outcome) 
 52-week 
Bacteriologic/ 
Clinical Efficacy 
(Secondary 
Outcome; 
10.2.2.1A) 
52-week 
Composite 
Treatment 
Outcome 
(Secondary 
Outcome; 
10.2.2.1B) (mITT) 
52-week 
Composite 
Treatment 
Outcome 
(Secondary 
Outcome; 
10.2.2.1B) (Per 
Protocol) 
PanACEA [107] 70.1% (12-week) 
-- 
-- 
-- 
Adopted A5362 
parameters 
70% 
88-92% 
84-90% 
90-94% 
Please see section 10.2.4 for definition of efficacy outcomes.  
1  24 months from end of treatment; other values are from time of randomization 
2  Performed only on solid culture 
3  MGIT only performed at certain sites and only at week 8 
4  Only 76-week outcome available  
 
Primary Safety Outcome 
For the primary safety outcome, we will compare proportions of participants with any 
Grade 3 or higher AE between arms. Table 10.4-2 gives the power we would have to 
detect that Arm 1 is inferior to Arm 2 assuming a two-sided type 1 error of 0.10, 10% 
probability of developing an AE in the SOC arm, and varying probabilities (15-30%) of 
developing an AE in experimental arm. The 90% confidence interval width is also 
provided for the comparison. 
 
Table 10.4-2: Primary Safety Outcome Comparison 
Power 
N1 
N2 
N 
Arm 1 
Proportion 
with 
Grade ≥3 
AE 
Arm 2 
Proportion 
with 
Grade ≥3 
AE Arm 2 
Two-
sided 
type 1 
error 
90% CI 
Width 
0.13 
100 
50 
150 
0.15 
0.10 
0.10 
0.210 
0.36 
100 
50 
150 
0.20 
0.10 
0.10 
0.218 
0.64 
100 
50 
150 
0.25 
0.10 
0.10 
0.225 
0.85 
100 
50 
150 
0.30 
0.10 
0.10 
0.230 
 
Secondary Efficacy Outcome 
For the secondary clinical/bacterial efficacy outcome (10.2.2.1A), we assume a favorable 
proportion of 88-92% in the control arm by week 65 (Col 2, Table 10.4-3). This estimate 
is based on the mITT control arms of the RIFAQUIN and REMox trials. Therefore, we 
assume a favorable proportion of 84-92% in the control arm by week 65 for efficacy 
outcome 10.2.2.1B. 
 


 
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For secondary outcome 10.2.2.1 (proportion with favorable composite outcome at 65 
weeks), using an unpooled Z-test with one-sided alpha of 0.05 and sample sizes of 100 
in Arm 1 and 50 in Arm 2, the power for a range of non-inferiority margins and favorable 
outcome proportions from 84% to 92% is given in Table 10.4-3. Note that a margin of 6-
7% (with a one-sided alpha of 0.025) is commonly used in Phase III drug-sensitive TB 
treatment-shortening trials [107-110], but we would have little power on this secondary 
endpoint to show non-inferiority based on that margin.  
 
Table 10.4-3: Composite Secondary Efficacy Outcome Power 
Favorable proportion in each arm 
NI Margin 
Power (%) 
0.84 
0.08 
35.0 
0.84 
0.10 
47.2 
0.84 
0.12 
59.7 
0.88 
0.08 
41.2 
0.88 
0.10 
55.2 
0.88 
0.12 
68.7 
0.92 
0.08 
52.3 
0.92 
0.10 
68.6 
0.92 
0.12 
81.8 
 
 
For this reason, we will not be making a formal comparison with a pre-specified margin, 
and will solely provide the 95% confidence interval for the difference in proportions 
between arms. If observed sample proportions in both arms were 0.84, 0.88, or 0.92, the 
95% one-sided lower confidence bound for the difference in proportions between arms 
would be -0.106, -0.094, or -0.080, respectively, using a Score confidence interval with 
continuity correction.  
 
Accrual 
The accrual rate is expected to be 30-40 participants per month, so the study is 
expected to fully accrue within approximately 6 months. 
 
Sample Size for PK Study 
Table 10.4-4 provides a summary of the expected margin of error (ME) under different 
levels of variability (quantified as coefficient of variance, CV%) and sample sizes. The 
sample size was selected to give sufficient precision in the estimation of geometric mean 
AUC0-24h for both CFZ and P. To account for a worst-case scenario, the highest identified 
and reported CV% was used which in this case is up to 83% variability in CFZ AUC 
reported by Nix et al. The variability in P is expected to be much lower, ~40 CV% 
according to Savic et al. Twenty patients with rich PK sampling is expected to be 
sufficient to get a margin of error of ~20% for the geometric mean of AUC0-24h for both 
CFZ and P. There will be 20 participants randomized to Arm C, the intensive PK 
sampling arm. Additionally, the first 20 participants on Arm 1 who consent to 
intensive PK sampling will be registered to the Intensive PK Sampling subgroup. 
 


 
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Table 10.4-4: Margin of Error (ME) for PK Parameter Estimates Given Different 
Expected Levels of Variability (CV%) and Sample Size (N) 
CV% 
30 
50 
80 
100 
N 
ME 
ME 
ME 
ME 
10 
0.136 
0.219 
0.327 
0.387 
15 
0.106 
0.171 
0.255 
0.312 
20 
0.090 
0.145 
0.216 
0.256 
25 
0.080 
0.128 
0.191 
0.226 
30 
0.072 
0.116 
0.173 
0.205 
60 
0.050 
0.080 
0.120 
0.142 
 
Sample Size for Qualitative Interview Subgroup  
For the qualitative study assessing social stigma related to skin color changes, we plan 
to sample a total of 40 participants (20 participants in Arm 1 and 20 participants in Arm 
2), balanced by site and treatment arm. The first 20 participants in each of Arm 1 and 
Arm 2 who consent to participation in the open-ended qualitative interview will be 
registered to the Qualitative Interview subgroup. 
 
10.5 
Data and Safety Event Monitoring  
 
Section 7.4 describes study monitoring, including details of reviews by the DSMB. 
In this section, the statistical considerations of stopping guidelines and interim 
analysis are described. 
 
For all reviews, the DSMB will be provided detailed information on safety, tolerability, 
and administrative aspects (including accrual, retention, and compliance with study 
requirements).  
 
10.5.1 Interim Monitoring Guidelines 
 
Early Assessment of QT Prolongation in Arm 1 
After we enroll the first 12 participants to Arm 1 and have evaluable AE data 
through week 2, we will assess the proportion of participants with prolonged QT 
interval defined by QTcF >500 ms. If the upper bound of the two-sided Pearson-
Klopper exact 95% confidence interval (CI) around the proportion of Arm 1 
participants exhibiting this AE (QTcF >500 ms) exceeds a threshold of 40%, the 
team will evaluate the events carefully in conjunction with the DAIDS Clinical 
Representatives and the DSMB to consider whether there should be a reduction 
in the CFZ loading dose to 200 mg daily for 2 weeks. Based on 12 participants 
having data, if two or more participants experience the AE, this evaluation will be 
prompted (i.e., the upper confidence limit would be >40%). Otherwise, if one or no 
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Ideal characteristics of the trigger for DAIDS Clinical Representatives and DSMB 
evaluation are that the threshold is: (1) unlikely to be exceeded for low 
probabilities of the targeted AE (e.g., less than 5%) and (2) likely to be exceeded 
for high probabilities of the AE (e.g., 20% and above). Table 10.5-1 shows the 
probabilities of a trigger occurring for a range of considered scenarios defined by 
the number of evaluated participants and several threshold values for a range of 
true AE rates. The team selected to evaluate the first 12 participants using a 
threshold of 40% because of its good operating characteristics. Specifically, if the 
true probability of the targeted AE is 5%, there is a low probability (11%) of 
triggering evaluation. Conversely, if the true AE probability is 30%, there is a high 
probability (91%) of triggering evaluation.  
 
Table 10.5-1: Probability that Upper Bound of an Exact Pearson-Klopper 95% 
 
Confidence Interval for the Probability of Adverse Event (AE, QTcF >500 ms) Is 
 
Above Several Thresholds for Selected Number of Observed Participants and 
 
True Rates of AE 
Number of 
Participants 
Evaluated 
True probability of 
QTcF 500 ms 
Threshold 
0.3 
0.35 
0.4 
8 
0.01 
1.0 
1.0 
0.08 
0.05 
1.0 
1.0 
0.34 
0.10 
1.0 
1.0 
0.58 
0.20 
1.0 
1.0 
0.83 
0.30 
1.0 
1.0 
0.94 
0.50 
1.0 
1.0 
1.0 
12 
0.01 
0.11 
0.12 
0.01 
0.05 
0.47 
0.46 
0.11 
0.10 
0.71 
0.72 
0.34 
0.20 
0.93 
0.93 
0.72 
0.30 
0.99 
0.99 
0.91 
0.50 
1.0 
1.0 
1.0 
15 
0.01 
0.14 
0.01 
0.01 
0.05 
0.55 
0.17 
0.17 
0.10 
0.79 
0.44 
0.45 
0.20 
0.97 
0.82 
0.83 
0.30 
1.0 
0.97 
0.97 
0.50 
1.0 
1.0 
1.0 
 
 


 
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Interim Futility Analysis  
There will be one interim futility analysis for the primary efficacy endpoint once 
50% of participants have reached week 12 of follow-up. The conditional 
power given the data available will be computed, and the DSMB could consider 
using a conditional power <0.2 as one criterion among many for early stoppage. 
 
Unfavorable Composite Outcome Monitoring in Arm 1 
Monitoring for unfavorable composite outcome will begin approximately 1 
month after the first participant completes treatment in Arm 1 and will continue 
approximately monthly and for each DSMB review until the end of the 
study. Two-sided 95% confidence bands for the cumulative probability of 
unfavorable outcome over time will be generated. If the lower confidence band 
for the cumulative probability exceeds 12% at any time, this will trigger a DSMB 
review. 
 
Early Recurrence Monitoring in Arm 1 
TB recurrence monitoring will begin approximately 2 months after the first 
participant completes treatment in Arm 1 and will continue approximately 
monthly and for each DSMB review until the end of the study. Two-sided 95% 
confidence bands for the cumulative probability of recurrence over time will be 
generated. If the lower confidence band for the cumulative probability exceeds 3% at 
any time, this will trigger a DSMB review. 
 
10.5.2 Interim Analysis Plan 
 
Conditional Power for the Futility Analysis 
The conditional power of the test statistic will be estimated once 50% of 
participants have reached week 12 of follow-up using two methods. The first 
method will be under the assumption that the future data follows the 
hypothesized difference between Arm 1 and Arm 2 (hazard ratio of 1.8 between 
arms). The second method will use the assumption that future data follows the 
estimated difference between Arm 1 and Arm 2 at the time of the review (the 
estimated hazard ratio). 
 


 
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Confidence Bands for Unfavorable Composite Outcome Probabilities 
The unfavorable composite outcome will only include treatment failures, 
treatment extensions, loss to follow-up while culture positive, recurrences, 
and deaths. Two-sided 95% confidence bands will be generated for the 
cumulative unfavorable composite outcome probability in Arm 1. Since Arm 2 
data will be lagging 3 months behind Arm 1, the will be presented alongside 
historical unfavorable proportions for SOC on the REMox, OFLOTUB, and 
RIFAQUIN trials, and A5362 SOC data as it becomes available. There will be no 
adjustment to the confidence bands for multiple looks. 
 
Confidence Bands for Early Recurrence Probabilities 
Recurrence captures both relapses and reinfections. Two-sided 95% 
confidence bands will be generated for the cumulative recurrence probability in 
Arm 1. Since Arm 2 data will be lagging 3 months behind Arm 1, the 
recurrence data will be presented alongside historical recurrence proportions 
for SOC on the REMox, OFLOTUB, and RIFAQUIN trials, and A5362 SOC data 
as it becomes available. There will be no adjustment to the confidence bands for 
multiple looks.  
 
10.6 
Analysis Sets 
• 
Efficacy set: 
All participants who are randomized to study treatment and are not late 
exclusions. (Participants will be late exclusions if they do not have any positive 
culture at screening, entry, or week 1, or if they have TB that is RIF resistant or 
INH resistant.) 
 
• 
Safety set: 
All participants who start assigned study treatment. 
 
• 
Start treatment/not late exclusion set: 
All participants who start assigned study treatment and are not late exclusions.  
 
• 
Alive/adequate treatment set: 
All participants who complete an adequate course of treatment as defined within 
sections 10.2.5 and 10.2.6 of the protocol and who do not die during treatment.  
 
• 
Per protocol set: 
All participants who start and complete assigned study treatment.  
 
10.7 
Analyses 
 
A separate Statistical Analysis Plan document describes the analysis of each 
outcome measure in detail.  
 


 
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Primary Outcome Measures 
 
Analysis of Outcome Measure 10.2.1.1 
The hazard ratio and 95% one-sided lower confidence interval for time to stable culture 
conversion in liquid media up to 12 weeks will be estimated using a Cox proportional 
hazards model in the efficacy set, comparing Arm 1 with Arm 2. The model will be 
adjusted for, at a minimum, stratification variables (HIV status, and radiographically 
advanced disease status), and site. Participants lost to follow-up prior to week 12 will be 
censored, and all participants who do not achieve culture conversion will be censored at 
week 12. If the lower confidence bound is greater than 0 (i.e., superiority/faster time to 
culture-conversion is demonstrated), we would conclude that the experimental arm has 
superior time to culture conversion and adequate clinical benefit to be studied further. 
 
Hazard ratios and confidence intervals will also be reported within subgroups of natal 
sex and race/ethnicity, and we will formally test if hazard ratios are independent of natal 
sex and race/ethnicity using interaction terms. 
 
As noted earlier, this analysis will be completed prior to the end of the study, and results 
will be provided to the DSMB as soon as they are available. 
 
Analysis of Outcome Measure 10.2.1.2 
We will estimate the proportion of participants with any AE Grade 3 or higher during 
follow-up that is at least one grade increase from baseline in the safety set comparing 
Arm 1 with Arm 2. Proportions will be estimated using the Kaplan-Meier estimator, with 
participants who are lost to follow-up censored at the time of their last follow-up visit. 
 
Secondary Outcome Measures 
 
Analysis of Outcome Measures 10.2.2.1A and 10.2.2.1B 
For the composite efficacy outcomes 10.2.2.1 A and B, we will calculate the 90% and 
95% two-sided confidence intervals for the difference in cumulative proportion having a 
favorable outcome by the final follow-up visit (week 65) between Arm 1 and Arm 2. The 
analysis for 10.2.2.1A will be carried out in the safety set, defined as all randomized 
participants who started their assigned study treatment. Participants who never started 
study treatment in either arm will be excluded from the analysis because including these 
participants would make the arms more similar and bias the comparison toward non-
inferiority. The favorable outcome proportion at week 65 will be estimated using a 
Kaplan-Meier estimator, with Greenwood’s estimate for the standard error. For outcome 
10.2.2.1A, participants who are re-infected, are late screening failures, or are lost to 
follow-up and culture negative at their last visit, will be censored at the time of their last 
follow-up. For the secondary composite outcome measure 10.2.2.1B, the analysis will 
be carried out in the per protocol set, defined as all participants who start and 
complete assigned study treatment. The same censoring criteria apply.  
 
Analysis of Outcome Measure 10.2.2.2 
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and prematurely discontinue study treatment between Arm 1 and Arm 2 using 
binomial proportions. We will report the exact 95% confidence interval for the 
difference in proportions. We will carry out this analysis in the start treatment/not 
late exclusion set.  
 
Analysis of Outcome Measure 10.2.2.3 
Change from baseline in QTcF over time will be compared between Arm 1 and Arm 2 
using a linear mixed-effects model. We will carry out this analysis in the safety set. 
Proportions of participants in each arm with maximum observed QTcF above 500 ms, 
between 480 and 500 ms, and 480 ms or less will be compared between arms using 
multinomial logistic regression; analogously for proportions of participants with observed 
change in QTcF from baseline above 60 ms, between 30 and 60 ms, and 30 ms or less. 
 
Analysis of Outcome Measure 10.2.2.4 
Time to stable culture conversion at week 65 will be assessed separately in liquid 
and solid media in each CFZ arm against the control arm using log-rank tests, and 
hazard ratios with two-sided 95% confidence intervals will be provided. Time to 
stable culture conversion within each study arm will be described graphically 
using Kaplan-Meier estimates. We will carry out this analysis in the efficacy set.  
 
Analysis of Outcome Measure 10.2.2.5 
We will estimate the proportion with culture conversion separately for liquid and 
solid media at weeks 8 and 12 in Arm 1 and Arm 2 with the Kaplan-Meier 
estimator. We will carry out the analysis in the efficacy set.  
 
Analysis of Outcome Measure 10.2.2.6 
Time to positivity will be compared separately at weeks 1, 2, 3, 4, 6, 8, 10, and 12 
using Cox proportional hazards models or log-rank tests. We will carry out this 
analysis in the efficacy set. 
 
Analysis of Outcome Measure 10.2.2.7 
The Chest X-ray Score (CXR Score) will be computed based on the chest x-rays 
conducted during screening and at the end of treatment using the following 
validated formula [106]: CXR Score = percent of total lung affected by any 
pathology + 40 (if cavitation is present). We will compute the CXR scores based on 
both site assessment of the chest x-ray and an assessment by independent 
central reviewers blinded to study treatment. We will compare the mean change in 
CXR score between Arms 1 and 2 from baseline to end of treatment using t-tests. 
We will carry out this analysis in the efficacy set.  
 
Analysis of Outcome Measure 10.2.2.8 
We will estimate the proportion of participants in Arm 1 and Arm 2 with one or more 
SAEs using the Kaplan-Meier estimator. We will carry out this analysis in the safety set. 
 
Analysis of Outcome Measure 10.2.2.9 
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estimated using the Kaplan-Meier estimator. We will carry out this analysis in the 
start treatment/not late exclusion set.  
 
Analysis of Outcome Measure 10.2.2.10 
The proportion of participants who experience recurrence will be estimated 
similarly as above. 
 
Analysis of Outcome Measure 10.2.2.11 
A population PK model will be developed based on the intensive and sparse PK 
sampling. The PK parameters for CFZ in Arm 1 and Arm C will be estimated using 
non-compartmental methods applied to concentrations from intensive PK 
sampling visits. We will estimate the geometric mean ratio for each PK parameter 
together with the 90% confidence interval using available data in the 
alive/adequate treatment set.  
 
Analysis of Outcome Measure 10.2.2.12 
We will estimate the total color difference scores using the CIE76 formula. We will 
compare the mean change in total color difference from week 0 to each of weeks 
8, 13, 26, and 65 at each anatomical location of interest. We will compare 
differences between arms with a t-test. We will carry out each of these analyses in 
the safety set.  
 
Analysis of Outcome Measure 10.2.2.13 
We will compare the subjective “mean change in coloration score” and “mean 
distress related to skin coloration score” for Arm 1 versus Arm 2 with t-tests. We 
will compare the proportion of participants with each degree of skin discoloration 
in Arm 1 and Arm 2 using subjective assessments of clinical imaging. We will 
provide point estimates together with Pearson Klopper exact 95% confidence 
intervals. We will carry out each of these analyses in the safety set.  
 
Analysis of Exploratory Outcome Measures  
 
A separate statistical analysis plan will be developed for the exploratory 
objectives and corresponding outcome measures.  
 
11.0 
PHARMACOLOGY PLAN 
 
A combined intensive and sparse sampling strategy will be used to characterize the CFZ 
PK in Arms 1 and C. Sparse sampling will enrich these data and provide exposure over 
the study duration to assess the relationship between CFZ PK parameters and study 
related outcomes. Finally, RPT exposure will be assessed in Arms 1 and C. 
 
11.1 
Pharmacology Objectives 
 
See section 1.4. Additionally, exposure-response will be evaluated using (1) a time-to-
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modeling where more complex parametric hazard functions and continuous covariates 
(for example PK) can be evaluated [111]; (2) a model-based PK-PD analysis of the 
quantitative culture data (time to positivity in MGIT). 
 
11.2 
Pharmacology Study Design 
 
11.2.1 Intensive PK Sampling: Arms 1 and C only 
 
Forty participants (20 participants in Arm 1 and 20 participants in Arm C) will 
have an intensive PK sampling at week 2. 
 
Week 2: The exact date and time, plus information about concurrent food intake 
(±1 hour) (yes/no, if yes also date and time of the meal) of the two doses of 
PHZE and CFZ prior to the intensive PK visit should be recorded on the eCRF. 
During the PK visit, plasma will be collected pre-dose (0h), and then PHZEC will 
be administered with food. Following PHZEC administration, plasma will be 
collected 1, 2, 4, 6, 8, 10, and 24 hours post-CFZ dose. The exact time of study 
medication doses, meals, potential vomiting in connection to the drug 
administration, and samples collected during the PK day should be recorded.  
 
Twenty participants in Arm 1 will have an intensive PK sampling at week 13. 
 
Week 13: The exact date and time, plus information about concurrent food intake 
(yes/no, if yes also time of the meal) of the two doses of PHZ-CFZ prior to the 
intensive PK visit should be recorded on the eCRF. Ideally, this PK visit should 
occur surrounding the last dose of CFZ in each respective experimental arm, but 
this is not required. PHZ -CFZ should be administered with food; plasma will be 
collected pre- PHZ -CFZ dose (0h), and then 1, 2, 4, 6, 8, 10, and 24 hours post-
CFZ dose. If the observed dose is the last CFZ dose, an additional sample 
should be drawn 48 hours post-CFZ dose. This final sample may be drawn up to 
96 hours post-dose to accommodate weekend clinic closures. The exact time of 
doses, meals, potential vomiting in connection to the drug administration, 
and samples collected during the PK day should be recorded.  
 
11.2.2 Sparse PK Sampling: Arms 1 and C only 
 
For participants in Arm 1: Sparse PK sampling at weeks 2 and 13 will occur only 
for those not completing intensive PK visits. For all other occasions sampling will 
occur in all Arm 1 participants as described in section 6.1.  
 
For participants in Arm C: Only one sparse PK sampling will occur at week 4.  
 
Sparse plasma samples should ideally be collected 22-26 hours after the last 
dose of CFZ and RPT; however, the sample should be collected irrespective of 
time since last CFZ dose. The participants should be instructed to bring their 
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is collected; the time of the dose administered after PK sampling is not required 
on the eCRF. The exact time of the PK sample collection should be recorded at 
all visits. The exact date and time, plus information about concurrent food intake  
(yes/no, if yes also time of the meal) and potential vomiting in connection to 
the drug administration, of the two doses of CFZ and RPT prior to the PK 
sample collection should be recorded on the eCRF.  
 
Additional sparse PK samples collected after CFZ therapy is discontinued:  
Because of the long half-life of CFZ, samples for quantitation of CFZ will be 
collected after therapy is complete, according to section 6.1. Samples at these 
visits can be collected at any time during the study visit, irrespective of any 
medication dosing. The exact time of the PK sample should be recorded at all 
visits. The exact date and time of the final dose of CFZ should be collected. 
 
11.2.3  Protein Binding: Arms 1 and C only 
 
A single, serum sample will be collected from all participants at each study visit 
where intensive or sparse PK is measured to assess protein binding of CFZ. 
Both alpha- and beta-lipoprotein (apoA1 and apoB) can be assessed in one 
serum sample. 
 
11.2.4 Pharmacogenetic Sampling 
 
A single, whole blood sample will be collected at entry. 
 
11.3 
Primary and Secondary Data, Modeling and Data Analysis 
 
11.3.1 CFZ PK Assessment 
  
Standard non-compartmental techniques will be used to determine PK 
parameters (Cmin, Cmax, Tmax, AUC0-24h) from the intensive PK studies. The AUC 
will be determined using the trapezoidal rule. Cmin will be taken as the minimum 
observed concentration after the observed dose. Cmax will be taken as the 
maximum observed concentration. Tmax is the time at which Cmax occurs. The 
software package Phoenix (Certara Corporation) will be used for this analysis.  
 
This non-compartmental analysis will be in conjunction with non-linear mixed-
effects modeling to estimate the primary PK parameters (e.g., apparent oral 
clearance (CL/F), volume of distribution, rate of absorption). The model-based 
analysis will use the intensive PK samples as well as the sparse samples 
collected throughout the study period and all protein concentration data. The PK 
observations will be modeled continuously over time, taking in account each 
participant’s actual dosing history. A covariate analysis to evaluate the potential 
impact of demographics and concomitant medications will be conducted. In 
addition to the primary population PK parameters, summaries of derived PK 
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visit. The derived secondary metrics will be compared with the non-
compartmental analysis results in a posterior predictive check [112]. 
Furthermore, the accumulation of CFZ at weeks 2 and 4 in the arms with and 
without CFZ loading dose will be compared. 
 
11.3.2 Rifapentine PK Assessment 
  
Standard non-compartmental techniques will be used to determine PK 
parameters (Cmin, Cmax, Tmax, AUC0-24h, CL/F) from the intensive PK studies. The 
AUC will be determined using the trapezoidal rule. Cmin will be taken as the 
minimum observed concentration after the observed dose. Cmax will be taken as 
the maximum observed concentration. Tmax is the time at which Cmax occurs. 
Apparent oral clearance will be calculated as CL/F = dose/AUC0-24h. The 
elimination half-life will be determined using regression analysis when possible. 
The software package Phoenix (Certara Corporation) will be used for this 
analysis.  
 
11.3.3 Pharmacogenetic Analyses  
 
Evaluation of pharmacogenetic associations between human pharmacogenetic 
polymorphisms that may affect metabolism, disposition and toxicity of study 
drugs and concomitant medications, and study drug efficacy, safety, and PK. 
 
In all study participants who provide DNA for genetic testing, assays will be 
performed for polymorphisms in genes relevant to study drugs (e.g., NAT2 which 
affects PK and hepatotoxicity of INH) and concomitant medications (e.g., 
CYP2B6 which affects plasma PK and central nervous system side effects of 
EFV). Associations will be explored between selected genetic polymorphisms 
and outcome measures. Among the outcome measures to be studied will be 
study culture conversion, treatment failure, relapse, TB-related death, premature 
discontinuation of regimen other than due to violent death, natural disaster, or 
administrative censoring, premature discontinuation of regimen due to 
hyperpigmentation, gastrointestinal intolerance, ichthyosis, or QTcF interval 
prolongation, new Grade 3 or Grade 4 laboratory value or sign or symptom that is 
at least one grade increase from baseline, occurrence of SAEs, WHOQOL-BREF 
scores, CES-D scores, change in objective skin color parameters measured, 
plasma PK parameters for CFZ, plasma PK parameters for rifampicin, QTcF 
interval prolongation, participant subjective assessment of hyperpigmentation, 
physician subjective assessment of hyperpigmentation, and acquired CFZ 
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11.3.4 Pharmacodynamic Analyses 
 
Following finding the model that best describes the plasma PK characteristics of 
CFZ, we will next develop a linked PK and PD model to investigate relationships 
among the PK parameters of CFZ, and measures of safety and tolerance and TB 
outcomes. These PD models may be in the form of a linear or a sigmoid Emax 
relationship where, for example, higher CFZ concentrations are related to CFZ 
associated AEs. In addition to the pharmacologic assessment of PK-PD, PK 
measures will be used in the statistical analysis (see section 10.0) to evaluate the 
study outcomes associated with the CFZ-containing regimens.  
 
11.4 
Anticipated Outcomes 
 
The pharmacologic evaluations will provide information on the steady-state PK of CFZ 
under two proposed dose strategies (Arms 1 and C). The measures of drug exposure 
determined from the PK data will be used to evaluate the relationship between the CFZ 
PK parameters achieved in the CFZ-containing regimens and study outcomes.  
 
12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Records to Be Kept 
 
Electronic case report forms (eCRFs) will be provided for each participant. Participants 
must not be identified by name on any eCRFs. Participants will be identified by the 
patient identification number (PID) and study identification number (SID) provided by the 
ACTG DMC upon registration. 
 
12.2 
Role of Data Management 
 
12.2.1 Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 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. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
12.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, eCRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, participants’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
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12.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the ACTG, local IRB/EC, the site monitors, the FDA, 
the NIAID, the OHRP, the industry supporter(s) or designee, other local, US, and 
international regulatory authorities for confirmation of the study data. 
 
12.3.3 Monitoring visits may be conducted on-site or remotely. Remote visits may 
include remote source document verification using methods specified for 
this purpose by NIAID. Remote monitoring visits may be performed in place 
of, or in addition to, onsite visits to ensure the safety of study participants 
and data integrity [113]. The site will make available study documents for site 
monitors to review utilizing a secure platform that is HIPAA and 21 CFR Part 
11 compliant. Potential platform options include: Veeva SiteVault, site-
controlled SharePoint or cloud-based portal, direct access to Electronic 
Medical Record (EMR), and Medidata Rave Imaging Solutions. Other secure 
platforms that are 21 CFR Part 11 compliant may be utilized, as allowed by 
the DAIDS Office of Clinical Site Oversight (OCSO). 
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol, the informed consent documents (Appendices I, I-A, and I-B), and any 
subsequent modifications will be reviewed and approved by the IRB/EC 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. 
 
13.2 
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, or international regulatory authorities as part of their duties, or 
the industry supporter(s) or designee.  
 


 
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13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, FDA, IRB/EC, NIAID, industry 
supporter, OHRP, or other government agencies as part of their duties to ensure that 
research participants are protected.  
 
14.0 
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 
supporter prior to submission.  
 
15.0 
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. 
 
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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16.0 
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APPENDIX A: A5362 PROHIBITED AND PRECAUTIONARY MEDICATIONS 
 
Following is a list of A5362 precautionary and prohibited medications. To avoid adverse drug 
interactions, package inserts of antiretroviral agents and other concomitant medications should 
be referenced whenever a concomitant medication is initiated or dose changed to avoid drug 
interaction adverse events. 
 
PROHIBITED MEDICATIONS 
 
Arm 1 and C Prohibited Medications  
• 
Protease inhibitors (HIV and HCV) 
• 
HIV entry and fusion inhibitors 
• 
Elvitegravir/cobicistat 
• 
Bictegravir 
• 
Non-nucleoside reverse transcriptase inhibitors (except efavirenz) 
• 
Prohibited medications during administration of DLM because of potential for QTc 
prolongation:  
• 
Anti-arrhythmic medications (e.g., quinidine, procainamide, disopyramide, encainide, 
flecainide, sotalol, amiodarone, dofetilide, ibutilide) 
• 
Certain antimalarials with QT-prolonging potential (e.g., halofantrine, quinine, 
chloroquine, artesunate/amodiaquine, dihydroartemisinin/piperaquine) 
• 
Neuroleptics (e.g., phenothiazines, thioridazine, haloperidol, chlorpromazine, 
trifluoperazine, pericycline, prochlorperazine, fluphenazine, sertindole, sultopride, and 
pimozide) 
• 
Tricyclic antidepressants: (e.g., amitriptyline, doxepin, desipramine, imipramine, and 
clomipramine) 
• 
Some antimicrobials, including: 
o Fluoroquinolones (e.g., moxifloxacin and sparfloxacin)  
o Macrolides (e.g., azithromycin, clarithromycin, erythromycin)  
o Pentamidine 
o Triazole antifungal agents (e.g., fluconazole, itraconazole, posaconazole, 
voriconazole) 
• 
Miscellaneous: Droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, 
methadone, vinca alkaloids, arsenic trioxide, ziprasidone, terfenadine 
 
Contact the protocol team with questions about other QT prolonging therapies 
 
Arm 2 Prohibited Medications 
• 
No specific prohibited medications. Follow local treatment guidelines for co-therapy with 
RHZE. 
 


 
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PRECAUTIONARY MEDICATIONS 
 
Arm 1 and C Precautionary Medications  
• 
Rifapentine is an inducer of cytochrome P4503A4 and 2C8/9. Therefore, it may increase the 
metabolism and decrease the activity of other co-administered drugs that are metabolized 
by these enzymes.  
 
Arms 1, 2 and C Precautionary Medications 
• 
Rifapentine and rifampicin are potent inducers of the cytochrome P450 enzyme system 
(CYP) and concomitant use with drugs metabolized by this enzyme system may result in 
suboptimal exposure of the co-administered medication. Carefully review all concomitant 
therapies during TB treatment. 
• 
Acetaminophen 
• 
Carbamazepine 
• 
Chlorzoxazone 
• 
Disulfiram 
• 
Ketoconazole 
• 
Phenytoin 
• 
Propacetamol 
• 
Theophylline 
• 
Valproate 
• 
Aluminum hydroxide containing antacids within 4 hours of ethambutol administration 
 
Please contact the A5362 protocol team if you have any questions. 
 
 
 


 
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APPENDIX B: A5362 PERMITTED ANTIRETROVIRALS MEDICATIONS 
 
Permitted antiretroviral metications are: 
• 
Efavirenz 600 mg with dual NRTIs  
• 
Dolutegravir 50 mg 12 hourly (reduced to 50 mg daily 2 weeks after stopping rifampicin) with 
dual NRTIs 
 
 


 
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APPENDIX I: SAMPLE INFORMED CONSENT  
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
For protocol A5362 
 
A5362, FINAL Version 2.0, 08Jul2022, A Phase IIc Trial of Clofazimine- and Rifapentine-
Containing Treatment Shortening Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST 
Study  
 
SHORT TITLE FOR THE STUDY: A5362, FINAL Version 2.0, 08Jul2022, Clofazimine and 
Rifapentine for Drug-Susceptible Tuberculosis  
 
SUMMARY 
 
PURPOSE 
This is a research study and your participation in this study is voluntary. 
The purpose of this study is to determine if taking a 3-month TB treatment 
including rifapentine/isoniazid/pyrazinamide/ethambutol/clofazimine 
(PHZEC) is better than taking a 6-month standard of care TB treatment. 
Studies have suggested a powerful effect for the combination of drugs in 
the 3-month treatment, such that standard TB treatment can be shortened 
by half. Standard of care TB treatment includes rifampicin/isoniazid/ 
pyrazinamide/ethambutol (RHZE) given for 2 months, then 
rifampicin/isoniazid (RH) given for 4 months. This study will also look at 
the tolerability of the study drugs, the effect the drugs have on the 
electrical activity of the heart, and will measure the level of these drugs in 
blood. 
 
NUMBER OF  
There will be a total of 185 participants. 
PARTICIPANTS 
 
LENGTH OF  
STUDY  
The study will last about 65 weeks.  
 
REQUIRED  
ACTIVITIES 
Blood and urine collections 
• 
At most visits, blood will be collected from a vein in your arm.  
• 
You will be asked to provide a urine sample. 
 
Special procedures  
• 
At several visits, you will have a chest X-ray and ECG (looks at the 
electrical activity of your heart.).  
• 
At several visits, you will be asked to provide sputum samples by 
coughing deeply and then spitting into a cup. You may also be asked 


 
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to provide a sputum sample by briefly breathing a mist of saltwater 
through a tube or a mask followed by coughing and spitting into a cup. 
• 
Because the medication may cause skin discoloration, you will have 
pictures taken of sites on your body (forehead, left cheek, right 
cheek, chin, and arm) to look for any changes in the color of your 
skin.  
 
RISKS 
The following are possible: 
 
Clofazimine 
Rare: 
• 
Colicky (cramping) or burning abdominal or stomach pain 
• 
Mental depression 
• 
Loss of appetite 
• 
Changes in taste 
• 
Dryness, burning, itching, or irritation of the eyes 
• 
Increased sensitivity of skin to sunlight 
• 
Bloody or black, dark red stools 
• 
Disturbance in heart rhythm 
 
More common: 
• 
Diarrhea, nausea or vomiting, or abdominal pain 
• 
Dry, rough, or scaly skin, which may or may not be itchy  
• 
Red-brown skin, urine, sweat, tears, or stool discoloration. This side 
effect goes away after stopping clofazimine but it may take months to 
(rarely) years. 
 
Rifapentine/rifampicin/isoniazid/pyrazinamide/ethambutol  
• 
Tears, sweat, saliva, feces, urine may turn orange-colored while 
taking medicines; contact lenses may be stained permanently 
 
BENEFITS 
You may receive a direct benefit from participating in this study, but no 
guarantee can be made. 
 
 
OTHER CHOICES 
Instead of being in this study, you have the option of continuing with your 
current treatment or starting a new treatment under the care of your 
regular doctor or other health care provider. You also have the choice to 
be referred to the National Tuberculosis Program for TB treatment 
according to local standard of care, or the option of no treatment. 
 
 
INTRODUCTION: 
 


 
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You are being asked to take part in this research study because you have pulmonary 
tuberculosis (TB) of your lungs that can treated by drugs generally used to treat it. This is known 
as drug-susceptible TB. If someone is infected with TB bacteria that are fully susceptible, it 
means that all of the TB drugs will be effective (work against TB) as long as they are taken 
properly. It still means that several drugs need to be taken together to provide effective TB 
treatment. 
 
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? 
 
The purpose of this study is to determine if taking a 3-month TB treatment including 
rifapentine/isoniazid/pyrazinamide/ethambutol/clofazimine (PHZEC) is better than taking a 6-
month standard of care TB treatment. Studies have suggested a powerful effect for the 
combination of drugs in the 3-month treatment, such that standard TB treatment can be 
shortened by half. Standard of care TB treatment includes the combination of four drugs, 
rifampicin/isoniazid/ pyrazinamide/ethambutol (RHZE) given for 2 months, then 
rifampicin/isoniazid (RH) given for 4 months. The safety and effectiveness of the PHZEC arms 
will be compared to standard combination TB therapy. This study will also look at the tolerability 
of the study drugs, the effect the drugs have on the electrical activity of the heart, and will 
measure the level of these drugs in blood. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to take part in this research study, you will be asked to sign this consent form. A 
screening visit will be done to make sure you are eligible to join the study. If you are found 
eligible, you will be in the study for 65 weeks. The schedule of visits and study procedures are 
explained in Appendix I-A. 
 
Information collected at screening 
There is some information that we collect on everyone who is screened for an ACTG study. The 
ACTG is a group of researchers that conducts research related to HIV and TB infection. As part 
of your screening visit, some demographic (for example, age, gender, race), clinical (for 
example, disease condition, diagnosis), and laboratory (for example, CD4 cell count, viral load) 
information will be collected from you. We also collect information on whether you use (or have 
used) IV drugs. 
  


 
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We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may determine whether there are patterns and/or common 
reasons why people do not join a study. 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Some of your blood and/or sputum will be stored and used for study-required immunologic 
(structure and function of the immune system) testing and pharmacogenetic testing (testing of 
material passed from parent to child that determines the makeup of the body and mind that can 
affect your response to the study drugs). Some of your blood may be used for whole 
genome sequencing (researchers look at all of your genes and at almost all of your DNA).  
Some of these samples will be shipped and stored outside of the country from which they are 
collected. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
 
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not join this study.  
  
If you enter the study 
There are three treatment groups in this study; Arm 1, Arm 2, and Arm C. At the study entry 
visit, you will be asked if you agree to be in Arm C. In Arm C, participants will have fewer study 
visits than participants in Arm 1 or Arm 2. If you agree to be in Arm C, you will be randomized 
(like the flip of a coin) to be in Arm 1, Arm 2, or Arm C. Once 20 participants agree to be in Arm 
C, enrollment in Arm C will stop. If you are not willing to consent to be in Arm C, you will be 
randomized (like the flip of a coin) to be in Arm 1 or Arm 2. More participants will be assigned to 
Arm 1 than to Arm 2 or Arm C, so it is more likely that you will be in this arm. You will not be 
able to choose your group, though you and the study staff will know which group you are in.  
• 
If you are in Arm 1, you will take rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + 
clofazimine (CFZ) 300 mg for 2 weeks; then PHZE + CFZ 100 mg for 6 weeks; then 
rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 100 mg for 5 weeks, for a total of 13 weeks 
of study treatment. Study treatment may be extended to 17 weeks on study treatment if you 
continue to have symptoms consistent with active TB, and tests show that your TB infection 
has worsened or has not improved. If this continues after 17 weeks of study treatment, you 
will remain on the study and receive treatment consistent with standard of care for TB. 
• 
If you are in Arm 2, you will take rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) for 8 
weeks; then rifampicin/isoniazid (RH) for 18 weeks, for a total of 26 weeks of study 
treatment. Thus the standard of care for TB treatment. 
• 
If you are in Arm C, you will take rifapentine/isoniazid/pyrazinaminde/ethambutol (PHZE) + 
clofazimine (CFZ) 100 mg daily for 4 weeks. This will be followed by standard of care TB 
treatment (received from your health care provider) that will include 4 weeks of 
rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) and 18 weeks of rifampicin/isoniazid 
(RH).  


 
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• 
You will also take pyridoxine (vitamin B6) with each dose of isoniazid prescribed by your 
health care provider. Vitamin B6 plays an important role in the body. It is needed to maintain 
the health of nerves, skin, and red blood cells. Pyridoxine has been used to prevent or treat 
a certain nerve disorder (peripheral neuropathy) caused by certain medications (such as 
isoniazid). 
If you join the study and are living with HIV (the virus that causes AIDS), your doctor will talk 
with you about the best options for treating your HIV. If you are taking anti-HIV drugs that are 
not recommended to be used with the TB drugs used in this study, the doctor will advise you to 
change your HIV drug treatment. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 185 participants will take part in the study; 110 in Arm 1, 55 in Arm 2, and 20 in Arm C. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in the study for 65 weeks. 
 
 
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. 
• 
Your doctor decides the study is no longer in your best interest or that it is unlikely that you 
will be able to comply with the study requirements.  
• 
The study is stopped or cancelled.  
 
The study doctor may also need to take you off the study drug(s) without your permission if: 
 
• 
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 found to have TB with INH or rifampicin resistance. 
• 
Your screening, entry, and first post-entry visit sputum cultures all fail to grow Mtb complex. 
• 
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, you will be asked to complete 
an Early Treatment Discontinuation Visit, and the study doctor will ask you to continue to be part 
of the study and return for all study visits and procedures through week 65. 
 
 


 
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IF I HAVE TO PERMANENTLY STOP TAKING STUDY-PROVIDED DRUGS, OR STANDARD 
COMBINATION TB THERAPY, HOW WOULD THESE BE PROVIDED? 
 
During the study: 
If you must permanently stop taking study-provided drugs or standard combination TB therapy 
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 CFZ or standard combination TB therapy that you received on the study. If 
continuing to take these or similar drugs 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 medications, and use of a non-standard regimen may have unexpected 
consequences. 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 
study. Also, you must tell the study doctor or nurse before enrolling in any other clinical trials 
while on this study. 
 
Clofazimine 
Rare:  
• 
Colicky or burning abdominal or stomach pain 
• 
Mental depression, followed with use of a validated questionnaire 
• 
Loss of appetite 
• 
Changes in taste 
• 
Dryness, burning, itching, or irritation of the eyes 
• 
Increased sensitivity of skin to sunlight 
• 
Bloody or black, dark red stools 
• 
Disturbance in heart electrical activity (prolonging the QTcF interval). While on the study, 
your heart rhythm will be monitored with an ECG test at multiple visits. If a disturbance in 
electrical activity is found, you will be monitored more closely with once weekly ECG testing. 
The severity of the disturbance in electrical activity will be evaluated with specific criteria. 
Depending on the severity, clofazimine and other study medications may be discontinued, 
and in extreme cases you may even be hospitalized for monitoring until your QTcF interval 


 
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improves. In this case, you would be referred to the National Tuberculosis Program for TB 
treatment according to local standard of care. 
 
More common:  
• 
Diarrhea, nausea or vomiting, or abdominal pain 
• 
Dry, rough, or scaly skin, which may or may not be itchy  
• 
Red-brown skin, urine, sweat, tears, or stool discoloration. This side effect goes away after 
stopping clofazimine but it may take months to (rarely) years. 
 
Rifapentine 
• 
Some medications used to treat TB may be associated with diarrhea (loose or watery 
bowels), including bloody diarrhea, which may be serious. 
• 
Reddish coloring of sputum and breast milk. Tears, sweat, saliva, feces, urine may turn 
orange-colored. Stains to your dentures or contact lenses that may not go away. 
• 
Liver damage; if you develop any of the following symptoms, you should call your doctor 
right away: 
o Unexplained loss of appetite 
o Nausea and or vomiting 
o Pale colored stools 
o Yellowing of the eyes or skin 
o Pain in the upper abdomen (where your stomach is) 
o Dark urine 
• 
Additional side effects may include: 
o Loss of appetite 
o Low blood counts 
o Low blood sugar 
o Decreased effectiveness of hormonal birth control (contraceptives) and other 
medications, including some anti-HIV medications. Tell your doctor about all 
medications that you are taking. 
• 
Although rare, flu-like symptoms or a severe allergic reaction may occur. The reaction 
should go away when you stop the rifapentine. Symptoms may include:  
o Fever 
o Rash 
o Inflammation of the liver 
o Low blood pressure  
o Muscle aches 
o Temporary decrease in white blood cells called lymphocytes  
o Headache 
o Nausea 
o Vomiting 
 
 
Rifampicin/isoniazid/pyrazinamide/ethambutol  
Common, not serious: 


 
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• 
Tears, sweat, saliva, feces, urine may turn orange-colored while taking medicines; contact 
lenses may be stained permanently 
 
Occasional, some may be serious: 
• 
Upset stomach, nausea, vomiting, belly pain 
• 
Diarrhea 
• 
Poor appetite 
• 
Dizziness 
• 
Rash 
• 
Headaches 
• 
Low blood count 
• 
Inflammation of the liver 
• 
Joint pain 
• 
Flu-like symptoms: fever, chills, headache, body ache, fatigue 
• 
Numbness and/or tingling of arms, legs 
 
Rare and serious: 
• 
Allergic reaction that may cause rash, low blood pressure, shortness of breath, swelling of 
face or throat 
• 
Low blood platelets 
• 
Loss of vision (temporary or permanent) 
• 
Seizures or trouble thinking or depression 
• 
Kidney damage 
 
Risks of Nitrosamine Impurities 
The US Food and Drug Administration (FDA) has been investigating the presence of 
impurities called nitrosamines in some types of medications, including rifapentine (RPT). 
Low amounts of nitrosamines are common in water and foods, including cured and 
grilled meats, dairy products, and vegetables. Everyone is exposed to some level of 
nitrosamines through their diet. Some types of nitrosamines have been shown to cause 
cancer in laboratory animals. Nitrosamine impurities may increase the risk of cancer if 
people are exposed to them above acceptable levels. 
 
The study drug RPT contains small amounts of a nitrosamine impurity. The FDA recently 
noted that, because tuberculosis is a potentially deadly disease that affects the lungs 
and sometimes other parts of the body, the risk of not taking the medicine outweighs any 
potential risk from nitrosamine. 
 
Seventeen weeks of daily RPT has been shown to be safe for treatment of active TB. Use 
of the currently available RPT for treatment of active TB has clear benefits, while the 
cancer risk is very low. All medications have risks and benefits. You should talk with 
your study doctor about any concerns. 
 
Risks of Drug Interactions (Arm 1) 


 
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Although felt to be unlikely, it is currently unknown if clofazimine (CFZ) may interact with anti-
HIV drugs. If you are living with HIV, your HIV viral load (how much HIV is in your blood) will be 
monitored during study treatment to find out if CFZ interacts with your anti-HIV drugs. This 
information can be used by your treatment site to make decisions about your HIV treatment. 
Risks of Looking for Changes in Skin Color 
There is no risk to you when pictures of your skin are taken. 
 
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 Electrocardiogram (ECG) 
The electrodes from the ECG machine are small, plastic patches that stick to the skin. 
Therefore, you may experience mild irritation, slight redness and itching on your skin where the 
electrodes are placed.  
 
Risks of Chest X-Rays 
The amount of radiation exposure from chest X-rays is very low. Your chest X-rays will be read 
at a central location by two Board Certified Chest Radiologists. Your screening chest X-ray will 
also be read at your local clinic. Chest X-ray reading is used to determine how advanced your 
TB disease is.  
 
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 
about this. 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known if the drug or drug combinations in this study harm unborn babies. If you are a 
woman and having sex that could lead to pregnancy, you must agree not to become pregnant. 
If you are participating in sexual activity that could lead to pregnancy, you must agree to use an 
adequate method of contraception (acceptable forms of contraception include condoms, 
intrauterine device or intrauterine system, cervical cap with spermicide, and diaphragm with 
spermicide; hormonal birth control alone is not acceptable) before you start taking the study 
drugs, while you are taking the study drugs, and for 30 days after you stop taking the study drug. 
 
If you can become pregnant, you must have a pregnancy test before you enter this study. The 
test must show that you are not pregnant. If you think you may be pregnant at any time during 
the study, tell your study staff right away. The study staff will talk to you about your choices. You 
will be referred for TB treatment and prenatal care, and if applicable, to a local HIV clinic. You 
will be followed on the study through the end of the study period. 
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If 


 
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you are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to 
the Antiretroviral Pregnancy Registry, an international database that collects information about 
pregnancies in women taking anti-HIV drugs. This report will not use your name or other 
information that could be used to identify you. 
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 TB. 
 
 
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. You have the option of continuing 
with your current treatment or starting a new treatment under the care of your regular 
doctor or other health care provider. 
• 
Referral to the National Tuberculosis Program for TB treatment according to local standard 
of care. You have the option to receive standard therapy, which contains rifampicin. 
The standard therapy rifampicin also contains nitrosamine levels similar to the study-
provided drugs that are above normally acceptable levels. Any possible nitrosamine 
risk is therefore likely to be similar. 
• 
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 U.S. Food and Drug Administration (FDA), the ACTG, the 
U.S. Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site) institutional review board (IRB) or 
Ethics Committee (a committee that protects the rights and safety of participants in research), 
National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study, and their designees.  
 
All information collected about you as part of the study will be sent securely to the ACTG 
Statistical and Data Management Center in the United States for combining with 
information from other study participants and statistical analysis of study results. Your 
name and other personal identifiers will not be sent. Your research site is responsible for 


 
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sending your information in accordance with the laws, regulations, and policies of your 
country and research site. 
 
A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required 
by US 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.  
 
 
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. There is no cost to you for study medications, standard of care 
TB medications, study-related visits, physical examinations, laboratory tests, or other study 
procedures. Anti-HIV medicines and vitamin B6 will not be provided by the study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You may be reimbursed for your time and travel expenses as part of your participation in this 
study. (Site to 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 NIH does not have a mechanism to provide direct compensation for research related injury. 
[Sites: Please modify (if necessary) and insert one of these two statements, as appropriate to 
your site. If your site is required to carry CTI, this must be indicated in the informed consent.] 
• 
This site has clinical trials insurance. This insurance will allow the site to provide you with 
monetary compensation if you suffer harm as a result of participating in this research study.  
The cost for this treatment will be charged to you or your insurance company.  
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. 
 
 


 
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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 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 I-A: A5362 STUDY VISITS  
 
The study staff can answer any questions you have about individual study visits, and 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 
Day 3 
Visits 
During 
Treatment 3 
Follow-
Up 
Visits4 
Suspected TB 
Treatment 
Failure or 
Recurrence or 
Poor Treatment 
Response5 
Early Treatment 
or Study 
Discontinuation6 
Consent/contact 
information 
√ 
 
 
 
 
 
 
HIV status  
√ 
 
 
 
 
 
 
Medical, medication history 
√ 
√ 
 
 
 
 
 
Physical exam/concomitant 
medications/skin changes 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Blood collection (see blood 
tests below) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Pregnancy test 
√ 
As clinically indicated 
Urinalysis 
 
√ 
 
 
 
 
 
Sputum collection 
√ 
√ 
 
√ 
√ 
√ 
√ 
Sputum RS Ratio 
(optional) 
 
√ 
 
√ 
 
√ 
√ 
Chest X-ray 
√ 
 
 
√ 
 
√ 
 
ECG 
√ 
 
√ 
√ 
 
 
√ 
Directly observed therapy 
(DOT) 
 
 
 
√ 
 
 
 
Quality of life questions 
 
√ 
 
√ 
√ 
 
√ 
Questions about 
depression 
 
√ 
 
√ 
√ 
 
√ 
Questions about your 
experience with treatment 
 
 
 
√ 
 
 
 
1 Screening 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.  
2 Entry Visit: If you are able to join the study, you will enter the study and receive your treatment 
assignment. 
3 Visits During Treatment:  
If you are in Arm 1, you will have a visit at day 3, weekly through week 4, and then biweekly visits to 
week 12, and then at week 13; Arm 1 intensive PK participants will also have visits at weeks 1 
and 3. 
If you are in Arm 2, you will have a visit at day 3, then biweekly visits to week 12, and then at weeks 13, 
17, 21, and 26.  
If you are in Arm C, you will have a visit at day 3, and then weekly visits to week 4. 
4 Follow-up Visits: 
If you are in Arm 1, your follow-up visits will be at weeks 17, 21, 26, 34, 42, 52, and 65.  
If you are in Arm 2, your follow-up visits will be at weeks 34, 42, 52, and 65. 
If you are in Arm C, your follow-up visits will be at weeks 8, 26, and 65. 
5  Suspected TB Treatment Failure, or TB Recurrence, or Poor Treatment Response: If the study drugs 
fail to treat your TB infection or if you have a recurrent TB infection, you will be asked to come in for a 


 
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visit. For example, you may need to come in for a visit if: 
• You have signs or symptoms that are consistent with TB, have a chest X-ray that indicates 
worsening TB, or have sputum test positive for TB at or after week 13 (Arm 1) or week 17 (Arm 2) 
• The study doctor is considering extending or changing your TB treatment 
6 Early Treatment or Study Discontinuation:  
If you leave the study early, you will be asked to come in for an early study discontinuation. You will 
leave the study early if, after you enter the study, tests show that you do not have TB, or if your TB 
infection is resistant to anti-TB drugs (some drugs are not effective at treating the TB infection).  
 
If you discontinue study drug early, you will come in for an Early Treatment Discontinuation Visit, and 
you will be encouraged to continue on study and receive all evaluations through week 65. 
 
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 
blood 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 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 Status  
If there is no record of your HIV status, a HIV test will be done. If a HIV test has to be 
done, you may have to sign a separate consent form before this is done. You will be told 
the result of the HIV 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 are taking now. At the entry visit, your medical and medication history 
will be taken. 
 
Skin Changes  
If you are in Arm 1 or Arm 2, a small camera will be used to take pictures of your 
forehead, left cheek, right cheek, chin, and arm to look for and measure any changes in 
the color of your skin. Each area will be washed with alcohol skin cleanser. A small 
circular mark will be made on each of area of your skin where the photograph will be 
taken. You will be asked not to apply any creams or lotions for at least 1 hour prior to 
being measured. Identifiable parts of your face in the pictures will be blocked out so that 
others should not be able to identify you. 
 
Blood Collection  
Blood may be collected at any visit. If you have Intensive PK Sampling, as described 
below, up to about 18 tablespoons of blood may be collected from you (in total). If you 
do not have Intense PK Sampling, up to about 13 tablespoons of blood may be collected 


 
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from you (in total). Blood collected from you will be used for various tests during the 
study, including:  
 
Stored serum: 
Blood will be stored and may be tested after the study is over to see if you had 
other infections that occurred during the study. Blood will be collected at Entry 
(all participants), at end of treatment (Weeks 13 and 26 for Arms 1 and 2, 
respectively), and at end of follow-up (Week 65, Arms 1 and 2 only). 
 
Hematology, chemistry, and liver function tests: 
These are routine blood tests for safety. You will be asked not to eat or drink for a period 
of time before you have blood collected for these tests. 
If you are in Arm 1 you will have blood drawn at screening, day 3, and weeks 1, 2, 4, 8, 
13, and 26.  
If you are in Arm 2, you will have blood drawn at screening, day 3, and weeks 2, 4, 8, 13, 
and 26. 
If you are in Arm C, you will have blood drawn at screening, day 3, and weeks 1, 2, and 
4. 
Your blood drawn at entry will be tested for diabetes. 
 
HIV viral load: 
This is a test that shows how much HIV is in your blood.  
If you are living with HIV and are in Arm 1 or Arm 2, you will have blood drawn for this 
test at entry and week 12. 
If you are living with HIV and are in Arm C, you will have blood drawn for this test at 
entry and week 8. 
 
CD4+ count: 
This is a test that shows how many infection-fighting cells you have in your blood. If you 
are living with HIV and are in Arm 1, Arm 2, or Arm C, you will have blood drawn for this 
test at screening. 
 
Pharmacokinetic (PK) sampling: 
Blood samples will be taken during the study to measure the levels of anti-TB drugs in 
the body.  
• 
Intensive PK sampling:  
o Some participants in Arm 1 will have blood samples drawn at week 2 and week 
13. If you are in Arm 1 and are chosen to have this testing, blood samples will be 
drawn: 
• 
At the week 2 visit, eight blood samples will be taken over a 24-hour period, before 
you take your medicine and then at 1, 2, 4, 6, 8, 10, and 24 hours later. You may 
have to stay in the clinic for when some or all of these samples are taken.  
• 
At the week 13 visit, nine blood samples will be taken over a 48-hour period, before 
you take your medicine, and then at 1, 2, 4, 6, 8, 10, 24, and 48 hours later. You may 
have to stay in the clinic for when some or all of these samples are taken. 


 
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o If you are in Arm C, at the week 2 visit, eight blood samples will be taken over a 
24-hour period, before you take your medicine and then at 1, 2, 4, 6, 8, 10, and 
24 hours later. 
• 
Sparse PK sampling:  
o If you are in Arm 1 and not chosen to have intensive PK sampling at weeks 2 and 
13, you will have one blood sample drawn for sparse PK testing at weeks 2, 4, 8, 
12, 13, 17, 21, 26, 34, at the time of suspected TB treatment failure, TB 
recurrence, or poor treatment response, and at the early treatment or study 
discontinuation visit. 
o If you are in Arm 1 and have been chosen to have intensive PK sampling at 
weeks 2 and 13, you will have one blood sample drawn for sparse PK testing at 
weeks 4, 8, 12, 17, 21, 26, 34, at the time of suspected TB treatment failure, TB 
recurrence, or poor treatment response, and at the early treatment or study 
discontinuation visit. 
o If you are in Arm C, you will have one blood sample drawn for sparse PK testing 
at the week 4 visit. 
 
Lipoprotein test 
You will have blood samples collected to measure the levels of lipoprotein (substances made up 
of protein and fat) in your blood. Results of this test help to determine your risk of developing 
heart disease. 
 
Pharmacogenetic analyses: 
You will have one blood sample collected and stored at entry to look at how your genes 
(material passed from parent to child that determines the makeup of the body and mind) affect 
your response to the study drugs.  
 
Pregnancy Test  
If you are a female who is 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. 
 
If you are in Arm 1, this test will be done at screening, at week 13, and at other times during the 
study if you think you might be pregnant.  
If you are in Arm 2, this test will be done at screening, and at other times during the study if you 
think you might be pregnant. 
If you are in Arm C, this test will be done at screening, at week 4, and at other times during the 
study if you think you might be pregnant. 
 
Urinalysis 
You will be asked to provide a urine sample at entry. 
 
Sputum Collection  
You will be asked to provide sputum samples (a mixture of saliva and mucus coughed up from 
the respiratory tract) by coughing deeply and then spitting into a cup.  
 
If you are in Arm 1, this procedure will be done at screening, entry, weekly through week 4, 


 
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biweekly through week 12, and then at weeks 13, 17, 21, 26, 34, 42, 52, 65, at the time of 
suspected TB treatment failure, TB recurrence, or poor treatment response, and at the early 
treatment or study discontinuation visit.  
 
If you are in Arm 2, this procedure will be done at screening, entry, bi-weekly through week 12, 
and then at weeks 13, 17, 21, 26, 34, 42, 52, and 65, at the time of suspected TB treatment 
failure, TB recurrence, or poor treatment response, and at the early treatment or study 
discontinuation visit.  
 
If you are in Arm C, this procedure will be done at screening, entry, and at weeks 1, 2, 3, and 4, 
and at the time of suspected TB treatment failure, TB recurrence, or poor treatment response, 
and at the early treatment or study discontinuation visit. Some of these collections can be done 
during a clinic visit or in your home. These samples will be used for TB drug susceptibility tests, 
to see if your TB infection responds to TB drugs.  
 
Sputum Ribosomal RNA Synthesis (RS) Ratio (optional) 
Your site may ask if you are interested in participating in the collection of sputum for RS 
ratio. RS ratio measures how the study treatment effects the growth of TB bacteria 
present in your body. If you decide to participate, you will provide additional sputum at 
entry, weeks 2 and 4, and at the time of suspected TB treatment failure, TB recurrence, or 
poor treatment response, and at the early treatment or study discontinuation visit. If you 
are participating in intensive PK sampling, additional sputum will be collected at weeks 
1, 2, 3, and 4.  
 
Chest X-ray  
If you are in Arm 1, you will have a chest X-ray at screening, and at weeks 8 and 13, and at the 
time of suspected TB treatment failure, TB recurrence, or poor treatment response. 
If you are in Arm 2, you will have a chest X-ray at screening, and at weeks 8, 13, and 26, and at 
the time of suspected TB treatment failure, TB recurrence, or poor treatment response. 
 
If you are in Arm C, you will have a chest X-ray at screening and at the time of suspected TB 
treatment failure, TB recurrence, or poor treatment response. 
 
ECG 
You will have an ECG to look at the electrical activity of your heart.  
 
If you are in Arm 1, this test will be done at screening, day 3, and at weeks 2, 8, and 13, and at 
the early treatment or study discontinuation visit.  
 
If you are in Arm 2, this test will be done at screening, day 3, and at weeks 2, 8, and 13, and at 
the early treatment or study discontinuation visit.  
 
If you are in Arm C, this test will be done at screening, day 3 and week 2. 
 
DOT 
Study staff will watch you take your study medication [Site to insert site-specific information 


 
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about directly observed therapy].  
 
Quality of Life Questions 
If you are in Arm 1 or Arm 2, you will be asked questions about how you feel about your quality 
of life, health, or other areas of your life. These questions will be asked at entry and weeks 8, 
13, 26, and 65, and at the early treatment or study discontinuation visit. 
 
Questions about Depression 
You will be asked questions relating to symptoms of depression such as sadness, loss of 
interest, loss of appetite, problems in sleeping, thinking and concentration, as well as physical 
symptoms such as fatigue and weight loss. If you experience moderate depression, you will be 
referred to mental health services; if you experience severe depression, you will be escorted to 
mental health services. These will be recorded as adverse events that occurred on the study.  
If you are in Arm 1 or Arm 2, these questions will be asked at entry and weeks 8, 13, 26, and 
65, and at the early treatment or study discontinuation visit. 
 
If you are in Arm C, these questions will be asked at entry and week 8. 
 
Questions about your experience with treatment 
If you are in Arm 1 or Arm 2, you may be asked to participate in a 30 to 60-minute interview to 
understand more what life is like on the study treatment. You can still be in this study if you do 
not agree to the interview. If you agree to be interviewed, the study staff will ask you questions 
about your experience living with TB and to describe any challenges you face. 
 
If you are in Arm 1, you will be asked these questions once during the study at week 13. 
 
If you are in Arm 2, you will be asked these questions once during the study at week 26. 
 
 


 
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SIGNATURE PAGE 
 
Intensive Pharmacokinetic (PK) sampling: 
Please choose the response that matches whether you are willing to participate in the  
 
PK portion of the study by putting your initials in the space provided. Please ask the staff 
any questions that you have before you indicate your selection. 
 
____ (initials) I agree to participate.  
 
OR 
____ (initials) No, I do not agree to participate. 
 
 
 
Sputa collection for the RS ratio (if your site is participating): 
 
Please choose the response that matches whether you are willing to provide a 
sputum sample for the RS ratio by putting your initials in the space provided. Please 
ask the staff any questions that you have before you indicate your selection. 
 
____ (initials) I agree to participate.  
 
OR 
____ (initials) No, I do not agree to participate. 
 
 
 
Questions about your experience with treatment 
 
Please choose the response that matches whether you are willing to answer questions 
related to your quality of life, depression, and experience with treatment (qualitative 
interviews) by putting your initials in the space provided. Please ask the staff any 
questions that you have before you indicate your selection. 
 
____ (initials) I agree to participate.  
 
OR 
____ (initials) No, I do not agree to participate. 
 
 
 
 
 
 


 
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APPENDIX I-B: SAMPLE CONSENT FORM FOR USE OF SAMPLES AND INFORMATION IN 
OTHER STUDIES 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
For protocol: 
A5362 
 
A5362, FINAL, 08Jul2022, A Phase IIc Trial of Clofazimine- and Rifapentine-Containing 
Treatment Shortening Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST Study  
 
SHORT TITLE FOR THE STUDY: A5362, FINAL Version 2.0, 08Jul2022, Clofazimine and 
Rifapentine for Drug-Susceptible Tuberculosis 
 
When samples are no longer needed for this study, the ACTG may want to use them in other 
studies and share them with other researchers. These samples are called “extra samples.” 
The ACTG will only allow your extra samples to be used in other studies if you agree to this. 
If you have any questions, please ask. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
 
Extra samples are stored in a secure central place called a repository. Your samples will be 
stored in the ACTG repository in the United States. 
 
There is no limit on how long your extra samples will be stored.  
[Site: Revise the previous sentence to insert limits if your regulatory authority imposes them.] 
 
When a researcher wants to use your samples and information, their research plan must be approved 
by the ACTG. Also, the researcher’s institutional review board (IRB) or ethics committee (EC) will 
review their plan. [Site: If review by your institution’s IRB/EC/RE is also required, insert a sentence 
stating this.] IRBs/ECs protect the rights and well-being of people in research. If the research plan is 
approved, the ACTG will send your samples to the researcher’s location. This means that researchers 
who are not part of the protocol team may use your samples without asking you again for your consent.  
 
You will not be paid for your samples. Also, a researcher may make a new scientific discovery 
or product based on the use of your samples. If this happens, there is no plan to share any 
money with you. The researcher is not likely to ever know who you are. 
 
You may withdraw your consent for research on your extra samples at any time and the 
specimens will be discarded. 
 


 
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Please choose the response that matches what you want by putting your initials in the space 
provided. Please ask the staff any questions that you have before you indicate your selection. 
 
Research without Human Genetic Testing  
If you agree, your extra samples may be stored (with usual protection of your identity) and used 
for ACTG-approved HIV-related research that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my samples.  
 
OR 
____ (initials) I understand but I do not agree to this storage and possible use of my samples. 
 
Research with Human Genetic Testing  
  
The ACTG has two different studies that collect samples for genetic testing. 
  
If you live in the US, this study is called ACTG A5128, Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses. 
  
If you live outside of the US, this study is called ACTG A5243, Plan for Obtaining Human 
Biological Samples at Non-US Clinical Research Sites for Currently Unspecified Genetic 
Analyses. 
  
Your site might ask you if you would like to participate in one of these studies if it is 
being done where you live. If you would like to participate, you will sign a separate 
consent form. 
  
Your extra samples will not be used for human genetic testing unless you sign and date 
a consent form for A5128 or A5243. 
 
 
 

Prot_002.pdf: 
A5362, Version 2.0 LOA #1 (22Jun2023) 
IND Number: 147535 
Page 1 of 13 
 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems, Inc., a DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
 
 
 
LETTER OF AMENDMENT #1 
 
DATE:  
June 22, 2023 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5362 Protocol Team  
 
SUBJECT: 
Letter of Amendment #1 for Protocol A5362, Version 2.0 
 
 
The following information affects the A5362 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) should be implemented 
immediately, prior to IRB/EC approval, to eliminate immediate hazard to participants.  
 
The following information also affects the Sample Informed Consent (SIC). A letter 
informing participants about the contents of this LOA and an addendum to the SIC were 
provided electronically to sites on 16Jun2023.  
 
Sites should implement the LOA immediately and inform IRB/EC and any other applicable 
regulatory entities of the LOA. Sites are still required to submit an LOA registration packet 
to the DAIDS Protocol Registration Office (PRO) at the Regulatory Support Center (RSC). 
Sites will receive a registration notification for the LOA once the DAIDS PRO verifies that 
all required LOA registration documents have been received and are complete. An LOA 
registration notification from the DAIDS PRO is not required prior to implementing the 
LOA. A copy of the LOA registration notification, along with this letter and any IRB/EC 
correspondence, should be retained in the site’s regulatory file. 
 
In April 2023, the study temporarily closed to screening and accrual due to an unanticipated 
trend in outcome events, which triggered review by the National Institute of Allergy and 
Infectious Diseases (NIAID) Therapeutic and Prevention Data and Safety Monitoring Board 
(DSMB), which met on 01Jun2023 to review all available safety and efficacy data from A5362. 
The DSMB recommended that A5362 permanently close to accrual because of the high rate of 
treatment failure and TB recurrence. There were no other safety concerns related to study 
regimen. The A5362 team, NIAID and DAIDS leadership, and ACTG leadership concur with the 
following DSMB recommendations for implementation: 
• 
Permanently close A5362 to accrual. 


A5362, Version 2.0 LOA #1 (22Jun2023) 
IND Number: 147535 
Page 2 of 13 
 
• 
Participants currently receiving treatment in the experimental arm (Arm 1) should finish 
their 3-month experimental regimen 
[rifapentine/isoniazid/pyrazinamide/ethambutol/clofazimine (PHZEC)] and then be placed 
on an additional 3 months of continuation phase rifampicin/isoniazid (RH) regimen. 
• 
Participants in Arm 1 who have already finished the experimental regimen in Arm 1 
without an unfavorable outcome, should be followed closely for the duration of the trial. 
The DSMB suggests that the investigators consider strategies for more intensive follow-
up of these participants to ascertain recurrences, and that those diagnosed with 
recurrence be referred for 6 months of SOC treatment. 
• 
Participants in Arm 1 follow-up will be extended to 117 weeks, as outlined below. 
 
As referenced in the investigator and IRB/EC letters sent to A5362 sites on 16Jun2023, this 
LOA formally outlines changes to Version 2.0 of A5362, dated 08Jul2022, given the 
abovementioned DSMB recommendations.  
 
There are no changes to the Sample Informed Consent (SIC) in this LOA. Refer to the SIC 
addendum for the updated information to provide to participants and for reconsenting 
participants. 
 
This LOA also includes revisions from the 26Sep2022 DSMB review, in which the DSMB 
requested that the team specify the monitoring of the unfavorable composite outcome per 
definition 10.2.4A. 
 
 


A5362, Version 2.0 LOA #1 (22Jun2023) 
IND Number: 147535 
Page 3 of 13 
 
TABLE OF CONTENTS 
 
1. 
Section SCHEMA, DESIGN ............................................................................................ 4 
2. 
Section SCHEMA, DURATION ....................................................................................... 5 
3. 
Section SCHEMA, REGIMEN ......................................................................................... 5 
4. 
Section 1.4, Exploratory Objectives ................................................................................ 5 
5. 
Section 3.0, STUDY DESIGN ......................................................................................... 5 
6. 
Section 6.1, Schedule of Evaluations ............................................................................. 6 
7. 
Section 6.2.3 Post-Entry Evaluations .............................................................................. 7 
8. 
Section 6.3, Instructions for Evaluations ......................................................................... 7 
9. 
Section 10.5.1, Interim Monitoring Guidelines ................................................................. 7 
10. 
Section 10.5.2, Interim Analysis Plan ............................................................................. 7 
11. 
Appendix I-C, ADDENDUM TO SAMPLE INFORMED CONSENT ................................. 8 
12. 
Protocol Signature Page (PSP) ...................................................................................... 8 
 
 
 
 


A5362, Version 2.0 LOA #1 (22Jun2023) 
IND Number: 147535 
Page 4 of 13 
 
The following are changes (noted in bold or strikethrough) to A5362, Version 2.0, 08Jul2022, 
titled A “Phase IIc Trial of Clofazimine- and Rifapentine-Containing Treatment Shortening 
Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST Study.” These changes will be 
included in the next version of the A5362 protocol if it is amended at a future date. Changes that 
have already been made (Clarification Memo #1) have been incorporated in the excerpted text 
shown below (and are no longer presented in bold or strikethrough).  
 
1. Section SCHEMA, DESIGN 
 
The following information has been added to reference the change in study design due to a 
DSMB review. 
 
Per the June 1, 2023 DSMB review, and permanent closure of accrual, the follow-
up schedules for Arm 1 participants will be revised as follows: 
 
• 
Participants currently on Arm 1 study treatment should complete the 3-
month regimen and then be placed on an additional 3 months of 
continuation phase rifampicin/isoniazid (RH). Based on the DSMB 
recommendations, an additional 3 months of treatment is necessary to 
decrease the likelihood of treatment failure and TB relapse in study 
participants.  
 
• 
Participants who have already completed Arm 1 treatment should be seen 
for a follow-up visit within the next 4 weeks of the date of this LOA, at a 
scheduled or unscheduled visit, to assess whether further treatment is 
needed.  
 
• 
Additional extended follow-up visits for participants in Arm 1 will be added 
at weeks 30, 38, 60, 91 and 117 unless the participant has already been 
referred for, or already received, 6 months of SOC through the local TB 
program. The additional visits at weeks 30, 38, and 60 may be performed by 
telephone only; these calls are to assess the participant’s TB symptoms 
and determine if it is clinically indicated that the participant should come in 
for an in-person visit to assess the need for possible poor treatment 
response (PPTR) assessments and/or referral to SOC treatment.  
 
• 
If the site investigator diagnoses TB recurrence at any time during Arm 1 
follow up, the participant should be referred to 6 months of SOC treatment 
by the national TB program. For study purposes, such participants should 
continue to be followed in the study for outcome determination, unless the 
participant withdraws consent. 
 
Participants in Arm 2 and Arm C should complete their treatment and follow-up 
schedule as planned; no additional visits are planned for these groups.  
 


A5362, Version 2.0 LOA #1 (22Jun2023) 
IND Number: 147535 
Page 5 of 13 
 
2. Section SCHEMA, DURATION  
 
Arm 1: 
• 
Up to 117 weeks. 
• 
65 weeks for participants who are or have been diagnosed with TB 
treatment failure or recurrence and are or have been referred to six months 
of local SOC treatment by the national/local TB program.  
 
Arm 2: 65 weeks 
 
Arm C: 65 weeks 
 
3. Section SCHEMA, REGIMEN  
 
The following paragraph has been included to add three months of rifampicin/isoniazid for 
Arm 1 participants who are currently receiving the experimental 3-month treatment regimen 
as of 16Jun2023. The treatment regimen for all other participants will remain the same. 
 
Arm 1 participants receiving the experimental 3-month treatment regimen as of 
16Jun2023: 
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 300 mg 
once daily for 2 weeks; then PHZE + CFZ 100 mg once daily for 6 weeks; then 
rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 100 mg once daily for 5 weeks; 
then rifampicin/isoniazid (RH) for 13 weeks for a total of 26 weeks of study 
treatment.  
 
4. Section 1.4, Exploratory Objectives 
 
The following objective has been added to align with the addition of Drug-Susceptibility 
Testing and Sputum AFB Smear and Culture at weeks 91 and 117: 
 
1.4.8 To explore long term outcomes in Arm 1 participants through 117 weeks 
after randomization. 
 
5. Section 3.0, STUDY DESIGN  
 
The following update to the Arm 1 regimen and follow-up has been added to the end of the 
section:  
 
Updates following the DSMB reviews in April and June 2023 
Following the DSMB reviews in April and June 2023, and the premature closure to 
accrual of the study, Arm 1 treatment duration and follow-up was revised for 
participants who are currently on or have completed Arm 1 study treatment 
without experiencing treatment failure or TB recurrence, and have not already 
been referred to six months local SOC treatment. Participants in Arm 1 who have 
not already been referred to six months local SOC treatment will have follow-up 
extended through week 117.  


A5362, Version 2.0 LOA #1 (22Jun2023) 
IND Number: 147535 
Page 6 of 13 
 
6. Section 6.1, Schedule of Evaluations 
 
A new Table 6.1-2 has been inserted for the additional visits and assessments for Arm 1 after week 26. The SOE table for Arm C has been 
renumbered to Table 6.1-3. 
 
Table 6.1-2: Schedule of Evaluations for Arm 1 Who Have Not Been Referred to Local SOC, Additional Visits and Assessments After 
Week 26 
Evaluation 
Follow-up 
After Week 65 
Visit Window is ±7 days 
Visit Window is 
±14 days 
Time of 
Suspected 
Treatment Failure 
or Recurrence or 
Poor Treatment 
Response 
Premature 
Treatment/Study 
Discontinuation 
304 
34 
384 
42 
52 
604 
65 
91 
117 
Targeted Physical Exam 
(X) 
Refer 
to 
Table 
6.1-1 
(X) 
Refer 
to 
Table 
6.1-1 
Refer 
to 
Table 
6.1-1 
(X) 
Refer 
to 
Table 
6.1-1 
X 
X 
X 
X 
Concomitant Medications 
(X) 
(X) 
(X) 
X 
X 
X 
X 
Pregnancy Testing 
As clinically indicated 
Sputum AFB Smear and Culture1 
(X) 
Refer 
to 
Table 
6.1-1 
(X) 
Refer 
to 
Table 
6.1-1 
Refer 
to 
Table 
6.1-1 
(X) 
Refer 
to 
Table 
6.1-1 
X 
X 
X 
X 
Molecular Assay to Detect Mtb INH- and RIF- 
Resistance 
(X) 
(X) 
(X) 
X 
X 
X 
X 
Whole Genome Sequencing2 
 
 
 
 
 
X 
X 
Drug-Susceptibility Testing3 
(X) 
(X) 
(X) 
X 
X 
X 
X 
TB Symptom Assessment (See Section 6.3.18) 
X 
X 
X 
 
 
 
 
(X) = If clinically indicated. 
 
1 
Two sputum samples for AFB smear microscopy and culture in liquid and solid media will be collected at each time point. Sputum 
specimens and culture isolates will be stored for targeted deep sequencing and phenotypic drug-susceptibility testing in the event of TB 
treatment failure or TB recurrence.   
2 
For participants with suspected recurrence, whole genome sequencing performed on the baseline and recurrent isolate pair. 
3 
See section 6.3.9. 
4  Telephone visit for Arm 1 participants who did not receive 6 months of SOC. If concerning symptoms are reported in the opinion of the site 
investigator, the patient should be seen in person and the conditional evaluations noted in the SOE performed. 


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7. Section 6.2.3 Post-Entry Evaluations 
 
The revision below has been made to update the study duration for follow-up:  
 
Post-Treatment Evaluations  
Arm 1: The window for study visits during weeks 17-26 is ±3 days. The window for study 
visits during weeks 34-65 is ±7 days. The window for study visits during weeks 66 -
117 is ±14 days.   
 
8. Section 6.3, Instructions for Evaluations 
 
The following evaluation has been added: 
 
6.3.18 TB Symptom Assessment 
 
At weeks 30, 38, and 60, participants in Arm 1, who have not already been referred 
for 6 months of SOC, will have telephone follow-up visits to assess participants’ 
TB symptoms and determine if it is clinically indicated that the participant should 
come in for an in-person visit and further TB treatment. If the participant has 
symptoms concerning for TB in the opinion of the site investigator, an 
unscheduled in-person visit should be conducted within 1 week to determine if 
PPTR reporting and evaluations are appropriate, and whether the participant 
should be referred to the local TB program for 6 months of SOC treatment. 
 
9. Section 10.5.1, Interim Monitoring Guidelines 
 
The first and last sentences have been updated as follows: 
 
Unfavorable Composite Outcome Monitoring in Arm 1 
Monitoring for unfavorable composite clinical efficacy outcome (per definition 
10.2.4A) will begin approximately 1 month after the first participant completes treatment 
in Arm 1 and will continue approximately monthly and for each DSMB review until the 
end of the study. Two-sided 95% confidence bands for the cumulative probability of 
unfavorable outcome over time will be generated. If the lower confidence band for the 
cumulative probability exceeds 12% at any time, this will trigger a DSMB review. At all 
DSMB reviews, the DSMB will also be provided with the cumulative probability of 
unfavorable composite outcome (and corresponding two-sided 95% confidence 
interval) according to definition 10.2.4B. 
 
10. Section 10.5.2, Interim Analysis Plan 
 
The first and third sentences have been revised to read: 
 
Confidence Bands for Unfavorable Composite Outcome Probabilities 
Monitoring of the unfavorable composite outcome will be according to definition 
10.2.4A. only include treatment failures, treatment extensions, loss to follow-up while 
culture positive, recurrences, and deaths. Two-sided 95% confidence bands will be 


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generated for the cumulative unfavorable composite outcome probability in Arm 1. Since 
Arm 2 data will be lagging 3 months behind Arm 1, the data will be presented alongside 
historical unfavorable proportions for SOC on the REMox, OFLOTUB, and RIFAQUIN 
trials, and A5362 SOC data as it becomes available. There will be no adjustment to the 
confidence bands for multiple looks. 
 
11. Appendix I-C, ADDENDUM TO SAMPLE INFORMED CONSENT 
 
An addendum to the Sample Informed Consent has been added as Appendix I-C. Appendix 
I-C is included in this LOA on pages 9-12. 
 
12. Protocol Signature Page (PSP)  
 
A PSP is appended for submission to DAIDS Protocol Registration System (DPRS) as part 
of the LOA registration packet. 
 
 
 


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APPENDIX I-C: ADDENDUM TO SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
For protocol A5362 
 
A5362, FINAL Version 2.0, 08Jul2022, A Phase IIc Trial of Clofazimine- and 
Rifapentine-Containing Treatment Shortening Regimens in Drug-Susceptible 
Tuberculosis: The CLO-FAST Study  
 
SHORT TITLE FOR THE STUDY: A5362, FINAL Version 2.0, 08Jul2022, 
Clofazimine and Rifapentine for Drug-Susceptible Tuberculosis 
 
We have important information to share with you about the A5362 (CLO-FAST) 
study. This study is reviewed by the National Institute of Allergy and Infectious 
Diseases (NIAID) Therapeutic and Prevention Data and Safety Monitoring Board 
(DSMB) at least every 6 months. This Board is a group of people who are experts 
in the fields of medicine and statistics, none of whom are directly involved with 
the study. Their role is to review the conduct of the study and ensure the safety of 
participants. 
  
The DSMB met on June 1, 2023 to review the A5362 study.  
  
DSMB RECOMMENDATIONS 
 
After looking at the information about how participants who were receiving the 3-
month experimental treatment (Arm 1) were doing, the DSMB concluded that 
participants who were treated with 3-months of experimental treatment were not 
doing as well as people who were treated with standard of care [SOC] (Arm 2). 
Because of this, the DSMB recommended that the study close to enrollment, and 
recommended that participants currently receiving the 3-month experimental 
treatment continue to finish the treatment and then receive an additional 3 
months of SOC rifampicin/isoniazid treatment. The Board did not find any safety 
concerns, so there is no concern about harm if you received the 3-month 
experimental treatment.  
 
WHAT WILL HAPPEN TO ME NOW? 
 
Participants randomized to Arm 1 and are still on study treatment  
• If you are currently completing the 13 weeks of study treatment, you will 
complete your current course of 
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 


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300 mg for 2 weeks; then PHZE + CFZ 100 mg for 6 weeks; then 
rifapentine/isoniazid/pyrazinamide (PHZ) + CFZ 100 mg for 5 weeks, for a 
total of 13 weeks of study treatment. 
• Once you have completed the 13 weeks of study treatment, you will take 
rifampicin/isoniazid (RH) for 12 weeks. 
• You will complete all study visits and follow-up through 117 weeks.  
 
Participants randomized to Arm 1 and have completed study treatment 
• You will be contacted by study staff to discuss how you are feeling and 
decide whether further TB treatment is needed. 
• You will attend an additional 5 follow-up visits through 117 weeks. Three of 
these visits will be conducted by telephone.  
 
Participants randomized to Arm 2  
• Study treatment and follow-up visit schedule is not changing. 
• You will complete your current course of 
rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) for 8 weeks; then 
rifampicin/isoniazid (RH) for 18 weeks, for a total of 26 weeks of study 
treatment. Thus, the standard of care for TB treatment. 
•  You will complete all study visits and follow-up through 65 weeks. 
 
Participants randomized to Arm C  
• Study treatment and follow-up visit schedule is not changing. 
• You will complete your course of 
rifapentine/isoniazid/pyrazinaminde/ethambutol (PHZE) + clofazimine (CFZ) 
100 mg daily for 4 weeks. This will be followed by standard of care TB 
treatment (received from your health care provider) that will include 4 
weeks of rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) and 18 
weeks of rifampicin/isoniazid (RH). 
• You will complete all study visits and follow-up through 65 weeks. 
 
WHAT DO I HAVE TO DO IF I STAY ON THE STUDY? 
 
If you are in Arm 1 and stay on study, you will have up to 5 additional follow up 
visits than you were previously scheduled for, to make sure you are safe and 
well. Three of these follow up visits may occur on the telephone. If you are on 
Arm 2 or Arm C, you will continue with the current study visits and follow-up 
schedule.  
 
You may also choose to stop being followed on the study at any time as well, but 
we encourage you to discuss this with your health care provider. Once you leave 
the study, you will not be able to return to the study.  
 


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We appreciate your efforts and thank you for being a part of this study and for 
your continued participation.  
 
WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study contact: 
• Site add Name and telephone number for the investigator or other study staff. 
 
 
 
 


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SIGNATURE PAGE 
 
 
I have been notified of the new study findings and have discussed these findings 
and my treatment options.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Name 
 
 
 
 
Participant Signature and Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
 
 
Study Staff Signature and Date 
Consent Discussion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name 
 
 
 
 
Witness Signature and Date 
 
 
 


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A Phase IIc Trial of Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens in 
Drug-Susceptible Tuberculosis: The CLO-FAST Study 
 
 
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 US 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 (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
Name/Title 
 
 
 
 
 
 

SAP_003.pdf: 
Approvals 


 
 
 
 
A5362 
Primary Statistical Analysis Plan 
Version 3.0  
 
A Phase IIc Trial of Clofazimine- and Rifapentine-Containing 
Treatment Shortening Regimens in Drug-Susceptible 
Tuberculosis: The CLO-FAST Study 
Protocol Version 2.0 and LOA #1  
 
ClinicalTrials.gov Identifier: NCT04311502 
 
 13 October 2023 
 
Created by: 
Isabelle R. Weir, Jorge Leon-Cruz, and Luke Hall 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 


A5362 
 
Primary Statistical Analysis Plan 
Version 3.0  
 
13 October 2023 
 
Page 1 of 29 
 
 
Table of Contents 
 
TABLE OF CONTENTS .............................................................................................................. 1 
VERSION HISTORY ................................................................................................................... 3 
1.1 
Purpose ...................................................................................................................... 4 
2 
STUDY OVERVIEW .............................................................................................................. 4 
2.1 
Overview of Study Design ......................................................................................... 4 
2.2 
Hypotheses ................................................................................................................. 5 
2.3 
Study Objectives ........................................................................................................ 5 
2.3.1 
Primary Objectives ............................................................................................ 6 
2.3.2 
Secondary Objectives ....................................................................................... 6 
2.4 
Overview of Sample Size Considerations ................................................................. 7 
2.5 
Overview of Formal Interim Monitoring ..................................................................... 7 
3 
OUTCOME MEASURES ....................................................................................................... 8 
3.1 
Primary Outcome Measures ...................................................................................... 8 
3.1.1 
Early Efficacy .................................................................................................... 8 
3.1.2 
Safety ............................................................................................................... 8 
3.2 
Secondary Outcome Measures.................................................................................. 8 
3.2.1 
Composite Efficacy ........................................................................................... 8 
3.2.2 
Tolerability ...................................................................................................... 10 
3.2.3 
QT interval ...................................................................................................... 10 
3.2.4 
Time to stable culture conversion in liquid and solid media through week 65 ... 10 
3.2.5 
Proportion of participants with culture conversion at weeks 8 and 12 across all 
study arms. ............................................................................................... 10 
3.2.6 
Time (days) to positivity in liquid culture (MGIT) after start of treatment through 
week 65 .................................................................................................... 10 
3.2.7 
Change in chest X-ray (CXR) score from baseline to end of treatment (EOT). . 10 
3.2.8 
Proportion of participants with one or more serious adverse events (SAEs) 
through week 65 ....................................................................................... 11 
3.2.9 
Proportion of participants who have a TB relapse from EOT until week 65 ....... 11 
3.2.10 
Proportion of participants who have a TB recurrence from EOT until week 65.. 11 
3.2.11 
Plasma pharmacokinetic parameters for CFZ .................................................. 11 
3.2.12 
Change from baseline in skin pigmentation (colorimetric L*, a*, b* parameters) 
utilizing ambient light-independent reflectance mapping at weeks 8, 13, 26, 
and 65. ..................................................................................................... 12 
3.2.13 
Change from baseline in participant-reported changes in skin pigment and  
distress related to perceived skin hyperpigmentation at weeks 8, 13, 26, and 
65. ............................................................................................................ 12 
4 
STATISTICAL PRINCIPLES ............................................................................................... 12 
4.1 
General Considerations ........................................................................................... 12 
4.1.1 
Analysis set definitions .................................................................................... 13 


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4.1.2 
Subgroups of interest ...................................................................................... 13 
4.1.3 
Interim Monitoring ........................................................................................... 13 
5 
ANALYSIS APPROACHES ................................................................................................ 15 
5.1.1 
Primary Estimands .......................................................................................... 15 
5.1.2 
Secondary Estimands ..................................................................................... 18 
5.1.3 
Secondary Objectives ..................................................................................... 22 
6 
PRIMARY ANALYSIS REPORT CONTENTS ..................................................................... 26 
6.1 
Study Entry ............................................................................................................... 26 
6.2 
Baseline Characteristics .......................................................................................... 26 
6.3 
Study Status ............................................................................................................. 26 
6.4 
Treatment Status ...................................................................................................... 26 
6.5 
Adverse Events ........................................................................................................ 26 
6.6 
Primary Outcome Measures .................................................................................... 27 
6.7 
Secondary Outcome Measures................................................................................ 27 
7 
ASSOCIATED DOCUMENTS ............................................................................................. 28 
 
 
 


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Version History 
Version 
Changes Made 
Date Finalized 
1 
Original Version (protocol v1.0, LOA #1, LOA #2) 
6/2/2021 
1.1 
Minor version update for LOA #3. No changes necessary. 
February 1, 2022 
2.0 
Revised to align with protocol v2.0 and CM #1.  
January 10, 2023 
3.0 
• 
Revised to align with protocol v2.0 and LOA #1 
• 
Details added to reflect early close to accrual and data 
that will contribute to the primary analysis report 
• 
Revisions to analysis specifications for time to event 
outcomes 
• 
Additional details added for some outcome measures 
for clarity 
• 
Edits throughout to remove redundant or duplicated 
information 
• 
Updated writing team members and statisticians 
October 13, 2023 
 
 
 


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Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and key secondary estimands 
and other outcome measures that will address specific study objectives and interim monitoring of 
the A5362 study. The Primary SAP includes general approaches for all primary estimands, key 
secondary estimands, and other outcome measures in the primary manuscript(s) or submitted to 
ClinicalTrials.gov (regardless of the reporting timeline). The Primary SAP facilitates discussion of 
the statistical analysis components among the lead study investigators and statisticians, helping 
them agree on the statistical analyses to be performed and presented in the primary analysis 
report.  
Detailed outlines of tables, figures, and coding descriptions that will be included in the primary 
analysis report are included in the Analysis Implementation Plan (AIP). Outlines of analyses for 
the exploratory objectives and exploratory outcome measures (which we do not describe in the 
Primary SAP) are provided in a separate SAP.  
2 
Study Overview 
2.1 
Overview of Study Design 
A5362 is an open-label, randomized phase IIc study to evaluate whether a 3-month regimen of 
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) with clofazimine (CFZ) dosed as 100 mg 
daily with a 2-week 300 mg daily loading dose is superior to the standard of care (SOC) 6-month 
regimen of rifampin/isoniazid/pyrazinamide/ethambutol (RHZE) for DS-TB with respect to (1) 
early bacteriologic efficacy defined as time to culture conversion by 12 weeks post-randomization 
and (2) safety over 65 weeks. 
Participants will be randomized to one of three treatment arms; Arm 1 with treatment for 13 
weeks (including a 2-week CFZ loading dose of 300 mg daily; Arm 2 with treatment for 26 weeks; 
or Arm C with treatment for 4 weeks with an experimental regimen and the remaining 22 weeks 
with SOC (PK subgroup)). 
• 
Arm 1 (Experimental): PHZE + CFZ 300 mg once daily for 2 weeks, PHZE + CFZ 100 mg 
once daily for 6 weeks; then PHZ + CFZ 100 mg once daily for 5 weeks 
 
• 
Arm 2 (SOC): RHZE for 8 weeks; then RH for 18 weeks 
 
• 
Arm C (PK subgroup): PHZE + CFZ 100 mg once daily for 4 weeks; then on study, off 
study medications and treated according to SOC (RHZE for 4 weeks; RH for 18 weeks)  
 
We will follow all participants in Arms 1, 2, and C from randomization to week 65 for the primary 
and secondary objectives. Protocol v2.0 LOA #1 also includes extended follow-up for some 
participants corresponding to new exploratory objectives which will be detailed in a separate SAP.  
Participants who consent to intensive PK sampling visits will be randomized to Arms 1, 2, or C in 
a 2:1:1 ratio, respectively, while participants who do not consent to intensive PK sampling will be 


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randomized only to Arms 1 or 2 in a 2:1 ratio, respectively. We will stratify randomization based 
on HIV status and the presence of advanced disease as determined by chest X-ray. We will 
balance randomization by institution. 
The primary efficacy analysis will be a superiority comparison of time to liquid culture conversion 
through 12 weeks in Arm 1 compared with Arm 2. The primary safety analysis will estimate and 
compare the proportions of participants who have a Grade 3 or higher safety event that is at least 
one grade higher than baseline at any time during the study. Important secondary analyses 
include 65-week favorable composite efficacy outcome, including cumulative relapse proportion 
versus 6-month SOC controls; and safety and tolerability (regimen discontinuation) in Arms 1 and 
2. 
The primary completion date for A5362 is the final visit date that is included in the primary safety 
analysis, which will occur approximately 65 weeks after the last participant enrolls. With the early 
closure to accrual in June 2023, the primary analysis report forming the basis of the primary 
manuscript will occur earlier than the original planned timepoint. We will prepare the primary 
analysis report using data collected at visits up to and including the date when the last enrolled 
participant completes the week 26 study visit. We will later conduct a supplemental analysis using 
data through week 65, which will form the basis of a secondary manuscript and the 
clinicaltrials.gov requirements.  
2.2 
Hypotheses 
A 3-month regimen of rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) with clofazimine 
(CFZ) dosed as 100 mg daily with a 2-week 300 mg daily loading dose (Arm 1) will demonstrate 
early efficacy (time to 12-week liquid culture conversion) relative to standard of care (SOC) 
(RHZE; Arm 2), and will have acceptable safety and tolerability. 
2.3 
Study Objectives 
This Primary SAP addresses the following primary and secondary objectives listed in the study 
protocol. We address other study objectives outlined in the protocol in subsequent secondary 
analysis plans.  
We will analyze the primary efficacy objective below (2.3.1.1) using a superiority framework 
based on a one-sided 0.05 alpha level test. For analyses of other objectives, we will present 
estimates of the parameter of interest alongside their respective two-sided confidence intervals, 
as specified in Section 5. 
We will finalize all analyses for the primary analysis report once the last enrolled participant has 
completed the week 26 study visit and all queries have been resolved.  


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2.3.1 
Primary Objectives 
2.3.1.1 
To compare time to 12-week liquid culture conversion for Arm 1 with Arm 2 (SOC 
controls). 
2.3.1.2 
To compare the proportion of adverse events (safety) over 65 weeks between 
Arm 1 and Arm 2 (SOC controls). 
2.3.2 
Secondary Objectives 
Each is a comparison between Arm 1 and Arm 2 unless otherwise specified. 
2.3.2.1 
To compare proportion of participants who experience a favorable composite 
efficacy outcome at 65 weeks between Arm 1 and Arm 2 participants 
2.3.2.2 
To compare premature regimen discontinuation (tolerability) between Arm 1 and 
Arm 2 participants 
2.3.2.3 
To estimate and compare CFZ-associated increases in QT interval (QTcF, using 
the Fridericia correction) 
2.3.2.4 
To estimate and compare time to stable liquid and solid mycobacterial culture 
conversion 
2.3.2.5 
To compare proportion of participants with liquid and solid culture conversion at 
weeks 8 and 12 between Arm 1 and Arm 2 participants 
2.3.2.6 
To compare days to positivity in automated liquid mycobacterial culture over 
treatment time 
2.3.2.7 
To compare chest radiographic score (with specific attention to resolution of 
cavitary disease) between Arms from baseline to end of treatment (Arm 1, week 
13; Arm 2, week 26) between Arm 1 and Arm 2 participants 
2.3.2.8 
To compare proportions of participants who experience a favorable 
clinical/bacteriologic treatment outcome at 65 weeks between Arm 1 and Arm 2 
participants 
2.3.2.9 
To estimate cumulative relapse and recurrence proportions up to week 65 for 
participants on Arm 1 and Arm 2 
2.3.2.10 To determine CFZ pharmacokinetic (PK) parameters in plasma in Arm 1 
2.3.2.11 To compare PK parameters when CFZ is given with a loading dose in Arm 1 and 
without a loading dose in Arm C  
2.3.2.12 To objectively and subjectively assess CFZ-associated skin hyperpigmentation 
between Arm 1 and Arm 2 participants 
 
 


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2.4 
Overview of Sample Size Considerations 
We plan to enroll a total of 185 participants; approximately 110 in Arm 1, 55 in Arm 2, and 20 in 
Arm C. We estimate that we will have at least 90% power to detect an effect between Arm 1 and 
Arm 2 with respect to the primary efficacy outcome. We assume 70% culture conversion by week 
12 in Arm 2 and a hazard ratio of 1.8. We use a 2:1 allocation ratio and assume that 10% of 
participants will have unevaluable culture conversion results.  
For the primary safety outcome, we will compare proportions of participants with any Grade 3 or 
higher adverse events (AE) between Arms. Table 10.4-2 from the study protocol (copied below) 
gives the power we would have to detect that Arm 1 is inferior to Arm 2 assuming a two-sided 
type 1 error of 0.10, 10% probability of developing an AE in the SOC Arm, and varying 
probabilities (15-30%) of developing an AE in experimental Arm. We also provide the 90% 
confidence interval (CI) width for the comparison. 
Protocol Table 10.4-2 
 
2.5 
Overview of Formal Interim Monitoring 
The Data and Safety Monitoring Board (DSMB) will perform an initial review of the study between 
4-6 months after the first enrollment, and thereafter at least every 6 months or on another 
schedule requested by the DSMB. For all reviews, we will provide the DSMB with detailed 
information on safety, tolerability, and administrative aspects (including accrual, retention, and 
compliance with study requirements). 
There was one planned interim analysis for futility of the primary efficacy outcome using a 
conditional power approach. This analysis was to be conducted once 50% of participants had 
reached week 12 of follow-up. However, due to the early close to accrual, this interim analysis will 
not be completed. 
 
 
Power 
N1 
N2 
N 
Arm 1 Proportion 
with ≥Grade 3 AE 
Arm 2 Proportion 
with ≥ Grade 3 AE 
Two-sided 
type 1 error 
90% CI Width 
0.13 
100 
50 150 
0.15 
0.10 
0.10 
0.210 
0.36 
100 
50 150 
0.20 
0.10 
0.10 
0.218 
0.64 
100 
50 150 
0.25 
0.10 
0.10 
0.225 
0.85 
100 
50 150 
0.30 
0.10 
0.10 
0.230 


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3 
Outcome Measures 
3.1 
Primary Outcome Measures 
3.1.1 Early Efficacy  
Time to stable culture conversion in liquid media, defined as the first of two (consecutive 
or non-consecutive) negative sputum cultures without an intervening positive culture, 
and/or visits wherein the participant is unable to produce sputum and has no signs of 
active TB, up to 12 weeks post-randomization. 
3.1.2 Safety 
Proportion across study arms experiencing any Grade 3 or higher AE that is at least a 
one-grade increase from baseline over 65 weeks 
3.2 
Secondary Outcome Measures  
3.2.1 Composite Efficacy 
A: Proportion with favorable clinical/bacteriologic outcome at 65 weeks post 
randomization 
B: Proportion with favorable composite outcome including treatment completion at 65 
weeks post-randomization. 
Favorable, unfavorable, and unevaluable clinical/bacteriological outcomes (A) are defined 
as follows: 
Favorable Outcome (any one of the following scenarios) 
• 
Participants with liquid culture negative status at week 65.  
• 
Participants without signs or symptoms of ongoing active TB and are unable 
to produce a sputum specimen at 65 weeks. 
• 
Participants who at the end of the follow-up period are clinically without 
symptoms/signs of ongoing active TB and produce a sputum specimen that 
is contaminated in two liquid cultures without evidence of TB. 
 
For any of the above to be considered favorable, participants must not already 
have been considered unfavorable, as defined below. 
Unfavorable Outcome 
• 
Absence of cure. A participant will be considered to have absence of 
bacteriological cure if a sputum sample obtained at or after end of treatment 
for Arm 1 (week 13), or at or after week 17 for Arm 2 is culture-positive in 
liquid or solid media for an Mtb strain genotypically matched with the initial 
isolate. A second sputum sample, obtained at least four hours following the 
first sputum collection (see section 6.2.3 of protocol), is required to confirm 
absence of bacteriological cure.  
• 
Participants who die from any cause during study treatment or follow-up 
except from violent or accidental cause (e.g., road traffic accident). 


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• 
Participants who had a positive culture for Mtb when last seen, whether 
confirmed by a second sample or not, unless determined to have been re-
infected. 
• 
Participants experiencing extension of treatment beyond the nominal level 
(week 13 for Arm 1 and week 26 for Arm 2) due to clinically inadequate 
response. These cases should be managed individually in conjunction with 
and after having notified the A5362 Clinical Management Committee (CMC). 
Extension of treatment to make up missed doses will not count as 
unfavorable. 
Unevaluable Outcome 
• 
Participants lost to follow-up during treatment or post-treatment follow-up 
with their last culture being negative for Mtb.  
• 
Violent or accidental death.  
• 
Participants with recurrent TB due to a new strain of Mtb confirmed by 
conventional molecular genotyping (as defined by MIRU and IS6110 typing). 
• 
Women who become pregnant during their assigned active treatment and 
stop their assigned treatment. 
Favorable, unfavorable, and unevaluable composite outcomes (B) are defined as follows: 
Favorable Outcome 
Same as in outcome measure 3.2.1 A. 
 
Unfavorable Outcome 
Same as in outcome measure 3.2.1 A, and: 
• 
Participants lost to follow-up during treatment phase of each Arm (i.e., 13 
weeks and 26 weeks for Arms 1 and 2, respectively). 
• 
Participants failing to complete treatment (see below for Definitions of 
Adequate Treatment) and not assessable at the end of the follow-up period. 
• 
Participants receiving any one or more of the following: 
o 
extension of treatment beyond the nominal level, except to make up 
missed doses 
o 
a re-start of treatment following ≥30 consecutive days lost to follow-up 
o 
a change in at least one drug in treatment regimen for any reason except 
re-infection, pregnancy, or temporary drug challenge. 
 
Unevaluable Outcome 
• 
Participants lost to follow-up after treatment phase, and not assessable at the 
end of follow-up, with their last culture being negative for Mtb.  
• 
Violent or accidental death. 
• 
Participants re-infected with a new strain of Mtb confirmed by conventional 
molecular genotyping (as defined by MIRU and IS6110 typing). 
• 
Women who become pregnant during their assigned active treatment and 
stop their assigned treatment. 
 
 
Definitions of Adequate Treatment Within 3-month Regimen (Arm 1) 
• 
Taken a total of at least 56 doses of allocated intensive phase treatment 
within 70 days of starting treatment 
• 
AND taken at least 28 doses of continuation phase treatment within 49 days 
(7 weeks) of completion of the intensive phase 
• 
AND missed no more than 21 doses of medication overall. 


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Definitions of Adequate Treatment within 6-month Regimen (Arm 2) 
• 
Taken a total of at least 56 doses of allocated intensive phase treatment 
within 70 days of starting treatment 
• 
AND taken at least 100 doses of continuation phase treatment within 154 
days (22 weeks) of completion of the intensive phase 
• 
AND missed no more than 42 doses of medication overall. 
 
3.2.2 
Tolerability 
Proportion with premature discontinuation through 65 weeks, defined as 
discontinuation other than due to violent death, natural disaster, or administrative 
censoring. 
3.2.3 
QT interval  
We derive the outcome measures defined below from ECG readings, which the 
site conducts in triplicate (three ECGs 5-10 minutes apart). We will use the mean 
of all measurements (up to 3) that are readable and available.  
3.2.3.1 Mean baseline QTcF and change from baseline in mean QTcF at weeks 
2, 8, and end of treatment (EOT) (Arm 1, week 13; Arm 2, week 26) 
3.2.3.2 Occurrence of absolute QTcF ≥480 ms and <500 ms, and ≥500 ms, at 
any time during study treatment 
3.2.3.3 Occurrence of QTcF change from baseline of ≥30 ms and <60 ms, and 
≥60 ms, at any time during study treatment 
3.2.4 
Time to stable culture conversion in liquid and solid media through week 65 
Defined as the first of two (consecutive or non-consecutive) negative sputum 
cultures without an intervening positive culture, and/or visits wherein the 
participant is unable to produce sputum and has no signs of active TB. 
Conducted separately for liquid and solid media.  
3.2.5 
Proportion of participants with culture conversion at weeks 8 and 12 across all 
study arms. 
Liquid (MGIT) and solid media analyzed separately. 
3.2.6 
Time (days) to positivity in liquid culture (MGIT) after start of treatment through 
week 65 
We will report the median (Q1, Q3) times to positivity in liquid culture at each 
time point (weeks 1, 2, 3, 4, 6, 8, 10, and 12) in Arm 1 and Arm 2. 
3.2.7 
Change in chest X-ray (CXR) score from baseline to end of treatment (EOT).  
Sites conduct the baseline chest X-ray during screening. We will compute the 
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CXR Score = percent of total lung affected by any pathology + 40 (if cavitation is 
present). 
We will compute the CXR scores based on both site assessment of the chest X-
ray and an assessment by independent central reviewers blinded to study 
treatment. 
3.2.8 
Proportion of participants with one or more serious adverse events (SAEs) 
through week 65  
3.2.9 
Proportion of participants who have a TB relapse from EOT until week 65  
For participants who had successful culture conversion through the end of study 
treatment, TB relapse is defined as a recurrence of TB emanating from the same 
strain as the participant’s originally diagnosed TB, which will be determined 
through molecular genotyping.  
3.2.10 Proportion of participants who have a TB recurrence from EOT until week 65 
3.2.11 Plasma pharmacokinetic parameters for CFZ  
Arm 1  
We will report the minimum concentration (Cmin), maximum concentration 
(Cmax), time of Cmax (Tmax), and area under the concentration curve (AUC0-
24h) estimated though non-compartmental analysis for weeks 2 and 13 
summarized separately. 
Arm C 
We will report the estimated minimum concentration (Cmin), maximum 
concentration (Cmax), time of Cmax (Tmax), and area under the concentration 
curve (AUC0-24h) estimated though non-compartmental analysis for week 2. 
Arm 1 versus Arm C  
We will compare the estimated minimum concentration (Cmin), maximum 
concentration (Cmax), time of Cmax (Tmax), and area under the concentration 
curve (AUC0-24h) at week 2 between Arm 1 and Arm C intensive PK 
participants. We will estimate the geometric mean ratio comparing Arm 1 to Arm 
C and corresponding 90% confidence interval. As a supplemental analysis, we 
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3.2.12 Change from baseline in skin pigmentation (colorimetric L*, a*, b* parameters) 
utilizing ambient light-independent reflectance mapping at weeks 8, 13, 26, and 
65. 
Mean change in total color difference from week 0 to each of weeks 8, 13, 26, 65 
in Arm 1 vs Arm 2 at each of the following locations; (1) left cheek, (2) right 
cheek, (3) forehead, (4) chin.  
Mean change in total color difference from week 0 to each of weeks 8, 13, 26, 65 
in Arm 1 vs Arm 2 using, for each participant, the location with the maximum 
change.  
3.2.13 Change from baseline in participant-reported changes in skin pigment and 
 
distress related to perceived skin hyperpigmentation at weeks 8, 13, 26, and 65. 
Mean subjective ‘change in coloration’ score between week 0 and weeks 8, 13, 
26, and 65 in Arm 1 vs Arm 2 (10-point numeric rating scale where 0=none, 
10=most significant possible).  
Mean subjective ‘distress related to skin coloration’ score at each of weeks 0, 8, 
13, 26, and 65 in Arm 1 vs Arm 2 (10-point numeric rating scale where 0=none, 
10=worst possible) 
  
4 
Statistical Principles 
4.1 
General Considerations 
All statistical comparisons described in Section 3 are between Arms 1 and 2, unless 
otherwise noted. The analysis set or study population is specified for the analysis of each 
study objective. We explicitly define these in the next section. 
 
For time-to-event analyses, we will base each participant’s follow-up time from the date of 
randomization. We will compute the time to event as the weeks from randomization to the 
study visit week when the event occurred, not the actual date of the visit. Similarly, 
participants who do not have an event by the last scheduled visit and are not lost to follow-up 
are censored on the respective study visit week, not the actual date of their last visit. This 
ensures there are not major artificial fluctuations in the risk set near the end of the period for 
the outcomes in which we estimate Kaplan-Meier proportions at a fixed time point. 
 
For analyses where we estimate Kaplan-Meier proportions at a fixed time point, we will use 
Greenwood’s estimator to estimate the variance of the proportions in each arm, and the 
variance for the difference in proportions between arms will be computed as the sum of the 
squared variance estimates for Arms 1 and 2.  
 


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4.1.1 
Analysis set definitions 
4.1.1.1 
Analysis sets (used for primary (5.1.1) and key secondary (5.1.2) estimands): 
• 
Efficacy Set: 
All participants who are randomized to study treatment and are not late exclusions. 
(Participants will be late exclusions if they do not have any positive culture (liquid or solid) 
at screening, entry, or week 1, or if they have TB that is RIF-resistant or INH-resistant 
identified at screening or entry.)  
 
• 
Safety Set: 
All participants who start assigned study treatment.  
 
• 
Start treatment/not late exclusion set: 
All participants who start assigned study treatment and are not late exclusions. 
 
• 
Alive/adequate treatment set:  
All participants who complete an adequate course of treatment as defined within Sections 
10.2.5 and 10.2.6 of the protocol and who do not die during treatment. 
 
• 
Per protocol Set: 
All participants who start and complete assigned study treatment.  
4.1.2 
Subgroups of interest 
Subgroups defined by levels of sex 
Subgroups defined by levels of race/ethnicity 
Subgroups defined by levels of HIV status 
Subgroups defined by presence (or absence) of advanced disease on chest x-ray conducted at 
screening.  
4.1.3 
Interim Monitoring 
4.1.3.1 
Early Assessment of QT Prolongation 
After 12 Arm 1 participants have evaluable AE data through week 2, we will find the point 
estimate of the proportion of participants in the ITT population on Arm 1 with prolonged QT 
interval (defined by QTcF > 500 ms) and corresponding two-sided Pearson-Klopper exact 95% 
confidence interval.  
4.1.3.2 
Interim Futility Analysis 
Note: Due to the early closure to accrual, this analysis will not be conducted.  
We will estimate the conditional power of the test statistic at the second DSMB review using two 
methods in the efficacy set.  
1) Under the assumption that the future data follows the hypothesized difference between 
Arm 1 and Arm 2 (hazard ratio of 1.8 between arms).  


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2) Under the assumption that future data follows the estimated difference between Arm 1 
and Arm 2 at the time of the review (the estimated hazard ratio). 
4.1.3.3 
Unfavorable Composite Outcome Monitoring in Arm 1 
We will find the two-sided 95% confidence bands for cumulative unfavorable outcome 
probabilities in Arm 1 in the safety set approximately one month after the first participant 
completes treatment, and will continue approximately monthly and for each DSMB review until 
the end of the study. We will present these estimates alongside historical unfavorable proportions 
for SOC on the REMox, OFLOTUB, RIFAQUIN, and Study31 trials, and A5362 SOC data as 
available. There will be no adjustment to the confidence bands for multiple looks. 
4.1.3.4 
Early Recurrence Monitoring in Arm 1 
We will find the two-sided 95% confidence bands for cumulative relapse probabilities in Arm 1 
beginning approximately 2 months after the first participant completes treatment, and will 
continue approximately monthly and for each DSMB review until the end of the study. We will 
present these results alongside historical relapse proportions for SOC on the REMox, OFLOTUB, 
and RIFAQUIN trials, and A5362 SOC data as available. There will be no adjustment to the 
confidence bands for multiple looks. 
 
 


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5 
Analysis Approaches 
5.1.1 
Primary Estimands  
Primary Objective 2.3.1.1: To compare time to 12-week liquid culture conversion for Arm 
1 with SOC controls (Arm 2) 
Estimand 
description 
Time to liquid culture conversion through 12 weeks of follow-up among individuals aged 
≥18 years and with pulmonary TB without demonstrated isoniazid or rifampicin 
resistance. 
Treatment 
13-week Experimental Regimen:  
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 
 
26-week Standard of Care:  
rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) followed by rifampicin/isoniazid 
(RH) 
Target population  
Analysis set  
Individuals aged ≥18 years living with confirmed 
pulmonary TB without demonstrated isoniazid or 
rifampicin resistance. 
Efficacy set (All participants who are randomized 
to study treatment and are not late exclusions) 
Variable 
Outcome measure 3.1.1 
Time to stable culture conversion based on sputum 
samples taken at serial collections up to 13 weeks 
after treatment initiation. 
 
Note: The time of stable culture conversion will be 
the time of the sampling date of the first of two 
culture negative sputum samples in liquid media 
(MGIT) without an intervening positive culture. We 
also consider a participant’s inability to produce 
sputum with no signs of active TB at a given visit as a 
negative sputum culture. A negative culture at week 
13 can be used as the confirmatory second culture to 
determine stable culture conversion at week 12. 
 
Time to stable culture conversion in liquid media, 
defined as the first of two (consecutive or non-
consecutive) negative sputum cultures without an 
intervening positive culture, and/or visits wherein 
the participant is unable to produce sputum and 
has no signs of active TB, up to 12 weeks post-
randomization. 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to the 
estimand:  
 
1. 
Failure to start TB treatment 
Observations will be used to determine the 
variable (treatment policy strategy) 
 
2. Premature treatment discontinuation due to 
suspected TB treatment failure or TB recurrence 
or poor treatment response.  
Observations will be used to determine the 
variable (treatment policy strategy) 
 
3. 
Premature TB treatment discontinuation due to 
TB death 
Observations will be used to determine the 
variable (treatment policy strategy) 
 
4. 
Premature treatment discontinuation for other 
reason  
Observations will be used to determine the 
variable (treatment policy strategy) 
 
5. 
Non-TB death 
Participants who have contaminated or missing 
samples leading up to and including week 12 will 
be censored at the last sampling date for which 
they had a valid sputum culture assessment.  
 
Participants who experience premature TB 
treatment discontinuation due to TB death will be 
censored at week 12.  


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Observations will be used to determine the 
variable (treatment policy strategy) 
 
Population-level summary measure 
Analysis approach 
 
Hazard ratio of culture conversion through 12 weeks 
of follow-up.  
We will estimate the treatment effect with a 
hazard ratio and corresponding 90% two-sided 
confidence interval. We consider Arm 1 superior 
to Arm 2 if the one-sided p-value is less than 
0.05 in favor of Arm 1. The hazard ratio (HR) will 
be estimated from a Cox proportional-hazards 
model, with HIV status (positive; negative) and 
advanced disease according to chest X-ray 
(yes/no) treated as stratification factors. We will 
assess the proportional hazards assumption 
visually by plotting the scaled Schoenfeld 
residuals against the natural logarithm of the time 
to event. In the event that the data violate the 
proportional hazards assumption, we will conduct 
the primary analysis with a stratified log-rank 
test. 
 
Participants who do not achieve stable culture 
conversion, but who are on study and have 
contaminated or missing cultures leading up to 
and including week 12 will be censored at the 
last sampling visit for which they had a valid 
sputum culture assessment. Participants who are 
lost to follow-up prior to 12 weeks with their last 
culture being positive will be censored at 12 
weeks (i.e. assumed they did not have a culture 
conversion by week 12), and participants who 
are lost to follow-up prior to 12 weeks with their 
last culture being negative will be censored at the 
last sampling visit for which they had a valid 
culture result. Participants who die prior to week 
12 will be censored at 12 weeks.  
Sensitivity Analyses  
None. 
Supplemental Analyses 
We will also test the treatment by sex and treatment by race/ethnicity interaction terms in separate Cox 
proportional hazards models. These models will also include the same stratification factors as the primary 
analysis: HIV status and advanced disease according to chest X-ray reading. In a supplemental analysis, we 
will estimate the difference in restricted mean survival times (difference in restricted mean time to culture 
conversion) for a time horizon of 12 weeks.  
 
 


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Primary Objective 2.3.1.2: To compare the proportion of adverse events (safety) over 65 
weeks between Arm 1 and Arm 2 
Estimand 
description 
Probability of having at least one grade 3 or higher adverse event through 65 weeks 
that is at least a one-grade increase from baseline among patients aged ≥18 years 
living with pulmonary TB without demonstrated isoniazid or rifampicin resistance. 
Treatment 
 
13-week Experimental Regimen:  
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 
 
26-week Standard of Care:  
rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) followed by rifampicin/isoniazid 
(RH) 
Target population  
Analysis set  
Patients aged ≥18 years living with pulmonary TB 
without demonstrated isoniazid or rifampicin 
resistance who initiate TB therapy. 
Safety Set (All participants who start their 
assigned study treatment) 
Variable(s) 
Outcome measure 3.1.2 
Occurrence of a Grade 3 or higher adverse event 
through 65 weeks that is new in onset or aggravated 
in severity of frequency from the baseline condition.  
Proportion across study arms experiencing any 
Grade 3 or higher AE that is at least a one-grade 
increase from baseline over 65 weeks. 
Handling of intercurrent events  
Handling of missing data 
1. 
Persistent clinical disease and extension of 
treatment  
Observations will be used to determine the 
variable (treatment policy strategy) 
 
2. 
Premature treatment discontinuation 
Observations will be used to determine the 
variable (treatment policy strategy) 
 
3. 
Premature treatment discontinuation due to 
suspected TB treatment failure or TB 
recurrence or poor treatment response.  
Observations will be used to determine the 
variable (treatment policy strategy) 
 
Participants who discontinue follow-up before 
week 65 will have their outcome determined 
based on data available until the time of 
discontinuation (i.e., missing observations after 
discontinuation that would be relevant to the 
variable are considered missing completely at 
random).  
 
Sensitivity analyses will consider participants who 
discontinue follow-up before week 65 as having 
at least one Grade 3 or higher adverse event that 
is at least a one-grade increase from baseline. 
 
Population-level summary measure 
Analysis approach 
Probability of having at least one Grade 3 or higher 
AE that is at least one-grade increase from baseline 
at any time during the 65 weeks after treatment 
initiation.  
We will compare the cumulative proportion of 
participants experiencing a Grade 3 or higher AE 
that is at least one-grade increase from baseline 
at any time during the 65-week study period 
between Arm 1 and Arm 2 using the Kaplan-
Meier estimator at week 65. Participants who 
have not experienced an event will be censored 
at the last completed study visit.  For participants 
who experience more than one event, we will use 
the time of the first occurrence as the time of 
event. We will present the point estimate and 
90% two-sided confidence intervals for the 
difference in cumulative proportions.  
 
Supplemental Analyses: 
As supplementary analyses, we will also estimate the Kaplan-Meier proportions and confidence intervals for 
the outcome measure up to week 13, and up to week 26. These time horizons correspond to the end of 
treatment for Arm 1, and Arm 2, respectively. 


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5.1.2 
Secondary Estimands 
Secondary Objective 2.3.2.1:  
To compare proportions of participants treated with RPT/CFZ-containing regimens who 
experience favorable composite efficacy outcome at 65 weeks with Arm 2 (6-month SOC 
controls) 
Estimand 
description 
Difference in proportion with favorable outcomes 65 weeks after initiation of TB therapy 
(PHZE+CFZ versus RHZE) among individuals aged ≥18 years and with pulmonary TB 
without demonstrated isoniazid or rifampicin resistance. 
Treatment 
13-week Experimental Regimen:  
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 
 
26-week Standard of Care:  
rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) followed by rifampicin/isoniazid 
(RH) 
Target population  
Analysis set  
Individuals aged ≥18 years with confirmed pulmonary 
TB without demonstrated isoniazid or rifampicin 
resistance who initiate TB therapy. 
Efficacy set (All participants who are randomized 
to study treatment and are not late exclusions) 
Variables 
Outcome measure 3.2.1 A 
Favorable outcome 65 weeks after initiation of TB 
therapy following evidence of cure at treatment 
completion where favorable outcome is defined by any 
one of the following: 
 
• 
Liquid culture negative at 65 weeks after TB 
therapy initiation 
 
• 
No signs or symptoms of ongoing active TB and 
unable to produce a sputum specimen at 65 
weeks after TB therapy initiation 
 
• 
No signs or symptoms of ongoing active TB and 
a sputum specimen that is contaminated in two 
liquid cultures without evidence of TB at 65 
weeks after TB therapy initiation 
  
Absence of cure at or after treatment completion is an 
unfavorable outcome. 
 
Favorable clinical/bacteriologic outcome at the 
65 week study visit.  
 
 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to the 
estimand.  
 
1. 
Death except from violent or accidental cause (e.g., 
road traffic accident) 
Unfavorable outcome (composite strategy)  
 
2. Violent or accidental death  
Unevaluable outcome* (hypothetical strategy) 
 
3. Extension of treatment beyond the nominal duration 
due to clinically inadequate response 
Unfavorable outcome (composite strategy) 
 
4. New TB diagnosis due to a new strain of Mtb  
Unevaluable outcome* (hypothetical strategy) 
 
 
Participants lost to follow-up and culture negative 
at their last visit meet the definition of 
“unevaluable” and will be censored at the time of 
their last follow-up visit  
 
Participants with a positive culture for Mtb when 
last seen, whether confirmed by a second 
sample or not, unless determined to have been 
re-infected will be considered to have an 
unfavorable outcome and the event time will be 
the visit when last seen.  
 
Participants with a new TB diagnosis due to a 
new strain of Mtb will be censored at the time of 
their last follow-up visit.  


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5. Pregnancy during treatment resulting in 
discontinuation of initial therapy  
Unevaluable outcome* (hypothetical strategy) 
 
6. Failure to complete treatment (except for 2 and 5 
above)  
All follow-up through to 65 weeks will be used to 
determine the variable irrespective of duration of 
treatment (treatment policy strategy) 
 
* See handling of missing data for imputation rules for 
unevaluable outcomes 
 
Participants who become pregnant during 
assigned active treatment and discontinue 
treatment will be censored at the time of 
treatment discontinuation. 
Population-level summary measure 
Analysis approach 
 
Difference in cumulative probability of having a 
favorable clinical/bacteriologic outcome at 65 weeks 
after TB therapy initiation.  
 
 
 
Difference in cumulative proportion of 
participants at 65 week visit together with 90% 
and 95% two-sided confidence intervals. We will 
use the Kaplan-Meier estimator and 
Greenwood’s estimate for the standard error. 
 
 
 
 


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Secondary Objective 2.3.2.1:  
To compare proportions of participants treated with RPT/CFZ-containing regimens who 
experience favorable composite efficacy outcome at 65 weeks with Arm 2 (6-month SOC 
controls) 
Estimand 
description 
Difference in proportion favorable outcomes 65 weeks after initiation of TB therapy 
(PHZE+CFZ versus RHZE) among individuals aged ≥18 years and with pulmonary TB 
without demonstrated isoniazid or rifampicin resistance who complete TB treatment. 
Treatment 
13-week Experimental Regimen:  
rifapentine/isoniazid/pyrazinamide/ethambutol (PHZE) + clofazimine (CFZ) 
 
26-week Standard of Care:  
rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE) followed by rifampicin/isoniazid 
(RH) 
Target population  
Analysis set  
Individuals aged ≥18 years living with confirmed 
pulmonary TB without demonstrated isoniazid or 
rifampicin resistance who complete TB therapy. 
Efficacy set (All participants who are randomized 
to study treatment and are not late exclusions) 
Variables 
Outcome measure 3.2.1B 
Favorable outcome 65 weeks after initiation of TB 
therapy following evidence of cure at treatment 
completion where favorable outcome is defined by any 
one of the following: 
 
• 
Liquid culture negative at 65 weeks after TB 
therapy initiation 
 
• 
No signs or symptoms of ongoing active TB and 
unable to produce a sputum specimen at 65 
weeks after TB therapy initiation 
 
• 
No signs or symptoms of ongoing active TB and 
a sputum specimen that is contaminated in two 
liquid cultures without evidence of TB at 65 
weeks after TB therapy initiation 
  
Absence of cure at or after treatment completion is an 
unfavorable outcome. 
Favorable clinical/bacteriologic outcome at the 
65 week study visit.  
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to the 
estimand:  
 
Intercurrent events that occur during therapy: 
 
1. 
Death except from violent or accidental cause (e.g., 
road traffic accident) 
Unfavorable outcome* (Composite strategy)  
 
2. Violent or accidental death  
Unevaluable outcome* (Composite strategy) 
 
3. A re-start of therapy following > 30 consecutive 
days without therapy 
Unfavorable outcome (Composite strategy) 
 
4. A change in at least one drug in treatment regimen 
for any reason except re-infection, pregnancy, or 
temporary drug challenge. 
Unfavorable outcome (Composite strategy) 
 
 
Participants lost to follow-up during the treatment 
phase are considered to have an unfavorable 
outcome (regardless of TB culture result at the 
last available visit) and the event time is the time 
of the last visit.  
 
Participants failing to complete treatment and not 
assessable at the end of the follow-up period are 
considered to have an unfavorable outcome and 
the event time is the time of the last treatment 
dose received.  
 
Participants receiving an extension of treatment, 
re-start of treatment, or change in treatment (see 
full definition B of unfavorable outcome) are 
considered to have an unfavorable outcome and 
the event time is the time of the treatment 
modification.  
 


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5. Pregnancy during treatment resulting in 
discontinuation of initial therapy  
Unevaluable outcome* (Composite strategy) 
 
Intercurrent events that occur after adequate** 
completion of therapy: 
 
6. 
Death except from violent or accidental cause (e.g., 
road traffic accident) 
Unfavorable outcome (Composite strategy)  
 
7. Violent or accidental death  
Unevaluable outcome* (Hypothetical strategy) 
 
8. Extension of treatment beyond the nominal duration 
except to make up missed doses 
Unfavorable outcome (Composite strategy) 
 
9. New TB diagnosis due to a new strain of Mtb 
Unevaluable outcome* (Hypothetical strategy) 
 
* See handling of missing data for imputation rules for 
unevaluable outcomes 
 
Participants lost to follow-up after the treatment 
phase with their last available TB culture being 
negative are considered unevaluable and are 
censored at the time of the last visit.  
 
Participants who experience violent or accidental 
death are considered to have an unevaluable 
outcome and will be censored at the time of their 
last follow-up visit.  
 
Participants reinfected with a new strain of Mtb 
are considered to have an unevaluable outcome 
and will be censored at the time of their last 
follow-up visit.  
 
Participants who become pregnant during their 
assigned active treatment and who stop their 
assigned treatment are considered to have an 
unevaluable outcome and will be censored at the 
time of the last treatment dose received.  
 
 
  
Population-level summary measure 
Analysis approach 
 
Difference in cumulative probability of having a 
favorable clinical/bacteriologic outcome at 65 weeks 
after TB therapy initiation .  
 
 
Difference in cumulative proportion of 
participants at 65 week visit together with 90% 
and 95% two-sided confidence intervals. We will 
use the Kaplan-Meier estimator and 
Greenwood’s estimate for the standard error. 
 
 
** Adequate completion of therapy is determined by the following definitions:  
Definitions of Adequate Treatment Within 3-month Regimen (Arm 1 in the setting of this 
trial) 
• 
Taken a total of at least 56 doses of allocated intensive phase treatment 
within 70 days of starting treatment 
• 
AND taken at least 28 doses of continuation phase treatment within 49 days 
(7 weeks) of completion of the intensive phase 
• 
AND missed no more than 21 doses of medication overall. 
 


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Definitions of Adequate Treatment within 6-month Regimen (Arm 2 in the setting of this 
trial) 
• 
Taken a total of at least 56 doses of allocated intensive phase treatment 
within 70 days of starting treatment 
• 
AND taken at least 100 doses of continuation phase treatment within 154 
days (22 weeks) of completion of the intensive phase 
• 
AND missed no more than 42 doses of medication overall. 
5.1.3 
Secondary Objectives 
5.1.3.1 
Tolerability (Objective 2.3.2.2; Outcome Measure 3.2.2) 
We will compare the proportion of participants who permanently and prematurely discontinue 
study treatment for any reason between arms in the start treatment/not late exclusion set. 
Permanent and premature discontinuation of study treatment is defined as not having completed 
an adequate dose of treatment as defined in Section 3.2.1. We will exclude participants who 
discontinued due to violent or accidental death, natural disaster, or administrative censoring (e.g. 
site closure), from the analysis. The difference in proportions will be estimated using binomial 
proportions, and we will provide exact 95% confidence intervals. 
5.1.3.2 
QT Prolongation (Objective 2.3.2.3; Outcome Measures 3.2.3.1, 3.2.3.2, 3.2.3.3) 
We will compare the mean change in QTcF from screening to weeks 2, 8, and 13 (3.2.3.1) 
between Arm 1 and Arm 2 in the safety set using a GEE model with exchangeable correlation 
structure and time by treatment interaction terms (treating time as a categorical variable).  
We will compare the change from baseline in QTcF over time between arms using a linear mixed 
effects model. Randomization arm and week (time) will be fixed effects and participant ID will be 
a random effect.  
We will compare the odds of participants having maximum occurrence of absolute QTcF ≥ 480 
ms and <500 ms, or ≥ 500 ms (3.2.3.2) between Arm 1 and Arm 2 in the safety set using a 
proportional odds model, if the proportional odds assumption is satisfied. We will assess the 
proportional odds assumption using the score test for the proportional odds assumption 
implemented in SAS PROC LOGISTIC. If the score test indicates a statistically significant result 
at the 0.05 level, we will also assess the proportional odds assumption graphically to confirm. If 
graphical evidence suggests the proportional odds model is valid, we will use it for analysis. 
If the proportional odds assumption does not hold, we will instead estimate the difference in 
binomial proportions and 95% confidence intervals for the collapsed category of QTcF ≥ 480 ms 
(including QTcF ≥ 500 ms), and separately for the category QTcF ≥ 500 ms. 
The analysis of outcome measure 3.2.3.3 will follow the same approach as that of 3.2.3.2.  
5.1.3.3 
Time to stable culture conversion in liquid media, and solid media at week 26 
(Objective 2.3.2.4; Outcome Measure 3.2.4) 
Time to stable culture conversion in liquid media will follow the same approach as described in 
Section 5.1.1, except we will censor participants at week 26 instead of week 12. 


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Time to stable culture conversion in solid media will be analyzed separately, and also follow the 
same approach as described in Section 5.1.1, except we will censor participants at week 26 
instead of week 12. 
5.1.3.4 
Proportion with culture conversion at week 8 and 12 (Objective 2.3.2.5; Outcome 
Measure 3.2.5) 
We will compare the proportion of participants with stable culture conversion by week 8 and week 
12 between Arm 1 and Arm 2 in the efficacy set. We will analyze liquid and solid cultures 
separately. We will present the difference in proportions and exact 95% confidence intervals.  
5.1.3.5 
Proportion with one or more SAE (Outcome Measure 3.2.8) 
We will estimate the proportion of participants with one or more SAEs of any grade between Arm 
1 and Arm 2 in the safety set using the same approach as described in Section 5.1.1 
As in Section 5.1.1, supplementary analyses will compare SAEs between arms up to week 13 
and up to week 26. 
5.1.3.6 
Time to Positivity (Objective 2.3.2.6, Outcome Measure 3.2.6) 
We will compare time (days) to positivity of TB cultures between Arm 1 and Arm 2 in the efficacy 
set separately at weeks 1, 2, 3, 4, 6, 8, 10, and 12 using Cox proportional hazards models or log-
rank tests. We will present the hazard ratios and 95% confidence intervals for each week. 
We will include side-by-side box plots to show the distribution of time to positivity at each visit in 
each of Arms 1 and 2. In exploratory analyses, we may consider comparing time (days) to 
positivity of TB cultures between Arm 1 and Arm 2 in the efficacy set using a random effects joint 
model for time-to-event data with repeated measures. We may also consider other models and 
mechanistic approaches.  
5.1.3.7 
Chest X-Ray Scores (Objective 2.3.2.7; Outcome Measure 3.2.7) 
Each participant will have a CXR Score computed at screening and at EOT (week 13 for Arm 1; 
week 26 for Arm 2). We will compute the difference in scores from baseline to EOT between arms 
in the efficacy set using linear regression, with adjustment for stratification factors of HIV status 
and advanced disease status. 
We will carry out two analyses for this outcome; (1) based on the site reading of CXR, and (2) 
based on the central reading of CXR. The central reading will take precedence when presenting 
results.  
5.1.3.8 
Proportion of participants who have a TB relapse (Objective 2.3.2.9; Outcome 
Measure 3.2.8) 
We will estimate the proportion of participants in Arm 1 and Arm 2 with TB relapse using Kaplan-
Meier estimates and 95% confidence intervals at 6 months (Arm 1), 9 months (Arms 1 and 2), 
and 12 months post-treatment (Arm 1 only) in the start treatment/not late exclusion set. We define 
the time of relapse as the time from end of treatment until the first sputum sample that is culture 


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positive in liquid or solid media for an Mtb strain that has matching genotype with the baseline 
isolate. A second positive sputum sample obtained at least 4 hours following the first sputum 
collection is required to confirm a relapse. If the second sputum sample is negative, this will not 
be counted as a relapse. If a participant is lost to follow-up without a second sputum sample 
confirmation of relapse (including contaminated or missing), it will be counted as a relapse. 
For monitoring and interim reviews, we will estimate the proportion of participants with a 
confirmed relapse over time with 95% pointwise confidence bands. In addition, we will estimate 
the proportion of participants with a suspected TB recurrence or poor treatment response after 
successful culture conversion, even if relapse/recurrence has yet to be confirmed 
bacteriologically. 
5.1.3.9 
Proportion of Participants who have a TB recurrence (Objective 2.3.2.9; Outcome 
Measure 3.2.10) 
The analysis for the proportion of participants with a TB recurrence will follow the same approach 
described in Section 5.1.3.8. We define recurrence in the same way as relapse, except it is not 
required that the TB strain has matching genotype with the baseline sample. 
5.1.3.10 Plasma Pharmacokinetic Parameters for CFZ (Objectives 2.3.2.10 and 2.3.2.11; 
Outcome Measures 3.2.11) 
Elin Svensson and team at Radboudumc, The Netherlands, will conduct this analysis. 
The PK parameters of interest (Cmin, Cmax, Tmax, AUC0-24h) for CFZ in Arm 1 and Arm C of 
the alive/adequate treatment set will be estimated using non-compartmental methods applied to 
concentrations from intensive PK sampling visits. The AUC will be determined using the 
trapezoidal rule. Cmin will be the minimum observed concentration after the observed dose. 
Cmax will be the maximum observed concentration. Tmax is the time at which Cmax occurs.  
Arm 1 versus Arm C 
We will estimate the geometric mean ratio for each PK parameter (Cmin, Cmax, Tmax, AUC0-
24h) together with the 90% confidence interval using available data in the alive/adequate 
treatment set. 
This non-compartmental analysis will be in conjunction with non-linear mixed-effects modeling to 
estimate the primary PK parameters (e.g., apparent oral clearance (CL/F), volume of distribution, 
rate of absorption). The model-based analysis will use the intensive PK samples as well as the 
sparse samples collected throughout the study period and all protein concentration data. We will 
model the PK observations continuously over time, taking in account each participant’s actual 
dosing history. We will conduct a covariate analysis to evaluate the potential impact of 
demographics and concomitant medications. We will compare the derived secondary metrics with 
the non-compartmental analysis results in a posterior predictive check. 


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5.1.3.11 CFZ-associated skin hyperpigmentation (Objective 2.3.2.12; Outcome Measures 
3.2.12 and 3.2.13) 
We will compute the total color difference scores using the CIELAB color space output values, (L, 
a, b), from the colorimeter device. Since each reading is done in triplicate, we will use the 
average scores from the three readings for L, A, and b for each participant. The analysis for each 
anatomical locations will be separate.  
The CIE76 formula for total color difference, Delta E, is given by: ∆𝐸𝐸= √∆𝐿𝐿2 + ∆𝑎𝑎2+∆𝑏𝑏2 
We will compare the mean change in total color difference (∆𝐸𝐸) from week 0 (entry) to each of 
weeks 8, 13, 26, 65 in Arm 1 vs Arm 2 at each of the following locations; (1) forehead, (2) left 
cheek, (3) right cheek, (4) chin in the mITT-B population. That is, for each anatomical location, we 
will compute the difference between ∆𝐸𝐸 at week 0 and week 8 for each of Arm 1 and Arm 2. We 
will compare the differences with a t-test.  
We will also compare the mean change in total color difference (∆𝐸𝐸) from week 0 (entry) to each 
of weeks 8, 13, 26, 65 in Arm 1 vs Arm 2 using, for each participant in the safety set, the location 
with the maximum change. We will compare differences between arms with a t-test.  
We will compare the ‘mean change in coloration score’ and ‘mean distress related to skin 
coloration score’ for Arm 1 vs Arm 2 at each of weeks 0, 8, 13, 26, and 65 in the safety set.  
Using subjective assessments of clinical images, we will compare the proportion of participants 
with each degree of skin discoloration in Arm 1 vs Arm 2 in the safety set. We will provide the 
point estimates together with the Pearson Klopper exact 95% confidence intervals. 
 


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6 
Primary Analysis Report Contents 
All tables, listings, and figures provided in the final report will include totals and percentages by 
arm and overall unless otherwise specified. At a minimum, the final report will have the following 
contents. 
6.1 
Study Entry 
• 
Accrual by site, country, and month 
• 
Summary of late exclusions (number and reasons, by arm) 
o 
Participants whose screening, entry, and first post-entry visit sputum cultures all 
fail to grow Mtb complex,  
Or  
o 
Participants whose molecular or drug susceptibility test results demonstrate 
resistance to INH or RIF after enrollment 
6.2 
Baseline Characteristics 
• 
Summary of age, sex, gender, country, Karnofsky Score (50-70, 80-100), BMI, HIV 
Status (stratification factor), advanced disease status determined by chest x-ray 
(stratification factor), Total CES Depression Scale Score, CD4 count among those HIV 
positive, viral load among those HIV positive 
• 
Baseline TB diagnostic test results (AFB smear, drug susceptibility tests) 
• 
Baseline lab results for AST, ALT, bilirubin, hemoglobin 
• 
2x2 table displaying concordance of site classification and central reader classification of 
advanced disease status by chest x-ray 
6.3 
Study Status 
• 
Summary of off-study reasons 
• 
Summary of participants last study visit week 
6.4 
Treatment Status 
• 
Summary of number of participants who did not start study treatment 
• 
Summary of extensions, changes, and restarts of study treatment 
• 
Summary of reasons for permanently discontinuing study treatment 
• 
Summary of number of participants who had an adequate dose of study treatment as 
defined in the protocol and Section 3.2.1 of this document. 
6.5 
Adverse Events 
• 
Summary of post-entry reportable adverse events according to Section 7 of the protocol 
• 
Summary of post-entry SAE 
• 
Summary of QTcF at screening, weeks 2, 8, and 13 
• 
Summary of difference in QTcF between screening, and weeks 2, 8, and 13 
• 
Proportion with a maximum occurrence of QTcF ≥ 480 ms and < 500 ms, and ≥ 500 ms 


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• 
Proportion with a maximum change from screening of QTcF ≥30 ms and <60 ms, and 
≥60 ms, at any time during study treatment 
• 
Summary of Grade 3 or higher post-entry QT prolongation adverse events 
6.6 
Primary Outcome Measures 
• 
Kaplan-Meier curve of time to stable culture conversion in liquid media, censored at 12 
weeks (outcome measure 3.1.1) 
• 
Hazard ratio and 90% two-sided confidence interval for time to stable culture conversion 
in liquid media (outcome measure 3.1.1) 
• 
Proportions in each arm, and difference in proportions with 90% confidence interval of 
primary safety outcome at weeks 13, 26, and 65 (outcome measure 3.1.2) 
6.7 
Secondary Outcome Measures 
• 
Proportions in each arm, and difference in proportions with corresponding confidence 
interval for outcome measures 3.2.1A and B, 3.2.2, 3.2.5, 3.2.6, 3.2.9, 3.2.10.  
• 
Contrasts that estimate the difference between in mean change in QTcF scores between 
Arm 1 and Arm 2 from screening to weeks 2, 8, and 13 with corresponding 95% 
confidence intervals (outcome measure 3.2.3.1) 
• 
Odds ratio and 95% confidence interval from proportional odds model for outcome 
measures 3.2.3.2 and 3.2.3.3. If proportional odds model does not hold, then difference 
in proportions for categories QTcF ≥ 480 ms and QTcF ≥ 500 ms between arms with 
corresponding 95% confidence intervals. 
• 
Kaplan-Meier curves of time to culture conversion in liquid media, and solid media, 
censored at 26 weeks (outcome measure 3.2.4).  
• 
Hazard ratio and 95% confidence intervals for time to culture conversion in liquid media, 
and solid media, censored at 65 weeks (outcome measure 3.2.4). 
• 
 Hazard ratio and 95% confidence intervals for time to positivity in liquid media at each 
time point. If proportional hazards does not hold, then we will report log-rank test. Side-
by-side box plots of time to positivity (Days) at each time point (weeks 1, 2, 3, 4, 6, 8, 0, 
12) (outcome measure 3.2.6) 
• 
Estimates for changes in chest x-ray score in each arm from screening to EOT, and 
estimate of difference in change with 95% confidence interval (outcome measure 3.2.7) 
• 
Contrasts that estimate the difference with corresponding 95% confidence interval 
between Arm 1 and Arm 2 for the change in total skin hyperpigmentation color difference 
from week 0 to each of weeks 8, 13, 26, and 65 at each of the following locations; (1) left 
cheek, (2) right cheek, (3) forehead, (4) chin, (5) using the location with the maximum 
change in total skin hyperpigmentation color difference. (outcome measure 3.2.12) 
• 
Contrasts that estimate the difference in mean subjective ‘change in coloration score’ at 
each of weeks 0, 8, 13, 26, and 65 in Arm 1 vs Arm 2 with corresponding 95% confidence 
intervals (outcome measure 3.2.13)  
Contrasts that estimate the difference in mean subjective ‘distress to skin coloration’ 
score at each of weeks 0, 8, 13, 26, and 65 in Arm 1 vs Arm 2 with corresponding 95% 
confidence intervals (outcome measure 3.2.12) 
 


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7 
Associated Documents 
Attachment 1: Writing Team Roster 
Protocol Chair 
John Metcalfe, MD, PhD, MPH 
Protocol Vice Chairs 
Samuel Pierre, MD 
Kimberly Scarsi, PharmD, MS 
DAIDS Clinical Representatives Melanie Goth 
Statisticians  
Isabelle Weir, PhD 
Jorge Leon-Cruz, MS 
Pharmacologists 
Gary Maartens 
Elin Svenson 
Dermatologist 
Leo Shmuylovich 
The reports will also be distributed to the TB TSG chair/vice chair and the ACTG network 
chair. The clinical trials specialist (CTS) and ACTGPublications@mednet.ucla.edu will be 
notified when the analysis report has been sent.  
Attachment 2: Timetable for primary analysis and manuscript preparation 
Event 
Responsible party 
Weeks from primary 
completion date (PCD) 
Pre-closure conference call 
- 
Create specimen shipping and testing plan for 
laboratory data 
- 
Check about MTAs 
- 
Initiate DTAs 
CTS 
Protocol team 
 
NCC 
LDM 
PCD - 26 weeks 
Primary completion date (PCD) 
 
PCD 
Clinical data entry termination 
Sites 
PCD + 1 week 
Final specimen shipping request of samples to testing 
laboratories 
LDM 
PCD + 2 weeks 
Initial database clean-up complete, including  
- 
DAERS reconciliation complete 
- 
TSDV complete 
 
PDM and LDM 
PCD + 12 weeks 
Laboratory data submitted to Frontier Science 
Assay laboratory 
PCD + 12 weeks 


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Clinical database closure/freeze complete/eCRF sign-
off by site investigators 
PDM and Sites 
PCD + 15 weeks 
SDTM ARMCD populated 
SDTM Specialist 
PCD + 16 weeks 
Processing & QC of laboratory data complete 
LDM 
PCD + 16 weeks 
Complete SDTM on production server 
SDTM Specialist 
PCD + 18 weeks 
Clinical database lock and primary laboratory database 
lock 
Chief Data Manager 
and LDM Leadership 
PCD + 21 weeks 
Final SDTM on production server 
SDTM Specialist 
PCD + 22 weeks 
Primary analysis report to protocol Chairs/Writing Team 
Protocol statisticians 
PCD + 26 weeks 
 
 

Prot_001.pdf: 
 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems, Inc., a DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
 
 
 
CLARIFICATION MEMO 
 
DATE:  
December 12, 2022 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5362 Protocol Team  
 
SUBJECT: 
Clarification Memo #1 for Protocol A5362, Version 2.0 
 
 
This clarification memo (CM) does not result in a change in the protocol informed 
consent document. The Division of AIDS does not require you to forward it to your 
institutional review board (IRB); however, you must follow your IRB’s policies and 
procedures. If IRB review of clarification memos is required at your site, please submit 
this document for review. 
 
Each site should file a copy of this CM with the protocol for reference. 
 
Clarifications are being made to Protocol A5362, Version 2.0, 08Jul2022, titled, “A Phase 
IIc Trial of Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens in 
Drug-Susceptible Tuberculosis: The CLO-FAST Study.” The clarifications are described 
below and should be implemented immediately. These clarifications will be included in 
the next version of the A5362 protocol if it is amended at a future date. 
 
This CM is being issued to: 
• 
Clarify inclusion criterion 4.1.1, for the identification of pulmonary TB within 5 days prior to 
entry by sputum sample. 
• 
Move section 5.3 (Pharmacy: Product Supply, Distribution, and Accountability) to the correct 
location in the protocol.  
• 
Clarify site enrollment capacity for the qualitative interview subgroup in section 6.3.17. 
• 
Remove duplicate secondary outcome 10.2.2.1.B. 
 
1. Inclusion criterion 4.1.1 reads: 
 
Pulmonary TB (among participants with or without history of prior TB treatment) identified 
within 5 days prior to entry by: At least one sputum specimen positive for M. tuberculosis by 
molecular TB assay (Xpert) or line probe assay [LPA]) OR At least one sputum specimen 
positive (1+ or greater) for acid-fast bacilli (AFB) on smear microscopy.  
 
Note: TB diagnosis for purposes of meeting 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 5 days prior to entry. 
 


 
The team would like to clarify that the sputum sample does not have to be collected within 5 
days of the initial diagnosis, but can be any positive sputum sample collected within 5 days 
prior to study entry.  
 
2. Section 5.3 (Pharmacy: Product Supply, Distribution, and Accountability) was inadvertently 
placed in section 6.0 (Clinical and Laboratory Evaluations); therefore, section 5.3 is being 
moved to its correct location (noted in bold or strikethrough) between section 5.2 
(Formulations and Preparation) and section 5.4 (Concomitant Medications).  
 
• 
Section 5.3 (Pharmacy: Product Supply, Distribution, and Accountability) 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability  
 
5.3.1  Study Product Acquisition/Distribution  
 
Clofazimine (Lamprene®) will be manufactured by Novartis.  
 
Rifapentine (Priftin®) will be manufactured by Sanofi.  
 
Isoniazid, pyrazinamide, ethambutol, and rifampicin will be 
manufactured by Macleods Pharmaceuticals. 
 
Study products will be purchased through ACTG Leadership and 
Operations and made available through the NIAID Clinical Research 
Products Management Center (CRPMC). The site pharmacist should 
obtain the study product(s) for this protocol by following the 
instructions in the Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks. 
 
Antiretroviral medications are NOT provided through the study and 
must be obtained locally by the site. Selection and dosing of ART in 
combination with RIF or RPT should adhere to local guidelines at 
each site.  
 
Pyridoxine (vitamin B6) will NOT be provided through the study and 
must be obtained locally by the site. 
 
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. The site pharmacist at non-US CRSs must follow the 
instructions in the Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks for the destruction of unused study 
products. 
 
• 
Section 6.0 (Clinical and Laboratory Evaluations) 
 
6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability  
 


 
5.3.1  Study Product Acquisition/Distribution  
 
Clofazimine (Lamprene®) will be manufactured by Novartis.  
 
Rifapentine (Priftin®) will be manufactured by Sanofi.  
 
Isonazid, pyrazinamide, ethambutol and rifampicin will be manufactured 
by Macleods Pharmaceuticals. 
 
Study products will be purchased through the ACTG Leadership and 
Operations and made available through the NIAID Clinical Research 
Products Management Center (CRPMC). The site pharmacist should 
obtain the study product(s) for this protocol by following the instructions in 
the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks. 
 
Antiretroviral medications are NOT provided through the study and must 
be obtained locally by the site. Selection and dosing of ART in 
combination with RIF or RPT should adhere to local guidelines at each 
site.  
 
Pyridoxine (vitamin B6) will NOT be provided through the study and must 
be obtained locally by the site. 
 
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. 
The site pharmacist at non-US CRSs must follow the instructions in the 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks 
for the destruction of unused study products. 
 
3. The team added the site enrollment capacity for the qualitative interview subgroup to section 
6.3.17 (Open-Ended Qualitative Interview: Arm 1 and Arm 2 Only). To note, once sites reach 
enrollment capacity of six participants (three per Arm 1 and three per Arm 2), sites are 
responsible for updating their site-specific informed consent, following their local standard 
operating procedures and institutional review board guidelines. 
 
6.3.17 Open-Ended Qualitative Interview: Arm 1 and Arm 2 Only 
 
An open-ended interview will be conducted in 20 consenting participants in each arm 
balanced by site to obtain ethnographic data on the impact of perceived skin color 
changes on their quality of life. Each site has an enrollment capacity of six 
participants (three per Arm 1 and three per Arm 2) to the qualitative interview 
subgroup. The protocol data managers will inform sites when they reach their 
enrollment capacity.  
 
4. The definitions for secondary outcomes 10.2.2.1.B and 10.2.2.1.C are the same; therefore, 
secondary outcome 10.2.2.1.B is being removed and secondary outcome 10.2.2.1.C will 
remain since 10.2.2.1.C includes reference to the corresponding objective. 
 
10.2.2 Secondary Outcomes 


 
 
10.2.2.1   A. 
Efficacy: proportion with favorable clinical/bacteriologic outcome     
(definition 10.2.4.A) at 65 weeks post-randomization. [Objective 
1.3.8] 
 
B.  Efficacy: proportion with favorable composite outcome including 
treatment completion (definition 10.2.4.B) at 65 weeks post-
randomization.  
 
 
B. Efficacy: proportion with favorable composite outcome including 
treatment completion (definition 10.2.4.B) at 65 weeks post-
randomization. [Objective 1.3.1]