Conditions: Tuberculosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2516
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether one or two four-month regimens of tuberculosis treatment are as effective as a standard six-month regimen for treatment of pulmonary tuberculosis (TB). All three regimens are administered daily, seven days each week, with direct observation of each dose by a health-care worker at least five of the seven days of each week.

The standard six-month regimen is two months of isoniazid, rifampin, ethambutol, and pyrazinamide followed by four months of isoniazid and rifampin.

The first short regimen is a single substitution of rifapentine for rifampin: two months of isoniazid, rifapentine, ethambutol, and pyrazinamide, followed by two months of isoniazid and rifapentine.

The second short regimen is a double substitution of rifapentine for rifampin and moxifloxacin for ethambutol: two months of isoniazid, rifapentine, moxifloxacin, and pyrazinamide, followed by two months of isoniazid, rifapentine, and moxifloxacin.

Target enrollment is 2500 participants. Each study participant will remain in the study for 18 months in order to include at least 12 months of evaluation of whether the participant's TB recurs.

Detailed description:
Title:

Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, open-label, controlled, phase 3 clinical trial

Hypotheses:

A) Seventeen (17) week rifapentine-based regimen In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine (P), isoniazid (H), pyrazinamide (Z) and ethambutol (E) followed by nine weeks of rifapentine plus isoniazid, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin (R), isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout.

B) Seventeen (17) week rifapentine- plus moxifloxacin-containing regimen In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine, isoniazid, pyrazinamide and moxifloxacin (M), followed by nine weeks of rifapentine, isoniazid, and moxifloxacin, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin, isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout.

Phase: 3

Design: This will be an international, multicenter, randomized, controlled, open-label, 3-arm, phase 3 non-inferiority trial.

Population: Patients with newly diagnosed, previously untreated pulmonary tuberculosis.

Number of Sites: Multiple international sites, primarily sites of the Tuberculosis Trials Consortium and the AIDS Clinical Trials Group.

Study Duration: Duration per participant is approximately 18 months.

Description of Agent or Intervention: After written informed consent, participants will be randomly assigned to receive one of the following oral regimens:

Regimen 1 (control regimen): 2RHZE/4RH

* Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by
* Eighteen weeks of daily treatment with rifampin and isoniazid

Regimen 2 (investigational regimen): 2PHZE/2PH

* Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by
* Nine weeks of daily treatment with rifapentine and isoniazid

Regimen 3 (investigational regimen): 2PHZM/2PHM

* Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by
* Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin

Objectives:

Primary:

* To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis
* To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis

Secondary:

* To evaluate the safety of the investigational regimens
* To evaluate the tolerability of the investigational regimens
* To collect and store biospecimens from consenting participants for the purpose of future research on discovery and validation of TB biomarkers
* To determine the correlation of mycobacterial and clinical markers with time to culture conversion, culture status at completion of eight weeks of treatment, treatment failure, and relapse.
* To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs. The main objectives of the PK/PD study are to characterize study drug PK parameters and to determine relationships between treatment outcomes and PK parameters.
* To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with TB/HIV co-infection taking efavirenz-based combination antiretroviral therapy and TB treatment with rifapentine

Endpoints:

Primary Endpoints:

* Efficacy: TB disease-free survival at twelve months after study treatment assignment.
* Safety: Proportion of participants with grade 3 or higher adverse events during study drug treatment

Secondary Endpoints:

* TB disease-free survival at eighteen months after study treatment assignment
* Time to stable sputum culture conversion (solid and liquid media considered separately)
* Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection
* Proportion of participants who are culture negative at completion of eight weeks of treatment (solid and liquid media considered separately)
* Sensitivity analyses assuming all participants classified as 'not assessable' have a favorable outcome
* Discontinuation of assigned treatment for a reason other than microbiological ineligibility
* Estimated steady state efavirenz PK parameters including mid-dosing interval concentration

Arms:
arm 1: Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by Eighteen weeks of daily treatment with rifampin and isoniazid

All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose.

study drug doses: rifampin, 600 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; ethambutol, \< 55kg 800 mg, \>= 55-75 kg 1200 mg, \>75 kg 1600 mg arm 2: Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by Nine weeks of daily treatment with rifapentine and isoniazid

All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose.

study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; ethambutol, \< 55kg 800 mg, \>= 55-75 kg 1200 mg, \>75 kg 1600 mg arm 3: Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin

All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose.

study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; moxifloxacin, 400 mg

Interventions: intervention 1: rifapentine intervention 2: rifapentine and moxifloxacin intervention 3: control
Intervention descriptions: intervention 1: Regimen 2: Rifapentine is substituted for rifampin as the basis of 4-month treatment intervention 2: Regimen 3: In addition to the single substitution described for regimen 2, a second substitution is added, of moxifloxacin for ethambutol. intervention 3: standard six-month treatment

Protocol document:
Prot_SAP_000.pdf: 
Rifapentine-containing treatment shortening regimens for 
pulmonary tuberculosis: A randomized, open-label, controlled 
phase 3 clinical trial 
 
Final and original study protocol and statistical analysis plans 
 
Consortium Identifiers: 
• Tuberculosis Trials Consortium Study 31 
• AIDS Clinical Trials Group A5349 
 
 
Table of contents: 
Document 
Version and date 
Page 
Final version of the study protocol 
v2.0, 14 May 2015 
2 
List of changes from protocol v1.1 to v2.0 
 
82 
Original version of the protocol 
v1.1*, 24 Nov 2014 
90 
Final version of statistical analysis plan (SAP) 
v2.0, 9 Jul 2019 
169 
List of changes from SAP an v1.0 to v2.0 
Section 10 of SAP 
202 
Addendum to SAP 
v1.0, 22 Jul 2020 
204 
Whole Genome Sequencing SAP 
v1.0, 7 Jul 2020 
206 
First version of SAP 
v1.0, 12 Dec 2018 
212 
 
*v1.1 (24 Nov 2014) was the first version of the study protocol that was implemented, amended from 
v1.0 after comments from IRBs prior to study start.  


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TITLE 
 
Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis:  
A randomized, open-label, controlled phase 3 clinical trial 
 
 
 
Consortium Identifiers: 
Tuberculosis Trials Consortium Study 31 
AIDS Clinical Trials Group A5349 
 
 
Funding Agencies:  
U.S. Centers for Disease Control and Prevention 
U.S. National Institute of Allergy and Infectious Diseases, National Institutes of Health 
 
 
Pharmaceutical Support Provided by: 
Sanofi  
 
 
IND Number: 
46,954 
 
 
IND Sponsor: 
U.S. Centers for Disease Control and Prevention 
 
 
ClinicalTrials.gov Identifier: 
NCT02410772 
 
 
Study Chairs: 
Payam Nahid, M.D., M.P.H. 
Susan Dorman, M.D. 
 
 
 
Version Number: 2.0 
 
 
14 May 2015 
 
 
 


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ii 
Statement of Compliance 
This trial will be conducted in compliance with the protocol, International Conference on Harmonisation 
Good Clinical Practice E6 (ICH-GCP), U.S. Code of Federal Regulations 45 CFR 46 and 21 CFR, and 
applicable site-specific regulatory requirements.   
 
 


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Table of Contents 
 
Statement of Compliance ............................................................................................................................... ii 
Protocol Summary ........................................................................................................................................ vii 
Study Schematic  
 ...................................................................................................................................... x 
 
1 
Key Roles ............................................................................................................. 11 
2 
Background Information and Scientific Rationale ........................................... 13 
2.1 
Background Information ......................................................................................... 13 
2.2 
Rationale ................................................................................................................ 19 
2.3 
Potential Harms and Benefits ................................................................................. 22 
2.3.1 
Potential harms ........................................................................................... 22 
2.3.2 
Potential benefits ........................................................................................ 23 
3 
DESCRIPTIONS OF STUDY DRUGS .................................................................. 24 
3.1 
Rifapentine ............................................................................................................. 24 
3.2 
Rifampin ................................................................................................................. 24 
3.3 
Moxifloxacin ............................................................................................................ 25 
3.4 
Isoniazid ................................................................................................................. 26 
3.5 
Pyrazinamide .......................................................................................................... 27 
3.6 
Ethambutol ............................................................................................................. 28 
3.7 
Vitamin B6 (Pyridoxine) .......................................................................................... 28 
4 
Objectives ............................................................................................................ 29 
4.1 
Primary: .................................................................................................................. 29 
4.2 
Secondary: ............................................................................................................. 29 
5 
Study Design ....................................................................................................... 30 
6 
Study Population ................................................................................................. 31 
6.1 
Subject Inclusion Criteria ........................................................................................ 31 
6.2 
Criteria for Exclusion from Enrollment .................................................................... 32 
6.3 
Criteria for Exclusion after Enrollment (‘Late Exclusion’) ....................................... 33 
7 
Enrollment, Randomization, and Masking Procedures .................................... 34 
7.1 
Enrollment Procedures ........................................................................................... 34 
7.2 
Randomization ....................................................................................................... 34 
8 
Study Procedures ............................................................................................... 35 
8.1 
Clinical Evaluations ................................................................................................ 35 
8.1.1 
Interview for demographic and contact information .................................... 35 
8.1.2 
Obtaining a medical history ........................................................................ 35 
8.1.3 
Obtaining sputum specimens ..................................................................... 35 
8.1.4 
Performing visual acuity and color vision testing ........................................ 35 
8.1.5 
Symptom assessment ................................................................................ 35 
8.1.6 
Assessment for adverse events ................................................................. 35 
8.1.7 
Chest Radiograph ....................................................................................... 36 
8.2 
Concomitant Medications/Treatments .................................................................... 36 


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8.3 
Laboratory Evaluations ........................................................................................... 37 
8.3.1 
Sputum mycobacterial tests ....................................................................... 37 
8.3.2 
Hematology ................................................................................................ 37 
8.3.3 
Biochemistry ............................................................................................... 37 
8.3.4 
HIV testing .................................................................................................. 37 
8.3.5 
CD4 testing ................................................................................................. 37 
8.3.6 
HIV viral load testing ................................................................................... 37 
8.3.7 
Pregnancy testing ....................................................................................... 37 
8.3.8 
Diabetes screening ..................................................................................... 38 
8.3.9 
Pharmacokinetic sampling: Tuberculosis Drugs ......................................... 38 
8.3.10 Pharmacokinetic sampling: Efavirenz ......................................................... 38 
8.3.11 Pharmacogenomic testing: Host Genetic Analysis ..................................... 41 
8.3.12 Storage of M. tuberculosis bacterial isolates .............................................. 41 
8.3.13 Samples for analyses to identify potential biomarkers of tuberculosis 
treatment response ..................................................................................... 41 
8.4 
Specimen preparation, handling and shipping ..................................................... 422 
8.5 
Loss to follow-up .................................................................................................... 42 
8.6 
Participants with a positive sputum culture for M. tuberculosis at or after week 17 42 
8.7 
Participants with a positive sputum smear at or after week 17 .............................. 42 
8.8 
Participants with a possible poor treatment response ............................................ 42 
8.9 
Management of a participant who is discontinued from study treatment................ 43 
8.9.1 
Management of a participant who is discontinued from study treatment 
because s/he is determined to be ineligible after enrollment (‘late 
exclusions’) ................................................................................................. 43 
8.9.2 
Management of participants who become pregnant during the study ........ 43 
8.9.3 
Management of participants who are discontinued from study treatment in 
the setting of an adverse event or the investigator judges that 
discontinuation of study treatment is in the participant’s best interest ........ 43 
8.9.4 
Management of a participant who requests premature discontinuation from 
study treatment ........................................................................................... 44 
8.9.5 
Management of a participant who is incarcerated after enrollment ............ 44 
8.10 
Premature termination of the study or closure of a study stratum or a study site .. 44 
9 
Study Schedule ................................................................................................... 45 
9.1 
Screening ............................................................................................................... 45 
9.2 
Baseline .................................................................................................................. 45 
9.3 
Study Visits at Weeks 2, 4, 8, and 12 ..................................................................... 46 
9.4 
Week 17 ................................................................................................................. 47 
9.5 
Week 22 ................................................................................................................. 48 
9.6 
Week 26 ................................................................................................................. 48 
9.7 
Study Visits at Months 9, 12, 15, and 18 ................................................................ 49 
9.8 
Study Procedures for Participants with Possible Poor Treatment Response ......... 49 


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9.9 
Post Early Termination Visit (Visit after Early Termination) for Participants 
Terminating before Completion of their Assigned Study Treatment ....................... 50 
9.10 
Early Termination Visit for Participants Stopping Study Participation after 
Completion of their Assigned Study Treatment ...................................................... 50 
9.11 
Missed Visit ............................................................................................................ 51 
9.12 
Unscheduled Visit ................................................................................................... 51 
10 
Study Intervention/Investigational DRUGS ....................................................... 52 
10.1 
Study Drugs ............................................................................................................ 52 
10.2 
Study Drug Acquisition ........................................................................................... 53 
10.3 
Study Drug Storage and Stability ........................................................................... 53 
10.4 
Administration and Dosage of Study Drugs ........................................................... 53 
10.5 
Dose Modifications for a Participant ....................................................................... 54 
10.5.1 Dose Modifications for a Change in Participant’s Weight ........................... 54 
10.5.2 Drug Re-challenges .................................................................................... 54 
10.6 
Criteria for Discontinuation of Study Drugs ............................................................ 54 
10.7 
Accountability Procedures for the Study Drugs ...................................................... 54 
10.8 
Assessment of Subject Compliance with Study Treatment .................................... 54 
11 
Assessment of Efficacy ...................................................................................... 55 
11.1 
Summary of Bacteriological Methods ..................................................................... 55 
12 
Assessment of Safety ......................................................................................... 56 
12.1 
Specification of Safety Parameters ........................................................................ 56 
12.1.1 Primary Outcome Measure ......................................................................... 56 
12.1.2 Secondary Outcome Measure .................................................................... 56 
12.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ............................................................................................................. 56 
12.2.1 Adverse Events and Serious Adverse Events ............................................ 56 
12.3 
Recording and Reporting Procedures .................................................................... 57 
12.3.1 Overview ..................................................................................................... 57 
12.3.2 Reporting Procedures ................................................................................. 57 
12.3.3 Pregnancy .................................................................................................. 57 
12.4 
Management of adverse events ............................................................................. 57 
12.4.1 Type and Duration of the Follow-up of Subjects after Adverse Events ...... 58 
12.5 
Data and Safety Monitoring Board ......................................................................... 58 
12.6 
Interim Monitoring and Analyses by the Data and Safety Monitoring Board .......... 58 
13 
Statistical Considerations .................................................................................. 59 
13.1 
Study Hypotheses .................................................................................................. 59 
13.2 
Study Outcome Measures ...................................................................................... 59 
13.3 
Definition of primary outcome status ...................................................................... 60 
13.4 
Analysis Groups ..................................................................................................... 61 
13.5 
Analysis Plan .......................................................................................................... 61 
13.5.1 Co-Primary efficacy analyses ..................................................................... 61 
13.5.2 Primary safety analysis ............................................................................... 62 


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13.5.3 Secondary efficacy analyses ...................................................................... 62 
13.5.4 Secondary safety analyses ......................................................................... 62 
13.5.5 Secondary Efavirenz PK analysis ............................................................... 62 
13.6 
Sample Size Considerations .................................................................................. 62 
14 
Quality Control and Quality Assurance ............................................................. 64 
14.1 
Local quality control ................................................................................................ 64 
14.2 
External monitoring ................................................................................................ 64 
15 
Ethics/Protection of Human Subjects ............................................................... 65 
15.1 
Institutional Review Board ...................................................................................... 65 
15.2 
Informed Consent Process ..................................................................................... 65 
15.3 
Subject Confidentiality ............................................................................................ 65 
15.4 
Study Discontinuation ............................................................................................. 66 
16 
Data Handling and Record Keeping .................................................................. 67 
17 
Publications and Dissemination of Study Results ........................................... 68 
18 
Literature References ......................................................................................... 69 
APPENDICES 
A: Schedule of Procedures/Evaluations 
B: Abbreviations 


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Protocol Summary 
 
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Title: 
Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, 
open-label, controlled, phase 3 clinical trial 
 
Hypotheses: 
A) Seventeen (17) week rifapentine-based regimen 
 
In previously untreated individuals with active drug-susceptible pulmonary 
tuberculosis treated with eight weeks of rifapentine (P), isoniazid (H), 
pyrazinamide (Z) and ethambutol (E) followed by nine weeks of rifapentine plus 
isoniazid, all given daily throughout, the proportion of participants who 
experience absence of cure (unfavorable outcome) will not be inferior to that 
observed in participants who are treated with a standard regimen (eight weeks of 
rifampin (R), isoniazid, pyrazinamide and ethambutol followed by eighteen weeks 
of rifampin plus isoniazid), all given daily throughout.  
 
B) Seventeen (17) week rifapentine- plus moxifloxacin-containing regimen 
 
In previously untreated individuals with active drug-susceptible pulmonary 
tuberculosis treated with eight weeks of rifapentine, isoniazid, pyrazinamide and 
moxifloxacin (M), followed by nine weeks of rifapentine, isoniazid, and 
moxifloxacin, all given daily throughout, the proportion of participants who 
experience absence of cure (unfavorable outcome) will not be inferior to that 
observed in participants who are treated with a standard regimen (eight weeks of 
rifampin, isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of 
rifampin plus isoniazid), all given daily throughout. 
 
Phase: 
3 
Design: 
This will be an international, multicenter, randomized, controlled, open-label, 3-
arm, phase 3 non-inferiority trial. 
Population: 
Patients with newly diagnosed, previously untreated pulmonary tuberculosis.  
Number of Sites: 
Multiple international sites, primarily sites of the Tuberculosis Trials Consortium 
and the AIDS Clinical Trials Group.   
Study Duration: 
Duration per participant is approximately 18 months. 
 
 
 


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Description of Agent or Intervention: After written informed consent, participants will be randomly 
assigned to receive one of the following oral regimens: 
 
 
Regimen 1 (control regimen): 2RHZE/4RH 
• Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed 
by  
• Eighteen weeks of daily treatment with rifampin and isoniazid 
 
 
Regimen 2 (investigational regimen): 2PHZE/2PH 
• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, 
followed by  
• Nine weeks of daily treatment with rifapentine and isoniazid  
 
 
 
Regimen 3 (investigational regimen): 2PHZM/2PHM 
• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, 
followed by  
• Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin 
 
Objectives: 
Primary: 
• 
To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single 
substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of 
treatment for drug-susceptible pulmonary tuberculosis 
• 
To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin 
for ethambutol and continues moxifloxacin during the continuation phase to determine whether it is 
possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary 
tuberculosis  
 
Secondary: 
• 
To evaluate the safety of the investigational regimens 
• 
To evaluate the tolerability of the investigational regimens  
• 
To collect and assess biospecimens from consenting participants for the purpose of research on 
discovery and validation of TB biomarkers 


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• 
To determine the correlation of mycobacterial and clinical markers with time to culture conversion, 
culture status at completion of eight weeks of treatment, treatment failure, and relapse. 
• 
To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs.  The main 
objectives of the PK/PD study are to characterize study drug PK parameters and to determine 
relationships between treatment outcomes and PK parameters.  
• 
To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with 
TB/HIV co-infection taking efavirenz-based combination antiretroviral therapy and TB treatment with 
rifapentine 
 
 
Endpoints: 
Primary Endpoints: 
• 
Efficacy: TB disease-free survival at twelve months after study treatment assignment.   
• 
Safety: Proportion of participants with grade 3 or higher adverse events during study drug treatment 
 
Secondary Endpoints:  
• 
TB disease-free survival at eighteen months after study treatment assignment 
• 
Time to stable sputum culture conversion (solid and liquid media considered separately) 
• 
Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection 
• 
Proportion of participants who are culture negative at completion of eight weeks of treatment (solid 
and liquid media considered separately) 
• 
Sensitivity analyses assuming all participants classified as ‘not assessable’ have a favorable 
outcome 
• 
Discontinuation of assigned treatment for a reason other than microbiological ineligibility 
• 
Estimated steady state efavirenz PK parameters including mid-dosing interval concentration 
 
 
 
 
 
 
 


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Schematic of Study Design:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screen for eligibility 
Enroll
Randomize 1:1:1
Regimen 1 
(control regimen) 
2RHZE/4RH 
(26 weeks) 
Regimen 2 
(investigational) 
2PHZE/2PH 
(17 weeks) 
Regimen 3 
(investigational) 
2PHZM/2PHM 
(17 weeks) 
Participant follow-up: 
18 months after treatment assignment 
Analysis of Outcome Measures 
Primary at 12 months; secondary at 18 months 


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1 
KEY ROLES 
Funding Agencies:   
U.S. Centers for Disease Control and Prevention through the Tuberculosis Trials Consortium;  
U.S. National Institute of Allergy and Infectious Diseases of the National Institutes of Health through the 
AIDS Clinical Trials Group 
 
IND Sponsor: 
U.S. Centers for Disease Control and Prevention (IND# 46,954) 
 
Pharmaceutical Support: 
Sanofi  
 
Protocol Chairs: 
Payam Nahid, M.D., M.P.H. 
University of California, San Francisco 
1001 Potrero Ave, 5K1 
San Francisco, CA 94110 
Phone: 415-206-5464 
Email: pnahid@ucsf.edu 
 
Susan E. Dorman, M.D. 
Johns Hopkins University School of Medicine 
1550 Orleans Street, CRB2, 1M-12 
Baltimore, Maryland, USA 21231 
Phone 410-502-2717 
Email: dsusan1@jhmi.edu 
  
Project Officer: 
 
Stefan Goldberg, M.D. 
US Centers for Disease Control and Prevention 
1600 Clifton Road, MS E-10 
Atlanta, GA, USA  30333 
Phone: 404-639-5339 
Email: ssg3@cdc.gov 
 
 
Central Study Clinician: 
 
TB clinician(s), TBD  
 
 
 
 


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Protocol Team 
Name 
Institution 
Janet Andersen 
Harvard School of Public Health, Boston, Massachusetts, USA 
Richard Chaisson 
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 
Kwok-Chiu Chang 
TB and Chest Service of Hong Kong, China 
Michael Chen 
US Centers for Disease Control and Prevention, Atlanta, Georgia, USA 
Mark Cotton 
Stellenbosch University, Cape Town, South Africa 
Dalene von Delft 
Community Research Advisory Group, Cape Town, South Africa 
Kelly Dooley 
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 
Melissa Engle 
University of Texas Health Science Center, San Antonio, Texas, USA 
Pei-Jean Feng 
US Centers for Disease Control and Prevention, Atlanta, Georgia, USA 
Courtney Fletcher 
University of Nebraska Medical Center, Omaha, Nebraska, USA 
Phan Ha 
National TB Program, Hanoi, Vietnam 
Charles M Heilig 
US Centers for Disease Control and Prevention, Atlanta, Georgia, USA 
Daniel Johnson 
Division of AIDS, National Institutes of Health, Bethesda, Maryland, USA 
John L. Johnson 
Case Western Reserve University, Cleveland, Ohio, USA 
Marilyn Maroni 
Sanofi, Paris, France 
Cynthia Merrifield 
University of California, San Francisco, San Francisco, California, USA 
Jose M. Miro 
Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain 
Sachiko Miyahara 
Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA 
Nguyen Viet Nhung 
National TB Program, Hanoi, Vietnam 
April Pettit 
Vanderbilt University, Nashville, Tennessee, USA 
Anthony Podany 
University of Nebraska Medical Center, Omaha, Nebraska, USA 
Kathleen Robergeau 
Westat, Inc., Rockville, Maryland, USA 
Wadzanai Samaneka 
Parirenyatwa Clinical Research Site, Harare, Zimbabwe 
Erin Sizemore 
US Centers for Disease Control and Prevention, Atlanta, Georgia, USA 
Susan Swindells 
University of Nebraska Medical Center, Omaha, Nebraska, USA 
 
Andrew Vernon 
Centers for Disease Control and Prevention, Atlanta, Georgia, USA 
Marc Weiner 
Audie L. Murphy Veterans Affairs Medical Center / University of Texas Health 
Science Center, San Antonio, Texas, USA 
 
Lisa Wolf 
 
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 
 
Suria Yesmin 
 
Social & Scientific Systems, Inc., Silver Spring, Maryland, USA 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
Tuberculosis as a global health problem 
Tuberculosis (TB) is one of the most important global health problems. According to recent estimates 
from the World Health Organization (WHO), 8.6 million new cases and 1.3 million deaths from TB 
occurred in 2012 (World Health Organization 2013).  The vast majority of TB cases and TB deaths are in 
developing countries. The spread of HIV has fueled the TB epidemic, and TB is the leading cause of 
death among patients infected with HIV (Corbett et al., 2003). TB predominantly affects young adults in 
their most productive years of life and has substantial impact on economic development.   
Need for new treatment regimens for tuberculosis 
Although effective therapy for drug susceptible Mycobacterium tuberculosis is available, TB continues to 
cause significant morbidity and mortality worldwide, and rates of multi-drug resistant (MDR) and 
extensively-drug resistant (XDR) TB cases are on the rise. A major obstacle to the control of TB is poor 
adherence with lengthy (at minimum 6 months) and complicated treatment regimens. Incomplete TB 
treatment can lead to increased morbidity and mortality, prolonged infectiousness and transmission, and 
the development of drug resistance.  The use of directly observed therapy (DOT) can improve patient 
adherence and reduce the emergence of resistant microorganisms, but is logistically difficult and 
expensive to implement (McDonald et al., 1982).  The development of new treatment strategies with more 
potent antimycobacterial activity could lead to shorter and better tolerated regimens.  A TB treatment 
regimen that allowed a decrease in treatment duration would potentially have important public health 
implications by facilitating DOT, increasing cure rates, potentially reducing transmission and preventing 
emergence of MDR TB. It is estimated that improved regimens that shorten treatment duration for drug-
susceptible strains and are efficacious against resistant strains could reduce the incidence of TB by up to 
27% by 2050 and reduce deaths by 25% from current global numbers of incident cases and deaths per 
year (Abu-Raddad et al, 2009). 
Current standard treatment for pulmonary tuberculosis  
Modern short course treatment for pulmonary tuberculosis is comprised of two treatment phases.  The 
intensive phase is the initial 8 weeks of treatment, and typically is comprised of isoniazid, rifampin, 
pyrazinamide, and ethambutol.  Continuation phase follows intensive phase, and continuation phase 
typically is comprised of isoniazid plus rifampin for an additional 18 weeks, to complete a total of 26 
weeks (6 months) of treatment.    
Rifamycins in tuberculosis treatment  
Rifamycins are the key drugs in modern short-course TB chemotherapy of 6 months duration.  
Rifamycins, including rifampin and rifapentine, have concentration-dependent activity against M. 
tuberculosis.  Rifamycins are considered critical for sterilization, that is, prevention of relapse after 
cessation of TB treatment.  For rifapentine, the minimum inhibitory concentration (MIC)50 and MIC90 are 
one- to two-fold dilutions lower than those of rifampin (for the 7H10 agar system, rifapentine’s MIC50 and 
MIC90 are 0.125 and 0.25 mg/L, compared with 0.5 and 1.0 mg/L for rifampin) (Bemer-Melchior et al., 
2000).  In addition, rifapentine’s half-life (t1/2) is five times longer than that of rifampin (14-18 hours vs. 2-
5 hours).   
Preclinical studies of rifapentine 
Murine model of tuberculosis treatment 


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The murine model of TB has been used for more than 50 years for the development and evaluation of 
new antituberculosis drugs and regimens (Veziris et al., 2005). Importantly, the mouse model of TB 
treatment has been shown to recapitulate human TB treatment with regard to treatment-shortening 
effects of rifampin and pyrazinamide. In the mouse model, the standard 6-month rifampin plus isoniazid 
plus pyrazinamide (RHZ)-based regimen cures mice in 6 months, followed by relapse rates of 0-10%.  On 
the basis of its recapitulation of outcomes in humans, the murine TB treatment model is the reference 
standard against which new treatments are compared. 
Preclinical studies of tuberculosis treatment regimens containing rifapentine 
Pre-clinical studies suggest that improved antimycobacterial activity can be achieved with rifamycin 
exposure greater than that of the current standard regimen in which rifampin is used at a dose of 10 
mg/kg/dose (almost always given as 600 mg) once daily.  Increased rifamycin exposure can be achieved 
by using rifapentine.  Of note, the pharmacokinetics of rifapentine have been shown to be similar in mice 
and in humans (Rosenthal et al., 2005). In the murine model of TB treatment, once-daily rifapentine 
administered during intensive phase has very potent antimycobacterial activity that results in durable cure 
after only 3 to 4 months of total treatment (Rosenthal et al., 2008).  After aerosol infection, mice achieved 
a bacillary burden of 7.21 log10 cfu per lung.  Treatment with a standard regimen of daily rifampin (10 
mg/kg) plus isoniazid and pyrazinamide resulted in a decrease in bacillary burden of approximately 3 logs 
at completion of 4 weeks of treatment.  However, treatment with a regimen of daily rifapentine (10 mg/kg) 
plus isoniazid and pyrazinamide was significantly more active at 4 weeks (mean lung cfu counts that were 
1.00 log10 cfu lower than those for the standard regimen, p<0.001) and at 8 weeks (mean lung cfu counts 
that were >2 log10 cfu lower than those for the standard regimen, p<0.001). Furthermore, after 12 weeks 
of treatment, 100% (15/15) of mice treated with the standard regimen had bacteriological relapse, 
compared to 0/15 mice treated with the rifapentine regimen.  In fact, the rifapentine regimen resulted in 
cure of 15/15 (100%) of mice after treatment for only 10 weeks.      
Thus, murine studies indicate that rifapentine administered daily during combination intensive phase 
treatment has potent antimycobacterial activity that is associated with ability to achieve durable cure 
without relapse after about 3 months of total treatment. 
Clinical trials of daily rifapentine 
Phase I 
Dooley and colleagues conducted a phase I dose-escalation study among healthy adult volunteers to 
determine the safety and pharmacokinetics of escalating daily doses of rifapentine (Dooley et al, 2012).  
Participants received 5, 10, 15, or 20 mg/kg/dose rifapentine given once daily for 15 consecutive days; 20 
mg/kg/dose was the pre-specified maximum dose; a cohort of additional participants received rifampin 10 
mg/kg/dose.  Of note, this study used strict weight-based dosing, such that the average rifapentine dose 
administered in the 20 mg/kg/dose cohort was 1650 mg daily.  A total of 33 participants received study 
drugs.  There were no grade 2 or higher clinical adverse events.  Dose-limiting toxicities were observed in 
three participants, one each in the rifampin (grade 3 neutropenia), rifapentine 10 mg/kg (grade 3 serum 
liver transaminase elevation), and rifapentine 15 mg/kg (grade 3 lymphopenia) cohorts.  In this study, the 
safety profile of rifapentine was similar to that of rifampin 10 mg/kg/dose, and it was concluded that 
rifapentine administered daily was tolerated and safe at doses as high as 20 mg/kg/dose.  From a PK 
perspective, increases in rifapentine dosage resulted in less-than-dose proportional increases in single 
and multiple dose maximal concentrations.   
Phase 2 


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The TBTC recently completed two phase 2 studies to assess the antimicrobial activity, safety, and 
tolerability of daily rifapentine administered with isoniazid, PZA, and ethambutol during the first eight 
weeks of pulmonary TB treatment.  In TBTC Study 29, 531 adults with sputum smear positive pulmonary 
TB were randomized to receive rifapentine approximately 10 mg/kg/dose or rifampin 10 mg/kg/dose 
administered 5 days per week for 8 weeks (intensive phase) with isoniazid, PZA, and ethambutol; study 
drugs were administered on an empty stomach (Dorman et al, 2012).  The co-primary endpoints were 
negative sputum cultures on liquid and on solid media at the end of intensive phase; safety and 
tolerability were also assessed.  This study demonstrated no significant difference between regimens in 
antimicrobial activity based on the surrogate marker of culture status at completion of intensive phase 
(culture conversion on solid media 83.3% vs. 86.4% for the rifampin vs. rifapentine groups; and 
conversion in liquid media 65.1% vs. 67.9% in the rifampin vs. rifapentine groups).  The rifapentine 
regimen was well tolerated based on similar proportions of participants discontinuing assigned treatment 
overall (15.7% in the rifampin group vs. 14.5% in the rifapentine group) or due to toxicity (1.2% in the 
rifampin group vs. 1.5% in the rifapentine group). There were no differences, by treatment group, in 
proportions of participants with a serious adverse event related to study treatment (0.4% in the rifampin 
group vs. 1.1% in the rifapentine group), or by type or severity of adverse events.  Hepatitis occurred in 
2.8% of rifampin group participants vs. 4.0% of rifapentine group participants (p=0.48).  The investigators 
concluded that the rifapentine regimen administered on an empty stomach 5 days/week for 8 weeks was 
safe and well-tolerated but not significantly more active than the conventional rifampin regimen. 
 
The TBTC subsequently conducted a randomized, multicenter, dose-ranging study to determine the 
optimal dose of daily rifapentine during the first 8 weeks of pulmonary TB treatment.  In TBTC Study 29X, 
334 adults with sputum smear positive pulmonary TB were randomized to receive rifampin (approximately 
10 mg/kg/dose) or rifapentine (approximately 10, 15, or 20 mg/kg/dose, maximum dose 1500 mg) 
administered with a high fat meal once daily for 8 weeks, in addition to isoniazid, PZA, and ethambutol.  
Rifapentine was well-tolerated across all treatment arms based on a pre-specified definition and also 
based on comparison with the rifampin group.  Percentages of participants discontinuing assigned 
treatment were: rifampin 11/85 (12.9%; upper bound of 90% one-sided CI 19.0); rifapentine 10 mg/kg 
5/87 (5.7%; 10.5); rifapentine 15 mg/kg 5/81 (6.2%; 11.3); and rifapentine 20 mg/kg 9/81 (11.1%; 17.1).  
There were two deaths – one in the rifapentine 15 mg/kg group due to hematemesis, and one sudden 
death in the rifapentine 20 mg/kg group in a 61 year old male with untreated hypertension and diabetes 
mellitus and a strong family history of cardiac disease and sudden death.   There were no differences 
between treatment groups in the percentages of participants with a serious adverse event associated with 
study treatment, or by type or severity of adverse events.  Serious adverse events attributed to study 
treatment were as follows, by treatment assignment: two events among 85 participants in the rifampin 
group (one hepatitis, one drug allergy); one event among 87 in the rifapentine 10 mg/kg group 
(leukocytosis); no events among 81 participants in the rifapentine 15 mg/kg group; one event among 81 
participants in the rifapentine 20 mg/kg group (hepatitis).  With respect to antimicrobial activity (efficacy), 
the rifapentine regimens were substantially more active than the standard rifampin regimen based on 
week 8 (end of intensive phase) culture status (Table 1) as well as time to stable culture conversion. 
 
Antimicrobial activity was associated with rifapentine exposure (area under the concentration time curve 
[AUC]) (Table 1B).  The higher rifapentine exposures were associated with very high rates of sputum 
sterilization at two months, a very good indicator of overall efficacy of an anti-tuberculosis regimen. 
Findings were consistent with a steep exposure-response relationship.  Pharmacodynamic models were 
used to further elucidate the relationships between antimycobacterial activity and assigned rifapentine 
treatment arm, administered rifapentine dose, and rifapentine drug exposure. For efficacy outcomes of 
time to stable culture conversion in solid media and time to stable culture conversion in liquid media, 
there was a significant association with rifapentine AUC (p=0.0002 for solid media and p=0.001 for liquid 


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media) but not for assigned rifapentine mg/kg group (p=0.6 for solid media and p=0.36 for liquid media) or 
for  administered rifapentine dose in mg (p=0.17 for solid media and p=0.17 for liquid media).  For 
rifapentine, the exposure-response relationship was best described by a sigmoidal Emax function (Figure 
1), with the greatest change in effect per change in exposure occurring between exposures of 
approximately 200 mcg*h/L and 550 mcg*h/L, with a plateau in efficacy at higher exposures.  In addition 
to identifying a target AUC of approximately 500 to 600 mcg*h/L, pharmacokinetic studies yielded 
additional information pertinent for rifapentine dosing.  Specifically, the relationship between participant 
body weight and rifapentine clearance was examined, and clearance was not significantly affected by 
body weight, thereby supporting ‘flat’ dosing of rifapentine (i.e. rifapentine dose is not adjusted for body 
weight) (Figure 2).  In addition, pharmacokinetic/pharmacodynamic modeling also predicted that a 
rifapentine dose of 1200 mg without food would yield an AUC of approximately the same as that of a 
rifapentine dose of 900 mg with a very high fat meal.  Given that target rifapentine AUC lies somewhere 
between that achieved with a very high fat meal and rifapentine dose of 900 to 1200 mg, the strategy 
proposed in the current phase 3 trial is a rifapentine dose of 1200 mg with a modest food requirement, 
with the rationale that a very high fat meal is poorly feasible under phase 3 trial or routine TB care 
conditions whereas a more general recommendation of dosing with food is likely to be broadly feasible.    
 
Table 1A.  Percentages of participants with negative cultures at completion of intensive phase 
treatment, by treatment assignment, for the modified intention-to-treat analysis group, S29X 
 
Rifampin 
Rifapentine 
10 mg/kg 
Rifapentine 
15 mg/kg 
Rifapentine 
20 mg/kg 
Solid culture medium 
% (n/n) with negative cultures  
% difference vs. Rifampin 
(95% CI) 
p-value 
 
81.3 (52/64) 
 
 
 
92.5 (62/67) 
11.3  
(-1.7, 24.3) 
0.10 
 
89.4 (59/66) 
8.1  
(-5.5, 21.8) 
0.29 
 
94.7 (54/57) 
13.5  
(0.6, 26.3) 
0.05 
Liquid culture medium 
% (n/n) with negative cultures  
% difference vs. Rifampin 
(95% CI) 
p-value 
 
56.3 (36/64) 
 
74.6 (50/67) 
18.4  
(0.8, 35.9) 
0.04 
 
69.7 (46/66) 
13.4 
(-4.5, 31.4) 
0.16 
 
82.5 (47/57) 
26.2  
(8.9, 43.5) 
<0.01 
 
Table 1B.  Percentages of participants with negative cultures at completion of intensive phase 
treatment, by rifapentine area under the concentration-time curve tertile, for the modified intention-to-
treat analysis group, S29X 
 
Rifampin 
Rifapentine 
AUC < 323 
mcg*h/L 
Rifapentine 
AUC 324 to 513 
mcg*h/L 
Rifapentine 
AUC > 513 
mcg*h/L 
Solid culture medium 
% (n/n) with negative cultures  
% difference vs. Rifampin 
(95% CI) 
p-value 
 
81.3 (52/64) 
 
 
 
83.9 (52/62) 
2.6 
(-12.2, 17.4) 
0.88 
 
100.0 (63/63) 
18.8 
(7.6, 29.9) 
<0.01 
 
92.3 (60/65) 
11.1 
(-2.0, 24.2) 
0.11 
Liquid culture medium 
% (n/n) with negative cultures  
% difference vs. Rifampin 
(95% CI) 
p-value 
 
56.3 (36/64) 
 
54.8 (34/62) 
-1.4 
(-20.4, 17.5) 
1.00 
 
90.5 (57/63) 
34.2 
(18.5, 50.0) 
<0.01 
 
80.0 (52/65) 
23.8 
(6.6, 40.9) 
<0.01 
 
 


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Moxifloxacin for TB treatment 
Moxifloxacin is a fluoroquinolone with potent activity against M. tuberculosis in vitro and in animal models, 
including sterilizing activity in animal models.  In animal models, moxifloxacin’s potent activity is partly 
explained by the fact that it accumulates in granulomas and pulmonary lesions at higher concentrations 
than found in plasma and lung tissue (Kjellson et al., 2012; Prideaux et al., 2011). In humans, data on the 
long-term use of moxifloxacin have shown that it has an excellent safety profile.  Three phase 2 TB 
clinical trials have shown that substitution of moxifloxacin for ethambutol during the intensive phase of 
pulmonary TB treatment increases the antimicrobial activity of the regimen, as assessed using surrogate 
markers (Burman et al., 2006; Rustomjee et al., 2008; Conde et al., 2009).  A recently completed phase 3 
trial found that treatment with a weekly regimen of rifapentine and moxifloxacin during the continuation 
phase of therapy (Rifaquin 6 month regimen, Jindani, 2014) was non-inferior to daily isoniazid plus 
rifampin; the efficacy of rifapentine plus moxifloxacin in this trial is significant because once-weekly 
rifapentine with isoniazid (instead of moxifloxacin) is associated with higher rates of relapse and treatment 
failure (Vernon et al., 1999).  Two phase 3 treatment shortening studies using fluoroquinolone-based 4-
month regimens administered daily have been completed recently. The Oflotub Trial was an open-label, 
Phase 3 multicenter trial evaluating the efficacy and safety of a 4-month gatifloxacin (G) containing 
regimen compared to the standard 6-month HRZE regimen (Merle et al, 2014).  The Oflotub 4 month 
regimen consisted of a 2 month intensive phase of GHRZ, followed by a 2 month continuation phase of 
GRH (2GRHZ/2GRH) versus a control arm of 2ERHZ/4RH, administered 6 days per week. The 
investigational 4 month regimen failed to achieve non-inferiority at a 6% margin: in a modified intention-to-
treat analysis unfavorable outcomes at 24 months from end-of-treatment had occurred in 21.0% 
(146/694) in the gatifloxacin-containing arm vs. 17.2% (114/662) in the control arm (difference +3.5%, 
95% CI -0.7% to +7.7%). The REMox phase 3 study was a randomized placebo-controlled double-blind 
trial comparing two treatment shortening regimens, namely 2MHRZ/2MHR and 2EMRZ/2MR, with the 
standard control regimen 2EHRZ/4HR (Gillespie et al 2014).  The primary end point was treatment failure 
or relapse within 18 months after randomization.  In the REMox study, neither of the investigational 
moxifloxacin-containing regimens was shown to be non-inferior to the control.  Specifically, of the 1931 
Figure 1.  Exposure-response relationship 
for rifapentine
8
AUC (mcg*h/L)
effect
Median AUC, 1200 mg group
Median AUC, 900 mg group
Median AUC, 600 mg group
Body weight (kg)
Clearance (individual difference)
Figure 2.  Rifapentine clearance is not 
meaningfully affected by body weight


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patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in 
fewer patients in the 2MHRZ/2MHR group (85%) and the 2EMRZ/2MR group (80%) than in the control 
group (2EHRZ/4HR; 92%). A difference favoring the control group of 6.1 percentage points (97.5% 
confidence interval [CI], 1.7 to 10.5) was noted comparing to the 2MHRZ/2MHR group, and a difference 
favoring the control group of 11.4 percentage points (97.5% CI, 6.7 to 16.1) was noted when comparing 
to the 2EMRZ/2MR group.  Overall the 2MHRZ/2MHR group performed slightly better than the 
2EMRZ/2MR group, and achieved non-inferiority in certain sub-groups (e.g. females).   In the REMox 
study the two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load as 
compared to the control group. As in the Oflotub Trial, however, overall the experimental moxifloxacin 
single-substitution regimen was also not shown to be non-inferior to the control.  The fluoroquinolone-
containing regimens were safe and well-tolerated in both the Oflotub (gatifloxacin) and the REMox 
(moxifloxacin) studies. Overall, pre-clinical and clinical studies have shown that the single substitution of 
moxifloxacin for ethambutol increases antimicrobial activity of the regimen, but this increase is not 
sufficient to achieve acceptable cure rates after truncation of therapy to four months (Burman et al., 2006; 
Rustomjee et al., 2008; Conde et al., 2009, Merle et al, 2014, Gillespie et al., 2014). 
 
Quantitative capability of the Xpert MTB/RIF assay and its correlation with smear microscopy and 
culture. 
The Xpert MTB/RIF Assay, endorsed by the WHO in 2010 and FDA approved for marketing in the US in 
2013 for diagnosing TB, simultaneously detects the presence of M. tuberculosis in sputum and 
determines if genetic markers for rifampin resistance are present. Two studies have compared Xpert 
MTB/RIF results with sputum smear results in newly suspected pulmonary TB (Blakemore et al, 2011; 
Friedrich et al 2011). Medium and high qualitative readings from Xpert MTB/RIF correlate well with finding 
acid fast bacilli on sputum smears.  The quantitative capability of the Xpert MTB/RIF assay will be used in 
this trial at baseline to permit participant randomization based on a medium or high semi-quantification of 
M. tuberculosis copies on their Xpert test at screening. Drug susceptibility results as provided by the 
Xpert MTB/RIF assay or the Hain MTBDRplus assay, will also be used as part of screening and 
enrollment procedures.  
 
Efavirenz and Rifapentine Drug-Drug Interactions 
Rifamycin antibiotics such as rifapentine have the potential to cause significant drug-drug interactions 
with antiretroviral therapy. Rifapentine is a known inducer of various cytochrome P450 iso-enzymes.  The 
nonnucleoside reverse transcriptase inhibitor efavirenz is a cytochrome P450 substrate, leading to 
concern for decreased efavirenz concentrations and an increased risk of virologic failure if dosed 
concurrently with rifapentine. Exposure-response relationships between efavirenz concentrations and 
virologic failure have been demonstrated. For example, Cohen et al. reported that in an evaluation of 142 
HIV-infected persons, efavirenz mid-dosing interval concentrations <1 mg/L were strongly associated with 
an increased risk for virologic failure (odds ratio 12.5, 95% CI, 2.7-57.3) (Cohen, 2009). The collective 
data for efavirenz indicate an increased risk of virologic failure if mid-dosing interval (or trough) 
concentrations are less than 1 mg/L. 
  
Clinical studies evaluating the effects of rifapentine co-administration on efavirenz pharmacokinetics and 
efficacy have shown mixed results.  Among individuals with HIV infection enrolled in a clinical trial of 
treatment for latent TB infection, preliminary data recently presented by Podany et al. suggest no clinically 
relevant increase in efavirenz oral clearance when dosed together with isoniazid and rifapentine (10 
mg/kg) once daily for four weeks.  In this study of 87 patients, median mid-dosing interval efavirenz 
concentrations decreased in the presence of rifapentine (2588ng/mL vs 2460ng/mL), suggestive of an 
induction effect on efavirenz by rifapentine; however, the geometric mean ratio of efavirenz oral clearance 


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increased by only 4%.  Additionally, virologic suppression was maintained in 97% of the patients in the 
study (Podany, 2014).  A second study, from Farenc et al. investigated the effect of repeated once weekly 
900mg rifapentine dosing on efavirenz pharmacokinetics.  In 12 HIV-infected, TB free adults, the authors 
found a minimal decrease in efavirenz exposure, as measured by a mean decrease in AUC0-24 of 14% 
(Farenc, 2014). A third study investigated the effect of daily rifapentine dosing (15mg/kg) for 21 days in 
HIV-infected, TB free adults receiving efavirenz based ART with baseline suppressed viral load (VL< 20 
copies/mL).  After a single dose of rifapentine efavirenz PK was unchanged (Cmax, AUC0-24, Cmin).  
However, after 21 once-daily doses of 15 mg/kg rifapentine, decreases of 17%, 37% and 33% were seen 
in Cmax, AUC0-24 and Cmin respectively (Sanofi, 2014).  All patients maintained viral suppression while 
taking RPT. While these studies are encouraging in that co-administration of rifapentine at daily doses of 
10 and 15 mg/kg with EFV-based ART did not appear to increase risk of HIV treatment failure, further 
investigations of efavirenz PK and HIV treatment response when rifapentine is given at 1200 mg daily for 
a longer duration are needed.  
 
The Tuberculosis Trials Consortium (TBTC) 
The mission of the TBTC, funded by the U.S. Centers for Disease Control and Prevention, is to conduct 
programmatically relevant clinical, laboratory and epidemiologic research concerning the diagnosis, 
clinical management, treatment and prevention of tuberculosis infection and disease.  The TBTC has 
sites in the United States, Spain, South Africa, Hong Kong, Kenya, Vietnam, Peru, and Uganda.  All sites 
have close connections with the local TB control program; some sites are based in the TB control 
program.  All sites work with experienced mycobacterial laboratories, and the CDC’s Mycobacteriology 
Laboratory serves as the central laboratory for confirmation of drug-susceptibility testing, DNA 
fingerprinting, and further characterization of drug-resistant isolates.  Since its inception in 1994 over 
13,000 patients have been enrolled in TBTC clinical trials.  
 
The AIDS Clinical Trials Group (ACTG) 
The mission of the ACTG, established in 1987, is to develop and conduct scientifically rigorous 
translational research and therapeutic clinical trials, in the U.S. and internationally, related to HIV infection 
and its complications including tuberculosis.  The ACTG is funded by the U.S. National Institutes of 
Health through the National Institute of Allergy and Infectious Diseases.  ACTG units and investigators 
serve their communities as major resources for HIV/AIDS research, treatment, care, and education.  The 
ACTG tuberculosis laboratory infrastructure consists of one international tuberculosis specialty laboratory 
as well as regional tuberculosis diagnostic laboratories.  
2.2 
Rationale 
Rationale for regimen selection 
The current standard six-month TB treatment regimen for drug-susceptible pulmonary tuberculosis is 
associated with unacceptably high rates of treatment default under program conditions, thereby 
contributing to individual morbidity and mortality, M. tuberculosis transmission, and drug resistance.  
Highly potent regimens of shorter treatment duration may facilitate treatment completion and direct 
observation of treatment, thereby improving individual and public health.  Studies using animal models of 
TB chemotherapy have shown a clear relationship between rifamycin exposure and reduction of bacillary 
burden.  Animal studies also indicate that rifapentine-based regimens are highly potent and can reduce 
overall tuberculosis treatment duration to approximately 3 months.  In humans, phase 1 and 2 clinical 
trials support the safety and tolerability of rifapentine at daily doses up to 20 mg/kg.  A phase 2 clinical 
trial has shown a strong drug exposure-response effect for rifapentine using a surrogate marker of time to 
stable culture conversion.  These results provide rationale for a phase 3 clinical trial to determine the 


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efficacy, using the definitive endpoint of durable cure, of a regimen containing rifapentine substituted for 
rifampin and administered in combination with other drugs for 17 weeks (approximately four months).  
This trial will also assess the efficacy of a second investigational 17-week regimen that incorporates two 
strategies to enhance antimicrobial activity. The first strategy is optimization of rifamycin exposure 
through the single substitution of high dose rifapentine for rifampin throughout treatment as described 
above. The second strategy is a dual substitution approach that seeks to further enhance the potency of 
the regimen by also replacing ethambutol (which has relatively weak activity) with moxifloxacin, in the 
context of optimized rifamycin exposure.  As described above, available evidence from animal models 
and in humans indicates that moxifloxacin, when substituted for ethambutol, will contribute to regimen 
bactericidal activity, even though that single substitution alone is insufficient to shorten treatment to four 
months. The investigational regimen that contains both rifapentine and moxifloxacin may well be the most 
potent regimen possible without new chemical entities.  Therefore if both investigational regimens fail in 
the proposed study, then the implications are that new drugs are required for treatment shortening, and 
that treatment shortening cannot be achieved with existing drugs.  Such a finding would push the drug-
susceptible TB therapeutics field in a different direction.    
Rationale for dosing strategy 
With respect to rifapentine dose and dosing strategy, this trial will use a flat dose of 1200 mg with food 
dosed daily. This is based on 1) demonstration of safety of rifapentine at 1200mg in phase 1 and 2 trials, 
2) demonstration that body weight does not significantly affect rifapentine clearance, 3) recognition of an 
effect of food in substantially increasing rifapentine absorption (Zvada et al., 2010) and 4) modeling 
predictions that the target rifapentine exposure (AUC of approximately 500 to 600 mcg*h/L) is achievable 
using this strategy.  
 
For rifampin, administration with food slows the rate of absorption and decreases the maximal 
concentration (Cmax) by about 36% in healthy adults but to a lesser extent (5 to 15%) in TB patients, with 
little to no effect on AUC (reduction of 6% in healthy adults; reduction of 4% to increase of 8% in TB 
patients) (Peloquin et al., 1999; Zent et al., 1995).  Overall the clinical consequences of these PK effects 
are unclear.  As a consequence rifampin will not be dosed with food.  
 
Rationale for an open-label (not blinded) study 
This study will be open-label; participants, study staff, and clinical care providers will have knowledge of 
treatment assignment.  While blinding is often incorporated into clinical trials as a strategy to reduce bias, 
blinding is not without cost.  Besides logistic complexity, there are two main reasons to not incorporate 
blinding into this trial.  First, if blinding through use of placebos were to be incorporated into this trial, the 
already substantial pill-burden would be further increased to approximately 20 pills per day, which will be 
difficult for participants to tolerate.  Poor tolerability of the pill burden may result in diminished adherence 
to treatment and in turn efficacy.  Besides tolerability, from a biological perspective the dissolution of pills 
in the gastrointestinal tract may be reduced with such a high pill burden, a situation that could result in 
diminished treatment efficacy and increased risk for acquisition of drug resistance. Reduced 
bioavailability due to the burden of added placebo pills also might reduce the generalizability of study 
findings to possible subsequent programmatic usage.  As noted above, there may be a differential effect 
of food on rifampin and rifapentine such that different food advice is required so as to optimize regimen 
pharmacokinetics and potential efficacy. The study will minimize any impact of ascertainment bias 
through the use of objective laboratory measures for the primary efficacy endpoint as well as 
incorporation of a central study clinician (who is blinded as to individual participants’ treatment 
assignments) to be available to advise on protocol procedural issues. Co-intervention bias is unlikely 
during the active treatment in the first four months, and it is unlikely that the use of placebo can effectively 


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avoid contamination bias in the last two months. Co-intervention bias is unlikely during active TB 
treatment, as site teams will closely monitor participants. Measures will be taken to evaluate participants 
equally, regardless of assigned study arm, such that timing of study visits and endpoints will be applied 
uniformly. 
 
Rationale for CD4 testing before enrollment 
HIV-infected individuals will be excluded from enrollment if, at the time of enrollment, their CD4 T cell 
count is known to be <100 cells/mm3.  The rationale for doing so is the challenge of starting concomitant 
treatment for HIV-infection and TB within a short period of time as recommended by WHO guidelines, the 
potential for severe immune reconstitution when antiretroviral therapy is initiated early in the course of 
anti-TB therapy, an increased probability for the diagnosis of conditions that would require therapy with 
medications that have drug-drug interactions with study drugs, and the indication for primary antimicrobial 
prophylaxis against opportunistic infections (such as toxoplasmosis and Mycobacterium avium) with 
consequent increase in the probability of drug-drug interactions and adverse events.  Additionally, 
treatment assignment is stratified by CD4 T cell count (Section 7.2). 
 
Rationale for including adolescents 
 
Inclusion of children in clinical trials of tuberculosis treatment increasingly has been called for to support 
the rational use and increased availability of anti-tuberculosis medications for children (Burman 2006, 
McKenna 2014). Tuberculosis disease characteristics, presentation, diagnosis, and treatment are similar 
for adults and adolescents.  
 
Rifapentine currently is approved in the United States for use in persons as young as 12 years old 
(Priftin® package insert). Rifapentine pharmacokinetic results have been found to be similar between 
adults and adolescents down to this age (Marshall 1999).  Rifapentine 900 mg once weekly, with 
isoniazid for 12 weeks has been used to treat children for latent TB infection (LTBI) (Villarino 2015): the 
rifapentine-containing regimen was found to be as safe and effective as a 9-month daily isoniazid 
regimen, among 552 children age 2-17 years old treated with the rifapentine-containing regimen. Based 
on a large clinical trial that reported treatment of patients as young as 12 years old (Sterling 2011), CDC 
recommends use of this rifapentine-containing regimen “as an equal alternative to 9 months of daily self-
supervised INH for treating LTBI in otherwise healthy patients aged ≥12 years.” (CDC 2011) Although the 
phase 2 trial of daily high-dose rifapentine enrolled 81 participants ≥ 18 years old (Dorman 2013), 
available animal and human data and a formal review by Sanofi support the safety of including 
adolescents in this clinical trial (Marilyn Maroni personal communication).                                                                               
 
Moxifloxacin usage in children has been limited because of findings that treating juvenile dogs with doses 
higher than recommended for humans (≥ 30 mg/kg/day) resulted in arthropathy (Avelox® package insert). 
Moxifloxacin has been recommended and used in children for treatment of multidrug resistant (MDR) TB 
although few safety data have been collected systematically (Bradley 2011). One recent report of a series 
of 9 children age 6 months to 13 years, treated with moxifloxacin for a range of 3-16 months, attributed 
side effects possibly to moxifloxacin in 2 patients (Garazzino 2014): A 6-year old girl developed arthritis of 
the ankle after 3 months, which “spontaneously resolved few days after drug cessation.” A 3-year old girl 
developed “grade three elevation of liver function tests after 9 months of treatment.” A more recent report 
of 23 children, median age 11.1 years (IQR 9.2-12.0 years), treated for MDR TB with moxifloxacin 
followed the children for a median of 236 days (IQR 142-541 days (Thee 2014). This group found lower 
exposures in children than in adults following an oral dose of 10 mg/kg and lower exposure with HIV 
infection. They found moxifloxacin to be safe and well tolerated, with a conservative approach to 
determining an event not to be related to moxifloxacin in the presence of multiple second line drugs. 


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Adverse events possibly, probably, or definitely related to moxifloxacin were arthralgia (4 patients, 5 
events, 4 grade 1, 1 grade 3), pain other than traumatic injury (1, grade 1), headache (5 patients, 5 
events, 4 grade 1, 3 grade 3), fatigue/malaise (1, grade 1), nausea (9 patients, 9 events) grade 1), 
vomiting (3 patients, 3 events, 3 grade 1),cutaneous reaction (1, grade 1), pruritus,(2 patients, 4 events, 4 
grade 1), elevated alanine-aminotransferase (ALT) (4 patients, 5 events, 2 grade 1, 2 grade 2 1 grade 3), 
bilirubin (1 grade 2). ECG data was available for 13 children: mean QTc was 403 ms (SD 30 ms); none 
had QTc interval >450ms. In a separate report, a case of self-limited polyarthritis was reported for a 12-
year old child who inadvertently received a single 2 gram dose of moxifloxacin (50 mg/kg/day) (Torres 
2008), illustrating the presence of some risk but also the difficulty of finding moxifloxacin toxicity in 
children with standard dose treatment. 
 
Daily treatment of adolescents and children with moxifloxacin and with high-dose rifapentine has been 
limited. The benefits of finding regimens that would substantially shorten treatment for this important 
subset of TB patients outweigh the theoretical risks. The frequent careful monitoring for signs and 
symptoms in a clinical trial provides the opportunity to respond quickly to abnormal findings if they occur 
in an individual, but also to document systematically the safety profile for these promising treatment 
regimens. 
2.3 
Potential Harms and Benefits 
2.3.1 Potential harms 
Risks associated with study participation include the possibilities that an investigational regimen 
has efficacy that is inferior to the standard regimen and/or an investigational regimen is more 
toxic than the standard regimen, and confidentiality risks.  
The investigational regimens could prove to have inferior efficacy compared to the standard 
regimen.  TBTC Study 29X showed that a regimen containing rifapentine administered daily at 
1200 mg (approximately 20 mg/kg) has sufficient antimicrobial activity to justify further evaluation 
compared to a regimen containing rifampin administered daily at approximately 10 mg/kg, using a 
surrogate marker for durable cure. Other recent phase 2 studies have demonstrated that 
substitution of moxifloxacin for ethambutol increases the antimicrobial activity of the regimen.  
Equipoise around whether these increases in antimicrobial activity can result in durable cure after 
four months of treatment forms the basis for inclusion of test regimens 2PHZE/2PH and 
2PHZM/2PHM.  Further, as described above, studies have shown that moxifloxacin substituted 
for ethambutol increases antimicrobial activity, and PZA has important bacterial sterilizing 
properties.  The following measures will minimize risk to participants: individual participants will 
be closely monitored clinically and bacteriologically, an interim efficacy analysis will be performed, 
and a Data and Safety Monitoring Board will review trial progress regularly.  In addition, it is 
anticipated that participants who are not cured will be re-treatable with conventional anti-
tuberculosis drugs as acquired drug resistance is very unlikely in the setting of highly monitored 
directly observed combination therapy (Johnson et al., 2009, Jindani et al., 2013).  
The investigational regimens could prove to have greater toxicity than the standard regimen.  This 
is unlikely given that toxicity data collected in the phase 2 clinical trial showed that rifapentine 
administered at a once daily dose of 20 mg/kg for eight weeks was well tolerated.  However, no 
clinical trial has included patients treated with daily rifapentine for more than 2 months.  With 
respect to the moxifloxacin-containing regimen, the toxicity profile of moxifloxacin is well known. 
Moxifloxacin is used regularly for prolonged periods during the treatment of patients with drug 


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resistant tuberculosis. Participants in this clinical trial will be monitored closely for adverse events.  
The Data and Safety Monitoring Board (DSMB) will review safety data regularly.   
Confidentiality risks will be minimized through the measures described in Section 15.3.  
2.3.2 Potential benefits 
All 3 study treatment regimens are offered with therapeutic warrant, meaning that it is reasonable 
to expect that these TB treatments will cure TB at an acceptable, if not yet uniformly 
demonstrated, rate. Study participants will benefit indirectly as it is well established that 
tuberculosis outcomes for participants in tuberculosis treatment trials are better than those for 
patients receiving routine care.  This study will benefit society by contributing to the 
understanding of optimal strategies for treating tuberculosis.  The inclusion of clinical specimen 
storage along with the combined use of two culture media types (solid and automated liquid) in 
this phase 3 trial will contribute urgently needed data that can help determine the optimal use of 
liquid culture in drug development and will facilitate discovery efforts for new surrogate markers.   


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3 
DESCRIPTIONS OF STUDY DRUGS 
Drugs (commercially available as brand or generic) to be administered during this study include the 
following: rifapentine, rifampin, moxifloxacin, isoniazid, pyrazinamide, ethambutol, and vitamin B6 
(pyridoxine).  Rifapentine and the other drugs are described in detail in their package inserts.  Key points 
are summarized below. 
3.1 
Rifapentine 
Rifapentine is indicated for the treatment of pulmonary tuberculosis caused by Mycobacterium 
tuberculosis, and must be used in combination with one or more antituberculosis drugs to which the 
bacterial isolate is susceptible (Priftin package insert, 2010).  Rifapentine, as Priftin® was approved by 
the U.S. FDA in 1998.  FDA approval was based on the results of “Clinical Study 008”, an open-label, 
prospective, randomized study of 722 patients with active pulmonary TB (Priftin package insert, 2010).  
Rifapentine is a semisynthetic rifamycin derivative with a microbiologic profile similar to that of rifampin.  
Its structure differs from that of rifampin by the presence of a cyclopentyl ring instead of a methyl group at 
the piperazinyl moiety.  It has a longer half-life than rifampin, and, like rifampin, rifapentine inhibits 
bacterial RNA synthesis by binding to the β-subunit of DNA-dependent RNA polymerase. Rifapentine is 
well absorbed from the gastrointestinal tract, with 70% bioavailability; when taken with food, its AUC and 
Cmax increase by 43% and 44%, respectively (Priftin package insert, 2010).  It reaches peak 
concentrations in the serum 5 to 6 hours after ingestion.  Rifapentine and its 25-desacetyl metabolite are 
highly protein-bound, 97.7% and 93%, respectively, primarily to albumin.  Rifapentine is metabolized by 
an esterase enzyme found in the liver and blood to 25-desacetylrifapentine, a microbiologically active 
metabolite that contributes about 40% of the drug’s overall activity.  For M. tuberculosis, the MIC of 25-
desacetyl rifapentine is 0.25 mcg/mL, while that of rifapentine is 0.05 mcg/ml.  The drug and the active 
metabolite have half-lives of 14-17 and 13 hours, respectively.  The drug is excreted in bile and 
eliminated in feces.  Less than 10% of rifapentine is excreted in the urine as unchanged drug.  
Rifapentine, 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 glucuronosyltransferase and sulphotransferase and may reduce levels of drugs 
metabolized by those pathways.  Rifapentine is available as 150 mg tablets.  Rifapentine, like other 
rifamycins, causes red-orange discoloration of body fluids and can stain contact lenses.  In clinical trials in 
which rifapentine was combined with isoniazid and other antituberculosis drugs and administered once or 
twice weekly, rates of adverse reactions were similar with rifampin and rifapentine, with increased liver 
aminotransferase activity in about 5% of patients.  The only adverse effect that has occurred more often 
with rifapentine than with rifampin has been hyperuricemia when the drug was given twice-weekly; of 
note, hyperuricemia was attributed to pyrazinamide that was administered concomitantly.  Other adverse 
reactions that occurred in 1-5% of patients included the following:  hemoptysis, dizziness, hypertension, 
headache, gastrointestinal upset, rash, cytopenias, hematuria, pyuria, and proteinuria   (Priftin package 
insert, 2010).   
3.2 
Rifampin 
Rifampin is a semi-synthetic rifamycin derivative that is highly active against mycobacteria, most gram-
positive bacteria, and some gram-negative bacteria.  It is bactericidal for both intracellular and 
extracellular microorganisms.  By inhibiting prokaryotic DNA-dependent RNA polymerase, it suppresses 
the early elongation of the nucleotide chain in RNA synthesis.  Rifampin is normally absorbed completely 
when taken orally, but food delays absorption. After 1.5 to 2 hours, a 600 mg dose yields a peak blood 


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level of 8-20 mcg/ml. The half-life of rifampin varies from 2 to 5 hours, and it is shortened by 
approximately 20-40% after the first week of daily treatment because of the induction of hepatic 
microsomal enzymes.  The half-life is unaffected by renal impairment but is increased by liver disease or 
biliary obstruction.  Rifampin is deacetylated to an enterohepatically-recirculated active metabolite, and 
50% to 60% is excreted in the feces.  Up to 30% of a dose is excreted in the urine.  Approximately 85% of 
circulating rifampin is bound to plasma proteins, and is widely distributed throughout the body.  Rifampin 
is a potent inducer of a number of hepatic enzymes involved in the metabolism of drugs and some 
hormones (Venkatesan, 1992).  This enzyme induction causes more rapid elimination (and potential loss 
of efficacy) of many drugs.  In the usual daily doses of 10 mg/kg (maximum 600 mg), rifampin is well 
tolerated.  It often causes harmless but disconcerting red-orange discoloration of tears, sweat, saliva, 
feces, and urine.  Less than 4% of TB patients experience significant adverse reactions to rifampin.  
Gastrointestinal adverse effects are the most common, and they include epigastric distress, anorexia, 
nausea, vomiting, cramps, and diarrhea.  Hepatitis rarely occurs in persons who have normal baseline 
hepatic function.  The incidence of hepatitis may be increased for older persons and those who have 
chronic liver disease or alcoholism, but remains substantially lower than that for pyrazinamide or 
isoniazid.  Rifampin can cause a flu-like syndrome of fever, chills, headache, dizziness, and bone pain, 
although this is uncommon using the 600 mg dose given daily.  In a very small proportion of patients the 
flu-like syndrome is associated with interstitial nephritis, acute tubular necrosis, thrombocytopenia, 
hemolytic anemia, and shock.  (Rifadin [rifampin] package insert. Sanofi, 2013). 
3.3 
Moxifloxacin 
Moxifloxacin is a fluoroquinolone antibacterial that is distinguished by a methoxy group at the C-8 position 
and an S,S-configured diazabicyclononyl ring moiety at the C-7 position.  The mechanism of action 
against M. tuberculosis is by inhibition of the DNA gyrase enzyme involved in DNA replication.  
Moxifloxacin is well absorbed, with a bioavailability of approximately 90% (Avelox package insert, 2012). 
Pharmacokinetics are linear in the range of 50-800 mg single dose and up to 600 mg once daily dosing 
over 10 days.  Steady state is reached within 3 days. The mean (+SD)  maximum concentration (Cmax ) 
and AUC values at steady state with a 400 mg once-daily dosage regimen are 4.5+0.53 mcg/ml and 
48+2.7 µg*h/ml, respectively.  Tmax  is  approximately 1-3 hours. The mean (+SD) plasma half-life is 12.1 + 
3.1 hours.  Trough plasma concentration at steady state (400 mg once daily) is 0.95 + 0.10 mcg/L.   Co-
administration with food may slightly prolong Tmax, and may reduce the Cmax by 16%; these effects are not 
believed to be clinically significant, and thus moxifloxacin can be administered with or without food.  
Moxifloxacin is 50% bound to plasma proteins.  It is widely distributed, with some tissue concentrations 
reported in excess of plasma levels. Moxifloxacin is metabolized by glucuronide and sulfate conjugation.  
The cytochrome p450 enzyme system is not involved in the metabolism of moxifloxacin, nor does the 
drug effect it.  Specifically, moxifloxacin does not affect CYP3A4, CYP2D6, CYP2C9, CYP2C19, or 
CYP1A2.  Moxifloxacin should not be administered at the same time as antacids containing magnesium 
and/or aluminum, sucralfate, antidiarrheals that contain kaolin, or iron and/or zinc containing medications 
or supplements.  As a class, fluoroquinolones are considered to be safe and relatively free of serious 
adverse effects (Ball, 1989). The safety and efficacy of moxifloxacin for the treatment of community 
acquired bacterial infections has been extensively studied.  In the usual daily doses of 400 mg/day, 
moxifloxacin is well tolerated.  Expected minor adverse events have occurred with a frequency similar to 
that for other fluoroquinolones in similar populations. Gastrointestinal adverse effects are the most 
common, and they include nausea (7%), diarrhea (6%), dizziness (3%), abdominal pain (2%), vomiting 
(2%), dyspepsia (1%), and taste perversion (1%).  There are no current reports of hepatitis, although 
abnormal liver function tests have been noted in 1% of patients. Of note, fluoroquinolones are generally 
used short-term for acute conditions.  However, fluoroquinolones have been found to be safe and 


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effective in long term use for chronic infections such as osteomyelitis, prostatitis, or chronic urinary tract 
infection, or skin and skin structure infections (Ball, 1989; Segev et al., 1999). In addition, Valerio et al. 
found that the combination of moxifloxacin, isoniazid, and rifampin given for 6 months was well tolerated 
(Valerio et al., 2003). For treatment of MDR-TB, a later-generation fluoroquinolone such as moxifloxacin 
is recommended for a duration of 8 months or more (WHO, 2011).  Moxifloxacin causes a mild 
prolongation of the corrected QT (QTc) interval.  The mean effect on QTc interval in 787 patients in Phase 
3 clinical trials was 6 + 26 milliseconds, but no morbidity or mortality was attributable to QTc prolongation.  
In a review of over 6,000 patients treated with moxifloxacin, there were no reports of changes in the 
frequency of QTc prolongation (Ball, 2000).  In over 10 million patients treated with moxifloxacin there has 
been no evidence for an increased incidence of ventricular arrhythmia when compared to the overall 
population.  Finally, the incidence of sudden death and syncope, both markers for sudden cardiac events, 
is not increased when compared to the incidence on the general population.  For these reasons, 
electrocardiographic monitoring is no longer recommended for clinical trials involving moxifloxacin.  In this 
study, moxifloxacin will not be used among patients with a known history of prolongation of the QT 
interval, patients with uncorrected hypokalemia and patients receiving class Ia (e.g. quinidine, 
procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents, due to the lack of clinical 
experience with the drug in these patient populations (see Eligibility criteria).  Pharmacokinetic studies 
between moxifloxacin and other drugs that prolong the QT interval such as cisapride, erythromycin, 
antipsychotics and tricyclic antidepressants have not been performed.  An additive effect of moxifloxacin 
and these drugs cannot be excluded, therefore moxifloxacin should be used with caution when given 
concurrently with these drugs.  The estimated incidence of fluoroquinolone-induced tendinopathy is 15 to 
20 per 100,000. Fluoroquinolone-induced tendinopathy is diagnosed by a sudden onset of swelling and 
tenderness concurrent with or shortly after fluoroquinolone therapy, which is accompanied by tendon 
rupture in about 33% of all cases.  The main site affected is the Achilles tendon, though tendinitis has 
been reported to involve the shoulder, knee, hand, and plantar aponeuroeses.  Achilles tendon ruptures 
have been noted even months after discontinuation (Pierfitte et al., 1996). Concomitant use of 
corticosteroids is considered to be a risk factor for developing tendinopathy while taking fluoroquinolones. 
In over 10 million patients treated with moxifloxacin only 3 patients with tendon rupture have been 
reported.  All had received concomitant corticosteroid treatment. 
3.4 
Isoniazid 
Isoniazid is the hydrazide of isonicotinic acid and is one of the primary drugs for TB treatment.  The 
activity of isoniazid is limited to the mycobacteria of the M. tuberculosis complex; it is bactericidal for 
rapidly dividing organisms and bacteriostatic for “resting” bacilli.  The probable mechanism of action is the 
inhibition of the biosynthesis of mycolic acids, a component of the mycobacterial cell wall.  Isoniazid is 
generally well absorbed; food and antacids decrease the rate, but not the extent of absorption. Peak 
blood levels of isoniazid, 3 to 5 mcg/ml, are obtained 30 minutes to 2 hours after ingestion of routine 
doses (Peloquin et al. 1999).  It diffuses into all body fluids and cells and penetrates into the caseous 
material of a tuberculoma or pulmonary cavity.  In the liver, it is acetylated to inactive metabolites, and 
75% to 95% of the dose is excreted as inactive metabolites in the urine within 24 hours.  Isoniazid 
clearance rates depend on 2 metabolic phenotypes, slow and fast acetylation, which are associated with 
race, but not gender (Ellard., 1984). The isoniazid AUC among persons who have fast acetylation is 30% 
to 50% of that among persons who have slow acetylation.  Because isoniazid is well tolerated over a wide 
range of therapeutic doses, a single dose per body mass is recommended.  Persons who have rapid 
acetylation achieve effective concentrations, while persons who have slow acetylation do not experience 
increased toxicity.  Half-life (t1/2) may vary from 1 hour in fast acetylators (t1/2 < 90min) to 3 hours in slow 
acetylators (t1/2 >90min).  The usual adult dose of isoniazid is 5 mg/kg given once daily, up to a maximum 


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of 300 mg given once daily.  Isoniazid decreases the clearance of some medications that are metabolized 
in the liver (particularly carbamazepine, phenytoin, and diazepam) (Baciewicz et al. 1985).  However in 
the context of multidrug therapy including rifampin, these potential drug-drug interaction are of little 
significance because the effect of isoniazid is counteracted by the more potent opposing effect of rifampin 
(Kay et al. 1985).  The total incidence of all adverse effects from isoniazid is approximately 5%, many of 
which do not require discontinuation of the drug.  Peripheral neurotoxicity is dose dependent and it is 
uncommon (<0.2%) at conventional doses. The risk of peripheral neuritis increases for persons who are 
malnourished or predisposed to neuritis by other illnesses.  Concomitant administration of pyridoxine 
(vitamin B6) is recommended for these persons, and will be given to all patients in this trial.  Other 
nervous system reactions are rare at normal doses, and they include convulsions, encephalopathy, optic 
neuritis, memory impairment, and psychosis.  Gastrointestinal adverse effects include nausea, vomiting, 
and epigastric distress.  Asymptomatic elevation of aminotransferases is common and occurs in 10-20% 
of persons receiving isoniazid. However, idiosyncratic severe hepatic reactions are uncommon but are 
more likely in older persons (up to 2.3% hepatitis incidence in persons more than 50 years old), and may 
be life threatening.  Daily consumption of alcohol increases the risk of isoniazid-associated hepatotoxicity 
by approximately 4-fold.   
3.5 
Pyrazinamide 
Pyrazinamide is an analog of nicotinamide and has unique activity against M. tuberculosis, allowing the 
duration of treatment to be decreased from 9 months to 6 months (assuming a rifamycin is used 
throughout).  The mechanism of action of pyrazinamide remains incompletely understood, but there is 
evidence that pyrazinamide inhibits M. tuberculosis trans-translation.  Pyrazinamide is well absorbed from 
the gastrointestinal tract and widely distributed into all tissues  (Ellard et al., 1987). Usual doses are 15-30 
mg/kg/d, up to 2 gm/d.  Peak serum concentrations of about 45 mcg/ml are achieved approximately 2-3 
hours after a dose. Food and antacids do not significantly affect the absorption of pyrazinamide.  The 
half-life of pyrazinamide is approximately 9-10 hours, and is prolonged in the presence of hepatic 
insufficiency (Lacroix et al., 1990).  Pyrazinamide is metabolized to pyrazinoic acid by the hepatic 
microsomal enzyme pyrazinamide deamidase.  Approximately 40% of a dose is recovered in the urine as 
pyrazinoic acid and an additional 4% is excreted in the urine as the unchanged parent drug (Ellard, 1969).  
The remaining drug is thought to be excreted in the bile.  There are no known clinically significant drug-
drug interactions involving pyrazinamide.  The most frequent side effects are skin rash, gastrointestinal 
intolerance, hepatotoxicity (1.3%), arthralgias (1-7%), hyperuricemia due to blockade of urate excretion 
(up to 66%), and rarely acute gouty arthritis (Patel et al., 1995; Ormerod et al., 1996).  These side effects 
are seldom dose-limiting. Asymptomatic elevations in serum uric acid are frequent, usually occur during 
the first or second month of treatment, and are self-limited and require no specific treatment (Zierski et al., 
1980). Minor arthralgias also may occur during pyrazinamide treatment and can usually be treated with 
salicylates or non-steroidal inflammatory agents such as indomethacin while continuing the drug.  The 
most common serious side effect of pyrazinamide is hepatotoxicity.  In 2 randomized clinical trials the 
addition of pyrazinamide to RH did not increase the rates of hepatotoxicity above that seen with the latter 
2 drugs alone (Zierski et al., 1980; Combs et al., 1990).  However, 3 recent retrospective cohort studies 
suggest that the incidence of pyrazinamide-induced hepatitis during active TB treatment is higher than 
that for other first-line TB drugs, and higher than previously recognized (Yee et al., 2003; Schaberg et al., 
1996; Dossing et al., 1996).  Hepatitis risk persists with prolonged use (Reves et al., 2014). 


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3.6 
Ethambutol 
Ethambutol is an ethylene derivative of butane that interferes with cell wall synthesis in mycobacteria; 
other bacteria are uniformly resistant to ethambutol.  In the treatment of human TB, ethambutol is 
effective in preventing the emergence of drug resistant strains, although it has no sterilizing activity at 
clinically-tolerated doses (Kohno et al. 1992).  Ethambutol is well absorbed from the gastrointestinal tract, 
reaching peak serum concentrations of 3-5 mcg/ml in normal volunteers 2-4 hours after a dose.  Food 
slows absorption and decreases the peak serum concentration by 10-20%, but has no effect on the total 
systemic exposure.  Antacids decrease both the peak serum concentration and AUC, and so should not 
be administered at the same time.  Ethambutol is primarily eliminated by the kidneys as unchanged drug; 
the serum half-life averages 4 hours.   Patients with renal insufficiency are prone to accumulation of the 
drug and the resultant toxicity.  There are no known drug–drug interactions involving ethambutol.  
Ethambutol is usually well-tolerated with low rates of skin rash, nausea, vomiting, or diarrhea.  Fever, 
allergic reactions, abdominal pain, mental status changes, peripheral neuropathy, and increased liver 
function tests have rarely been associated with ethambutol.  Adverse events occur in less than 2% of 
patients receiving ethambutol at the 15 mg/kg dose and include decreased visual acuity (0.8%), rash 
(0.5%) and asymptomatic hyperuricemia (Patel et al., 1995). The most common serious side effect of 
ethambutol is retinal toxicity, often first perceived as a decrease in color perception.  Patients receiving 
ethambutol should be instructed about symptoms of ocular toxicity.  If stopped promptly, permanent visual 
loss is rare among patients with ethambutol-related retinal toxicity.  Rates of retinal toxicity are very low 
when the drug is given for relatively short periods, as is the case in this study. 
3.7 
Vitamin B6 (Pyridoxine) 
Pyridoxine (vitamin B6) is an essential vitamin involved in carbohydrate, fat, protein and brain amine 
metabolism. Isoniazid competitively inhibits the action of pyridoxine in these metabolic functions and also 
causes increased urinary excretion of pyridoxine (Snider, 1980).  Chronic isoniazid administration can 
result in pyridoxine deficiency, which may manifest as acral paresthesias due to peripheral, predominantly 
sensory, axonal polyneuropathy. Isoniazid-associated peripheral neuropathy is dose related and occurs in 
less than 1% of persons receiving isoniazid at recommended doses (Blumberg et. al, 2003). It occurs 
more frequently in HIV-infected persons, malnourished individuals, persons with chronic renal failure or 
diabetes mellitus, pregnant and breastfeeding women, and persons with heavy chronic ethanol 
consumption. Pyridoxine 25 to 50 mg daily by mouth may be administered to prevent isoniazid-associated 
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4 
OBJECTIVES 
4.1 
Primary: 
• 
To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single 
substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of 
treatment for drug-susceptible pulmonary tuberculosis 
• 
To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin 
for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is 
possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary 
tuberculosis   
 
4.2 
Secondary: 
• 
To evaluate the safety of the investigational regimens 
• 
To evaluate the tolerability of the investigational regimens 
• 
To collect and assess biospecimens from consenting participants for the purpose of research on 
discovery and validation of TB biomarkers 
• 
To determine the correlation of mycobacterial and clinical markers with time to culture conversion, 
treatment failure, and relapse. 
• 
To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs.  The main 
objectives of the PK/PD study are to characterize study drug PK parameters and to determine 
relationships between treatment outcomes and PK parameters.  
• 
To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with 
TB/HIV co-infection taking efavirenz-based combination antiretroviral therapy and TB treatment with 
rifapentine. 
 
 
 


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5 
STUDY DESIGN 
This will be an international, multicenter, randomized, controlled, open-label, 3-arm, phase 3 non-
inferiority trial. 
As described in subsequent sections, participant safety will be maximized and risks will be minimized by 
frequent study visits for safety assessments, intensive microbiological monitoring for TB treatment failure 
and relapse, and periodic review of unfavorable outcome rates by a Data and Safety Monitoring Board.   
 
 
 


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6 
STUDY POPULATION 
This will be a multisite international study.  Male and female participants who are age 12 or older and 
suspected to have pulmonary tuberculosis will be enrolled into the study.   
Target enrollment is 2500 participants.   
Pregnant or breast-feeding women will be excluded from the study because of uncertainties about the 
safety of rifapentine, moxifloxacin, and pyrazinamide in these groups.  The sex, ethnicity, and 
socioeconomic background of study participants are expected to mirror those of the populations served 
by local tuberculosis clinics and the populations most affected by tuberculosis worldwide.   
Co-enrollment in other therapeutic clinical trials is not allowed.  
6.1 
Subject Inclusion Criteria 
Individuals must meet all of the following inclusion criteria in order to participate in this study:   
A. 
Suspected pulmonary tuberculosis plus one or both of the following: a) at least one 
sputum specimen positive for acid-fast bacilli on smear microscopy OR b) at least one 
sputum specimen positive for M. tuberculosis by Xpert MTB/RIF testing, with 
semiquantitative result of ‘medium’ or ‘high’ and rifamycin resistance not detected.   
B. 
Age twelve (12) years or older 
C. 
A verifiable address or residence location that is readily accessible for visiting, and 
willingness to inform the study team of any change of address during the treatment and 
follow-up period. 
D. 
Women of child-bearing potential who are not surgically sterilized must agree to practice 
an adequate method of contraception (barrier method or non-hormonal intrauterine 
device) or abstain from heterosexual intercourse during study drug treatment.  
E. 
Documentation of HIV infection status.  
F. 
For HIV-positive individuals, CD4 T cell count greater than or equal to 100 cells/mm3 
based on testing performed at or within 30 days prior to study entry.  HIV-positive 
individuals will be enrolled in a staged approach as described in Section 8.3.10.1, 
specifically:  
• 
Group 1 (“EFV1”): receipt of efavirenz-based antiretroviral therapy (ART) for a 
minimum of 30 days at the time of enrollment AND a documented HIV viral load 
less than 200 copies/mL at or within 30 days prior to study entry, OR 
• 
Group 2 (“EFV2”): for HIV-positive individuals not on ART at enrollment, planned 
initiation of efavirenz-based ART before or at study week 8  
G. 
Laboratory parameters done at or within 14 days prior to screening: 


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• 
Serum or plasma alanine aminotransferase (ALT) less than or equal to 3 times 
the upper limit of normal 
• 
Serum or plasma total bilirubin less than or equal to 2.5 times the upper limit of 
normal 
• 
Serum or plasma creatinine level less than or equal to 2 times the upper limit of 
normal 
• 
Serum or plasma potassium level greater than or equal to 3.5 meq/L 
• 
Hemoglobin level of 7.0 g/dL or greater 
• 
Platelet count of 100,000/mm3  or greater 
H. 
For all women who are not surgically sterilized or who do not meet the study definition of 
post-menopausal, a negative pregnancy test at or within seven (7) days prior to 
screening 
I. 
Karnofsky score greater than or equal to 60 
J. 
Written informed consent 
6.2 
Criteria for Exclusion from Enrollment  
An individual meeting any of the following exclusion criteria at the time of enrollment or initiation of study 
drugs will be excluded from study participation: 
A. Pregnant or breast-feeding 
B. Unable to take oral medications 
C. Previously enrolled in this study 
D. Received any investigational drug in the past 3 months 
E. More than five (5) days of treatment directed against active tuberculosis within 6 months 
preceding initiation of study drugs 
F. More than five (5) days of systemic treatment with any one or more of the following drugs within 
30 days preceding initiation of study drugs: isoniazid, rifampin, rifabutin, rifapentine, ethambutol, 
pyrazinamide, kanamycin, amikacin, streptomycin, capreomycin, moxifloxacin, levofloxacin, 
gatifloxacin, ofloxacin, ciprofloxacin, other fluoroquinolones, ethionamide, prothionamide, 
cycloserine, terizidone, para-aminosalicylic acid, linezolid, clofazimine, delamanid or bedaquiline 
G. Known history of prolonged QT syndrome 
H. Suspected or documented tuberculosis involving the central nervous system and/or bones and/or 
joints, and/or miliary tuberculosis and/or pericardial tuberculosis 


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I. 
Current or planned use within six months following enrollment of one or more of the following 
medications: HIV protease inhibitors, HIV integrase inhibitors, HIV entry and fusion inhibitors, HIV 
non-nucleoside reverse transcriptase inhibitors other than efavirenz; quinidine, procainamide, 
amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine.  
J. Weight less than 40.0 kg 
K. Known allergy or intolerance to any of the study medications 
L. Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis 
isolate is already known to be resistant to any one or more of the following:  rifampin, isoniazid, 
pyrazinamide, ethambutol, or fluoroquinolones.  
M. Other medical conditions, that, in the investigator’s judgment, make study participation not in the 
individual’s best interest. 
N. Current or planned incarceration or other involuntary detention. 
 
6.3 
Criteria for Exclusion after Enrollment (‘Late Exclusion’) 
Microbiological confirmation of drug-susceptible tuberculosis is not expected always to be available at the 
time of enrollment.  Enrolled individuals who are subsequently determined to meet either of the following 
criteria will be classified as ‘late exclusions’ and study treatment will be discontinued: 
A. Screening, baseline, and Week 2 study visit sputum cultures all fail to grow M. tuberculosis.  
B. M. tuberculosis cultured or detected through molecular assays (Cepheid Xpert MTB/RIF or Hain 
MTBDRplus assays) from sputum obtained around the time of study entry is determined 
subsequently to be resistant to one or more of isoniazid, rifampin, or fluoroquinolones.  


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7 
ENROLLMENT, RANDOMIZATION, AND MASKING 
PROCEDURES 
7.1 
Enrollment Procedures 
Individuals who are sputum smear microscopy positive for acid-fast bacilli AND/OR have at least one 
sputum specimen positive for M. tuberculosis with a semiquantitative result of ‘medium’ or ‘high’ by Xpert 
MTB/RIF testing (with rifampin resistance not detected) will be invited to participate in this study.  
Interested individuals will be provided with information about the study including risks and potential 
benefits of all study procedures.  If site staff are satisfied that the potential participant understands the 
information and the potential participant is willing, the potential participant will be asked to consent to 
participate in the study.  Study-specific procedures will be initiated only after an individual has provided 
written informed consent.   
7.2 
Randomization 
This will be a randomized trial.  Randomization and treatment arm assignment will be computer-
generated centrally by the TBTC Data and Coordinating Center.  Randomization will be stratified by site, 
by the presence of cavitation on chest radiograph at baseline (since cavitation is associated with a 
decreased rate of microbiological response to TB treatment), and by HIV status (HIV-uninfected vs. HIV-
infected).  Eligible participants (who meet all of the inclusion criteria and none of the exclusion criteria) will 
be randomly assigned in a 1:1:1 ratio to the study arms. Random assignment sequences will be 
generated in a way that limits the imbalance between arms within strata while also ensuring that the 
sequence is not predictable based on previous assignments. 
Cavitation is defined as a gas-containing lucent space at least 1 cm in diameter within the lung 
parenchyma surrounded by an infiltrate or fibrotic wall greater than 1 mm thick seen on chest radiograph.  
Cavitation seen only on chest tomography (e.g. CT), if done, does not satisfy this definition. Cavities 
should be distinguished from pulmonary cysts, which are usually thin walled, well-marginated lesions.  
 
 


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8 
STUDY PROCEDURES 
8.1 
Clinical Evaluations 
Clinical evaluations will be performed in accordance with a detailed Manual of Operating Procedures 
(MOOP). 
8.1.1 Interview for demographic and contact information 
Participants will be interviewed for demographic information including place of birth and date of 
birth.  Contact information will be obtained, including participant location of residence and 
participant phone number(s), and names and phone numbers of family members/friends who can 
be contacted by study staff in the event of emergency or if study staff are not able to locate the 
participant. Identifying and locating information will be maintained only at the site; it will not be 
entered into the study data base. 
8.1.2 Obtaining a medical history 
Participants will be interviewed to obtain medical information including tuberculosis signs and 
symptoms, prior tuberculosis history, other health conditions and treatments (including HIV 
infection), medicines used, and allergies to medicines.  
8.1.3 Obtaining sputum specimens 
Sputum may be spontaneously expectorated or induced by aerosol inhalation of sterile nebulized 
saline. Study sites will use their local procedure for sputum induction. Saliva should not be 
collected in place of a sputum specimen. 
8.1.4 Performing visual acuity and color vision testing 
Visual acuity will be tested using a Snellen-type chart.  Color vision will also be tested.  Results of 
this testing will not be collected centrally unless a new diagnosis (e.g. ≥ two lines on a Snellen-
type chart, or loss of color vision) are discovered.   
8.1.5 Symptom assessment 
Participants will be asked if they have experienced any of the following within 14 days prior to 
enrollment or since the previous study visit: fevers, cough, rash, itching, jaundice, nausea, 
vomiting, diarrhea, loss of appetite, vision problems, numbness/tingling of extremities, joint pain.  
In addition, participants will be asked if they have had other symptoms not listed above, and if 
yes, then those other symptoms will be recorded and graded. 
8.1.6 Assessment for adverse events 
Participants will be asked about symptoms and signs, new medical diagnoses, and 
hospitalizations since the last study visit.   


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8.1.7 Chest Radiograph 
A posteroanterior chest radiograph will be performed at screening and at the end-of-treatment 
visit (i.e. week 17 or week 26 visit), as well as for participants undergoing assessment for 
possible poor treatment response. 
 
8.2 
Concomitant Medications/Treatments 
The use of all non-study drugs (including over-the-counter medications) from 14 days before starting 
study drugs through the end of study drug treatment will be monitored and recorded.   
Antimicrobials with known antituberculosis activity (see MOOP) should not be used during study drug 
treatment, and any participant who receives more than five consecutive days of one or more of those 
medications will be classified as being on a non-study regimen.  Antimicrobials without significant anti-
tuberculosis activity may be prescribed for intercurrent infections at the discretion of the investigator and 
will be recorded on study forms.  
Participants requiring the use of iron-containing supplements, antacids containing aluminum and/or 
magnesium, sucralfate, and/or antidiarrheals that contain kaolin should take study drugs at least four 
hours before or eight hours after ingesting those products in order to avoid impaired absorption of study 
drugs. 
Rifamycins induce hepatic enzyme systems that are active in the metabolism of some other drugs.  A 
prominent drug interaction of rifamycins is that involving hormonal contraceptives. Women of child-
bearing potential who are not surgically sterilized must agree to practice an adequate method of 
contraception (barrier method or non-hormonal intrauterine device) or abstain from heterosexual 
intercourse during study drug treatment.  
Another medically important drug-drug interaction is that involving many antiretroviral drugs and the 
rifamycins, which are potent inducers of the cytochrome P450 system.  Nonetheless, in accordance with 
World Health Organization guidance, antiretroviral therapy is recommended for HIV-infected study 
participants; a regimen comprised of efavirenz, tenofovir, plus lamivudine or emtricitabine is 
recommended for use in study participants based on the absence of known clinically significant drug-drug 
interactions between these antiretrovirals and the rifamycins.  Efavirenz, nucleoside reverse transcriptase 
inhibitors, and nucleotide reverse transcriptase inhibitors are allowed while a participant is receiving study 
treatment, provided that the criteria outlined in Section 8.3.10 are met. Guidance with respect to other 
antiretroviral agents will be provided in the MOOP and will be updated as new information on drug-drug 
interactions emerges.  
Moxifloxacin has been shown to prolong the QT interval on the electrocardiogram in some patients.  
Study drugs should not be administered concomitantly with quinidine, procainamide, amiodarone, sotalol, 
disopyramide, ziprasidone, or terfenadine. 
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8.3 
Laboratory Evaluations 
8.3.1 Sputum mycobacterial tests 
See Section 11.1 ‘Summary of Bacteriological Methods’. 
8.3.2 Hematology 
Blood will be drawn for a complete blood count that includes a white blood cell differential, 
hemoglobin, and platelet count.  This will require approximately 5 mL of EDTA anticoagulated 
blood. 
8.3.3 Biochemistry 
Blood will be drawn for measurement of alanine aminotransferase (ALT; serum or plasma), and 
total bilirubin (serum or plasma); in addition at screening blood (serum or plasma) will be tested 
for creatinine, potassium, and albumin. This will require approximately 5 mL of blood. 
8.3.4 HIV testing 
Counseling prior to and following HIV testing, and reporting of HIV testing results will follow local 
guidelines and regulations at each site.  For study purposes, HIV-1 infection is defined as a 
positive result using any licensed rapid HIV test or any licensed HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit.  Confirmation of the initial study test result is 
required and must utilize a different method than the one used for the initial study assessment.  
The confirmatory study test must also be licensed and may include western blot, a second 
antibody test by a method other than the initial rapid HIV and/or E/CIA, HIV-antigen, or plasma 
HIV RNA viral load.  Two or more HIV-1 RNA viral loads of >1,000 copies/mL are also acceptable 
as documentation of HIV infection.  Negative study HIV testing does not require confirmatory 
testing.  Note: the term ‘licensed’ refers to an FDA-approved kit or, for study sites located in 
countries other than the United States, a kit that has been certified or licensed by an oversight 
body within that country.  
8.3.5 CD4 testing 
Individuals identified as being HIV-infected will have CD4 T cell count testing performed unless 
the results are available for a test performed at or within 30 days prior to screening.  This will 
require up to approximately 5 mL of blood.  
  
8.3.6 HIV viral load testing 
Individuals identified as being HIV-infected will have HIV viral load measured unless the results 
are available for a test at or within 30 days prior to screening.  This will require approximately 5 ml 
of blood.  Testing can be by any method used routinely at the study site as a standard of care 
test. 
8.3.7 Pregnancy testing 
Serum or urine testing methods are acceptable.   


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8.3.8 Diabetes screening 
Hemoglobin A1C is the preferred test.  If hemoglobin A1C testing is not available at the study site, 
then either fasting blood glucose (defined as no caloric intake for at least 8 hours) or random 
blood glucose can be measured.  
8.3.9 Pharmacokinetic sampling: Tuberculosis Drugs 
8.3.9.1 
Overview 
In the context of this overall study, two types of pharmacokinetic (PK) sampling will be 
used: ‘sparse’ sampling and ‘intensive’ sampling.  The intensive sampling component will 
be performed among a convenience sample of patients at a few selected sites with 
capacity to perform this activity; the intensive PK component will be described in a 
separate protocol and a separate intensive PK informed consent document will be used.  
Individuals not undergoing intensive PK sampling will have sparse PK sampling, 
regardless of assigned study arm. Sparse PK is described below and is a component of 
the main study protocol.   Blood specimens will be shipped to a designated laboratory in 
the U.S. or Europe, where concentrations of TB drugs and their metabolites will be 
measured. 
8.3.9.2 
Timing of sparse PK sampling during study participation 
The minimum number of study drug doses prior to the sparse PK blood draw is 14 
(including standard DOT and supplementary doses).  The preferable timing of sparse PK 
sampling is at the week 2, 4 or 8 visit (when sputum is also collected).  However, if 
dosing schedule or other factors do not permit sampling at one of these study visits, then 
sampling may be performed any time after 14 study drug doses and no later than the 
week 8 study visit.  
8.3.9.3 
Schedule of sparse PK blood samples 
All blood samples will be collected in reference to directly observed doses of intensive 
phase study drugs -- the reference dose of study drugs is preceded by three directly 
observed study drug doses given approximately 24 hours, 48 hours, and 72 hours prior. 
Two or three blood samples, 10 ml each, will be obtained over a 9 hour period as 
specified in the MOOP.      
8.3.9.4 
Administration of the Reference Dose of Study TB Drugs 
The reference dose of study drugs should be taken by the participant in a manner 
consistent with the way the participant usually takes the study drugs relative to 
consumption of (i.e. eating or fasting) and type of food. The timing of food relative to the 
reference dose of study drugs and a brief description of any food and liquids will be 
recorded.  Participants should abstain from alcohol for 48 hours prior to the reference 
dose of study drugs and until after the last PK blood specimen is collected.  
8.3.10 Pharmacokinetic sampling: Efavirenz 
A secondary objective of TBTC Study 31 will investigate efavirenz pharmacokinetics in HIV-
infected patients randomized to either of the rifapentine containing regimen arms (Investigational 


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Regimen 2 and 3). Participants receiving efavirenz-based ART and assigned to a rifapentine-
containing arm will fall into one of two groups for efavirenz PK evaluation: 1) on efavirenz for 30 
days or more at the time of study enrollment AND documented HIV viral load less than 200 
copies/mL at or within 30 days prior to study entry (Group 1, “EFV1”); or 2) HIV-infected 
participants not on ART at enrollment but started on efavirenz-based ART before or at study week 
8 (Group 2, “EFV2”).   
Participants randomized to the control 2RHZE/4RH arm may initiate efavirenz-based ART at or 
after study entry; initiation of ART within 8 weeks is strongly encouraged in accordance with 
international practice guidelines. Participants randomized to the control 2RHZE/4RH arm will not 
have efavirenz PK evaluations. 
 
Efavirenz plasma concentrations will be evaluated early in the study and in a limited number of 
participants to determine whether or not standard efavirenz dosing (600mg daily) results in 
adequate efavirenz exposure in the presence of daily 1200mg rifapentine treatment.  An initial 
group of 31 evaluable participants from EFV1 will be enrolled.  After the first 31 evaluable 
participants in EFV1 are enrolled, no further Group 1 participants will be permitted to enroll until 
data from these first 31 individuals are evaluated and proved to be clinically acceptable.  EFV2 
participants will not be allowed to enroll into the study until data from 31 evaluable individuals in 
EFV1 have been evaluated and deemed clinically acceptable, that is, there is no compelling 
evidence of lack of adequate exposure to efavirenz in EFV1 patients.   
 
The efavirenz PK data by Group will be judged acceptable if we have evidence that >80% of 
participants have estimated efavirenz mid-dosing interval concentrations ≥1 mg/L.  Any patient 
that has a baseline (pre-TB treatment) efavirenz concentration <1mg/L will be deemed non-
evaluable for the efavirenz pharmacokinetic study.  Methods for estimating efavirenz 
pharmacokinetic parameters are provided in Section 13.5.5.  Blood specimens will be shipped to 
a designated laboratory in the U.S. where concentrations of efavirenz will be measured. 
 
EFV1:  The first evaluation will be made when baseline, weeks 4 and 8 efavirenz concentrations 
are available for 31 evaluable participants; if ≤20 of the 31 have acceptable efavirenz 
concentrations at both Weeks 4 and 8, the team would consider this to be of concern. This rule 
was developed to have a high likelihood (95% or higher) of continuing to accrue participants if the 
true underlying rate of having acceptable efavirenz concentrations is greater than 80%. If accrual 
or shipping patterns warrant, then an interim analysis prior to assessment of 31 participants may 
be performed; in this case, an independent statistician who has not seen any PK data will develop 
the decision rule to protect the original PK study design and participant safety. The second 
evaluation will occur when 90 participants in EFV1 are enrolled. Additional details will be specified 
in the statistical analysis plan, including the role of viral load in initial evaluation. 
 
EFV2:  Once the efavirenz PK data have been evaluated in the first 31 patients from EFV1 and 
deemed clinically acceptable (that is, >20 of the 31 in EFV1 have acceptable efavirenz 
concentrations at both weeks 4 and 8) enrollment will open to patients in EFV2 (HIV-Infected 
participants starting on efavirenz early after initiation of study tuberculosis drugs). PK 
assessments in EFV2 will occur in a similar manner as in EFV1 participants with two phases of 
assessments (N=31 and 90 patients) except that sampling will occur approximately 4 and 8 
weeks following initiation of EFV. In addition, HIV-1 viral load measurements will be conducted 8 
weeks after starting efavirenz and at study week 22. Stopping rules for numbers of patients with 
acceptable efavirenz concentrations in EFV2 will be the same as those for EFV1.  Additional 


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details will be specified in the statistical analysis plan, including the role of viral load in initial 
evaluation.  
 
If stopping rules are met for unacceptable proportions of participants with acceptable efavirenz 
concentrations at any time (after 31 or after 90 patients in either Group), the TBTC 31 team may 
consider appropriate action based on study results, including whether to advise adjusting 
efavirenz dose or to exclude efavirenz use in subsequent study participants.  If dose adjustment 
of efavirenz is recommended the step-wise PK evaluations will continue in a similar fashion as 
with the 600mg dose to again determine if acceptable efavirenz concentrations are maintained 
with the increased dose.  Stopping rules for unacceptable proportions of patients with less than 
1mg/L concentrations of efavirenz will be the same as with the 600mg dose.         
 
8.3.10.1  Efavirenz Sampling Strategy  
8.3.10.1.1. HIV-infected participants on efavirenz at the time of study 
enrollment (EFV1):  Blood (approximately 6 ml) for measuring plasma efavirenz 
concentrations will be obtained at screening or at baseline (prior to initiation of study 
tuberculosis drugs) and additionally at weeks 4, 8 and 17 while on efavirenz.  Blood will be 
drawn approximately 12 hours (no sooner than 10 hours after and no later than 24 hours) 
after the previous dose of efavirenz was ingested. The time of that efavirenz dose and the 
time of blood collection will be recorded.  HIV viral load testing will also be performed at 
weeks 8 and 17; if a follow-up viral load result is greater than 200 copies/mL then, 
approximately 2 to 4 weeks after that test, blood should be drawn and a repeat HIV viral 
load test performed.   
8.3.10.1.2. HIV-infected participants started on efavirenz after initiation of 
study tuberculosis drugs (EFV2):   
Blood (approximately 6 ml) for measuring plasma efavirenz concentrations will be 
obtained at about 4 and 8 weeks following initiation of efavirenz (to coincide with study 
visits to the extent possible – see recommended schedule below), and in addition at the 
study week 22 visit. Blood should be drawn approximately 12 hours (no sooner than 10 
hours after and no later than 24 hours) after the previous dose of efavirenz was ingested. 
The time of that efavirenz dose and the time of blood collection should be recorded. HIV 
viral load testing will be performed at 8 weeks following initiation of efavirenz (to coincide 
with study visits to the extent possible – see recommended schedule below) and at study 
week 22; if the week 22 viral load result is greater than 200 copies/mL then, 
approximately 2 to 4 weeks after that test, blood should be drawn and a repeat HIV viral 
load test performed. 
EFV2.A. If efavirenz is initiated at or within one week after initiation of study TB drugs:  
obtain efavirenz sample at study week 4, study week 8, and study week 22; also obtain 
HIV viral load at study week 8 and study week 22 
 


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EFV2.B. If efavirenz initiated between weeks 1 and 4 of study TB treatment: obtain 
efavirenz sample at study week 8, study week 12, and study week 22; also obtain HIV 
viral load at study week 12 and study week 22 
EFV2.C. If efavirenz initiated between weeks 5 and 8 of study treatment: obtain efavirenz 
sample at study week 12, study week 17, and study week 22; also obtain HIV viral load at 
study week 17 and study week 22     
 
8.3.11 Pharmacogenomic testing: Host Genetic Analysis 
This study will evaluate human gene polymorphisms that may affect pharmacokinetics of 
tuberculosis drugs and antiretroviral drugs.  These include polymorphisms in SLCO1B1 (which 
may affect pharmacokinetics of rifamycins), NAT2 (which affects pharmacokinetics of isoniazid), 
and cytochrome P450 isoenzyme 2B6 (CYP2B6) (which affects pharmacokinetics of efavirenz).   
Data from these genetic assays may be used as covariates or for stratification in analyses of 
study endpoints. Consent will be obtained specifically for genetic testing; participants may opt out 
of genetic testing and still participate in the treatment study.  For consenting participants, blood 
(approximately 8.5 ml) will be collected once after enrollment as specified in the MOOP. Blood 
specimens will be shipped to a designated laboratory in the U.S. for analysis. 
 
8.3.12 Storage of M. tuberculosis bacterial isolates 
The M. tuberculosis bacterial isolates from screening and baseline, as well as isolates cultured 
from specimens obtained at or after week 17 will be stored.  Isolates should be labeled with study 
identification number and collection date, and not with participant name.  Isolates will be shipped 
to the CDC TB reference laboratory upon request.  These isolates will be used for confirmatory 
drug susceptibility testing, for study endpoint assessment and for genetic characterization of M. 
tuberculosis.  
8.3.13 Samples for analyses to identify potential biomarkers of tuberculosis 
treatment response 
At participating sites, sputum, urine, and blood will be collected from consenting participants for 
the purpose of  research to identify potential biomarkers of tuberculosis treatment response.  
Specimens collected for storage will be labeled with study identification number and collection 
date, and will not be labeled with participant name. Specimens will be centrally stored at 
Biomedical Research Institute, Rockville, MD, USA. Consenting patients will be asked to provide 
sputum, blood (approximately 8 ml blood per blood draw), and urine samples at 5 visits (baseline, 
week 2, week 4, week 8, and at end of treatment).  Additionally, samples should also be collected 
if a) failure or relapse is suspected and evaluated at an unscheduled visit or a visit other than one 
of the 5 visits indicated above; and/or b) the participant voluntarily withdraws from the study.  
Participant consent for collection and storage of specimens will be part of the study Informed 
Consent Form which will be administered during the Screening/Consenting visit, with an 
independent signature line.  As an alternative to the sample storage plan described above, 
participants enrolled in this clinical trial will be permitted to co-enroll in The Platform Study 
Biobank Substudy (TBTC Study 36A) at TBTC sites or the Biobank for Surrogate Marker 
Research for TB (A5302) at ACTG sites, which includes additional sample types and additional 
timepoints for collection, requiring a separate biobanking informed consent document.  
 


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8.4 
Specimen preparation, handling and shipping 
Specimen preparation and handling will be performed according to procedures set forth in the MOOP.  
Specimens will be labeled with study identification number and not with participant name.  Shipping will 
be performed by trained personnel according to the Manual of Procedures and in accordance with local 
and international regulations.  
8.5 
Loss to follow-up 
All efforts should be made to contact participants that miss DOT visits or scheduled study visits (unless 
the participant has withdrawn consent).   
For participants who fail to attend a scheduled study visit during study treatment and attempts to reach 
the participant by phone are not successful or not feasible, a home visit will be performed within one week 
of the scheduled study visit. 
For participants who fail to attend a study visit during study follow-up (off study treatment) and attempts to 
reach the participant by phone are not successful or not feasible, a home visit will be performed within 
approximately two weeks of the scheduled study visit.  If a participant misses their final scheduled visit 
then repeated efforts must be made to contact the participant, until six weeks after the Month 18 visit of 
the Last Participant In.  If these attempts are unsuccessful then the participant should be considered lost 
to follow-up and reported as such.  
8.6 
Participants with a positive sputum culture for M. tuberculosis at or after 
week 17  
In the event of a positive culture confirmed as M. tuberculosis from a sputum specimen obtained at or 
after week 17, procedures described in Section 9.8 “Study Procedures for Participants with Possible Poor 
Treatment Response” should be followed.   
TB treatment change (including restarting treatment) is usually not indicated by a single positive culture, 
and is usually not considered unless there is worsening of clinical signs/symptoms and/or chest X-ray 
findings. If the participant remains well clinically (i.e. there is no clinical or radiological evidence of failure 
or relapse), then follow-up off treatment should be considered, while culture results are pending.   
8.7 
Participants with a positive sputum smear at or after week 17 
In the event of a positive sputum smear from a specimen obtained at or after week 17, procedures 
described in Section 9.8 “Study Procedures for Participants with Possible Poor Treatment Response” 
should be followed.   
Sputum smear results alone should not be used for clinical decision-making during the study.   
8.8 
Participants with a possible poor treatment response 
In addition to Sections 8.6 and 8.7, for study purposes a possible poor treatment response evaluation 
also is triggered by any one or more of the following, but not limited to: 


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a) Worsening signs and/or symptoms consistent with TB at or after week 17 
b) Radiographic worsening consistent with TB at or after week 17 
c) The site investigator is considering extension of TB treatment beyond that of the participant’s 
assigned regimen 
d) The site investigator is considering retreatment with any TB therapy after the participant has 
completed assigned study treatment 
e) 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).   
In general, for any participants suspected of possible poor treatment response, procedures described in 
Section 9.8 “Study Procedures for Participants with Possible Poor Treatment Response” should be 
followed.   
8.9 
Management of a participant who is discontinued from study treatment 
For any participant who is discontinued from study treatment, the assessments listed in Section 9.9 “Post 
Early Termination Visit” should be performed.  
8.9.1 Management of a participant who is discontinued from study treatment 
because s/he is determined to be ineligible after enrollment (‘late 
exclusions’) 
These individuals should have study drugs discontinued, and undergo an early termination visit 
approximately 14 days after discontinuation of study drugs. Individuals should be referred to local 
sources of medical care.   
8.9.2 Management of participants who become pregnant during the study 
Women who become pregnant while receiving study therapy will be taken off of study treatment 
and treated according to National Tuberculosis Program or local guidelines.  The women will 
continue to receive scheduled study follow-up, will be classified as being on a non-study regimen, 
and will not receive study radiographs.  The outcome of the pregnancy will be reported on study 
forms.   
Women who become pregnant while in study follow-up (not on study treatment) will continue to 
receive scheduled study follow-up, and will not receive study radiographs.  The outcome of the 
pregnancy will be reported on study forms. 
8.9.3 Management of participants who are discontinued from study treatment in 
the setting of an adverse event or the investigator judges that 
discontinuation of study treatment is in the participant’s best interest 
The site investigator may discontinue a participant from treatment in the event of a severe or 
serious adverse event, or at any time if the investigator thinks discontinuation is in the 
participant’s best interest. For study purposes, such participants should continue to be followed in 


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the study for outcome determination in accordance with the study MOOP, unless the participant 
withdraws consent.   The participant should be referred to appropriate local sources of care for 
management of medical problems that cannot reasonably be managed by the study team.  
8.9.4 Management of a participant who requests premature discontinuation from 
study treatment 
A participant may request premature discontinuation from study treatment.  A post early 
termination visit should be performed and the participant should continue to be followed in the 
study per the study schedule, unless the participant withdraws consent.   The participant should 
be referred to appropriate local sources of care for management of tuberculosis.  
8.9.5 Management of a participant who is incarcerated after enrollment 
This study will not enroll prisoners. However, it is possible that a participant will be incarcerated 
after enrollment. If an enrolled individual is incarcerated, then study medications will be stopped 
and the participant will be treated for active TB according to the standards of the institution in 
which s/he is incarcerated. While incarcerated, individuals will not be followed in the study. When 
the individual is no longer incarcerated, study treatment and/or study follow-up may continue, at 
the discretion of the investigator. 
 
8.10 Premature termination of the study or closure of a study stratum or a study 
site 
The study or a study stratum can be terminated by the sponsor on the advice of the Data and Safety 
Monitoring Board.  The sponsor has the right to close the study and the sponsor has a right to close a 
site, although this should occur only after consultation between involved parties.  In the event of study 
termination or site termination, the central and local ethics committees/institutional review boards must be 
informed.  If the study or a study site is closed before the planned end of the study, all study materials 
(except documents required to be retained and stored on site) must be returned to the sponsor.  The site 
investigator will retain all other documents until notification is given by the sponsor and/or as required by 
the local regulatory authorities.  If the study or a study site is closed prematurely, participants should 
undergo a Post Early Termination Visit unless otherwise directed by the sponsor.  


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9 
STUDY SCHEDULE 
Activities to be conducted at study visits are also shown in Appendix A.   
9.1 
Screening  
The following will be performed after written informed consent: 
• 
Assessment of inclusion and exclusion criteria  
• 
Interview for demographic and contact information 
• 
Medical history 
• 
Height and weight will be measured 
• 
Chest radiograph unless results of a chest radiograph done within the previous fourteen 
(14) days are available.  
• 
An HIV test will be obtained when any one or more of the following apply: a) HIV 
serostatus is unknown; b) the last documented negative HIV test was > 3 months prior to 
screening; c) written documentation of HIV-1 infection at any time prior to study entry is 
not available for confirmation of HIV-infected status.  
• 
For individuals known or suspected to be HIV-infected, CD4 T cell enumeration should be 
performed unless the results are available for a test performed within 30 days prior to 
screening. 
• 
For individuals known to be HIV-infected, an HIV viral load should be performed unless 
results are available for a test performed within 30 days prior to screening.  
• 
Urine or serum pregnancy test for all women who are not surgically sterilized or who do 
not meet the study definition of post-menopausal, unless a negative result is available for 
a pregnancy test performed within seven (7) days prior to screening. 
• 
A sputum sample will be obtained and sent to the study laboratory for mycobacterial 
smear and culture. 
• 
Sputum for rapid molecular test, if available at site  
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
• 
Diabetes screening. 
• 
Blood will be obtained for a complete blood count (including white blood cell differential, 
hemoglobin, and platelet count), and serum or plasma will be tested for alanine 
aminotransferase (ALT), total bilirubin, creatinine, albumin, and potassium, unless results 
from those tests performed within fourteen (14) days prior to screening are available.   
9.2 
Baseline  
The baseline visit is defined as the visit at which study drug treatment is initiated.  A baseline visit will be 
performed for individuals who meet study eligibility criteria and are willing to participate in the study.  The 
baseline visit should be performed as soon as possible and up to 7 days after screening.  If applicable the 
screening and baseline activities may be performed in the same visit, with at least two sputa sent to the 


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study laboratory.  The baseline visit is defined as the visit during which study drug treatment is initiated.  
Participants who no longer meet eligibility criteria will be referred to a local source of tuberculosis care, 
and to other appropriate sources of clinical care as applicable.  A log will be maintained of individuals who 
are screened but not enrolled. 
The following will be performed at baseline: 
• 
Review of interval tuberculosis treatment to assess whether the participant continues to 
meet eligibility criteria 
• 
Review of concomitant medications to assess whether the participant continues to meet 
eligibility criteria 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
Visual acuity and color perception testing  
• 
At least ONE SPUTUM sample will be obtained and sent to the study laboratory for 
smear and culture. 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
• 
For participants consenting to collection of specimens for identification of potential 
biomarkers of TB treatment response: sputum, urine and blood specimens will be 
obtained..  
• 
For HIV-infected participants on efavirenz and rifapentine treatment (EFV1): plasma for 
efavirenz quantification (prior to taking study TB drugs) 
• 
Randomization 
9.3 
Study Visits at Weeks 2, 4, 8, and 12 
Study visits should be performed within a window of +/- three (3) days.  The following will be performed at 
each study visit: 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Blood creatinine, ALT, total bilirubin, and complete blood count (including WBC 
differential and platelets) 
• 
At least ONE SPUTUM obtained for mycobacterial smear and culture 
• 
Measurement of weight 
• 
In addition, at week 4 for all participants: testing of visual acuity and color perception 
should be performed. 


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• 
In addition for EFV1 group HIV-infected participants on efavirenz and a rifapentine 
regimen: plasma for efavirenz PK at weeks 4 and 8, as well as HIV viral load testing at 
week 8. 
• 
For EFV2 group HIV-infected participants, see Schedule in Section 8.3.10.1.2 
• 
At weeks 2, 4, and 8 (not at week 12), for participants consenting to collection of 
specimens for identification of potential biomarkers of TB treatment response: sputum, 
urine and blood specimens will be obtained.  
• 
In addition, any time after completion of 14 study drug doses and no later than the week 
8 study visit for all participants: PK sampling for TB drugs 
• 
In addition, once any time after enrollment for all participants: blood for 
pharmacogenomic testing 
 
9.4 
Week 17 
This visit should be performed within a window of +/- three (3 days).  The following will be performed: 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Blood creatinine, ALT, total bilirubin, and complete blood count (including WBC 
differential and platelets) 
• 
At least TWO SPUTA will be obtained for mycobacterial smear and culture 
• 
Chest radiograph (End-of-Treatment) for participants assigned to rifapentine regimens 
(Regimens 2 or 3) 
• 
Measurement of weight 
• 
In addition for EFV1 group HIV-infected participants on efavirenz and a rifapentine 
regimen: plasma for efavirenz PK; HIV viral load testing. 
• 
For EFV2 group HIV-infected participants, see Schedule in Section 8.3.10.1.2 
• 
For participants consenting to collection of specimens for identification of potential 
biomarkers of TB treatment response who in addition have been assigned to one of the 
17-week treatment arms: sputum, urine and blood specimens will be obtained.  
• 
For all participants (if not already done): blood for pharmacogenomics testing 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
 


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9.5 
Week 22 
This visit should be performed within a window of +/- three (3) days.  The following will be performed: 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
At least TWO SPUTA obtained for mycobacterial smear and culture 
• 
Measurement of weight 
• 
Blood creatinine, ALT, total bilirubin, and complete blood count including WBC differential 
and platelets 
• 
In addition, for all participants (if not already done): blood for pharmacogenomics testing 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
• 
For EFV2 group HIV-infected participants on efavirenz: plasma for efavirenz PK; HIV viral 
load testing 
 
9.6 
Week 26 
This visit should be performed within a window of +/- seven (7) days.  The following will be performed: 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
At least TWO SPUTA obtained for mycobacterial smear and culture 
• 
Chest radiograph (End-of-Treatment) for participants assigned to rifampin regimen 
(Regimen 1) 
• 
Measurement of weight 
• 
For participants consenting to collection of specimens for identification of potential 
biomarkers of TB treatment response who in addition have been assigned to the 26-week 
treatment arm: sputum, urine and blood specimens will be obtained.  
• 
In addition, for all participants (if not already done): blood for pharmacogenomics testing 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
 


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9.7 
Study Visits at Months 9, 12, 15, and 18 
Study visits should be performed at months 9, 12, 15, and 18.  Visits should be performed within a 
window of +/- seven (7) days.  The following will be performed at each study visit: 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Review of interval medical history 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
At least TWO SPUTA obtained for mycobacterial smear and culture.  For participants 
whose Month 18 sputa are both contaminated, at least two additional sputa should be 
obtained. 
• 
In addition, for all participants (if not already done): blood for pharmacogenomics testing 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
 
9.8 
Study Procedures for Participants with Possible Poor Treatment Response 
The following should be performed as soon as feasible when a possible poor treatment response is 
suspected, and ideally prior to a change or re-start of treatment (if change or re-start is considered to be 
warranted by the site investigator) if the participant’s clinical condition permits: 
• 
Contact the central study clinician, ideally prior to changing or re-starting TB treatment 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Review of interval medical history 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
At least THREE (3) SPUTA should be collected within one week of each other. At least TWO of 
these sputa should be collected prior to changing or re-starting TB treatment, and at least 4 hours 
apart. At least ONE sputum should be a first morning specimen, if feasible. These sputa should 
be sent to the study laboratory for smear and culture.  If M. tuberculosis is isolated in culture, drug 
susceptibility testing should be performed on one of the isolates. Then the isolate from each 
positive culture should be stored frozen. 
• 
Chest radiographComplete the Possible Poor Treatment Response case report form  


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• 
For participants consenting to collection of specimens for identification of potential biomarkers of 
TB treatment response: sputum, urine and blood specimens should be obtained. 
Treatment of participants in whom TB treatment is changed or re-initiated should be according to local 
guidelines. For study purposes, such participants should continue to be followed in the study for outcome 
determination in accordance with the study MOOP, unless the participant withdraws consent. 
 
9.9 
Post Early Termination Visit (Visit after Early Termination) for Participants 
Terminating before Completion of their Assigned Study Treatment 
The early termination visit should occur approximately 14 days after stopping study drugs, in order to 
assess for late manifesting adverse events.   The following should be performed: 
• 
Review of contact information 
• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Blood creatinine, ALT, total bilirubin, and complete blood count (including WBC 
differential and platelets) 
• 
Measurement of weight 
The intent is that the procedures for participants with possible poor treatment response occur before 
stopping study drugs, and that this post early termination visit occurs approximately 14 days after 
stopping study drugs. Participants experiencing an adverse event at the time of early termination should 
be followed until resolution or stabilization of the event (see Section 12).  Participants who were receiving 
study treatment at the time of early termination will be referred to local sources for tuberculosis care.  For 
study purposes, such participants should continue to be followed in the study for outcome determination 
in accordance with the study MOOP, unless the participant withdraws consent. 
A participant who withdraws consent will not have to undergo follow-up study procedures. 
9.10 Early Termination Visit for Participants Stopping Study Participation after 
Completion of their Assigned Study Treatment 
Study Procedures for Participants with Possible Poor Treatment Response (Section 9.8) should be 
followed.  In addition, the participant should be asked if they would be willing to have Month 12 and Month 
18 study procedures performed. 
Participants experiencing an adverse event at the time of early termination should be followed until 
resolution or stabilization of the event (see Section 12).  
A participant who withdraws consent will not have to undergo follow-up study procedures. 


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9.11 Missed Visit 
A visit is reported as missed if it does not occur within the time frame specified for that visit on the event 
schedule in Appendix A. Protocol-indicated sputum collection still should be performed within the 
scheduled visit window, if possible, even if the visit is reported as missed.  
9.12 Unscheduled Visit 
An unscheduled visit refers to a protocol-required study evaluation that did not occur within the allotted 
window around the visit date specified on the participant’s visit schedule. During an unscheduled visit, all 
procedures described in the protocol for the particular missed visit should be completed.  Study visits that 
occur solely because of an adverse event or a possible poor treatment response are not considered 
unscheduled visits.  


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10 
STUDY INTERVENTION/INVESTIGATIONAL DRUGS 
10.1 Study Drugs 
The study drugs are rifampin, rifapentine, pyrazinamide, ethambutol, isoniazid, moxifloxacin, and 
pyridoxine (vitamin B6).  Each of the study products is described in section 3.  
The study products will be combined into the following study treatment regimens: 
 
Regimen 1 (control regimen): 2RHZE/4RH 
• Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed 
by  
• Eighteen weeks of daily treatment with rifampin and isoniazid 
 
 
Regimen 2 (investigational regimen): 2PHZE/2PH 
• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, 
followed by  
• Nine weeks of daily treatment with rifapentine and isoniazid  
 
 
 
Regimen 3 (investigational regimen): 2PHZM/2PHM 
• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, 
followed by  
• Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin  
Rifampin, isoniazid, pyrazinamide, and ethambutol are the current first-line anti-tuberculosis drugs used 
worldwide for treatment of drug-susceptible tuberculosis.  Pyridoxine (vitamin B6) decreases the risk of 
isoniazid-related peripheral neurotoxicity and is commonly co-administered with isoniazid during 
tuberculosis therapy.  Each of these agents will be used at conventional doses and dosage schedules 
during this clinical trial.   
Rifapentine, a rifamycin antibiotic, is approved in the United States by the Food and Drug Administration 
for the treatment of pulmonary tuberculosis; the approved dose is 600 mg twice weekly for two months 
followed by 600 mg once weekly for four months, in combination with other anti-tuberculosis drugs.  As 
detailed above, pre-clinical and clinical studies indicate that maximal anti-tuberculosis activity is achieved 
at rifapentine doses higher than 600 mg and intervals shorter than twice weekly.  During this clinical trial 
rifapentine will be administered at a dose of 1200 mg, once daily for 17 weeks in Regimens 2 and 3.   
Moxifloxacin is a broad-spectrum fluoroquinolone antibiotic active against M. tuberculosis.  It is used 
worldwide for treatment of drug-resistant tuberculosis.  During this clinical trial moxifloxacin will be 
administered at the conventional adult dose of 400 mg once daily, and it will be administered for 
seventeen weeks in Regimen 3.    


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10.2 Study Drug Acquisition 
All study drugs, except for vitamin B6 for the full duration of study therapy will be provided by Sanofi.  
Vitamin B6 supplies will be obtained locally.  Study drugs will be distributed in bulk to study site 
pharmacies, which will dispense indicated supplies for individual participants according to individual 
pharmacy plans that will be approved by the sponsor or the sponsor’s designee. Treatment of participants 
who discontinue study treatment will be with locally supplied drugs. 
10.3 Study Drug Storage and Stability 
Study drugs will be stored in accordance with the written MOOP, and may not be used after their 
expiration date.    
10.4 Administration and Dosage of Study Drugs 
All drugs will be administered orally, seven days per week, throughout treatment.  Five of seven doses 
per week will be given as DOT by study personnel, or by a healthcare worker or lay treatment supervisor 
who is aware of the study protocol and trained regarding the study protocol.  Doses on weekends and on 
holidays up to three consecutive days may be either DOT or self-administered. Participants receiving a 
rifapentine-containing investigational regimen should take study drugs within one hour after ingesting 
food.  Participants receiving a rifampin-containing investigational regimen should take study drugs on an 
empty stomach; for participants on rifampin who have difficulty tolerating study drugs on an empty 
stomach, then administration with food is reasonable. Information about ingestion of food will be recorded 
for every study drug dose. 
Doses of study medications will be determined by body weight, as follows: 
Drug 
Dose 
Isoniazid 
300 mg 
Vitamin B6 
25 or 50 mg 
 
 
Pyrazinamide 
 
     < 55 kg 
1000 mg 
     ≥ 55-75 kg 
1500 mg 
     > 75 kg 
2000 mg 
 
 
Ethambutol 
 
     < 55 kg 
800 mg 
     ≥ 55-75 kg 
1200 mg 
     > 75 kg 
1600 mg 
 
 
Rifampin 
600 mg 
 
 
Rifapentine 
1200 mg 
 
 
Moxifloxacin 
400 mg 
Drugs and doses used to initiate treatment will be assigned by the enrollment application, based on 
weight reported at enrollment.  


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10.5 Dose Modifications for a Participant 
10.5.1 Dose Modifications for a Change in Participant’s Weight 
Study drug doses for pyrazinamide and ethambutol should be adjusted for the participant’s weight 
that was recorded at the most recent scheduled study visit.  
10.5.2 Drug Re-challenges 
In a participant experiencing side effects, whether to initiate a drug re-challenge as well as the 
drugs, dosages, and schedule for a drug re-challenge are at the discretion of the treating 
clinician.  General recommendations for consideration are provided within the MOOP.   
10.6 Criteria for Discontinuation of Study Drugs 
Participants who meet any one or more of the following criteria will be discontinued from study treatment: 
• 
Pregnancy 
• 
Any clinical adverse event, laboratory abnormality, intercurrent illness, other medical condition or 
situation occurs such that continued administration of study treatment is not in the best interest of 
the participant 
• 
Participant request for premature discontinuation of study treatment 
• 
Participants classified as ‘late exclusions’ 
Procedures for study follow-up are described in Section 9.  The decision to discontinue a participant from 
treatment should be discussed with the central study clinician or his/her designee.  
10.7 Accountability Procedures for the Study Drugs 
Study drugs will be shipped periodically to the study sites.  The investigator or designee will acknowledge 
receipt of and keep an inventory of study drugs.  Unused product should be stored at the site until 
directed by the study sponsor.  
10.8 Assessment of Subject Compliance with Study Treatment 
Each dose of study drugs given by DOT will be recorded by the healthcare worker.  Participants will be 
asked to record doses of study drugs not administered by DOT.  Adherence will be reviewed at each 
study visit.  Non-adherence should prompt an investigation into the cause of non-adherence and 
measures to address the non-adherence.  


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11 
ASSESSMENT OF EFFICACY 
11.1 Summary of Bacteriological Methods 
Detailed laboratory procedures for laboratory staff performing mycobacteriological tests are in the MOOP.  
The following brief description is intended to provide guidance to clinical study staff.   
All study sputa (expectorated or induced) should be sent to the designated study site laboratory.  Any 
anticipated changes in the designated site laboratory (i.e. to a different laboratory) and/or a change in the 
type of solid or liquid media used must be communicated in writing to the TBTC Project Officer prior to 
executing the change(s). 
The following will be performed for all study sputa:  Nalc-NaOH decontamination followed by culture using 
both solid medium and the Becton Dickinson Mycobacterial Growth Indicator Tube (MGIT) liquid culture 
automated system.  Bacterial load will be determined and recorded for all specimens using the time to 
positivity output automatically provided by the MGIT system. 
For all cultures showing growth of acid-fast bacilli, the acid fast bacilli will be species identified at least to 
the level of M. tuberculosis complex vs. not M. tuberculosis complex.   
For each participant, the first study isolate of M. tuberculosis will have culture-based phenotypic drug 
susceptibility testing performed at the study site-designated laboratory for isoniazid, rifampin, and 
fluoroquinolones.  In addition, phenotypic drug susceptibility testing should be performed for the first of 
any M. tuberculosis isolates obtained at/after the Week 17 study visit.  
For each participant, the first study isolate of M. tuberculosis as well as any M. tuberculosis isolates 
cultured from sputum obtained at/after the Week 17 study visit should be stored frozen.  The first study 
isolate of M. tuberculosis should be sent to the CDC laboratory.  Additional M. tuberculosis isolates 
pertinent to the participant’s treatment assignment should be sent to the CDC laboratory if requested by 
the CDC Data Center. 
  
 
 


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12 
ASSESSMENT OF SAFETY 
12.1 Specification of Safety Parameters 
12.1.1 Primary Outcome Measure 
Proportion of participants with grade 3 or higher adverse events during study drug treatment 
12.1.2 Secondary Outcome Measure 
Discontinuation of assigned treatment for a reason other than microbiological ineligibility 
12.2 Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
12.2.1 Adverse Events and Serious Adverse Events 
At each study visit up to and including Week 26, participants will be asked about adverse events 
that have occurred since their previous visit.  Solicited events will include symptoms, 
hospitalizations, and new medical diagnoses.  Participants will also be asked to describe other 
signs, symptoms, and events not captured by the solicited event listing.   
Monitoring of laboratory parameters will be performed as described in Section 9 and Appendix A.   
12.2.1.1 Definition of Adverse Event  
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product.  An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product.   
Any adverse events detected will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) toxicity tables and coded using MedDRA.   
12.2.1.2 Serious Adverse Event  
A Serious Adverse Event (SAE) is any adverse event that results in any of the following 
outcomes: 
• 
Death 
• 
Life-threatening (subject at immediate risk of death) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in congenital anomaly/birth defect 
• 
Results in a persistent or significant disability or incapacity 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 


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12.3 Recording and Reporting Procedures 
12.3.1 Overview 
A sign or symptom should be reported as an adverse event if it meets either (or both) of the 
following criteria: a) reaches severity of grade 3 or higher; b) represents a new diagnosis.  
Laboratory findings should be recorded as adverse events only if clinically significant.   
12.3.2 Reporting Procedures 
Any SAE or grade 4 toxicity must be reported by the site to the TBTC on an Adverse Event 
Report within 48 hours of the site’s awareness of the event. 
SAEs, death, or life-threatening problems that may reasonably be regarded as caused by or 
associated with the administration of the study drug regimen (defined as at least ‘possibly 
associated’ with the study drug regimen) must be reported by the site to the Sponsor (TBTC) and 
the local IRB within 48 hours of the site’s awareness of the event. For participants who die, as 
much information as possible on cause of death and details of the final illness will be obtained 
from relevant sources.   
Any adverse event that meets the definition of being a suspected unexpected serious adverse 
reaction (SUSAR) will be reported promptly by the Sponsor (TBTC) to the FDA, international 
regulatory agencies, the CDC IRB, and all clinical investigators.   A SUSAR is defined as an 
adverse reaction that is unexpected (i.e. not consistent with the applicable product information) 
AND also meets the definition of a serious adverse event AND also may reasonably be regarded 
as caused by or associated with the administration of the study drug regimen (i.e. at least 
‘possibly associated’ with the study drug regimen). 
The DAIDS Medical Officer will receive a copy of the IND safety reports that TBTC submits to the 
FDA. 
12.3.3 Pregnancy 
For study purposes, pregnancy must be recorded on an Adverse Event Report form.  
Management of women who become pregnant during the study is described in Section 8. 
12.4 Management of adverse events 
For AEs that in the investigator’s judgment may be due to study drugs, the following general 
approach to management should be applied.  In general, for grade 1 toxicities, the patient will be 
followed carefully and the study drugs will be continued.  For grade 2 toxicities, the patient will be 
followed more carefully, with additional laboratory and/or clinic visits as necessary, and the study 
drugs may be temporarily held if in the investigator’s judgment continuation of study drugs would 
be unsafe.  
 
Grade 3 and 4 AEs should be carefully assessed.  The site clinician should consider other 
possible causes for toxicity before discontinuing study medicines.  When possible, concomitant 
medicines should be withheld first at the discretion of the site clinician if it is suspected that 
concomitant medicines are contributing to the toxicity.  If after careful assessment and in the site 
investigator’s judgment the event is at least possibly attributable to study drug(s), then the 


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suspected causative study drug(s) may be withheld; the participant should be permanently 
discontinued from study drugs if it is in their best interest.   
 
For all toxicities that are treatment-emergent and that require the study therapy to be temporarily 
or permanently discontinued, relevant clinical and laboratory tests will be obtained as clinically 
indicated and repeated as needed until final resolution or stabilization of the toxicity.  Any 
participant for whom study drugs are temporarily held will be resumed on study medication as 
soon as possible.   
12.4.1 Type and Duration of the Follow-up of Subjects after Adverse Events 
Participants who experience adverse events that necessitate temporary or permanent 
discontinuation of study drugs will still be considered to be part of the study and will continue to 
be followed in the study in accordance with the study MOOP.  If study drugs are permanently 
discontinued, further anti-tuberculosis therapy may be administered at the clinic staff’s discretion 
according to local or National Tuberculosis Program guidelines.   
12.5 Data and Safety Monitoring Board 
The TBTC Data and Safety Monitoring Board (DSMB) will review the study protocol and oversee progress 
of the trial.  The TBTC DSMB is comprised of a clinical TB expert, an epidemiologist with extensive 
experience with TB and HIV, and an internationally recognized clinical trialist/statistician, all of whom are 
not otherwise involved in the study. The DSMB will convene approximately annually, or more often as 
needed. 
12.6 Interim Monitoring and Analyses by the Data and Safety Monitoring Board 
The DSMB will have access to data and interim results and may recommend early closure of any 
experimental arm or the trial if, in their judgment, interim evidence is sufficiently strong that one of the trial 
interventions is clearly indicated or clearly contraindicated because of a net difference in efficacy, safety, 
or tolerability as defined by the corresponding primary endpoints for the trial, with a difference between 
arms that is statistically significant at the 0.1% level, according to the Haybittle-Peto statistical criterion for 
monitoring interim efficacy data. The analysis sequence described in section 13.5 will be followed for 
interim analysis. It is possible that arm 3 could be inferior to arm 1 (e.g., due to less adherence, drug 
interactions), but arm 2 not inferior to arm 1. If this is occurs, the study team will discuss implications with 
the DSMB.   
 


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13 
STATISTICAL CONSIDERATIONS 
13.1 Study Hypotheses 
This study has two main hypotheses and consists of two comparisons: 
A) In previously untreated individuals with drug-susceptible pulmonary tuberculosis treated with eight 
weeks of rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by nine weeks of 
rifapentine, isoniazid, and moxifloxacin (2PHZM/2PHM), all given daily throughout, the proportion 
of participants who experience absence of cure (unfavorable outcome) will not be inferior to that 
observed in participants who are treated with the standard regimen (eight weeks of rifampin, 
isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid) all 
given daily throughout. 
B) In previously untreated individuals with drug-susceptible pulmonary tuberculosis treated with eight 
weeks of rifapentine, isoniazid, pyrazinamide, and ethambutol followed by nine weeks of 
rifapentine plus isoniazid (2PHZE/2PH), all given daily throughout, the proportion of participants 
who experience absence of cure (unfavorable outcome) will not be inferior to that observed in 
participants who are treated with the standard regimen (eight weeks of rifampin, isoniazid, 
pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given 
daily throughout. 
13.2 Study Outcome Measures 
 
Primary Efficacy Endpoint: 
• 
TB disease-free survival at twelve months after study treatment assignment 
Primary Safety Endpoint: 
• 
Proportion of participants with grade 3 or higher adverse events during study drug treatment 
 
Secondary Efficacy Endpoints: 
• 
TB disease-free survival at eighteen months after study treatment assignment 
• 
Proportion of participants who are culture negative at eight weeks (solid and liquid media considered 
separately) 
• 
Time to stable sputum culture conversion (solid and liquid media considered separately) 
• 
Speed of decline of sputum viable bacilli by automated MGIT days to detection 
• 
Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have an 
unfavorable outcome 
• 
Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have a favorable 
outcome 
• 
Discontinuation of assigned treatment for a reason other than microbiological ineligibility 
• 
Estimated steady state efavirenz PK parameters including mid-dosing interval concentration 


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13.3 Definition of primary outcome status 
The primary analysis will be conducted using culture results from solid media and liquid media. 
Each participant will be classified into one of the following 3 outcome categories of Absence of 
Cure (Unfavorable Outcome), Cure (Favorable Outcome), or Not Assessable.  An independent 
Endpoint Committee will be formed and be responsible for determining final outcome status. The 
primary efficacy endpoint will be assessed at 12 months after treatment assignment; a secondary 
efficacy endpoint will consider the follow-up period to be 18 months after treatment assignment. 
Absence of Cure (Unfavorable Outcome) meeting any one or more of the following: 
• 
Absence of bacteriological cure.  A participant will be considered to have absence of 
bacteriological cure if he/she has a sputum sample, obtained at or after Week 17, that is 
culture positive for an M. tuberculosis strain that is indistinguishable from the initial isolate, 
and this is confirmed by a second sample that is culture positive for M. tuberculosis. A 
second confirmatory sample is required as a single positive sputum culture in isolation will not 
be considered absence of bacteriological cure.   
• 
Participants who die from any cause during study treatment, except from violent or accidental 
cause (e.g. road traffic accident). 
• 
Participants failing to complete treatment and not assessable at the end of the follow-up 
period. 
• 
Participants who had a positive culture for M. tuberculosis when last seen, whether confirmed 
by a second sample or not, unless determined to have been re-infected 
• 
Participants receiving any one or more of the following: a) extension of treatment beyond that 
permitted by the protocol; b) a re-start of treatment; c) a change in treatment for any reason 
except re-infection, pregnancy, or temporary drug challenge 
Cure (Favorable Outcome) meeting any one of the following and not already classified as having 
an unfavorable outcome 
• 
Participants with negative cultures at the end of the follow-up period  
• 
Participants who at the end of the follow-up period are clinically without symptoms/signs of 
ongoing active TB and are unable to produce a sputum specimen 
• 
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 without evidence of 
M. tuberculosis 
Not Assessable (meeting any one or more of the following and not already classified as having an 
unfavorable outcome) 
• 
Participants who completed assigned treatment and then default from follow-up, with their 
last culture being negative for M. tuberculosis 


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• 
Women who become pregnant during their assigned active treatment and stop their assigned 
treatment  
• 
Participants who die during the follow-up phase (≥ 15 days after completion of study 
treatment) 
• 
Participants who die from a violent (e.g. homicide) or accidental (e.g. road traffic) cause 
during their assigned active treatment.  As above, suicide will be considered an unfavorable 
outcome  
• 
Participants re-infected with a new strain of M. tuberculosis, demonstrated to be different 
from that identified at study entry through genotyping methods 
13.4 Analysis Groups 
There will be 4 analysis groups, as follows: 
Intention-to-Treat (ITT) 
Includes all enrolled participants who receive a treatment assignment. 
Microbiologically Eligible 
Includes the subset of Intention-to-Treat participants who, in addition, have culture confirmation of 
drug-susceptible tuberculosis at study entry. Participants classified as ‘not assessable’ will be 
considered to have an unfavorable outcome.   
Assessable 
Includes the subset of Microbiologically Eligible participants who, in addition, are not classified as 
‘not assessable’.   
Adherent Per-Protocol 
Includes the subset of Assessable participants who, in addition, complete assigned study 
treatment and follow-up.   
13.5 Analysis Plan 
13.5.1 Co-Primary efficacy analyses 
There will be two co-primary efficacy analyses.  One will consider the Microbiologically Eligible 
analysis population, and the other will consider the Assessable population. The assessable group 
is defined by exclusions that do not introduce selection bias. For each, the comparison of 
Regimen 1 (control regimen) versus Regimen 3 (2PHZM/2PHM) will be considered first, and, if 
non-inferiority criteria are met then the comparison of Regimen 1 versus Regimen 2 
(2PHZE/2PH) will be considered.   In each comparison, non-inferiority will be assessed by 
comparing the upper bound of a 95%, 2-sided confidence interval for the difference between the 
proportion of participants who are classified as having an unfavorable outcome on the control 
regimen (Regimen 1) and the intervention regimen to the predefined non-inferiority margin of 
6.6%.  


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13.5.2 Primary safety analysis 
There will be two comparisons: for comparison 1, Regimen 1 (control regimen) will be compared 
against Regimen 2 (2PHZE/2PH); for comparison 2, Regimen 1 (control regimen) will be 
compared against Regimen 3 (2PHZM/2PHM).  The primary safety endpoint is proportion of 
participants with grade 3 or higher adverse events.  The primary safety analysis will include the 
Intention-to-Treat group. 
13.5.3 Secondary efficacy analyses 
In secondary efficacy analyses, the primary efficacy endpoint will be assessed in the Adherent 
Per-Protocol analysis population, and secondary efficacy endpoints will be assessed for the 
Microbiologically Eligible, the Assessable, and the Adherent Per-Protocol analysis populations.  
Regimen 1 (control regimen) will be compared against Regimen 2 (2PHZE/2PH), and Regimen 1 
will also be compared against Regimen 3 (2PHZM/2PHM). Secondary analyses will include those 
directed towards identification of clinical, microbiological, and/or radiological factors associated 
with favorable and unfavorable outcomes. 
13.5.4 Secondary safety analyses 
Tolerability will be assessed as discontinuation of the assigned treatment for a reason other than 
microbiological ineligibility.  Regimen 1 (control regimen) will be compared against Regimen 2 
(2PHZE/2PH) and Regimen 1 will also be compared against Regimen 3 (2PHZM/2PHM).  This 
analysis will include the Intention-to-Treat group. 
13.5.5 Secondary Efavirenz PK analysis 
Efavirenz pharmacokinetics will be evaluated in the first 31 and then a total of 90 patients from 
each of two groups of participants randomized to treatment regimen 2 or 3 of the study and 
receiving efavirenz based ART. Participants receiving efavirenz will fall into one of two groups for 
the PK evaluation: 1) HIV-infected participants on efavirenz with virologic suppression at the time 
of study enrollment (EFV1), or 2) HIV-infected participants started on efavirenz after initiation but 
before or at week 8 of study tuberculosis drugs (EFV2).  Individual-level measurements of 
efavirenz mid-dosing interval concentrations and estimates of efavirenz apparent oral clearance 
using a model-based post-hoc Bayesian approach will be performed. The efavirenz PK data will 
be judged acceptable if we have evidence that >80% of participants have estimated efavirenz 
mid-dosing interval concentrations ≥1 mg/L. 
 
13.6 Sample Size Considerations 
The primary objective of the trial is to evaluate whether rifapentine containing regimens can produce 
outcomes at least as favorable as standard therapy, but with a shorter treatment course.  Therefore, the 
trial is structured as a non-inferiority study.   
Key assumptions: 
• 
Primary endpoint rate: 15% absence of cure (unfavorable) in the standard regimen arm 
(Microbiologically Eligible population).   This rate is based on observed results for the control arm 
(MITT analysis group) in two recently completed phase 3 clinical trials (27/161 [14%] in the 


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Rifaquin trial [Jindani et al., 2013] and 100/743 [13.5%] at 18 months post randomization and 
114/679 [16.8%] at 24 months after the end of treatment in the Oflotub trial [Merle et al., 2013].)    
• 
Margin to define inferiority: 6.6% (δ = 0.066) 
• 
95% confidence (type 1 error, α = 0.05). The sequential testing of regimen 3 and regimen 2 
protects the type 1 error rate, as follows: If the statistical test for regimen 3 fails at 95% 
confidence, then conclude that both experimental regimens are not noninferior. If and only if 
regimen 3 is noninferior, then proceed to test regimen 2 at 95% confidence. A type 1 error occurs 
if either regimen is incorrectly deemed noninferior; the sequential approach limits the probability 
of this error to 5% overall. 
• 
Power: 80% (type 2 error, β = 0.20) for primary analysis among Microbiologically Eligible 
subgroup, with power recalculated for the restriction to Assessable subgroup (see below) 
• 
Proportion of enrolled patients who would be found to be late exclusions due to microbiological 
ineligibility – 12% (based on observed results in recent TBTC phase 2 studies) 
• 
Proportion of enrolled patients who would be found to be ‘not assessable’: 12% (based on 
observed results in the Rifaquin trial [Jindani et al., 2013]) 
With 816 per arm, we expect 612 assessable. With the expected 15% unfavorable outcomes among 
those who are assessable, then with the same noninferiority margin and type 1 error rate, we have 90% 
power to test the primary hypotheses among the Assessable subgroup. The 6.6% margin to define 
inferiority (6.6%) takes into consideration the following issues: (1) the rates in historical trials of inpatient 
TB treatment for 6-month and 4-month regimens conducted by the British Medical Research Council 
support a difference in relapse up to 6% (East African/British Medical Research Council 1976, 1977, 
1981; East and Central Africa/British Medical Research Council 1986; Singapore Tuberculosis 
Service/British Medical Research Council 1986; Nunn and Crook 2013); (2) recent trials in contemporary 
outpatient populations suggest a higher baseline proportion (15%) of unfavorable outcomes likely to be 
observed based on phase 3 trials and definitions; (3) the investigators in this trial and others perceive that 
the benefits of reducing treatment duration to 3 or 4 months would have advantages not outweighed by a 
possible increase in the relapse rate of up to 6%; and (4) the 6.6% margin does not imply that the 
experimental regimen may result in as much as 6.6% more unfavorable outcomes, but rather, for a fixed 
design, the maximum difference consistent with a non-inferior conclusion decreases as the proportion of 
unfavorable outcomes in the control arm increases. 


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14 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study staff will be trained in Good Clinical Practice and in performance of study procedures.  The sponsor 
or the sponsor’s delegate will conduct a meeting with each site prior to the trial opening at the site in order 
to ensure that everything is in place for the trial to start, the study file contains all the essential 
documents, and study staff understand procedures and their roles and responsibilities.  The study will be 
conducted in accordance with the protocol and study-specific procedures manuals.   
14.1 Local quality control 
Each site will have a written plan for local quality control including data quality management.  
14.2 External monitoring 
External monitoring will be conducted to ensure the safety and conduct of this study, which involves 
patients with a serious illness (i.e. tuberculosis), uses an investigational drug treatment, will take place in 
multiple international sites, and may be used to modify the license for rifapentine and moxifloxacin.   
External monitoring will be conducted periodically by a contract research organization (CRO).  Direct 
access to data at each site will be required for the purposes of monitoring and audit, and this will be made 
explicit in the consent form.  Local investigators and their institutions will provide direct access to source 
documents and data for trial-related monitoring, audit, and regulatory inspections, in the clinic, the 
pharmacy, and the mycobacteriology laboratory.  
External monitoring will be conducted according to a written manual of procedures.  Monitoring will focus 
on ensuring that the following study activities are conducted per the protocol and associated documents: 
consent procedures, enrollment, dispensing of trial medications, correct implementation of treatment and 
follow-up procedures, accurate recording and reporting of adverse events and appropriate reporting of 
adverse events, correct implementation and reporting of mycobacteriology laboratory testing, accurate 
completion of case report forms, and timely and accurate data entry.  Additional activities or study 
elements may be monitored as needed.   
 


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15 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
This study will be conducted in conformity with the ethical standards set out in the latest version of the 
Declaration of Helsinki.   
15.1 Institutional Review Board 
Each participating institution will provide for the review and approval of this protocol and the associated 
informed consent documents by an appropriate institutional ethics committee (IEC) or Institutional Review 
Board (IRB).  Any amendments to the protocol or consent materials must also be approved before they 
are placed into use. 
15.2 Informed Consent Process 
Adults:  Only individuals who provide written informed consent will be enrolled in this study.  Written 
informed consent is required before any study-specific procedures are performed.  Potential participants 
will have the conditions of the study explained to them, including potential harms and benefits, the nature 
and timing of study procedures, alternatives to study participation, that study participation is voluntary, 
that a decision to not participate in the study will not affect the quality of their future medical care, and that 
they may withdraw from participation at any time.  The information in the Informed Consent document will 
be translated into relevant local languages.  Literate individuals will be provided with a language-
appropriate document to read; illiterate individuals (i.e. individuals who speak and understand, but do not 
read and write, the language in which the consent discussion is conducted) will have the contents of the 
document explained to them by a trained study staff member; such individuals can be enrolled by ‘making 
their mark’ on the consent document.  Potential participants will have the opportunity to ask questions of 
the site investigator or delegate, and to discuss participation with their family and/or friends or think about 
the study prior to deciding whether or not to participate.  A copy of the signed informed consent document 
will be given to the participant for his/her records.   
Children:  For potential participants under 18 years of age, the assent of the child as well as the written 
informed consent of the child’s legal guardian will be required for enrollment in this study.  The child will 
receive, in language appropriate to the age and maturity of the child, an explanation of the research 
procedures; a description of the risks, discomforts, or inconveniences that the child might experience; and 
assurance that the child can withdraw from the study at any time.  The assent process will be conducted 
by a study staff member who is experienced in consent and assent procedures, and in accordance with 
IRB/IEC requirements.  All study participants age < 18 years will provide oral or written assent and written 
consent by the participant’s legal guardian, in accordance with national and/or local IRB/IEC 
requirements. 
15.3 Subject Confidentiality 
All records identifying the participant will be kept confidential and, to the extent permitted by the 
applicable laws and regulations, will not be made publicly available without sufficient de-identification 
procedures.   
Participant names will not be supplied to the sponsor.  All study documents and forms will be identified by 
a code only.  All paper study records will be stored in a locked office and electronic study records will be 
stored on password-protected computers; only designated trained study staff will have access to study 


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records.  Transmission of electronic records to the sponsor will occur through a web-based data entry 
application that conforms to the Federal Information Security Management Act, or using a secure CDC 
File Transfer Protocol (FTP).   
The study monitors, other authorized representatives of the sponsor, and regulatory authorities may 
inspect all documents and records required to be maintained by the Investigator, including but not limited 
to, medical records, primary laboratory data, and pharmacy records for study participants; this information 
will be provided to participants during the Informed Consent process.  The clinical study site will permit 
access to such records. 
15.4 Study Discontinuation 
The Data and Safety Monitoring Board may recommend study termination or the termination of a study 
arm.  In addition, after consultation with involved parties, the Sponsor has the right to close the study and 
the right to close a study site.  If the study is closed, all involved ethics committees should be notified.  If a 
site is closed, then the local IEC/IRB and the CDC IRB should be notified.  In the event that the study is 
discontinued or a study site is closed, participants will undergo an early termination study visit.  
Participants experiencing an adverse event at the time of early termination should be followed until 
resolution or stabilization of the event.  Participants who were receiving study treatment at the time of 
early termination will be referred to local sources for tuberculosis care.   


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16 
DATA HANDLING AND RECORD KEEPING 
ICH-GCP requirements for data documentation will be followed.   
Data handling and record keeping will be performed in accordance with a study MOOP.  Briefly, 
information from source documents will be recorded on study-specific case report forms, which will be 
entered into the study electronic information system.  The study electronic information system will be 
programmed to maintain an audit trail, perform consistency checks, and generate reports of 
missing/inconsistent data. After study completion, de-identified data that can be legally released to the 
public may be released through a public-use data set after the data are evaluated for quality and 
confidentiality and shared with any partners, per CDC’s policy on data sharing. 
The study file and source documents should be retained until the sponsor gives notification.   
 


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17 
PUBLICATIONS AND DISSEMINATION OF STUDY RESULTS 
The study lead investigators and the TBTC Publications and Presentations committee must approve the 
use of any coded study data for the purposes of publication or presentation in advance.  Any proposal for 
collection of additional data or analysis of study data must be agreed to in advance by the study lead 
investigators and the protocol team.  The preparation of and authorship of publications arising from this 
study will be in accordance with the TBTC Bylaws.   
These criteria will not apply to public-use data that have been made available in accordance with CDC’s 
policy on data sharing. Persons who use publicly available data will be asked to acknowledge the TBTC 
and the S31 Protocol Team.  
Updates on the progress of the trial will be presented at the twice-yearly TBTC meetings. Additional 
dissemination of results will be through the press, national governments at meetings and international 
organizations at conferences. Overall (aggregate) study results will be shared with study participants 
through mechanisms and materials reviewed and approved by the TBTC Community Research Advisors 
Group.  


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18 
LITERATURE REFERENCES 
Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr., Dye C, Halloran ME.  
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Aung KJ, Declercq E, Ali MA, Naha S, Datta Roy SC, Taleb MA, Hossain MA, Rigouts L, Gumusboga A, 
Van Deun A. Extension of the intensive phase reduces relapse but not failure in a regimen with rifampicin 
throughout. Int J Tuberc Lung Dis. 2012 Apr;16(4):455-61. 
Avelox (moxifloxacin) package insert.  Bayer HealthCare Pharmaceuticals, Inc, 2012. 
Ball P, Stahlmann R, Kubin R, Choudhri S, Owens R. Safety profile of oral and intravenous moxifloxacin: 
cumulative data from clinical trials and postmarketing studies. Clin Ther 2004;26:940-50. 
Baciewicz AM, Self TH. Isoniazid interactions. South Med J. Jun 1985;78(6):714-718. 
Bemer-Melchior P, Bryskier A, Drugeon HB. Comparison of the in vitro activities of rifapentine and 
rifampicin against Mycobacterium tuberculosis complex. J Antimicrob Chemother. 2000;46:571-6. 
Blakemore R, Nabeta P, Davidow AL, Vadwai V, Tahirli R, Munsamy V, Nicol M, Jones M, Persing DH, 
Hillemann D, Ruesch-Gerdes S, Leisegang F, Samudio C, Rodrigues C, Boehme CC, Perkins MD, Alland 
D. A multisite assessment of the quantitative capabilities of the Xpert MTB/RIF assay. Am J Respir Crit 
Care Med. 2011;184:1076-84. 
Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control 
and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care 
Med. Feb 15 2003;167(4):603-662. 
Bradley JS, Jackson MA; Committee on Infectious Diseases; American Academy of Pediatrics. The use 
of systemic and topical fluoroquinolones. Pediatrics. 2011;128:e1034–e1045. 
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, Choudhri S, Daley CL, Munsiff 
SS, Zhao Z, Vernon A, Chaisson RE. Moxifloxacin versus ethambutol in the first 2 months of treatment for 
pulmonary tuberculosis. Am J Respir Crit Care Med. 2006;174:331-8. 
Burman WJ, Cotton MF, Gibb DM, Walker AS, Vernon AA, Donald PR. Ensuring the involvement of 
children in the evaluation of new tuberculosis treatment regimens. PLoS Med 5(8):e176:1168-1172. 
Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine 
regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal 
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SUPPLEMENTS/APPENDICES 
 


TBTC S31/A5349:  Rifapentine-containing tuberculosis treatment shortening regimens 
Version 2.0 
 
14 May 2015 
 
 _____________________________________________________________________________________________  
 
 
Appendix A: Schedule of Procedures/Evaluations 
 
 _____________________________________________________________________________________________  
76 
Visit Window 
 
Up to 7 
days after 
screen 
+/- three (3) days 
+/- seven (7) days 
Possible Poor 
Treatment Response 
Post Early 
Termination Visith 
Visit 
Screen 
Baseline 
W
K 2 
WK 
4 
WK 
8 
WK 
12 
WK 
17 
WK 
22 
WK 
26 
MO 
9 
MO 
12 
MO 
15 
MO 
18 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms 
 
X 
X 
X 
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 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
Interval medical history 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest radiograph 
X 
 
 
 
 
 
Xf 
 
Xf 
 
 
 
 
X 
 
Visual tests 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 count (if HIV-pos) 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Viral load (if HIV-pos) 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum for smear and cultureb 
X 
X 
X 
X 
X 
X 
XX 
XX 
XX 
XX 
XXc 
XX 
XXc 
XXX 
 
Sputum for rapid molecular test, if 
available at site 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Storage of Mtb bacterial isolate 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
 _____________________________________________________________________________________________  
77 
Diabetes screend 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Bilirubin 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Creatinine 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Hemoglobin 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
WBC with differential 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Platelets 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Albumin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Potassium 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling for TB drugsg 
 
 
Obtain within this 
interval 
 
 
 
 
 
 
 
 
 
 
Blood sampling for 
pharmacogenomics testing 
 
 
Obtain any time after enrollment 
 
 
EFV1: Plasma for EFV PK  
Once at screening or 
baseline 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
EFV1: HIV viral load 
Required per 
eligibility criteria 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
EFV2: Plasma for EFV PK e 
 
 
 
Obtain at about 4 weeks 
after starting EFV AND 
at about 8 weeks after 
starting EFV 
X 
 
 
 
 
 
 
 
EFV2: HIV viral load e 
Required per 
eligibility criteria 
 
Obtain once at about 8 
weeks after starting EFV 
X 
 
 
 
 
 
 
 
Sputum, blood, and urine 
collections for research (consenting 
participant only) 
 
X 
X 
X 
X 
 
Xf 
 
Xf 
 
 
 
 
X 
 
Contact central study clinician 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Visit 
Screen 
Baseline 
W
K 2 
WK 
4 
WK 
8 
WK 
12 
WK 
17 
WK 
22 
WK 
26 
MO 
9 
MO 
12 
MO 
15 
MO 
18 
Possible Poor 
Treatment 
Response 
Post Early 
Termination Visith  
Visit Window 
 
Up to 7 
days after 
screen 
+/- three (3) days 
+/- seven (7) days 


 
 _____________________________________________________________________________________________  
78 
NOTES 
a Unless results of a test performed at or within 30 days prior to screening are available. 
 
b All sputa should be sent to the designated study laboratory with the exception of the screening specimen, which may be evaluated at any locally acceptable 
laboratory.  If a screening specimen has been found to be smear or culture positive at a non-study laboratory, then either store the isolate if culture positive from the 
non-study laboratory or get an additional specimen for culture and storage of isolate. Two specimens (i.e. one at screening and one at baseline) are required prior to 
initiation of study treatment. At least two (2) sputa should be obtained at each of weeks 17, 22, 26 and at each of months 9, 12, 15, and 18.   
 
c If both of the month 12 sputa or both of the month 18 sputa are contaminated, then the participant should be asked to provide at least two (2) additional sputa as 
soon as possible after contamination is recognized. 
 
d Hemoglobin A1C is the preferred test.  If such testing is not available, then fasting or random blood glucose can be measured. 
 
e see Section 8.3.10.1.2 for recommended schedule based on timing of initiation of efavirenz-based ART and coinciding with scheduled study visits 
 
f To be obtained at the end-of-study treatment visit (i.e. either week 17 or week 26). 
 
g See MOOP for guidance on selection of participants for this sampling 
 
h See Section 9.9 “Post Early Termination Visit (Visit after Early Termination) for Participants Terminating Before Completion of their Assigned Study Treatment.”  
This visit occurs approximately 14 days after stopping study drugs. 
 
 


 
 _____________________________________________________________________________________________  
79 
 
 
 
 
Appendix B:  Abbreviations 
 
Abbreviation 
Full-length identification 
ACTG 
AIDS Clinical Trials Group 
AE 
Adverse event 
ALT 
Alanine aminotransferase (alternative term is serum glutamic-
pyruvic transaminase [SGPT]) 
ART 
Anti-retroviral therapy 
AUC 
Area under the concentration-time curve 
CDC 
Centers for Disease Control and Prevention (United States) 
CFR 
Code of Federal Regulations (United States) 
CRO 
Contract research organization 
DOT 
Directly observed therapy 
DSMB 
Data and Safety Monitoring Board 
E 
Ethambutol 
EFV 
Efavirenz 
FDA 
Food and Drug Administration (United States) 
G 
Gatifloxacin 
GCP 
Good Clinical Practice 
H 
Isoniazid 
ICH 
International Conference on Harmonisation 
INH 
Isoniazid 
IEC 
Institutional ethics committee 
IRB 
Institutional review board 
ITT 
Intention-to-treat 
M 
Moxifloxacin 
MDR 
Multidrug-resistant 
MGIT 
Mycobacterial Growth Indicator Tube 


 
 _____________________________________________________________________________________________  
80 
 
 
 
 
MIC 
Minimum inhibitory concentration 
MITT 
Modified intention-to-treat 
MOOP 
Manual of Operating Procedures 
MTB 
Mycobacterium tuberculosis 
P 
Rifapentine 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PZA 
Pyrazinamide 
R 
Rifampin (alternative term is rifampicin) 
SAE 
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse reaction 
TBTC 
Tuberculosis Trials Consortium 
WHO 
World Health Organization 
XDR 
Extensively drug resistant 
Z 
Pyrazinamide 


 
Date: 
May 14, 2015 
Re: 
Protocol Amendment for: “Rifapentine-containing treatment shortening regimens for 
pulmonary tuberculosis: A randomized, open-label, controlled phase 3 clinical trial” 
from v1.1 to v2.0 
To: 
CDC IRB 
From: Stefan Goldberg 
 
We wish to amend the current protocol version to include the changes described below.  Tracked and 
clean versions of the consent, assent, and protocol are attached.   Thank you in advance for your 
consideration of these changes, which, from our perspective, will enhance successful implementation 
of this study.  
 
CONSENT AND PERMISSION FORM CHANGES 
 
• The new version is 2.0 and new date is 14 May 2015 
 
• The footer has been revised to now include the ACTG protocol number, A5349.  The footer 
now reads “Flesch-Kincaid Grade Level 7.5 / S31/A5349, Version 2.0, 14 May 2015.” The 
reading level increased from 7.2 to 7.5. 
 
• To the section, “your participation is voluntary,” we have added, “You will be informed of 
any new findings during the course of the study that may affect your willingness to continue 
participation. After the study is completed, you will be informed of the study results.” 
 
• To the section, “why is this study being done,” we have added, “The study will also see what 
side effects are caused by taking rifapentine and moxifloxacin for 4 months.” 
 
• To the section, “who has reviewed this study,” we have added, “The role of an IRB is to 
protect the rights, safety and wellbeing of people in a clinical trial.” 
 
• To the section, “other visits during study treatment,” we have added a description of the 
staged enrollment of persons co-infected with HIV, related to their efavirenz-treatment status, 
to help clarify this part of the protocol plan. We add names for the two evaluation stages: 
EFV1 and EFV2. We also add a statement that blood drawn for efavirenz evaluation will be 
sent to a laboratory in the U.S. 
 
•  Below the description of the efavirenz plan we add a term to start the next section, “Sparse 
PK,” which is defined after the first sentence. We deleted the limitation of sparse PK testing 
to research treatment groups 2 and 3. As stated in protocol section 8.3.9.1, individuals not 
undergoing intensive PK sampling will have sparse PK sampling regardless of assigned study 
arm. We deleted blood volume from this section because it is specified in a table below. We 
deleted South Africa from the statement of where these samples will be sent for testing. (On 
the submission date of this amendment, the selection process still is underway for the lab that 
will do these tests: remaining candidate labs are in the U.S. and Europe.) Detailed timing of 
these blood draws has been deleted, as unnecessarily technical for the consent form and to 


allow flexibility in the manual of operating procedures (MOOP) to specify ideal and 
acceptable time ranges. 
 
• The table of events has been modified for clarity and to match minor changes listed below for 
the protocol. 
 
• In the section, “could your participation end early,” we have inserted “study treatment 
and/or” in the statement about why your participation in the study might be stopped early, to 
clarify that study participation is not synonymous with study treatment. 
 
• To the section, “what happens if you are injured because you took part in this study,” we have 
added, “If you have a research-related injury or if you experience an adverse reaction, you 
should contact your study doctor.  See the section “Contact Information” for phone numbers 
and additional information.” 
 
• We have added an opt-in or opt-out section for genetic testing (pharmacogenomics only): 
“Collection of a blood sample for genetic testing,” to give participants these options. 
(protocol section 8.3.11). 
 
• We have modified the heading and text of the additional biomarker specimen signature block 
to emphasize collection in addition to storage of these specimens for additional research 
studies. We have deleted the sentence about genetic testing in these specimens, since genetic 
testing is not planned for these specimens (protocol section 8.3.13). We also added an 
instruction to sites that this section is to be included in their consent form if they are 
participating in this biomarker specimen collection activity.     
 
 
ASSENT FORM CHANGES 
 
• The new version is 2.0 and new date is 14 May 2015 
 
• The footer has been revised to now include the ACTG protocol number, A5349.  The header 
now reads “Flesch-Kincaid Grade Level 6.6 / S31/A5349, Version 2.0, May 14, 2015.” The 
reading level increased from 6.4 to 6.6. 
 
 
• The section on study procedures has been modified for clarity:  
 
o We added the purpose of drawing blood: “to check your liver, kidney, and blood 
counts.” 
o We added the purpose of sputum collection: “The sputum will be tested for the TB 
germ.” 
o We moved the end-of-treatment chest X-ray line to the subsection about procedures 
that follow completion of treatment. 
o We added a line describing blood collection for PK assessments 
o We added a statement about additional blood collection for efavirenz testing in 
persons with HIV infection. 
o We added a statement about optional additional blood collections for biomarker 
studies. 


 
• To the section, “why should I take part in this study,” we added the sentence, “There are no 
direct benefits to you for taking part in this study.” 
 
• We added a section, “what if I do not want to take part in this study?” 
 
o To this section we added that the participant and parent or guardian would be 
informed of new findings that might affect willingness to continue participating. 
o We added a statement that the participant and parent or guardian would be informed 
of study results after completion of the study. 
 
• To the section, “what if I have some questions or change my mind,” we have added “If you 
choose to take part in this study and then change your mind, your regular medical care will 
not be affected.  You can get TB treatment through the Health Department or your regular 
doctor” and moved “You may stop being in the study at any time, after talking about it with 
your parent or guardian.” 
 
• In the section, “how do I sign up,” we have changed the statement the reference to parental 
“consent” to a reference to a “permission form” needing to be signed by the parent or 
guardian. 
 
PROTOCOL CHANGES 
 
ADMINSTRATIVE CHANGES 
• The new version is 2.0 and new date is 14 May 2015 
 
• The header has been revised to now include the ACTG protocol number, A5349.  The header 
now reads “TBTC S31/A5349: Rifapentine-containing tuberculosis treatment shortening 
regimens” 
 
• The study has been registered on Clinicaltrials.gov as NCT02410772; this identifier has been 
placed on the protocol cover page. 
 
• The protocol team member listing has been updated.  Suria Yesmin (Social & Scientific 
Systems, Inc, Silver Spring, MD), Sachiko Miyahara (Harvard T.H. Chan School of Public 
Health, Boston, MA), and Lisa Wolf (Johns Hopkins University School of Medicine, 
Baltimore, MD) have been added at the request of ACTG leadership.  Statistician Michael 
Chen, as well as Pei-Jean Feng and Erin Sizemore from CDC/TBTC have been added; 
Patricia Bessler from CDC/TBTC is no longer serving on the protocol team and her name has 
been removed. 
 
SCIENTIFIC AND PROCEDURAL CHANGES 
• Section 7.2: the text has been revised to reflect that, for HIV, there will be two strata (HIV-
positive and HIV-negative) rather than three strata.  This change reduces the risk of assigning 
participants to strata that would be too small to analyze usefully. 
 


• Section 8.1.7: the timing of end-of-treatment chest radiographs has been corrected to reflect 
that the end-of-treatment chest radiograph will be performed at the completion of assigned 
treatment, which may be either at week 17 (investigational arms) or week 26 (control arm). 
The rationale is that the end-of-treatment chest radiograph is a clinically important tool for 
documenting extent of residual radiographic changes at the time of treatment completion, as 
this information can be used to help interpret the potential significance of future chest 
symptoms/signs, should they occur.  Sections 9.4 and 9.6, weeks 17 and 26 visit task lists, 
and the event schedule, appendix A, also has been updated with this change. 
 
• Section 8.3.9.3 has been revised to increase the volume of blood that will be collected at each 
of the tuberculosis drug sparse PK blood draws.  Formerly the volume was 6 ml, but the 
volume has been increased to 10 ml to ensure that the volume of serum is appropriate for two 
or more aliquots.  
 
• Section 8.3.10.1 has been revised to decrease the volume of blood that will be collected at 
each of the efavirenz PK blood draws.  Formerly the volume was 8 ml, but the volume has 
been reduced to 6 ml after discussions with the laboratory team. 
 
• Section 8.3.10.1 “Efavirenz Sampling Strategy” and the Appendix A Schedule of Events have 
been revised in order to assess the potential significance of low-positive viral load results.  
For HIV-infected participants undergoing protocol-specified HIV viral load testing while on 
study treatment and efavirenz (e.g. at weeks 8 and 17), if a viral load result is greater than 200 
copies/mL then approximately 2 to 4 weeks after that test, blood should be drawn and a 
repeat HIV viral load test performed.   
 
• Section 8.3.11 Pharmacogenomic testing: Specific consent for genetic testing is added, with a 
new section added to the consent form for participants to opt in or opt out of this testing, 
without affecting participation in the treatment study. 
 
• A new section entitled ‘Participants with a possible poor treatment response’ has been added 
(Section 8.8) to clarify the scenarios under which a participant should be considered to have a 
possible poor treatment response and therefore undergo assessment.  
 
• Sections 8.6 through 8.8 and 8.9.3 have been revised to now remove the requirement that the 
central study clinician be contacted prior to on-site clinical decision-making.  This change 
also has been made in the section 2.2, “rationale,” under “rationale for an open-label study:” 
clarifying that the central study clinician is “available to advise on protocol procedural 
issues,” and in Section 10.6 “Criteria for Discontinuation of Study Drugs.” 
 
• Section 9.8 has been revised to clarify and present in itemized fashion the study assessments 
that should be performed for participants deemed by the site investigator as having a possible 
poor treatment response.  This information has also been added to the Appendix A Schedule 
of Events. 
 


• Section 9.11 “Unscheduled Visit” has been expanded and revised.  Specifically, the section 
has been expanded now to two sections, named “Missed Visit” (9.11) and “Unscheduled 
Visit” (9.12).  Definitions of missed and unscheduled are provided.   
 
• Section 12.3.2 “Reporting Procedures” the following information has been added:  “The 
DAIDS Medical Officer will receive a copy of the IND safety reports that TBTC submits to 
the FDA”.  
 
• Section 13.5.3 “Secondary Efficacy Analyses” has been updated to add secondary analyses 
directed towards identification of clinical, microbiological, and/or radiological factors 
associated with favorable and unfavorable treatment outcomes. 
 
 
CLARIFICATIONS / CHANGES TO INCREASE CLARITY AND UNDERSTANDING 
• Section 3 Descriptions of study drugs. We add specification that the study drugs are 
“commercially available as brand or generic.” 
 
• Section 3.3 Moxifloxacin. We deleted the brand name, Avelox®, because moxifloxacin is 
available as a generic product and the protocol does not specify the use of Bayer’s brand 
name product.  
 
• Section 6.1: Subject Inclusion Criteria.  Eligibility criteria have not been changed.  However, 
in two instances additional information has been added for clarity and for consistency with 
other sections of the protocol: 
o Inclusion Criterion D has been clarified to indicate that a non-hormonal intrauterine 
device is considered (for study purposes) an adequate means of contraception 
 
o Inclusion Criterion F has been revised to now include the information about staged 
enrollment that previously was present only later on in the protocol (Section 8.3.10).  
Our perspective is that adding this detail directly to the Inclusion Criterion enhances 
clarity and therefore will help to ensure correct implementation of subject selection 
and enrollment procedures.   
 
o Inclusion criterion H has been modified to define childbearing potential more 
specifically, to improve guidance on the pregnancy test requirement. 
 
• Section 6.2 Criteria for Exclusion.  
o Exclusion criterion I: We have deleted the statement that individuals currently on or 
planning to start efavirenz-based antiretroviral treatment are included, as redundant 
and potentially confusing, especially since we have added efavirenz-related 
clarification to inclusion criterion F, as described above. 
 
• Section 8.2 Concomitant Medications/Treatments has been modified to describe the 
indication and use of non-hormonal contraception more clearly. 
 
• Section 8.3.9 Pharmacokinetic sampling: Tuberculosis drugs 


o 8.3.9.1 Overview: Europe has been added and South Africa deleted as possible 
locations for testing of blood specimens for concentrations of TB drugs and their 
metabolites. 
o 8.3.9.2 Timing of sparse PK sampling: “for rifapentine and moxifloxacin” has been 
deleted since this testing will be done regardless of treatment arm, as stated in section 
8.3.9.1 Overview. 
o 8.3.9.3 Schedule of sparse PK blood samples: “for rifapentine and moxifloxacin” has 
been deleted. Blood volume is corrected to 10 ml for each specimen, from 6. Time 
span for the two or three blood draws has been corrected to a 9 hour period from 8. 
Specific timing details for the blood draws have been deleted in order to allow the 
MOOP to specify ideal and acceptable time ranges. 
 
• Section 8.3.10 has been revised to clarify that participants randomized to the 2HRZE/4HR 
control arm will not have efavirenz PK evaluations. 
 
• In Section 8.3.10, what previously had been called ‘Group 1’ and ‘Group 2’ has been revised 
to ‘EFV1’ and ‘EVF2’ for clarity. These terms also are applied in the event schedule, 
Appendix A, and in the consent form, to match usage across these documents. 
 
• The protocol Appendix A Schedule of Events has been corrected in order to harmonize with 
protocol text.  Corrections to Appendix A are as follows: 
 
o Addition of efavirenz blood sampling at the week 4 visit for individuals in ‘EFV1’ in 
accordance with the information already contained in the protocol text in Section 
8.3.10.   
o For clarity, we have re-formatted the Appendix A information for EFV1 and EFV2 
(efavirenz PK procedures)  
o For clarity, we have added a column that indicates procedures and evaluations to be 
performed for participants with possible poor treatment response 
o For clarity we have renamed the final column “post early termination visit,” from 
“early termination during treatment,” matching the protocol sections 8.9.1 and 9.9 to 
clarify that the procedures in this column are to be done approximately 2 weeks after 
the last study dose, testing for late toxicity, rather than at the time of the last study 
dose. 
 
• Section 8.7 “Participants with a positive sputum smear or culture at or after week 17:” The 
word, “alone,” is inserted in the sentence, “Sputum smear results alone should not be used for 
clinical decision-making,” to acknowledge that smear results usually do contribute, while 
emphasizing that they should not be the only guiding factor. 
 
• Section 8.9 “Management of a participant who is discontinued from study treatment” has an 
added introductory sentence to clarify that “for any participant who is discontinued from 
study treatment, the assessments listed in Section 9.9 “Post Early Termination Visit” should 
be performed.” “Post early termination visit” is used in the protocol now to indicate the visit 
that occurs 14 days after early termination of study drugs, to evaluate for delayed toxicity. 
 


• Section 8.3.13 “Samples for analyses to identify potential biomarkers” has been modified to 
specify that these samples are collected only “at participating sites.” An ACTG substudy 
protocol, analogous to TBTC Study 36A (CDC IRB #6556), has been added for reference in 
this section: Biobank for Surrogate Marker Research for TB (A5302). With A5302, selected 
ACTG sites are contributing specimens to the same multi-consortium repository to which 
selected TBTC sites are contributing with Study 36A. 
 
• Section 9 “Study Schedule:” the procedure list for each visit after screening has been 
modified to add “at least” to the number of specified sputum specimens to collect, in order 
not to limit site staff from collecting more specimens if clinically indicated. 
 
• Section 9.9 is renamed, from “Early Termination Visit” to “Post Early Termination Visit” in 
order better to match the instruction in the section that this visit occurs “approximately 14 
days after stopping study drugs.” This label is updated elsewhere in the protocol too, 
especially in the event schedule, Appendix A. Review of contact information is added as a 
task for this visit and sputum collection and chest radiograph are deleted, as unnecessary for 
study purposes at this time point. A sentence is added to help distinguish procedures 
indicated at a visit at which possible poor treatment response is determined, from those 
indicated at this visit.  
 
• Section 9.10 “Early Termination Visit for Participants Terminating After Completion of their 
Assigned Study Treatment” has been renamed “Early Termination Visit for Participants 
Stopping Study Participation After …” This change and minor modifications in the first 
paragraph of the section are intended to maintain opportunities to assess crucial study 
questions to the extent that participants are willing to contribute. 
 
• Section 9.11 “Early/Late Visit” is deleted, as redundant after the minor procedural changes 
described above for Sections 9.11 Missed Visit and 9.12 Unscheduled Visit. 
 
• Section 12.2.1 “Adverse Events and Serious Adverse Events:” A time limit for ascertainment 
of AEs and SAEs is added to specify “up to and including Week 26.” This clarifies the 
ascertainment time frame for site staff with a consistent stopping time across treatment arms. 
 
• Section 12.3.2 “Reporting Procedures” has been clarified and corrected to add relatedness to 
the definition of suspected unexpected serious adverse reaction (SUSAR).  The correct 
information is “A SUSAR is defined as an adverse reaction that is unexpected (i.e. not 
consistent with the applicable product information) AND also meets the definition of a 
serious adverse event AND also may reasonably be regarded as caused by or associated with 
the administration of the study drug regimen (i.e. at least ‘possibly associated’ with the study 
drug regimen).” 
 
• Section 12.4: The word “suspected” has been inserted in the last sentence of the first 
paragraph before “causative study drug(s) may be withheld,” to clarify that withholding can 
be done without proof of attribution. 
 
MINOR CORRECTIONS AND EDITS 
• The Table of Contents has been updated to reflect the changes described above 


 
• Minor edits have been made to improve the accuracy of the information presented in the 
Background section on ‘Moxifloxacin for TB Treatment.’ 
 
• Section 9.3 has been corrected to remove from the Week 12 visit the collection of specimens 
for frozen storage, to match section 8.3.13 and the event schedule, Appendix A. 
 
• Section 12.2: We have corrected the name of the toxicity tables that will be used from 
‘Common Toxicity Criteria’ (the name formerly used) to now ‘Common Terminology 
Criteria for Adverse Events’.   
 
• Several typing, spelling, and line spacing errors have been corrected 
 


TBTC Study 31:  Rifapentine-containing tuberculosis treatment shortening regimens 
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TITLE 
 
Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis:  
A randomized, open-label, controlled phase 3 clinical trial 
 
 
 
 
Funding Agencies:  
U.S. Centers for Disease Control and Prevention 
U.S. National Institute of Allergy and Infectious Diseases, National Institutes of Health 
 
 
Pharmaceutical Support Provided by: 
Sanofi  
 
 
IND Number: 
46,954 
 
 
IND Sponsor: 
U.S. Centers for Disease Control and Prevention 
 
 
Study Chairs: 
Payam Nahid, M.D., M.P.H. 
Susan Dorman, M.D. 
 
 
 
Version Number: 1.1 
 
 
24 November 2014 
 
 
 


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ii 
Statement of Compliance 
This trial will be conducted in compliance with the protocol, International Conference on Harmonisation 
Good Clinical Practice E6 (ICH-GCP), U.S. Code of Federal Regulations 45 CFR 46 and 21 CFR, and 
applicable site-specific regulatory requirements.   
 
 


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Table of Contents 
 
Statement of Compliance ............................................................................................................................... ii 
Protocol Summary ......................................................................................................................................... vi 
Study Schematic  
 ...................................................................................................................................... ix 
 
1 Key Roles ............................................................................................................... 11 
2 Background Information and Scientific Rationale .............................................. 13 
2.1 
Background Information ........................................................................................... 13 
2.2 
Rationale ................................................................................................................. 19 
2.3 
Potential Harms and Benefits .................................................................................. 22 
2.3.1 
Potential harms ......................................................................................... 22 
2.3.2 
Potential benefits ....................................................................................... 23 
3 DESCRIPTIONS OF STUDY DRUGS ..................................................................... 24 
3.1 
Rifapentine .............................................................................................................. 24 
3.2 
Rifampin .................................................................................................................. 24 
3.3 
Moxifloxacin ............................................................................................................. 25 
3.4 
Isoniazid .................................................................................................................. 26 
3.5 
Pyrazinamide ........................................................................................................... 27 
3.6 
Ethambutol .............................................................................................................. 28 
3.7 
Vitamin B6 (Pyridoxine) ........................................................................................... 28 
4 Objectives .............................................................................................................. 29 
4.1 
Primary: ................................................................................................................... 29 
4.2 
Secondary: .............................................................................................................. 29 
5 Study Design .......................................................................................................... 30 
6 Study Population ................................................................................................... 31 
6.1 
Subject Inclusion Criteria ......................................................................................... 31 
6.2 
Criteria for Exclusion from Enrollment ...................................................................... 32 
6.3 
Criteria for Exclusion after Enrollment (‘Late Exclusion’) .......................................... 33 
7 Enrollment, Randomization, and Masking Procedures ...................................... 34 
7.1 
Enrollment Procedures ............................................................................................ 34 
7.2 
Randomization ........................................................................................................ 34 
8 Study Procedures .................................................................................................. 35 
8.1 
Clinical Evaluations ................................................................................................. 35 
8.1.1 
Interview for demographic and contact information.................................... 35 
8.1.2 
Obtaining a medical history ....................................................................... 35 
8.1.3 
Obtaining sputum specimens .................................................................... 35 
8.1.4 
Performing visual acuity and color vision testing ....................................... 35 
8.1.5 
Symptom assessment ............................................................................... 35 
8.1.6 
Assessment for adverse events................................................................. 35 
8.1.7 
Chest Radiograph ..................................................................................... 36 
8.2 
Concomitant Medications/Treatments ...................................................................... 36 


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8.3 
Laboratory Evaluations ............................................................................................ 37 
8.3.1 
Sputum mycobacterial culture ................................................................... 37 
8.3.2 
Hematology ............................................................................................... 37 
8.3.3 
Biochemistry.............................................................................................. 37 
8.3.4 
HIV testing ................................................................................................ 37 
8.3.5 
CD4 testing ............................................................................................... 37 
8.3.6 
HIV viral load testing ................................................................................. 37 
8.3.7 
Pregnancy testing ..................................................................................... 37 
8.3.8 
Diabetes screening.................................................................................... 38 
8.3.9 
Pharmacokinetic sampling: Tuberculosis Drugs ........................................ 38 
8.3.10 Pharmacokinetic sampling: Efavirenz ........................................................ 39 
8.4 
Specimen preparation, handling and shipping ......................................................... 41 
8.5 
Loss to follow-up ...................................................................................................... 41 
8.6 
Management of a participant with a positive sputum culture for M. tuberculosis at or 
after week 17 but before week 26 ......................................................................... 42 
8.7 
Management of a participant with a positive sputum smear at or after week 17 ....... 42 
8.8 
Management of a participant with a positive sputum culture for M. tuberculosis at or 
after week 26 ........................................................................................................ 42 
8.9 
Management of a participant in whom a treatment change is being considered....... 43 
8.10 
Management of a participant who is discontinued from study treatment ................ 43 
8.10.1 Management of a participant who is discontinued from study treatment 
because s/he is determined to be ineligible after enrollment (‘late 
exclusions’) ............................................................................................... 43 
8.10.2 Management of participants who become pregnant during the study ........ 43 
8.10.3 Management of participants who are discontinued from study treatment in 
the setting of an adverse event or the investigator judges that 
discontinuation of study treatment is in the participant’s best interest ........ 44 
8.10.4 Management of a participant who requests premature discontinuation from 
study treatment ......................................................................................... 44 
8.10.5 Management of a participant who is incarcerated after enrollment ............ 44 
8.11 
Premature termination of the study or closure of a study stratum or a study site .... 44 
9 Study Schedule ...................................................................................................... 45 
9.1 
Screening ................................................................................................................ 45 
9.2 
Baseline .................................................................................................................. 45 
9.3 
Study Visits at Weeks 2, 4, 8, and 12 ...................................................................... 46 
9.4 
Week 17 .................................................................................................................. 47 
9.5 
Week 22 .................................................................................................................. 47 
9.6 
Week 26 .................................................................................................................. 48 
9.7 
Study Visits At Months 9, 12, 15, and 18 ................................................................. 48 
9.8 
Early Termination Visit for Participants Terminating Before Completion of their 
Assigned Study Treatment .................................................................................... 49 


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9.9 
Early Termination Visit for Participants Terminating After Completion of their 
Assigned Study Treatment .................................................................................... 49 
9.10 
Unscheduled Visit .................................................................................................. 50 
9.11 
Early/Late Visit ....................................................................................................... 50 
10 Study Intervention/Investigational DRUGS ....................................................... 51 
10.1 
Study Drugs ........................................................................................................... 51 
10.2 
Study Drug Acquisition .......................................................................................... 52 
10.3 
Study Drug Storage and Stability ........................................................................... 52 
10.4 
Administration and Dosage of Study Drugs ........................................................... 52 
10.5 
Dose Modifications for a Participant ....................................................................... 53 
10.5.1 Dose Modifications for a Change in Participant’s Weight ........................... 53 
10.5.2 Drug Re-challenges ................................................................................... 53 
10.6 
Criteria for Discontinuation of Study Drugs ............................................................ 53 
10.7 
Accountability Procedures for the Study Drugs ...................................................... 53 
10.8 
Assessment of Subject Compliance with Study Treatment .................................... 53 
11 Assessment of Efficacy ...................................................................................... 54 
11.1 
Summary of Bacteriological Methods ..................................................................... 54 
12 Assessment of Safety ......................................................................................... 55 
12.1 
Specification of Safety Parameters ........................................................................ 55 
12.1.1 Primary Outcome Measure ........................................................................ 55 
12.1.2 Secondary Outcome Measure ................................................................... 55 
12.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 55 
12.2.1 Adverse Events and Serious Adverse Events ............................................ 55 
12.3 
Recording and Reporting Procedures .................................................................... 56 
12.3.1 Overview ................................................................................................... 56 
12.3.2 Reporting Procedures ............................................................................... 56 
12.3.3 Pregnancy ................................................................................................. 56 
12.4 
Management of adverse events ............................................................................. 56 
12.4.1 Type and Duration of the Follow-up of Subjects After Adverse Events ...... 57 
12.5 
Data and Safety Monitoring Board ......................................................................... 57 
12.6 
Interim Monitoring and Analyses by the Data and Safety Monitoring Board ........... 57 
13 Statistical Considerations ................................................................................... 58 
13.1 
Study Hypotheses ................................................................................................. 58 
13.2 
Study Outcome Measures ..................................................................................... 58 
13.3 
Definition of primary outcome status ...................................................................... 59 
13.4 
Analysis Groups .................................................................................................... 60 
13.5 
Analysis Plan ......................................................................................................... 60 
13.5.1 Co-Primary efficacy analyses .................................................................... 60 
13.5.2 Primary safety analysis ............................................................................. 61 
13.5.3 Secondary efficacy analyses ..................................................................... 61 
13.5.4 Secondary safety analyses ........................................................................ 61 
13.5.5 Secondary Efavirenz PK analysis .............................................................. 61 


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13.6 
Sample Size Considerations .................................................................................. 61 
14 Quality Control and Quality Assurance ............................................................. 63 
14.1 
Local quality control ............................................................................................... 63 
14.2 
External monitoring ................................................................................................ 63 
15 Ethics/Protection of Human Subjects ................................................................ 64 
15.1 
Institutional Review Board ..................................................................................... 64 
15.2 
Informed Consent Process .................................................................................... 64 
15.3 
Subject Confidentiality ........................................................................................... 64 
15.4 
Study Discontinuation ............................................................................................ 65 
16 Data Handling and Record Keeping ................................................................... 66 
17 Publications and Dissemination of Study Results ........................................... 67 
18 Literature References .......................................................................................... 68 
APPENDICES 
A: Schedule of Procedures/Evaluations 
B: Abbreviations 


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Protocol Summary 
 
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Title: 
Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, 
open-label, controlled, phase 3 clinical trial 
 
Hypotheses: 
A) Seventeen (17) week rifapentine-based regimen 
 
In previously untreated individuals with active drug-susceptible pulmonary 
tuberculosis treated with eight weeks of rifapentine (P), isoniazid (H), 
pyrazinamide (Z) and ethambutol (E) followed by nine weeks of rifapentine plus 
isoniazid, all given daily throughout, the proportion of participants who 
experience absence of cure (unfavorable outcome) will not be inferior to that 
observed in participants who are treated with a standard regimen (eight weeks of 
rifampin (R), isoniazid, pyrazinamide and ethambutol followed by eighteen weeks 
of rifampin plus isoniazid), all given daily throughout.  
 
B) Seventeen (17) week rifapentine- plus moxifloxacin-containing regimen 
 
In previously untreated individuals with active drug-susceptible pulmonary 
tuberculosis treated with eight weeks of rifapentine, isoniazid, pyrazinamide and 
moxifloxacin (M), followed by nine weeks of rifapentine, isoniazid, and 
moxifloxacin, all given daily throughout, the proportion of participants who 
experience absence of cure (unfavorable outcome) will not be inferior to that 
observed in participants who are treated with a standard regimen (eight weeks of 
rifampin, isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of 
rifampin plus isoniazid), all given daily throughout. 
 
Phase: 
3 
Design: 
This will be an international, multicenter, randomized, controlled, open-label, 3-
arm, phase 3 non-inferiority trial. 
Population: 
Patients with newly diagnosed, previously untreated pulmonary tuberculosis.  
Number of Sites: 
Multiple international sites, primarily sites of the Tuberculosis Trials Consortium 
and the AIDS Clinical Trials Group.   
Study Duration: 
Duration per participant is approximately 18 months. 
 
 
 


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Description of Agent or Intervention: After written informed consent, participants will be randomly 
assigned to receive one of the following oral regimens: 
 
 
Regimen 1 (control regimen): 2RHZE/4RH 
• Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed 
by  
• Eighteen weeks of daily treatment with rifampin and isoniazid 
 
 
Regimen 2 (investigational regimen): 2PHZE/2PH 
• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, 
followed by  
• Nine weeks of daily treatment with rifapentine and isoniazid  
 
 
 
Regimen 3 (investigational regimen): 2PHZM/2PHM 
• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, 
followed by  
• Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin 
 
Objectives: 
Primary: 
• 
To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single 
substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of 
treatment for drug-susceptible pulmonary tuberculosis 
• 
To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin 
for ethambutol and continues moxifloxacin during the continuation phase to determine whether it is 
possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary 
tuberculosis  
 
Secondary: 
• 
To evaluate the safety of the investigational regimens 
• 
To evaluate the tolerability of the investigational regimens  
• 
To collect and store biospecimens from consenting participants for the purpose of future research on 
discovery and validation of TB biomarkers 


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• 
To determine the correlation of mycobacterial and clinical markers with time to culture conversion, 
culture status at completion of eight weeks of treatment, treatment failure, and relapse. 
• 
To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs.  The main 
objectives of the PK/PD study are to characterize study drug PK parameters and to determine 
relationships between treatment outcomes and PK parameters.  
• 
To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with 
TB/HIV co-infection taking efavirenz-based combination antiretroviral therapy and TB treatment with 
rifapentine 
 
 
Endpoints: 
Primary Endpoints: 
• 
Efficacy: TB disease-free survival at twelve months after study treatment assignment.   
• 
Safety: Proportion of participants with grade 3 or higher adverse events during study drug treatment 
 
Secondary Endpoints:  
• 
TB disease-free survival at eighteen months after study treatment assignment 
• 
Time to stable sputum culture conversion (solid and liquid media considered separately) 
• 
Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection 
• 
Proportion of participants who are culture negative at completion of eight weeks of treatment (solid 
and liquid media considered separately) 
• 
Sensitivity analyses assuming all participants classified as ‘not assessable’ have a favorable 
outcome 
• 
Discontinuation of assigned treatment for a reason other than microbiological ineligibility 
• 
Estimated steady state efavirenz PK parameters including mid-dosing interval concentration 
 
 
 
 
 
 
 


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x 
Schematic of Study Design:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screen for eligibility
Enroll
Randomize 1:1:1
Regimen 1 
(control regimen) 
2RHZE/4RH 
(26 weeks) 
Regimen 2 
(investigational) 
2PHZE/2PH 
(17 weeks) 
Regimen 3 
(investigational) 
2PHZM/2PHM 
(17 weeks) 
Participant follow-up: 
18 months after treatment assignment 
Analysis of Outcome Measures 
Primary at 12 months; secondary at 18 months 


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1 
KEY ROLES 
Funding Agencies:   
U.S. Centers for Disease Control and Prevention through the Tuberculosis Trials Consortium;  
U.S. National Institute of Allergy and Infectious Diseases of the National Institutes of Health through the 
AIDS Clinical Trials Group 
 
IND Sponsor: 
U.S. Centers for Disease Control and Prevention (IND# 46,954) 
 
Pharmaceutical Support: 
Sanofi  
 
Protocol Chairs: 
Payam Nahid, M.D., M.P.H. 
University of California, San Francisco 
1001 Potrero Ave, 5K1 
San Francisco, CA 94110 
Phone: 415-206-5464 
Email: pnahid@ucsf.edu 
 
Susan E. Dorman, M.D. 
Johns Hopkins University School of Medicine 
1550 Orleans Street, CRB2, 1M-12 
Baltimore, Maryland, USA 21231 
Phone 410-502-2717 
Email: dsusan1@jhmi.edu 
  
Project Officer: 
 
Stefan Goldberg, M.D. 
US Centers for Disease Control and Prevention 
1600 Clifton Road, MS E-10 
Atlanta, GA, USA  30333 
Phone: 404-639-5339 
Email: ssg3@cdc.gov 
 
 
Central Study Clinician: 
 
TB clinician(s) external to the protocol team, TBD  
 
 
 
 


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Protocol Team 
Name 
Institution 
Janet Andersen 
Harvard School of Public Health, Boston, Massachusetts, USA 
Patricia Bessler 
US Centers for Disease Control and Prevention, Atlanta, Georgia, USA 
Richard Chaisson 
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 
Kwok-Chiu Chang 
TB and Chest Service of Hong Kong, China 
Mark Cotton 
Stellenbosch University, Cape Town, South Africa 
Dalene von Delft 
Community Research Advisory Group, Cape Town, South Africa 
Kelly Dooley 
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 
Melissa Engle 
University of Texas Health Science Center, San Antonio, Texas, USA 
Courtney Fletcher 
University of Nebraska Medical Center, Omaha, Nebraska, USA 
Phan Ha 
National TB Program, Hanoi, Vietnam 
Charles M Heilig 
US Centers for Disease Control and Prevention, Atlanta, Georgia, USA 
Daniel Johnson 
Division of AIDS, National Institutes of Health, Bethesda, Maryland, USA 
John L. Johnson 
Case Western Reserve University, Cleveland, Ohio, USA 
Marilyn Maroni 
Sanofi, Paris, France 
Cynthia Merrifield 
University of California, San Francisco, San Francisco, California, USA 
José M. Miro 
Hospital Clinic Universitari, Barcelona, Spain 
Nguyen Viet Nhung 
National TB Program, Hanoi, Vietnam 
April Pettit 
Vanderbilt University, Nashville, Tennessee, USA 
Anthony Podany 
University of Nebraska Medical Center, Omaha, Nebraska, USA 
Kathleen Robergeau 
Westat, Inc., Rockville, Maryland, USA 
Wadzanai Samaneka 
Parirenyatwa Clinical Research Site, Harare, Zimbabwe 
Susan Swindells 
University of Nebraska Medical Center, Omaha, Nebraska, USA 
 
Andrew Vernon 
Centers for Disease Control and Prevention, Atlanta, Georgia, USA 
Marc Weiner 
Audie L. Murphy Veterans Affairs Medical Center / University of Texas Health 
Science Center, San Antonio, Texas, USA 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
Tuberculosis as a global health problem 
Tuberculosis (TB) is one of the most important global health problems. According to recent estimates 
from the World Health Organization (WHO), 8.6 million new cases and 1.3 million deaths from TB 
occurred in 2012 (World Health Organization 2013).  The vast majority of TB cases and TB deaths are in 
developing countries. The spread of HIV has fueled the TB epidemic, and TB is the leading cause of 
death among patients infected with HIV (Corbett et al., 2003). TB predominantly affects young adults in 
their most productive years of life and has substantial impact on economic development.   
Need for new treatment regimens for tuberculosis 
Although effective therapy for drug susceptible Mycobacterium tuberculosis is available, TB continues to 
cause significant morbidity and mortality worldwide, and rates of multi-drug resistant (MDR) and 
extensively-drug resistant (XDR) TB cases are on the rise. A major obstacle to the control of TB is poor 
adherence with lengthy (at minimum 6 months) and complicated treatment regimens. Incomplete TB 
treatment can lead to increased morbidity and mortality, prolonged infectiousness and transmission, and 
the development of drug resistance.  The use of directly observed therapy (DOT) can improve patient 
adherence and reduce the emergence of resistant microorganisms, but is logistically difficult and 
expensive to implement (McDonald et al., 1982).  The development of new treatment strategies with more 
potent antimycobacterial activity could lead to shorter and better tolerated regimens.  A TB treatment 
regimen that allowed a decrease in treatment duration would potentially have important public health 
implications by facilitating DOT, increasing cure rates, potentially reducing transmission and preventing 
emergence of MDR TB. It is estimated that improved regimens that shorten treatment duration for drug-
susceptible strains and are efficacious against resistant strains could reduce the incidence of TB by up to 
27% by 2050 and reduce deaths by 25% from current global numbers of incident cases and deaths per 
year (Abu-Raddad et al, 2009). 
Current standard treatment for pulmonary tuberculosis  
Modern short course treatment for pulmonary tuberculosis is comprised of two treatment phases.  The 
intensive phase is the initial 8 weeks of treatment, and typically is comprised of isoniazid, rifampin, 
pyrazinamide, and ethambutol.  Continuation phase follows intensive phase, and continuation phase 
typically is comprised of isoniazid plus rifampin for an additional 18 weeks, to complete a total of 26 
weeks (6 months) of treatment.    
Rifamycins in tuberculosis treatment  
Rifamycins are the key drugs in modern short-course TB chemotherapy of 6 months duration.  
Rifamycins, including rifampin and rifapentine, have concentration-dependent activity against M. 
tuberculosis.  Rifamycins are considered critical for sterilization, that is, prevention of relapse after 
cessation of TB treatment.  For rifapentine, the minimum inhibitory concentration (MIC)50 and MIC90 are 
one- to two-fold dilutions lower than those of rifampin (for the 7H10 agar system, rifapentine’s MIC50 and 
MIC90 are 0.125 and 0.25 mg/L, compared with 0.5 and 1.0 mg/L for rifampin) (Bemer-Melchior et al., 
2000).  In addition, rifapentine’s half-life (t1/2) is five times longer than that of rifampin (14-18 hours vs. 2-
5 hours).   


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Preclinical studies of rifapentine 
Murine model of tuberculosis treatment 
The murine model of TB has been used for more than 50 years for the development and evaluation of 
new antituberculosis drugs and regimens (Veziris et al., 2005). Importantly, the mouse model of TB 
treatment has been shown to recapitulate human TB treatment with regard to treatment-shortening 
effects of rifampin and pyrazinamide. In the mouse model, the standard 6-month rifampin plus isoniazid 
plus pyrazinamide (RHZ)-based regimen cures mice in 6 months, followed by relapse rates of 0-10%.  On 
the basis of its recapitulation of outcomes in humans, the murine TB treatment model is the reference 
standard against which new treatments are compared. 
Preclinical studies of tuberculosis treatment regimens containing rifapentine 
Pre-clinical studies suggest that improved antimycobacterial activity can be achieved with rifamycin 
exposure greater than that of the current standard regimen in which rifampin is used at a dose of 10 
mg/kg/dose (almost always given as 600 mg) once daily.  Increased rifamycin exposure can be achieved 
by using rifapentine.  Of note, the pharmacokinetics of rifapentine have been shown to be similar in mice 
and in humans (Rosenthal et al., 2005). In the murine model of TB treatment, once-daily rifapentine 
administered during intensive phase has very potent antimycobacterial activity that results in durable cure 
after only 3 to 4 months of total treatment (Rosenthal et al., 2008).  After aerosol infection, mice achieved 
a bacillary burden of 7.21 log10 cfu per lung.  Treatment with a standard regimen of daily rifampin (10 
mg/kg) plus isoniazid and pyrazinamide resulted in a decrease in bacillary burden of approximately 3 logs 
at completion of 4 weeks of treatment.  However, treatment with a regimen of daily rifapentine (10 mg/kg) 
plus isoniazid and pyrazinamide was significantly more active at 4 weeks (mean lung cfu counts that were 
1.00 log10 cfu lower than those for the standard regimen, p<0.001) and at 8 weeks (mean lung cfu counts 
that were >2 log10 cfu lower than those for the standard regimen, p<0.001). Furthermore, after 12 weeks 
of treatment, 100% (15/15) of mice treated with the standard regimen had bacteriological relapse, 
compared to 0/15 mice treated with the rifapentine regimen.  In fact, the rifapentine regimen resulted in 
cure of 15/15 (100%) of mice after treatment for only 10 weeks.      
Thus, murine studies indicate that rifapentine administered daily during combination intensive phase 
treatment has potent antimycobacterial activity that is associated with ability to achieve durable cure 
without relapse after about 3 months of total treatment. 
Clinical trials of daily rifapentine 
Phase I 
Dooley and colleagues conducted a phase I dose-escalation study among healthy adult volunteers to 
determine the safety and pharmacokinetics of escalating daily doses of rifapentine (Dooley et al, 2012).  
Participants received 5, 10, 15, or 20 mg/kg/dose rifapentine given once daily for 15 consecutive days; 20 
mg/kg/dose was the pre-specified maximum dose; a cohort of additional participants received rifampin 10 
mg/kg/dose.  Of note, this study used strict weight-based dosing, such that the average rifapentine dose 
administered in the 20 mg/kg/dose cohort was 1650 mg daily.  A total of 33 participants received study 
drugs.  There were no grade 2 or higher clinical adverse events.  Dose-limiting toxicities were observed in 
three participants, one each in the rifampin (grade 3 neutropenia), rifapentine 10 mg/kg (grade 3 serum 
liver transaminase elevation), and rifapentine 15 mg/kg (grade 3 lymphopenia) cohorts.  In this study, the 
safety profile of rifapentine was similar to that of rifampin 10 mg/kg/dose, and it was concluded that 
rifapentine administered daily was tolerated and safe at doses as high as 20 mg/kg/dose.  From a PK 
perspective, increases in rifapentine dosage resulted in less-than-dose proportional increases in single 
and multiple dose maximal concentrations.   


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Phase 2 
The TBTC recently completed two phase 2 studies to assess the antimicrobial activity, safety, and 
tolerability of daily rifapentine administered with isoniazid, PZA, and ethambutol during the first eight 
weeks of pulmonary TB treatment.  In TBTC Study 29, 531 adults with sputum smear positive pulmonary 
TB were randomized to receive rifapentine approximately 10 mg/kg/dose or rifampin 10 mg/kg/dose 
administered 5 days per week for 8 weeks (intensive phase) with isoniazid, PZA, and ethambutol; study 
drugs were administered on an empty stomach (Dorman et al, 2012).  The co-primary endpoints were 
negative sputum cultures on liquid and on solid media at the end of intensive phase; safety and 
tolerability were also assessed.  This study demonstrated no significant difference between regimens in 
antimicrobial activity based on the surrogate marker of culture status at completion of intensive phase 
(culture conversion on solid media 83.3% vs. 86.4% for the rifampin vs. rifapentine groups; and 
conversion in liquid media 65.1% vs. 67.9% in the rifampin vs. rifapentine groups).  The rifapentine 
regimen was well tolerated based on similar proportions of participants discontinuing assigned treatment 
overall (15.7% in the rifampin group vs. 14.5% in the rifapentine group) or due to toxicity (1.2% in the 
rifampin group vs. 1.5% in the rifapentine group). There were no differences, by treatment group, in 
proportions of participants with a serious adverse event related to study treatment (0.4% in the rifampin 
group vs. 1.1% in the rifapentine group), or by type or severity of adverse events.  Hepatitis occurred in 
2.8% of rifampin group participants vs. 4.0% of rifapentine group participants (p=0.48).  The investigators 
concluded that the rifapentine regimen administered on an empty stomach 5 days/week for 8 weeks was 
safe and well-tolerated but not significantly more active than the conventional rifampin regimen. 
 
The TBTC subsequently conducted a randomized, multicenter, dose-ranging study to determine the 
optimal dose of daily rifapentine during the first 8 weeks of pulmonary TB treatment.  In TBTC Study 29X, 
334 adults with sputum smear positive pulmonary TB were randomized to receive rifampin (approximately 
10 mg/kg/dose) or rifapentine (approximately 10, 15, or 20 mg/kg/dose, maximum dose 1500 mg) 
administered with a high fat meal once daily for 8 weeks, in addition to isoniazid, PZA, and ethambutol.  
Rifapentine was well-tolerated across all treatment arms based on a pre-specified definition and also 
based on comparison with the rifampin group.  Percentages of participants discontinuing assigned 
treatment were: rifampin 11/85 (12.9%; upper bound of 90% one-sided CI 19.0); rifapentine 10 mg/kg 
5/87 (5.7%; 10.5); rifapentine 15 mg/kg 5/81 (6.2%; 11.3); and rifapentine 20 mg/kg 9/81 (11.1%; 17.1).  
There were two deaths – one in the rifapentine 15 mg/kg group due to hematemesis, and one sudden 
death in the rifapentine 20 mg/kg group in a 61 year old male with untreated hypertension and diabetes 
mellitus and a strong family history of cardiac disease and sudden death.   There were no differences 
between treatment groups in the percentages of participants with a serious adverse event associated with 
study treatment, or by type or severity of adverse events.  Serious adverse events attributed to study 
treatment were as follows, by treatment assignment: two events among 85 participants in the rifampin 
group (one hepatitis, one drug allergy); one event among 87 in the rifapentine 10 mg/kg group 
(leukocytosis); no events among 81 participants in the rifapentine 15 mg/kg group; one event among 81 
participants in the rifapentine 20 mg/kg group (hepatitis).  With respect to antimicrobial activity (efficacy), 
the rifapentine regimens were substantially more active than the standard rifampin regimen based on 
week 8 (end of intensive phase) culture status (Table 1) as well as time to stable culture conversion. 
 
Antimicrobial activity was associated with rifapentine exposure (area under the concentration time curve 
[AUC]) (Table 1B).  The higher rifapentine exposures were associated with very high rates of sputum 
sterilization at two months, a very good indicator of overall efficacy of an anti-tuberculosis regimen. 
Findings were consistent with a steep exposure-response relationship.  Pharmacodynamic models were 
used to further elucidate the relationships between antimycobacterial activity and assigned rifapentine 
treatment arm, administered rifapentine dose, and rifapentine drug exposure. For efficacy outcomes of 


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time to stable culture conversion in solid media and time to stable culture conversion in liquid media, 
there was a significant association with rifapentine AUC (p=0.0002 for solid media and p=0.001 for liquid 
media) but not for assigned rifapentine mg/kg group (p=0.6 for solid media and p=0.36 for liquid media) or 
for  administered rifapentine dose in mg (p=0.17 for solid media and p=0.17 for liquid media).  For 
rifapentine, the exposure-response relationship was best described by a sigmoidal Emax function (Figure 
1), with the greatest change in effect per change in exposure occurring between exposures of 
approximately 200 mcg*h/L and 550 mcg*h/L, with a plateau in efficacy at higher exposures.  In addition 
to identifying a target AUC of approximately 500 to 600 mcg*h/L, pharmacokinetic studies yielded 
additional information pertinent for rifapentine dosing.  Specifically, the relationship between participant 
body weight and rifapentine clearance was examined, and clearance was not significantly affected by 
body weight, thereby supporting ‘flat’ dosing of rifapentine (i.e. rifapentine dose is not adjusted for body 
weight) (Figure 2).  In addition, pharmacokinetic/pharmacodynamic modeling also predicted that a 
rifapentine dose of 1200 mg without food would yield an AUC of approximately the same as that of a 
rifapentine dose of 900 mg with a very high fat meal.  Given that target rifapentine AUC lies somewhere 
between that achieved with a very high fat meal and rifapentine dose of 900 to 1200 mg, the strategy 
proposed in the current phase 3 trial is a rifapentine dose of 1200 mg with a modest food requirement, 
with the rationale that a very high fat meal is poorly feasible under phase 3 trial or routine TB care 
conditions whereas a more general recommendation of dosing with food is likely to be broadly feasible.    
 
Table 1A.  Percentages of participants with negative cultures at completion of intensive phase 
treatment, by treatment assignment, for the modified intention-to-treat analysis group, S29X 
 
Rifampin 
Rifapentine 
10 mg/kg 
Rifapentine 
15 mg/kg 
Rifapentine 
20 mg/kg 
Solid culture medium 
% (n/n) with negative cultures  
% difference vs. Rifampin 
(95% CI) 
p-value 
 
81.3 (52/64) 
 
 
 
92.5 (62/67) 
11.3  
(-1.7, 24.3) 
0.10 
 
89.4 (59/66) 
8.1  
(-5.5, 21.8) 
0.29 
 
94.7 (54/57) 
13.5  
(0.6, 26.3) 
0.05 
Liquid culture medium 
% (n/n) with negative cultures  
% difference vs. Rifampin 
(95% CI) 
p-value 
 
56.3 (36/64) 
 
74.6 (50/67) 
18.4  
(0.8, 35.9) 
0.04 
 
69.7 (46/66) 
13.4 
(-4.5, 31.4) 
0.16 
 
82.5 (47/57) 
26.2  
(8.9, 43.5) 
<0.01 
 
Table 1B.  Percentages of participants with negative cultures at completion of intensive phase 
treatment, by rifapentine area under the concentration-time curve tertile, for the modified intention-to-
treat analysis group, S29X 
 
Rifampin 
Rifapentine 
AUC < 323 
mcg*h/L 
Rifapentine 
AUC 324 to 513 
mcg*h/L 
Rifapentine 
AUC > 513 
mcg*h/L 
Solid culture medium 
% (n/n) with negative cultures  
% difference vs. Rifampin 
(95% CI) 
p-value 
 
81.3 (52/64) 
 
 
 
83.9 (52/62) 
2.6 
(-12.2, 17.4) 
0.88 
 
100.0 (63/63) 
18.8 
(7.6, 29.9) 
<0.01 
 
92.3 (60/65) 
11.1 
(-2.0, 24.2) 
0.11 
Liquid culture medium 
% (n/n) with negative cultures  
% difference vs. Rifampin 
(95% CI) 
p-value 
 
56.3 (36/64) 
 
54.8 (34/62) 
-1.4 
(-20.4, 17.5) 
1.00 
 
90.5 (57/63) 
34.2 
(18.5, 50.0) 
<0.01 
 
80.0 (52/65) 
23.8 
(6.6, 40.9) 
<0.01 


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Moxifloxacin for TB treatment 
Moxifloxacin is a fluoroquinolone with potent activity against M. tuberculosis in vitro and in animal models, 
including sterilizing activity in animal models.  In animal models, moxifloxacin’s potent activity is partly 
explained by the fact that it accumulates in granulomas and pulmonary lesions at higher concentrations 
than found in plasma and lung tissue (Kjellson et al., 2012; Prideaux et al., 2011). In humans, data on the 
long-term use of moxifloxacin have shown that it has an excellent safety profile.  Three phase 2 TB 
clinical trials have shown that substitution of moxifloxacin for ethambutol during the intensive phase of 
pulmonary TB treatment increases the antimicrobial activity of the regimen, as assessed using surrogate 
markers (Burman et al., 2006; Rustomjee et al., 2008; Conde et al., 2009).  A recently completed phase 3 
trial found that treatment with a weekly regimen of rifapentine and moxifloxacin during the continuation 
phase of therapy (Rifaquin 6 month regimen, Jindani, 2014) was non-inferior to daily isoniazid plus 
rifampin; the efficacy of rifapentine plus moxifloxacin in this trial is significant because once-weekly 
rifapentine with isoniazid (instead of moxifloxacin) is associated with higher rates of relapse and treatment 
failure (Vernon et al., 1999).  Two phase 3 treatment shortening studies using fluoroquinolone-based 4-
month regimens administered daily have been completed recently. The Oflotub Trial was an open-label, 
Phase 3 multicenter trial evaluating the efficacy and safety of a 4-month gatifloxacin (G) containing 
regimen compared to the standard 6-month HRZE regimen (Merle et al, 2014).  The Oflotub 4 month 
regimen consisted of a 2 month intensive phase of GHRZ, followed by a 2 month continuation phase of 
GRH (2GRHZ/2GRH) versus a control arm of 2ERHZ/4RH, administered 6 days per week. The 
investigational 4 month regimen failed to achieve non-inferiority at a 6% margin: in a modified intention-to-
treat analysis unfavorable outcomes at 24 months from end-of-treatment had occurred in 21.0% 
(146/694) in the gatifloxacin-containing arm vs. 17.2% (114/662) in the control arm (difference +3.5%, 
95% CI -0.7% to +7.7%). The REMox phase 3 study was a randomized placebo-controlled double-blind 
trial comparing two treatment shortening regimens, namely 2MHRZ/2MHR and 2EMRZ/2MR, with the 
standard control regimen 2EHRZ/4HR (Gillespie et al 2014).  The primary end point was treatment failure 
or relapse within 18 months after randomization.  In the REMox study, neither of the investigational 
Figure 1.  Exposure-response relationship 
for rifapentine
8
AUC (mcg*h/L)
effect
Median AUC, 1200 mg group
Median AUC, 900 mg group
Median AUC, 600 mg group
Body weight (kg)
Clearance (individual difference)
Figure 2.  Rifapentine clearance is not 
meaningfully affected by body weight


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moxifloxacin-containing regimens was shown to be non-inferior to the control.  Specifically, of the 1931 
patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in 
fewer patients in the 2MHRZ/2MHR group (85%) and the 2EHRZ/4HR group (80%) than in the control 
group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence 
interval [CI], 1.7 to 10.5) versus the 2MHRZ/2MHR group and 11.4 percentage points (97.5% CI, 6.7 to 
16.1) versus the 2EHRZ/4HR group.  Overall the 2MHRZ/2MHR group performed slightly better than the 
2EHRZ/4HR group, and achieved non-inferiority in certain sub-groups (e.g. females).   In the REMox 
study the two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load as 
compared to the control group. As in the Oflotub Trial, however, overall the experimental moxifloxacin 
single-substitution regimen was also not shown to be non-inferior to the control.  The fluoroquinolone-
containing regimens were safe and well-tolerated in both the Oflotub (gatifloxacin) and the REMox 
(moxifloxacin) studies. Overall, pre-clinical and clinical studies have shown that the single substitution of 
moxifloxacin for ethambutol increases antimicrobial activity of the regimen, but this increase is not 
sufficient to achieve acceptable cure rates after truncation of therapy to four months (Burman et al., 2006; 
Rustomjee et al., 2008; Conde et al., 2009, Merle et al, 2014, Gillespie et al., 2014). 
 
Quantitative capability of the Xpert MTB/RIF assay and its correlation with smear microscopy and 
culture. 
The Xpert MTB/RIF Assay, endorsed by the WHO in 2010 and FDA approved for marketing in the US in 
2013 for diagnosing TB, simultaneously detects the presence of M. tuberculosis in sputum and 
determines if genetic markers for rifampin resistance are present. Two studies have compared Xpert 
MTB/RIF results with sputum smear results in newly suspected pulmonary TB (Blakemore et al, 2011; 
Friedrich et al 2011). Medium and high qualitative readings from Xpert MTB/RIF correlate well with finding 
acid fast bacilli on sputum smears.  The quantitative capability of the Xpert MTB/RIF assay will be used in 
this trial at baseline to permit participant randomization based on a medium or high semi-quantification of 
M. tuberculosis copies on their Xpert test at screening. Drug susceptibility results as provided by the 
Xpert MTB/RIF assay or the Hain MTBDRplus assay, will also be used as part of screening and 
enrollment procedures.  
 
Efavirenz and Rifapentine Drug-Drug Interactions 
Rifamycin antibiotics such as rifapentine have the potential to cause significant drug-drug interactions 
with antiretroviral therapy. Rifapentine is a known inducer of various cytochrome P450 iso-enzymes.  The 
nonnucleoside reverse transciptase inhibitor efavirenz is a cytochrome P450 substrate, leading to 
concern for decreased efavirenz concentrations and an increased risk of virologic failure if dosed 
concurrently with rifapentine. Exposure-response relationships between efavirenz concentrations and 
virologic failure have been demonstrated. For example, Cohen et al. reported that in an evaluation of 142 
HIV-infected persons, efavirenz mid-dosing interval concentrations <1 mg/L were strongly associated with 
an increased risk for virologic failure (odds ratio 12.5, 95% CI, 2.7-57.3) (Cohen, 2009). The collective 
data for efavirenz indicate an increased risk of virologic failure if mid-dosing interval (or trough) 
concentrations are less than 1 mg/L. 
  
Clinical studies evaluating the effects of rifapentine co-administration on efavirenz pharmacokinetics and 
efficacy have shown mixed results.  Among individuals with HIV infection enrolled in a clinical trial of 
treatment for latent TB infection, preliminary data recently presented by Podany et al. suggest no clinically 
relevant increase in efavirenz oral clearance when dosed together with isoniazid and rifapentine (10 
mg/kg) once daily for four weeks.  In this study of 87 patients, median mid-dosing interval efavirenz 
concentrations decreased in the presence of rifapentine (2588ng/mL vs 2460ng/mL), suggestive of an 


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induction effect on efavirenz by rifapentine; however, the geometric mean ratio of efavirenz oral clearance 
increased by only 4%.  Additionally, virologic suppression was maintained in 97% of the patients in the 
study (Podany, 2014).  A second study, from Farenc et al. investigated the effect of repeated once weekly 
900mg rifapentine dosing on efavirenz pharmacokinetics.  In 12 HIV-infected, TB free adults, the authors 
found a minimal decrease in efavirenz exposure, as measured by a mean decrease in AUC0-24 of 14% 
(Farenc, 2014). A third study investigated the effect of daily rifapentine dosing (15mg/kg) for 21 days in 
HIV-infected, TB free adults receiving efavirenz based ART with baseline suppressed viral load (VL< 20 
copies/mL).  After a single dose of rifapentine efavirenz PK was unchanged (Cmax, AUC0-24, Cmin).  
However, after 21 once-daily doses of 15 mg/kg rifapentine, decreases of 17%, 37% and 33% were seen 
in Cmax, AUC0-24 and Cmin respectively (Sanofi, 2014).  All patients maintained viral suppression while 
taking RPT. While these studies are encouraging in that co-administration of rifapentine at daily doses of 
10 and 15 mg/kg with EFV-based ART did not appear to increase risk of HIV treatment failure, further 
investigations of efavirenz PK and HIV treatment response when rifapentine is given at 1200 mg daily for 
a longer duration are needed.  
 
The Tuberculosis Trials Consortium (TBTC) 
The mission of the TBTC, funded by the U.S. Centers for Disease Control and Prevention, is to conduct 
programmatically relevant clinical, laboratory and epidemiologic research concerning the diagnosis, 
clinical management, treatment and prevention of tuberculosis infection and disease.  The TBTC has 
sites in the United States, Spain, South Africa, Hong Kong, Kenya, Vietnam, Peru, and Uganda.  All sites 
have close connections with the local TB control program; some sites are based in the TB control 
program.  All sites work with experienced mycobacterial laboratories, and the CDC’s Mycobacteriology 
Laboratory serves as the central laboratory for confirmation of drug-susceptibility testing, DNA 
fingerprinting, and further characterization of drug-resistant isolates.  Since its inception in 1994 over 
13,000 patients have been enrolled in TBTC clinical trials.  
 
The AIDS Clinical Trials Group (ACTG) 
The mission of the ACTG, established in 1987, is to develop and conduct scientifically rigorous 
translational research and therapeutic clinical trials, in the U.S. and internationally, related to HIV infection 
and its complications including tuberculosis.  The ACTG is funded by the U.S. National Institutes of 
Health through the National Institute of Allergy and Infectious Diseases.  ACTG units and investigators 
serve their communities as major resources for HIV/AIDS research, treatment, care, and education.  The 
ACTG tuberculosis laboratory infrastructure consists of one international tuberculosis specialty laboratory 
as well as regional tuberculosis diagnostic laboratories.  
2.2 
Rationale 
Rationale for regimen selection 
The current standard six-month TB treatment regimen for drug-susceptible pulmonary tuberculosis is 
associated with unacceptably high rates of treatment default under program conditions, thereby 
contributing to individual morbidity and mortality, M. tuberculosis transmission, and drug resistance.  
Highly potent regimens of shorter treatment duration may facilitate treatment completion and direct 
observation of treatment, thereby improving individual and public health.  Studies using animal models of 
TB chemotherapy have shown a clear relationship between rifamycin exposure and reduction of bacillary 
burden.  Animal studies also indicate that rifapentine-based regimens are highly potent and can reduce 
overall tuberculosis treatment duration to approximately 3 months.  In humans, phase 1 and 2 clinical 
trials support the safety and tolerability of rifapentine at daily doses up to 20 mg/kg.  A phase 2 clinical 
trial has shown a strong drug exposure-response effect for rifapentine using a surrogate marker of time to 


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stable culture conversion.  These results provide rationale for a phase 3 clinical trial to determine the 
efficacy, using the definitive endpoint of durable cure, of a regimen containing rifapentine substituted for 
rifampin and administered in combination with other drugs for 17 weeks (approximately four months).  
This trial will also assess the efficacy of a second investigational 17-week regimen that incorporates two 
strategies to enhance antimicrobial activity. The first strategy is optimization of rifamycin exposure 
through the single substitution of high dose rifapentine for rifampin throughout treatment as described 
above. The second strategy is a dual substitution approach that seeks to further enhance the potency of 
the regimen by also replacing ethambutol (which has relatively weak activity) with moxifloxacin, in the 
context of optimized rifamycin exposure.  As described above, available evidence from animal models 
and in humans indicates that moxifloxacin, when substituted for ethambutol, will contribute to regimen 
bactericidal activity, even though that single substitution alone is insufficient to shorten treatment to four 
months. The investigational regimen that contains both rifapentine and moxifloxacin may well be the most 
potent regimen possible without new chemical entities.  Therefore if both investigational regimens fail in 
the proposed study, then the implications are that new drugs are required for treatment shortening, and 
that treatment shortening cannot be achieved with existing drugs.  Such a finding would push the drug-
susceptible TB therapeutics field in a different direction.    
Rationale for dosing strategy 
With respect to rifapentine dose and dosing strategy, this trial will use a flat dose of 1200 mg with food 
dosed daily. This is based on 1) demonstration of safety of rifapentine at 1200mg in phase 1 and 2 trials, 
2) demonstration that body weight does not significantly affect rifapentine clearance, 3) recognition of an 
effect of food in substantially increasing rifapentine absorption (Zvada et al., 2010) and 4) modeling 
predictions that the target rifapentine exposure (AUC of approximately 500 to 600 mcg*h/L) is achievable 
using this strategy.  
 
For rifampin, administration with food slows the rate of absorption and decreases the maximal 
concentration (Cmax) by about 36% in healthy adults but to a lesser extent (5 to 15%) in TB patients, with 
little to no effect on AUC (reduction of 6% in healthy adults; reduction of 4% to increase of 8% in TB 
patients) (Peloquin et al., 1999; Zent et al., 1995).  Overall the clinical consequences of these PK effects 
are unclear.  As a consequence rifampin will not be dosed with food.  
 
Rationale for an open-label (not blinded) study 
This study will be open-label; participants, study staff, and clinical care providers will have knowledge of 
treatment assignment.  While blinding is often incorporated into clinical trials as a strategy to reduce bias, 
blinding is not without cost.  Besides logistic complexity, there are two main reasons to not incorporate 
blinding into this trial.  First, if blinding through use of placebos were to be incorporated into this trial, the 
already substantial pill-burden would be further increased to approximately 20 pills per day, which will be 
difficult for participants to tolerate.  Poor tolerability of the pill burden may result in diminished adherence 
to treatment and in turn efficacy.  Besides tolerability, from a biological perspective the dissolution of pills 
in the gastrointestinal tract may be reduced with such a high pill burden, a situation that could result in 
diminished treatment efficacy and increased risk for acquisition of drug resistance. Reduced 
bioavailability due to the burden of added placebo pills also might reduce the generalizability of study 
findings to possible subsequent programmatic usage.  As noted above, there may be a differential effect 
of food on rifampin and rifapentine such that different food advice is required so as to optimize regimen 
pharmacokinetics and potential efficacy. The study will minimize any impact of ascertainment bias 
through the use of objective laboratory measures for the primary efficacy endpoint as well as 
incorporation of a central study clinician (who is blinded as to individual participants’ treatment 


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assignments) to advise local site teams in instances of potential toxicity or treatment failure/recurrence. 
Co-intervention bias is unlikely during the active treatment in the first four months, and it is unlikely that 
the use of placebo can effectively avoid contamination bias in the last two months. Co-intervention bias is 
unlikely during active TB treatment, as site teams will closely monitor participants. Measures will be taken 
to evaluate participants equally, regardless of assigned study arm, such that timing of study visits and 
endpoints will be applied uniformly. 
 
Rationale for CD4 testing before enrollment 
HIV-infected individuals will be excluded from enrollment if, at the time of enrollment, their CD4 T cell 
count is known to be <100 cells/mm3.  The rationale for doing so is the challenge of starting concomitant 
treatment for HIV-infection and TB within a short period of time as recommended by WHO guidelines, the 
potential for severe immune reconstitution when antiretroviral therapy is initiated early in the course of 
anti-TB therapy, an increased probability for the diagnosis of conditions that would require therapy with 
medications that have drug-drug interactions with study drugs, and the indication for primary antimicrobial 
prophylaxis against opportunistic infections (such as toxoplasmosis and Mycobacterium avium) with 
consequent increase in the probability of drug-drug interactions and adverse events.  Additionally, 
treatment assignment is stratified by CD4 T cell count (Section 7.2). 
 
Rationale for including adolescents 
 
Inclusion of children in clinical trials of tuberculosis treatment increasingly has been called for to support 
the rational use and increased availability of anti-tuberculosis medications for children (Burman 2006, 
McKenna 2014). Tuberculosis disease characteristics, presentation, diagnosis, and treatment are similar 
for adults and adolescents.  
 
Rifapentine currently is approved in the United States for use in persons as young as 12 years old 
(Priftin® package insert). Rifapentine pharmacokinetic results have been found to be similar between 
adults and adolescents down to this age (Marshall 1999).  Rifapentine 900 mg once weekly, with 
isoniazid for 12 weeks has been used to treat children for latent TB infection (LTBI) (Villarino 2015): the 
rifapentine-containing regimen was found to be as safe and effective as a 9-month daily isoniazid 
regimen, among 552 children age 2-17 years old treated with the rifapentine-containing regimen. Based 
on a large clinical trial that reported treatment of patients as young as 12 years old (Sterling 2011), CDC 
recommends use of this rifapentine-containing regimen “as an equal alternative to 9 months of daily self-
supervised INH for treating LTBI in otherwise healthy patients aged ≥12 years.” (CDC 2011) Although the 
phase 2 trial of daily high-dose rifapentine enrolled 81 participants ≥ 18 years old (Dorman 2013), 
available animal and human data and a formal review by Sanofi support the safety of including 
adolescents in this clinical trial (Marilyn Maroni personal communication).                                                                               
 
Moxifloxacin usage in children has been limited because of findings that treating juvenile dogs with doses 
higher than recommended for humans (≥ 30 mg/kg/day) resulted in arthropathy (Avelox® package insert). 
Moxifloxacin has been recommended and used in children for treatment of multidrug resistant (MDR) TB 
although few safety data have been collected systematically (Bradley 2011). One recent report of a series 
of 9 children age 6 months to 13 years, treated with moxifloxacin for a range of 3-16 months, attributed 
side effects possibly to moxifloxacin in 2 patients (Garazzino 2014): A 6-year old girl developed arthritis of 
the ankle after 3 months, which “spontaneously resolved few days after drug cessation.” A 3-year old girl 
developed “grade three elevation of liver function tests after 9 months of treatment.” A more recent report 
of 23 children, median age 11.1 years (IQR 9.2-12.0 years), treated for MDR TB with moxifloxacin 
followed the children for a median of 236 days (IQR 142-541 days (Thee 2014). This group found lower 
exposures in children than in adults following an oral dose of 10 mg/kg and lower exposure with HIV 
infection. They found moxifloxacin to be safe and well tolerated, with a conservative approach to 
determining an event not to be related to moxifloxacin in the presence of multiple second line drugs. 
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events, 4 grade 1, 1 grade 3), pain other than traumatic injury (1, grade 1), headache (5 patients, 5 
events, 4 grade 1, 3 grade 3), fatigue/malaise (1, grade 1), nausea (9 patients, 9 events) grade 1), 
vomiting (3 patients, 3 events, 3 grade 1),cutaneous reaction (1, grade 1), pruritis,(2 patients, 4 events, 4 
grade 1), elevated alanine-aminotransferase (ALT) (4 patients, 5 events, 2 grade 1, 2 grade 2 1 grade 3), 
bilirubin (1 grade 2). ECG data was available for 13 children: mean QTc was 403 ms (SD 30 ms); none 
had QTc interval >450ms. In a separate report, a case of self-limited polyarthritis was reported for a 12-
year old child who inadvertently received a single 2 gram dose of moxifloxacin (50 mg/kg/day) (Torres 
2008), illustrating the presence of some risk but also the difficulty of finding moxifloxacin toxicity in 
children with standard dose treatment. 
 
Daily treatment of adolescents and children with moxifloxacin and with high-dose rifapentine has been 
limited. The benefits of finding regimens that would substantially shorten treatment for this important 
subset of TB patients outweigh the theoretical risks. The frequent careful monitoring for signs and 
symptoms in a clinical trial provides the opportunity to respond quickly to abnormal findings if they occur 
in an individual, but also to document systematically the safety profile for these promising treatment 
regimens. 
2.3 
Potential Harms and Benefits 
2.3.1 Potential harms 
Risks associated with study participation include the possibilities that an investigational regimen 
has efficacy that is inferior to the standard regimen and/or an investigational regimen is more 
toxic than the standard regimen, and confidentiality risks.  
The investigational regimens could prove to have inferior efficacy compared to the standard 
regimen.  TBTC Study 29X showed that a regimen containing rifapentine administered daily at 
1200 mg (approximately 20 mg/kg) has sufficient antimicrobial activity to justify further evaluation 
compared to a regimen containing rifampin administered daily at approximately 10 mg/kg, using a 
surrogate marker for durable cure. Other recent phase 2 studies have demonstrated that 
substitution of moxifloxacin for ethambutol increases the antimicrobial activity of the regimen.  
Equipoise around whether these increases in antimicrobial activity can result in durable cure after 
four months of treatment forms the basis for inclusion of test regimens 2PHZE/2PH and 
2PHZM/2PHM.  Further, as described above, studies have shown that moxifloxacin substituted 
for ethambutol increases antimicrobial activity, and PZA has important bacterial sterilizing 
properties.  The following measures will minimize risk to participants: individual participants will 
be closely monitored clinically and bacteriologically, an interim efficacy analysis will be performed, 
and a Data and Safety Monitoring Board will review trial progress regularly.  In addition, it is 
anticipated that participants who are not cured will be re-treatable with conventional anti-
tuberculosis drugs as acquired drug resistance is very unlikely in the setting of highly monitored 
directly observed combination therapy (Johnson et al., 2009, Jindani et al., 2013).  
The investigational regimens could prove to have greater toxicity than the standard regimen.  This 
is unlikely given that toxicity data collected in the phase 2 clinical trial showed that rifapentine 
administered at a once daily dose of 20 mg/kg for eight weeks was well tolerated.  However, no 
clinical trial has included patients treated with daily rifapentine for more than 2 months.  With 
respect to the moxifloxacin-containing regimen, the toxicity profile of moxifloxacin is well known. 
Moxifloxacin is used regularly for prolonged periods during the treatment of patients with drug 
resistant tuberculosis. Participants in this clinical trial will be monitored closely for adverse events.  
The Data and Safety Monitoring Board (DSMB) will review safety data regularly.   


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Confidentiality risks will be minimized through the measures described in Section 15.3.  
2.3.2 Potential benefits 
All 3 study treatment regimens are offered with therapeutic warrant, meaning that it is reasonable 
to expect that these TB treatments will cure TB at an acceptable, if not yet uniformly 
demonstrated, rate. Study participants will benefit indirectly as it is well established that 
tuberculosis outcomes for participants in tuberculosis treatment trials are better than those for 
patients receiving routine care.  This study will benefit society by contributing to the 
understanding of optimal strategies for treating tuberculosis.  The inclusion of clinical specimen 
storage along with the combined use of two culture media types (solid and automated liquid) in 
this phase 3 trial will contribute urgently needed data that can help determine the optimal use of 
liquid culture in drug development and will facilitate discovery efforts for new surrogate markers.   


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3 
DESCRIPTIONS OF STUDY DRUGS 
Drugs to be administered during this study include the following: rifapentine, rifampin, moxifloxacin, 
isoniazid, pyrazinamide, ethambutol, and vitamin B6 (pyridoxine).  Rifapentine and the other drugs are 
described in detail in their package inserts.  Key points are summarized below. 
3.1 
Rifapentine 
Rifapentine is indicated for the treatment of pulmonary tuberculosis caused by Mycobacterium 
tuberculosis, and must be used in combination with one or more antituberculosis drugs to which the 
bacterial isolate is susceptible (Priftin package insert, 2010).  Rifapentine, as Priftin® was approved by 
the U.S. FDA in 1998.  FDA approval was based on the results of “Clinical Study 008”, an open-label, 
prospective, randomized study of 722 patients with active pulmonary TB (Priftin package insert, 2010).  
Rifapentine is a semisynthetic rifamycin derivative with a microbiologic profile similar to that of rifampin.  
Its structure differs from that of rifampin by the presence of a cyclopentyl ring instead of a methyl group at 
the piperazinyl moiety.  It has a longer half-life than rifampin, and, like rifampin, rifapentine inhibits 
bacterial RNA synthesis by binding to the β-subunit of DNA-dependent RNA polymerase. Rifapentine is 
well absorbed from the gastrointestinal tract, with 70% bioavailability; when taken with food, its AUC and 
Cmax increase by 43% and 44%, respectively (Priftin package insert, 2010).  It reaches peak 
concentrations in the serum 5 to 6 hours after ingestion.  Rifapentine and its 25-desacetyl metabolite are 
highly protein-bound, 97.7% and 93%, respectively, primarily to albumin.  Rifapentine is metabolized by 
an esterase enzyme found in the liver and blood to 25-desacetylrifapentine, a microbiologically active 
metabolite that contributes about 40% of the drug’s overall activity.  For M. tuberculosis, the MIC of 25-
desacetyl rifapentine is 0.25 mcg/mL, while that of rifapentine is 0.05 mcg/ml.  The drug and the active 
metabolite have half-lives of 14-17 and 13 hours, respectively.  The drug is excreted in bile and 
eliminated in feces.  Less than 10% of rifapentine is excreted in the urine as unchanged drug.  
Rifapentine, 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 glucuronosyltransferase and sulphotransferase and may reduce levels of drugs 
metabolized by those pathways.  Rifapentine is available as 150 mg tablets.  Rifapentine, like other 
rifamycins, causes red-orange discoloration of body fluids and can stain contact lenses.  In clinical trials in 
which rifapentine was combined with isoniazid and other antituberculosis drugs and administered once or 
twice weekly, rates of adverse reactions were similar with rifampin and rifapentine, with increased liver 
aminotransferase activity in about 5% of patients.  The only adverse effect that has occurred more often 
with rifapentine than with rifampin has been hyperuricemia when the drug was given twice-weekly; of 
note, hyperuricemia was attributed to pyrazinamide that was administered concomitantly.  Other adverse 
reactions that occurred in 1-5% of patients included the following:  hemoptysis, dizziness, hypertension, 
headache, gastrointestinal upset, rash, cytopenias, hematuria, pyuria, and proteinuria   (Priftin package 
insert, 2010).   
3.2 
Rifampin 
Rifampin is a semi-synthetic rifamycin derivative that is highly active against mycobacteria, most gram-
positive bacteria, and some gram-negative bacteria.  It is bactericidal for both intracellular and 
extracellular microorganisms.  By inhibiting prokaryotic DNA-dependent RNA polymerase, it suppresses 
the early elongation of the nucleotide chain in RNA synthesis.  Rifampin is normally absorbed completely 


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when taken orally, but food delays absorption. After 1.5 to 2 hours, a 600 mg dose yields a peak blood 
level of 8-20 mcg/ml. The half-life of rifampin varies from 2 to 5 hours, and it is shortened by 
approximately 20-40% after the first week of daily treatment because of the induction of hepatic 
microsomal enzymes.  The half-life is unaffected by renal impairment but is increased by liver disease or 
biliary obstruction.  Rifampin is deacetylated to an enterohepatically-recirculated active metabolite, and 
50% to 60% is excreted in the feces.  Up to 30% of a dose is excreted in the urine.  Approximately 85% of 
circulating rifampin is bound to plasma proteins, and is widely distributed throughout the body.  Rifampin 
is a potent inducer of a number of hepatic enzymes involved in the metabolism of drugs and some 
hormones (Venkatesan, 1992).  This enzyme induction causes more rapid elimination (and potential loss 
of efficacy) of many drugs.  In the usual daily doses of 10 mg/kg (maximum 600 mg), rifampin is well 
tolerated.  It often causes harmless but disconcerting red-orange discoloration of tears, sweat, saliva, 
feces, and urine.  Less than 4% of TB patients experience significant adverse reactions to rifampin.  
Gastrointestinal adverse effects are the most common, and they include epigastric distress, anorexia, 
nausea, vomiting, cramps, and diarrhea.  Hepatitis rarely occurs in persons who have normal baseline 
hepatic function.  The incidence of hepatitis may be increased for older persons and those who have 
chronic liver disease or alcoholism, but remains substantially lower than that for pyrazinamide or 
isoniazid.  Rifampin can cause a flu-like syndrome of fever, chills, headache, dizziness, and bone pain, 
although this is uncommon using the 600 mg dose given daily.  In a very small proportion of patients the 
flu-like syndrome is associated with interstitial nephritis, acute tubular necrosis, thrombocytopenia, 
hemolytic anemia, and shock.  (Rifadin [rifampin] package insert. Sanofi, 2013). 
3.3 
Moxifloxacin 
Moxifloxacin (Avelox®, Bayer HealthCare Pharmaceuticals, Inc) is a fluoroquinolone antibacterial that is 
distinguished by a methoxy group at the C-8 position and an S,S-configured diazabicyclononyl ring 
moiety at the C-7 position.  The mechanism of action against M. tuberculosis is by inhibition of the DNA 
gyrase enzyme involved in DNA replication.  Moxifloxacin is well absorbed, with a bioavailability of 
approximately 90% (Avelox package insert, 2012). Pharmacokinetics are linear in the range of 50-800 mg 
single dose and up to 600 mg once daily dosing over 10 days.  Steady state is reached within 3 days. The 
mean (+SD)  maximum concentration (Cmax ) and AUC values at steady state with a 400 mg once-daily 
dosage regimen are 4.5+0.53 mcg/ml and 48+2.7 µg*h/ml, respectively.  Tmax  is  approximately 1-3 
hours. The mean (+SD) plasma half-life is 12.1 + 3.1 hours.  Trough plasma concentration at steady state 
(400 mg once daily) is 0.95 + 0.10 mcg/L.   Co-administration with food may slightly prolong Tmax, and 
may reduce the Cmax by 16%; these effects are not believed to be clinically significant, and thus 
moxifloxacin can be administered with or without food.  Moxifloxacin is 50% bound to plasma proteins.  It 
is widely distributed, with some tissue concentrations reported in excess of plasma levels. Moxifloxacin is 
metabolized by glucuronide and sulfate conjugation.  The cytochrome p450 enzyme system is not 
involved in the metabolism of moxifloxacin, nor does the drug effect it.  Specifically, moxifloxacin does not 
affect CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2.  Moxifloxacin should not be administered at 
the same time as antacids containing magnesium and/or aluminum, sucralfate, antidiarrheals that contain 
kaolin, or iron and/or zinc containing medications or supplements.  As a class, fluoroquinolones are 
considered to be safe and relatively free of serious adverse effects (Ball, 1989). The safety and efficacy of 
moxifloxacin for the treatment of community acquired bacterial infections has been extensively studied.  
In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated.  Expected minor adverse events 
have occurred with a frequency similar to that for other fluoroquinolones in similar populations. 
Gastrointestinal adverse effects are the most common, and they include nausea (7%), diarrhea (6%), 
dizziness (3%), abdominal pain (2%), vomiting (2%), dyspepsia (1%), and taste perversion (1%).  There 
are no current reports of hepatitis, although abnormal liver function tests have been noted in 1% of 


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patients. Of note, fluoroquinolones are generally used short-term for acute conditions.  However, 
fluoroquinolones have been found to be safe and effective in long term use for chronic infections such as 
osteomyelitis, prostatitis, or chronic urinary tract infection, or skin and skin structure infections (Ball, 1989; 
Segev et al., 1999). In addition, Valerio et al. found that the combination of moxifloxacin, isoniazid, and 
rifampin given for 6 months was well tolerated (Valerio et al., 2003). For treatment of MDR-TB, a later-
generation fluoroquinolone such as moxifloxacin is recommended for a duration of 8 months or more 
(WHO, 2011).  Moxifloxacin causes a mild prolongation of the corrected QT (QTc) interval.  The mean 
effect on QTc interval in 787 patients in Phase 3 clinical trials was 6 + 26 milliseconds, but no morbidity or 
mortality was attributable to QTc prolongation.  In a review of over 6,000 patients treated with 
moxifloxacin, there were no reports of changes in the frequency of QTc prolongation (Ball, 2000).  In over 
10 million patients treated with moxifloxacin there has been no evidence for an increased incidence of 
ventricular arrhythmia when compared to the overall population.  Finally, the incidence of sudden death 
and syncope, both markers for sudden cardiac events, is not increased when compared to the incidence 
on the general population.  For these reasons, electrocardiographic monitoring is no longer 
recommended for clinical trials involving moxifloxacin.  In this study, moxifloxacin will not be used among 
patients with a known history of prolongation of the QT interval, patients with uncorrected hypokalemia 
and patients receiving class Ia (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) 
antiarrhythmic agents, due to the lack of clinical experience with the drug in these patient populations 
(see Eligibility criteria).  Pharmacokinetic studies between moxifloxacin and other drugs that prolong the 
QT interval such as cisapride, erythromycin, antipsychotics and tricyclic antidepressants have not been 
performed.  An additive effect of moxifloxacin and these drugs cannot be excluded, therefore moxifloxacin 
should be used with caution when given concurrently with these drugs.  The estimated incidence of 
fluoroquinolone-induced tendinopathy is 15 to 20 per 100,000. Fluoroquinolone-induced tendinopathy is 
diagnosed by a sudden onset of swelling and tenderness concurrent with or shortly after fluoroquinolone 
therapy, which is accompanied by tendon rupture in about 33% of all cases.  The main site affected is the 
Achilles tendon, though tendinitis has been reported to involve the shoulder, knee, hand, and plantar 
aponeuroeses.  Achilles tendon ruptures have been noted even months after discontinuation (Pierfitte et 
al., 1996). Concomitant use of corticosteroids is considered to be a risk factor for developing tendinopathy 
while taking fluoroquinolones. In over 10 million patients treated with moxifloxacin only 3 patients with 
tendon rupture have been reported.  All had received concomitant corticosteroid treatment. 
3.4 
Isoniazid 
Isoniazid is the hydrazide of isonicotinic acid and is one of the primary drugs for TB treatment.  The 
activity of isoniazid is limited to the mycobacteria of the M. tuberculosis complex; it is bactericidal for 
rapidly dividing organisms and bacteriostatic for “resting” bacilli.  The probable mechanism of action is the 
inhibition of the biosynthesis of mycolic acids, a component of the mycobacterial cell wall.  Isoniazid is 
generally well absorbed; food and antacids decrease the rate, but not the extent of absorption. Peak 
blood levels of isoniazid, 3 to 5 mcg/ml, are obtained 30 minutes to 2 hours after ingestion of routine 
doses (Peloquin et al. 1999).  It diffuses into all body fluids and cells and penetrates into the caseous 
material of a tuberculoma or pulmonary cavity.  In the liver, it is acetylated to inactive metabolites, and 
75% to 95% of the dose is excreted as inactive metabolites in the urine within 24 hours.  Isoniazid 
clearance rates depend on 2 metabolic phenotypes, slow and fast acetylation, which are associated with 
race, but not gender (Ellard., 1984). The isoniazid AUC among persons who have fast acetylation is 30% 
to 50% of that among persons who have slow acetylation.  Because isoniazid is well tolerated over a wide 
range of therapeutic doses, a single dose per body mass is recommended.  Persons who have rapid 
acetylation achieve effective concentrations, while persons who have slow acetylation do not experience 
increased toxicity.  Half-life (t1/2) may vary from 1 hour in fast acetylators (t1/2 < 90min) to 3 hours in slow 


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acetylators (t1/2 >90min).  The usual adult dose of isoniazid is 5 mg/kg given once daily, up to a maximum 
of 300 mg given once daily.  Isoniazid decreases the clearance of some medications that are metabolized 
in the liver (particularly carbamazepine, phenytoin, and diazepam) (Baciewicz et al. 1985).  However in 
the context of multidrug therapy including rifampin, these potential drug-drug interaction are of little 
significance because the effect of isoniazid is counteracted by the more potent opposing effect of rifampin 
(Kay et al. 1985).  The total incidence of all adverse effects from isoniazid is approximately 5%, many of 
which do not require discontinuation of the drug.  Peripheral neurotoxicity is dose dependent and it is 
uncommon (<0.2%) at conventional doses. The risk of peripheral neuritis increases for persons who are 
malnourished or predisposed to neuritis by other illnesses.  Concomitant administration of pyridoxine 
(vitamin B6) is recommended for these persons, and will be given to all patients in this trial.  Other 
nervous system reactions are rare at normal doses, and they include convulsions, encephalopathy, optic 
neuritis, memory impairment, and psychosis.  Gastrointestinal adverse effects include nausea, vomiting, 
and epigastric distress.  Asymptomatic elevation of aminotransferases is common and occurs in 10-20% 
of persons receiving isoniazid. However, idiosyncratic severe hepatic reactions are uncommon but are 
more likely in older persons (up to 2.3% hepatitis incidence in persons more than 50 years old), and may 
be life threatening.  Daily consumption of alcohol increases the risk of isoniazid-associated hepatotoxicity 
by approximately 4-fold.   
3.5 
Pyrazinamide 
Pyrazinamide is an analog of nicotinamide and has unique activity against M. tuberculosis, allowing the 
duration of treatment to be decreased from 9 months to 6 months (assuming a rifamycin is used 
throughout).  The mechanism of action of pyrazinamide remains incompletely understood, but there is 
evidence that pyrazinamide inhibits M. tuberculosis trans-translation.  Pyrazinamide is well absorbed from 
the gastrointestinal tract and widely distributed into all tissues  (Ellard et al., 1987). Usual doses are 15-30 
mg/kg/d, up to 2 gm/d.  Peak serum concentrations of about 45 mcg/ml are achieved approximately 2-3 
hours after a dose. Food and antacids do not significantly affect the absorption of pyrazinamide.  The 
half-life of pyrazinamide is approximately 9-10 hours, and is prolonged in the presence of hepatic 
insufficiency (Lacroix et al., 1990).  Pyrazinamide is metabolized to pyrazinoic acid by the hepatic 
microsomal enzyme pyrazinamide deamidase.  Approximately 40% of a dose is recovered in the urine as 
pyrazinoic acid and an additional 4% is excreted in the urine as the unchanged parent drug (Ellard, 1969).  
The remaining drug is thought to be excreted in the bile.  There are no known clinically significant drug-
drug interactions involving pyrazinamide.  The most frequent side effects are skin rash, gastrointestinal 
intolerance, hepatotoxicity (1.3%), arthralgias (1-7%), hyperuricemia due to blockade of urate excretion 
(up to 66%), and rarely acute gouty arthritis (Patel et al., 1995; Ormerod et al., 1996).  These side effects 
are seldom dose-limiting. Asymptomatic elevations in serum uric acid are frequent, usually occur during 
the first or second month of treatment, and are self-limited and require no specific treatment (Zierski et al., 
1980). Minor arthralgias also may occur during pyrazinamide treatment and can usually be treated with 
salicylates or non-steroidal inflammatory agents such as indomethacin while continuing the drug.  The 
most common serious side effect of pyrazinamide is hepatotoxicity.  In 2 randomized clinical trials the 
addition of pyrazinamide to RH did not increase the rates of hepatotoxicity above that seen with the latter 
2 drugs alone (Zierski et al., 1980; Combs et al., 1990).  However, 3 recent retrospective cohort studies 
suggest that the incidence of pyrazinamide-induced hepatitis during active TB treatment is higher than 
that for other first-line TB drugs, and higher than previously recognized (Yee et al., 2003; Schaberg et al., 
1996; Dossing et al., 1996).  Hepatitis risk persists with prolonged use (Reves et al., 2014). 


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3.6 
Ethambutol 
Ethambutol is an ethylene derivative of butane that interferes with cell wall synthesis in mycobacteria; 
other bacteria are uniformly resistant to ethambutol.  In the treatment of human TB, ethambutol is 
effective in preventing the emergence of drug resistant strains, although it has no sterilizing activity at 
clinically-tolerated doses (Kohno et al. 1992).  Ethambutol is well absorbed from the gastrointestinal tract, 
reaching peak serum concentrations of 3-5 mcg/ml in normal volunteers 2-4 hours after a dose.  Food 
slows absorption and decreases the peak serum concentration by 10-20%, but has no effect on the total 
systemic exposure.  Antacids decrease both the peak serum concentration and AUC, and so should not 
be administered at the same time.  Ethambutol is primarily eliminated by the kidneys as unchanged drug; 
the serum half-life averages 4 hours.   Patients with renal insufficiency are prone to accumulation of the 
drug and the resultant toxicity.  There are no known drug–drug interactions involving ethambutol.  
Ethambutol is usually well-tolerated with low rates of skin rash, nausea, vomiting, or diarrhea.  Fever, 
allergic reactions, abdominal pain, mental status changes, peripheral neuropathy, and increased liver 
function tests have rarely been associated with ethambutol.  Adverse events occur in less than 2% of 
patients receiving ethambutol at the 15 mg/kg dose and include decreased visual acuity (0.8%), rash 
(0.5%) and asymptomatic hyperuricemia (Patel et al., 1995). The most common serious side effect of 
ethambutol is retinal toxicity, often first perceived as a decrease in color perception.  Patients receiving 
ethambutol should be instructed about symptoms of ocular toxicity.  If stopped promptly, permanent visual 
loss is rare among patients with ethambutol-related retinal toxicity.  Rates of retinal toxicity are very low 
when the drug is given for relatively short periods, as is the case in this study. 
3.7 
Vitamin B6 (Pyridoxine) 
Pyridoxine (vitamin B6) is an essential vitamin involved in carbohydrate, fat, protein and brain amine 
metabolism. Isoniazid competitively inhibits the action of pyridoxine in these metabolic functions and also 
causes increased urinary excretion of pyridoxine (Snider, 1980).  Chronic isoniazid administration can 
result in pyridoxine deficiency, which may manifest as acral paresthesias due to peripheral, predominantly 
sensory, axonal polyneuropathy. Isoniazid-associated peripheral neuropathy is dose related and occurs in 
less than 1% of persons receiving isoniazid at recommended doses (Blumberg et. al, 2003). It occurs 
more frequently in HIV-infected persons, malnourished individuals, persons with chronic renal failure or 
diabetes mellitus, pregnant and breastfeeding women, and persons with heavy chronic ethanol 
consumption. Pyridoxine 25 to 50 mg daily by mouth may be administered to prevent isoniazid-associated 
peripheral neuropathy. 


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4 
OBJECTIVES 
4.1 
Primary: 
• 
To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single 
substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of 
treatment for drug-susceptible pulmonary tuberculosis 
• 
To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin 
for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is 
possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary 
tuberculosis   
 
4.2 
Secondary: 
• 
To evaluate the safety of the investigational regimens 
• 
To evaluate the tolerability of the investigational regimens 
• 
To collect and store biospecimens from consenting participants for the purpose of future research on 
discovery and validation of TB biomarkers 
• 
To determine the correlation of mycobacterial and clinical markers with time to culture conversion, 
treatment failure, and relapse. 
• 
To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs.  The main 
objectives of the PK/PD study are to characterize study drug PK parameters and to determine 
relationships between treatment outcomes and PK parameters.  
• 
To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with 
TB/HIV co-infection taking efavirenz-based combination antiretroviral therapy and TB treatment with 
rifapentine. 
 
 
 


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5 
STUDY DESIGN 
This will be an international, multicenter, randomized, controlled, open-label, 3-arm, phase 3 non-
inferiority trial. 
As described in subsequent sections, participant safety will be maximized and risks will be minimized by 
frequent study visits for safety assessments, intensive microbiological monitoring for TB treatment failure 
and relapse, and periodic review of unfavorable outcome rates by a Data and Safety Monitoring Board.   
 
 
 


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6 
STUDY POPULATION 
This will be a multisite international study.  Male and female participants who are age 12 or older and 
suspected to have pulmonary tuberculosis will be enrolled into the study.   
Target enrollment is 2500 participants.   
Pregnant or breast-feeding women will be excluded from the study because of uncertainties about the 
safety of rifapentine, moxifloxacin, and pyrazinamide in these groups.  The sex, ethnicity, and 
socioeconomic background of study participants are expected to mirror those of the populations served 
by local tuberculosis clinics and the populations most affected by tuberculosis worldwide.   
Co-enrollment in other therapeutic clinical trials is not allowed.  
6.1 
Subject Inclusion Criteria 
Individuals must meet all of the following inclusion criteria in order to participate in this study:   
A. 
Suspected pulmonary tuberculosis plus one or both of the following: a) at least one 
sputum specimen positive for acid-fast bacilli on smear microscopy OR b) at least one 
sputum specimen positive for M. tuberculosis by Xpert MTB/RIF testing, with 
semiquantitative result of ‘medium’ or ‘high’ and rifamycin resistance not detected.   
B. 
Age twelve (12) years or older 
C. 
A verifiable address or residence location that is readily accessible for visiting, and 
willingness to inform the study team of any change of address during the treatment and 
follow-up period. 
D. 
Women of child-bearing potential who are not surgically sterilized must agree to practice 
a barrier method of contraception or abstain from heterosexual intercourse during study 
drug treatment.  
E. 
Documentation of HIV infection status.  
F. 
For HIV-positive individuals, CD4 T cell count greater than or equal to 100 cells/mm3 
based on testing performed at or within 30 days prior to screening.  
G. 
Laboratory parameters done at or within 14 days prior to screening: 
• 
Serum or plasma alanine aminotransferase (ALT) less than or equal to 3 times 
the upper limit of normal 
• 
Serum or plasma total bilirubin less than or equal to 2.5 times the upper limit of 
normal 


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• 
Serum or plasma creatinine level less than or equal to 2 times the upper limit of 
normal 
• 
Serum or plasma potassium level greater than or equal to 3.5 meq/L 
• 
Hemoglobin level of 7.0 g/dL or greater 
• 
Platelet count of 100,000/mm3  or greater 
H. 
For women of childbearing potential, a negative pregnancy test at or within seven (7) 
days prior to screening 
I. 
Karnofsky score greater than or equal to 60 
J. 
Written informed consent 
6.2 
Criteria for Exclusion from Enrollment  
An individual meeting any of the following exclusion criteria at the time of enrollment or initiation of study 
drugs will be excluded from study participation: 
A. Pregnant or breast-feeding 
B. Unable to take oral medications 
C. Previously enrolled in this study 
D. Received any investigational drug in the past 3 months 
E. More than five (5) days of treatment directed against active tuberculosis within 6 months 
preceding initiation of study drugs 
F. More than five (5) days of systemic treatment with any one or more of the following drugs within 
30 days preceding initiation of study drugs: isoniazid, rifampin, rifabutin, rifapentine, ethambutol, 
pyrazinamide, kanamycin, amikacin, streptomycin, capreomycin, moxifloxacin, levofloxacin, 
gatifloxacin, ofloxacin, ciprofloxacin, other fluoroquinolones, ethionamide, prothionamide, 
cycloserine, terizidone, para-aminosalicylic acid, linezolid, clofazimine, delamanid or bedaquiline 
G. Known history of prolonged QT syndrome 
H. Suspected or documented tuberculosis involving the central nervous system and/or bones and/or 
joints, and/or miliary tuberculosis and/or pericardial tuberculosis 
I. 
Current or planned use within six months following enrollment of one or more of the following 
medications: HIV protease inhibitors, HIV integrase inhibitors, HIV entry and fusion inhibitors, HIV 
non-nucleoside reverse transcriptase inhibitors other than efavirenz, quinidine, procainamide, 
amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine. Individuals who are currently 
taking efavirenz-based antiretroviral treatment or for whom initiation of efavirenz-based 


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antiretroviral treatment is planned within 17 weeks following enrollment may participate, as per 
Section 8.3.10.   
J. Weight less than 40.0 kg 
K. Known allergy or intolerance to any of the study medications 
L. Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis 
isolate is already known to be resistant to any one or more of the following:  rifampin, isoniazid, 
pyrazinamide, ethambutol, or fluoroquinolones.  
M. Other medical conditions, that, in the investigator’s judgment, make study participation not in the 
individual’s best interest. 
N. Current or planned incarceration or other involuntary detention. 
 
6.3 
Criteria for Exclusion after Enrollment (‘Late Exclusion’) 
Microbiological confirmation of drug-susceptible tuberculosis is not expected always to be available at the 
time of enrollment.  Enrolled individuals who are subsequently determined to meet either of the following 
criteria will be classified as ‘late exclusions’ and study treatment will be discontinued: 
A. Screening, baseline, and Week 2 study visit sputum cultures all fail to grow M. tuberculosis.  
B. M. tuberculosis cultured or detected through molecular assays (Cepheid Xpert MTB/RIF or Hain 
MTBDRplus assays) from sputum obtained around the time of study entry is determined to be 
resistant to one or more of isoniazid, rifampin, or fluoroquinolones.  


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7 
ENROLLMENT, RANDOMIZATION, AND MASKING 
PROCEDURES 
7.1 
Enrollment Procedures 
Individuals who are sputum smear microscopy positive for acid-fast bacilli AND/OR have at least one 
sputum specimen positive for M. tuberculosis with a semiquantitative result of ‘medium’ or ‘high’ by Xpert 
MTB/RIF testing (with rifampin resistance not detected) will be invited to participate in this study.  
Interested individuals will be provided with information about the study including risks and potential 
benefits of all study procedures.  If site staff are satisfied that the potential participant understands the 
information and the potential participant is willing, the potential participant will be asked to consent to 
participate in the study.  Study-specific procedures will be initiated only after an individual has provided 
written informed consent.   
7.2 
Randomization 
This will be a randomized trial.  Randomization and treatment arm assignment will be computer-
generated centrally by the TBTC Data and Coordinating Center.  Randomization will be stratified by site, 
by the presence of cavitation on chest radiograph at baseline (since cavitation is associated with a 
decreased rate of microbiological response to TB treatment), and by HIV status (HIV-uninfected vs. HIV-
infected with CD4 T cell count greater than or equal to 200 cells/mm3 vs. HIV-infected with CD4 T cell 
count less than 200 cells/mm3).  Eligible participants (who meet all of the inclusion criteria and none of the 
exclusion criteria) will be randomly assigned in a 1:1:1 ratio to the study arms. Random assignment 
sequences will be generated in a way that limits the imbalance between arms within strata while also 
ensuring that the sequence is not predictable based on previous assignments. 
Cavitation is defined as a gas-containing lucent space at least 1 cm in diameter within the lung 
parenchyma surrounded by an infiltrate or fibrotic wall greater than 1 mm thick seen on chest radiograph.  
Cavitation seen only on chest tomography (e.g. CT), if done, does not satisfy this definition. Cavities 
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8 
STUDY PROCEDURES 
8.1 
Clinical Evaluations 
Clinical evaluations will be performed in accordance with a detailed Manual of Operating Procedures 
(MOOP). 
8.1.1 Interview for demographic and contact information 
Participants will be interviewed for demographic information including place of birth and date of 
birth.  Contact information will be obtained, including participant location of residence and 
participant phone number(s), and names and phone numbers of family members/friends who can 
be contacted by study staff in the event of emergency or if study staff are not able to locate the 
participant. Identifying and locating information will be maintained only at the site; it will not be 
entered into the study data base. 
8.1.2 Obtaining a medical history 
Participants will be interviewed to obtain medical information including tuberculosis signs and 
symptoms, prior tuberculosis history, other health conditions and treatments (including HIV 
infection), medicines used, and allergies to medicines.  
8.1.3 Obtaining sputum specimens 
Sputum may be spontaneously expectorated or induced by aerosol inhalation of sterile nebulized 
saline. Study sites will use their local procedure for sputum induction. Saliva should not be 
collected in place of a sputum specimen. 
8.1.4 Performing visual acuity and color vision testing 
Visual acuity will be tested using a Snellen-type chart.  Color vision will also be tested.  Results of 
this testing will not be collected centrally unless a new diagnosis (e.g. ≥ two lines on a Snellen-
type chart, or loss of color vision) are discovered.   
8.1.5 Symptom assessment 
Participants will be asked if they have experienced any of the following within 14 days prior to 
enrollment or since the previous study visit: fevers, cough, rash, itching, jaundice, nausea, 
vomiting, diarrhea, loss of appetite, vision problems, numbness/tingling of extremities, joint pain.  
In addition, participants will be asked if they have had other symptoms not listed above, and if 
yes, then those other symptoms will be recorded and graded. 
8.1.6 Assessment for adverse events 
Participants will be asked about symptoms and signs, new medical diagnoses, and 
hospitalizations since the last study visit.   


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8.1.7 Chest Radiograph 
A posteroanterior chest radiograph will be performed at screening and at the week 26 visit, 
regardless of treatment arm. 
 
8.2 
Concomitant Medications/Treatments 
The use of all non-study drugs (including over-the-counter medications) from 14 days before starting 
study drugs through the end of study drug treatment will be monitored and recorded.   
Antimicrobials with known antituberculosis activity (see MOOP) should not be used during study drug 
treatment, and any participant who receives more than five consecutive days of one or more of those 
medications will be classified as being on a non-study regimen.  Antimicrobials without significant anti-
tuberculosis activity may be prescribed for intercurrent infections at the discretion of the investigator and 
will be recorded on study forms.  
Participants requiring the use of iron-containing supplements, antacids containing aluminum and/or 
magnesium, sucralfate, and/or antidiarrheals that contain kaolin should take study drugs at least four 
hours before or eight hours after ingesting those products in order to avoid impaired absorption of study 
drugs. 
Rifamycins induce hepatic enzyme systems that are active in the metabolism of some other drugs.  A 
prominent drug interaction of rifamycins is that involving hormonal contraceptives. Women of child-
bearing potential (i.e. not surgically sterilized or not postmenopausal for more than one year) will be 
advised to use one or more of the following contraceptive methods while on study treatment: non-
hormonal intrauterine device; barrier methods; abstinence from heterosexual vaginal intercourse. 
Another medically important drug-drug interaction is that involving many antiretroviral drugs and the 
rifamycins, which are potent inducers of the cytochrome P450 system.  Nonetheless, in accordance with 
World Health Organization guidance, antiretroviral therapy is recommended for HIV-infected study 
participants; a regimen comprised of efavirenz, tenofovir, plus lamivudine or emtricitabine is 
recommended for use in study participants based on the absence of known clinically significant drug-drug 
interactions between these antiretrovirals and the rifamycins.  Efavirenz, nucleoside reverse transcriptase 
inhibitors, and nucleotide reverse transcriptase inhibitors are allowed while a participant is receiving study 
treatment, provided that the criteria outlined in Section 8.3.10 are met. Guidance with respect to other 
antiretroviral agents will be provided in the MOOP and will be updated as new information on drug-drug 
interactions emerges.  
Moxifloxacin has been shown to prolong the QT interval on the electrocardiogram in some patients.  
Study drugs should not be administered concomitantly with quinidine, procainamide, amiodarone, sotalol, 
disopyramide, ziprasidone, or terfenadine. 
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8.3 
Laboratory Evaluations 
8.3.1 Sputum mycobacterial culture 
See Section 11.1 ‘Summary of Bacteriological Methods’. 
8.3.2 Hematology 
Blood will be drawn for a complete blood count that includes a white blood cell differential, 
hemoglobin, and platelet count.  This will require approximately 5 mL of EDTA anticoagulated 
blood. 
8.3.3 Biochemistry 
Blood will be drawn for measurement of alanine aminotransferase (ALT; serum or plasma), and 
total bilirubin (serum or plasma); in addition at screening blood (serum or plasma) will be tested 
for creatinine, potassium, and albumin. This will require approximately 5 mL of blood. 
8.3.4 HIV testing 
Counseling prior to and following HIV testing, and reporting of HIV testing results will follow local 
guidelines and regulations at each site.  For study purposes, HIV-1 infection is defined as a 
positive result using any licensed rapid HIV test or any licensed HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit.  Confirmation of the initial study test result is 
required and must utilize a different method than the one used for the initial study assessment.  
The confirmatory study test must also be licensed and may include western blot, a second 
antibody test by a method other than the initial rapid HIV and/or E/CIA, HIV-antigen, or plasma 
HIV RNA viral load.  Two or more HIV-1 RNA viral loads of >1,000 copies/mL are also acceptable 
as documentation of HIV infection.  Negative study HIV testing does not require confirmatory 
testing.  Note: the term ‘licensed’ refers to an FDA-approved kit or, for study sites located in 
countries other than the United States, a kit that has been certified or licensed by an oversight 
body within that country.  
8.3.5 CD4 testing 
Individuals identified as being HIV-infected will have CD4 T cell count testing performed unless 
the results are available for a test performed at or within 30 days prior to screening.  This will 
require up to approximately 5 mL of blood.  
  
8.3.6 HIV viral load testing 
Individuals identified as being HIV-infected will have HIV viral load measured unless the results 
are available for a test at or within 30 days prior to screening.  This will require approximately 5 ml 
of blood.  Testing can be by any method used routinely at the study site as a standard of care 
test. 
8.3.7 Pregnancy testing 
Serum or urine testing methods are acceptable.   


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8.3.8 Diabetes screening 
Hemoglobin A1C is the preferred test.  If hemoglobin A1C testing is not available at the study site, 
then either fasting blood glucose (defined as no caloric intake for at least 8 hours) or random 
blood glucose can be measured.  
8.3.9 Pharmacokinetic sampling: Tuberculosis Drugs 
8.3.9.1 
Overview 
In the context of this overall study, two types of pharmacokinetic (PK) sampling will be 
used: ‘sparse’ sampling and ‘intensive’ sampling.  The intensive sampling component will 
be performed among a convenience sample of patients at a few selected sites with 
capacity to perform this activity; the intensive PK component will be described in a 
separate protocol and a separate intensive PK informed consent document will be used.  
Individuals not undergoing intensive PK sampling will have sparse PK sampling, 
regardless of assigned study arm. Sparse PK is described below and is a component of 
the main study protocol.   Blood specimens will be shipped to a designated laboratory in 
the U.S. or South Africa where concentrations of TB drugs and their metabolites will be 
measured. 
8.3.9.2 
Timing of sparse PK sampling during study participation for rifapentine 
and moxifloxacin 
The minimum number of study drug doses prior to the sparse PK blood draw is 14 
(including standard DOT and supplementary doses).  The preferable timing of sparse PK 
sampling is at the week 2, 4or 8 visit (when sputum is also collected).  However, if dosing 
schedule or other factors do not permit sampling at one of these study visits, then 
sampling may be performed any time after 14 study drug doses and no later than the 
week 8 study visit.  
8.3.9.3 
Schedule of sparse PK blood samples for rifapentine and moxifloxacin 
All blood samples will be collected in reference to directly observed doses of intensive 
phase study drugs -- the reference dose of study drugs is preceded by three directly 
observed study drug doses given approximately 24 hours, 48 hours, and 72 hours prior. 
Two or three blood samples, 6 ml each, will be obtained over an 8 hour period as 
specified in the MOOP.  The first timed blood specimen will be obtained 24 hours ± 1 
hour after the most recent DOT study drug ingestion (defined as reference dose #1).  
After obtaining the first timed blood specimen, the reference dose of study drugs ingested 
(defined as reference dose #2)  will be ingested.  The second timed specimen should be 
obtained 25 to 40 minutes after ingestion of the reference dose #2 of study drugs.  The 
third timed specimen should be obtained 5 to 8 hours after ingestion of the reference 
dose #2.     
8.3.9.4 
Administration of the Reference Dose of Study TB Drugs 
The reference dose of study drugs should be taken by the participant in a manner 
consistent with the way the participant usually takes the study drugs relative to 
consumption of (i.e. eating or fasting) and type of food. The timing of food relative to the 
reference dose of study drugs and a brief description of any food and liquids will be 


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recorded.  Participants should abstain from alcohol for 48 hours prior to the reference 
dose of study drugs and until after the last PK blood specimen is collected.  
8.3.10 Pharmacokinetic sampling: Efavirenz 
A secondary objective of TBTC Study 31 will investigate efavirenz pharmacokinetics in patients 
randomized to either of the rifapentine containing regimen arms of TBTC 31 (Investigational 
Regimen 2 and 3). Participants receiving efavirenz based ART will fall into one of two groups for 
PK evaluation: 1) HIV-infected participants who meet both of the following criteria a) on efavirenz 
for 30 days or more at the time of study enrollment and b) with viral load less than 200 copies/mL 
based on testing performed within 90 days prior to screening (Group 1); or 2) HIV-infected 
participants started on efavirenz after initiation but before or at week 8 of study tuberculosis drugs 
(Group 2).   
 
Efavirenz plasma concentrations will be evaluated early in the study and in a limited number of 
participants to determine whether or not standard efavirenz dosing (600mg daily) results in 
adequate efavirenz exposure in the presence of daily 1200mg rifapentine treatment.  An initial 
group of 31 participants from Group 1 will be enrolled.  After the first 31 participants in Group 1 
are enrolled, no further Group 1 participants will be permitted to enroll until data from these first 
31 evaluable individuals are evaluated and proved to be clinically acceptable.  Group 2 
participants will not be allowed to enroll into the study until data from 31 evaluable individuals in 
Group 1 have been evaluated and deemed clinically acceptable, that is, there is no compelling 
evidence of lack of adequate exposure to efavirenz in Group 1 patients.   
 
The efavirenz PK data by Group will be judged acceptable if we have evidence that >80% of 
participants have estimated efavirenz mid-dosing interval concentrations ≥1 mg/L.  Any patient 
that has a baseline (pre-TB treatment) efavirenz concentration <1mg/L will be deemed non-
evaluable for the efavirenz pharmacokinetic study.  Methods for estimating efavirenz 
pharmacokinetic parameters are provided in Section 13.5.5.  Blood specimens will be shipped to 
a designated laboratory in the U.S. where concentrations of efavirenz will be measured. 
 
Group 1:  The first evaluation will be made when baseline, weeks 4 and 8 efavirenz 
concentrations are available for 31 evaluable participants; if ≤20 of the 31 have acceptable 
efavirenz concentrations at both Weeks 4 and 8, the team would consider this to be of concern. 
This rule was developed to have a high likelihood (95% or higher) of continuing to accrue 
participants if the true underlying rate of having acceptable efavirenz concentrations is greater 
than 80%. If accrual or shipping patterns warrant, then an interim analysis prior to assessment of 
31 participants may be performed; in this case, an independent statistician who has not seen any 
PK data will develop the decision rule to protect the original PK study design and participant 
safety. The second evaluation will occur when 90 participants in Group 1 are enrolled. 
 
Group 2:  Once the efavirenz PK data have been evaluated in the first 31 patients from Group 1 
and deemed clinically acceptable (that is, >20 of the 31 have acceptable efavirenz concentrations 
at both weeks 4 and 8) enrollment will open to patients in Group 2 (HIV-Infected participants 
starting on efavirenz early after initiation of study tuberculosis drugs). PK assessments will occur 
in a similar manner as in Group 1 participants with two phases of assessments (N=31 and 90 
patients) except that sampling will occur approximately 4 and 8 weeks following initiation of EFV. 


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In addition, HIV-1 viral load measurements will be conducted 8 weeks after starting efavirenz and 
at study week 17. Stopping rules for numbers of patients with acceptable efavirenz 
concentrations in Group 2 will be the same as those for Group 1.    
 
If stopping rules are met for unacceptable proportions of participants with acceptable efavirenz 
concentrations at any time (after 31 or after 90 patients in either Group), the TBTC 31 team may 
consider appropriate action based on study results, including whether to advise adjusting 
efavirenz dose or to exclude efavirenz use in subsequent study participants.  If dose adjustment 
of efavirenz is recommended the step-wise PK evaluations will continue in a similar fashion as 
with the 600mg dose to again determine if acceptable efavirenz concentrations are maintained 
with the increased dose.  Stopping rules for unacceptable proportions of patients with less than 
1mg/L concentrations of efavirenz will be the same as with the 600mg dose.         
 
8.3.10.1  Efavirenz Sampling Strategy  
8.3.10.1.1. HIV-infected participants on efavirenz at the time of study 
enrollment (Group 1):  Blood (approximately 8 ml) for measuring plasma efavirenz 
concentrations will be obtained at screening or at baseline (prior to initiation of study 
tuberculosis drugs) and additionally at weeks 4, 8 and 17 while on efavirenz.  Blood will 
be drawn approximately 12 hours (no sooner than 10 hours after and no later than 24 
hours) after the previous dose of efavirenz was ingested. The time of that efavirenz dose 
and the time of blood collection will be recorded.  HIV viral load testing will also be 
performed at weeks 8 and 17.   
8.3.10.1.2. HIV-infected participants started on efavirenz after initiation of 
study tuberculosis drugs (Group 2):   
Blood (approximately 8 ml) for measuring plasma efavirenz concentrations will be 
obtained at about 4 and 8 weeks following initiation of efavirenz (to coincide with study 
visits to the extent possible). Blood should be drawn approximately 12 hours (no sooner 
than 10 hours after and no later than 24 hours) after the previous dose of efavirenz was 
ingested. The time of that efavirenz dose and the time of blood collection should be 
recorded. HIV viral load testing will be performed at 8 weeks following initiation of 
efavirenz (to coincide with study visits to the extent possible) and at study week 17.  
 
8.3.11 Pharmacogenomic testing: Host Genetic Analysis 
This study will evaluate human gene polymorphisms that may affect pharmacokinetics of 
tuberculosis drugs and antiretroviral drugs.  Polymorphisms in SLCO1B1 (which may affect 
pharmacokinetics of rifamycins), NAT2 (which affects pharmacokinetics of isoniazid), cytochrome 
P450 isoenzyme 2B6 (CYP2B6) (which affects pharmacokinetics of efavirenz) and possibly other 
genes will be assessed.  Data from these genetic assays may be used as covariates or for 
stratification in analyses of study endpoints. Blood (approximately 8.5 ml) will be collected once 
after enrollment and stored frozen as specified in the MOOP. Blood specimens will be shipped to 
a designated laboratory in the U.S. for analysis. 
 


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8.3.12 Storage of M. tuberculosis bacterial isolates 
The M. tuberculosis bacterial isolates from screening and baseline, as well as isolates cultured 
from specimens obtained at or after week 17 will be stored.  Isolates should be labeled with study 
identification number and collection date, and not with participant name.  Isolates will be shipped 
to the CDC TB reference laboratory upon request.  These isolates will be used for confirmatory 
drug susceptibility testing, for study endpoint assessment and for genetic characterization of M. 
tuberculosis.  
8.3.13 Samples for future analyses to identify potential biomarkers of 
tuberculosis treatment response 
Sputum, urine, and blood will be stored from all consenting participants for the purpose of future 
research to identify potential biomarkers of tuberculosis treatment response.  Specimens 
collected for storage will be labeled with study identification number and collection date, and will 
not be labeled with participant name. Specimens will be centrally stored at Biomedical Research 
Institute, Rockville, MD, USA. Consenting patients will be asked to provide sputum, blood 
(approximately 8 ml blood per blood draw), and urine samples at 5 visits (baseline, week 2, week 
4, week 8, and at end of treatment).  Additionally, samples should also be collected if a) failure or 
relapse is suspected and evaluated at an unscheduled visit or a visit other than one of the 5 visits 
indicated above; and/or b) the participant voluntarily withdraws from the study.  Participant 
consent for stored specimens will be part of the study Informed Consent Form which will be 
administered during the Screening/Consenting visit, with an independent signature line.  As an 
alternative to the sample storage plan described above, participants enrolled in this clinical trial 
will be permitted to co-enroll in The Platform Study Biobanking Substudy (TBTC Study 36A), 
which includes additional sample types and additional timepoints for collection, requiring a 
separate TBTC Study 36A biobanking informed consent document.   Biomarker sampling for a 
given participant will be only for Study 36A or for Study 31 but not for both.   
8.4 
Specimen preparation, handling and shipping 
Specimen preparation and handling will be performed according to procedures set forth in the MOOP.  
Specimens will be labeled with study identification number and not with participant name.  Shipping will 
be performed by trained personnel according to the Manual of Procedures and in accordance with local 
and international regulations.  
8.5 
Loss to follow-up 
All efforts should be made to contact participants that miss DOT visits or scheduled study visits (unless 
the participant has withdrawn consent).   
For participants who fail to attend a scheduled study visit during study treatment and attempts to reach 
the participant by phone are not successful or not feasible, a home visit will be performed within one week 
of the scheduled study visit. 
For participants who fail to attend a study visit during study follow-up (off study treatment) and attempts to 
reach the participant by phone are not successful or not feasible, a home visit will be performed within 
approximately two weeks of the scheduled study visit.  If a participant misses their final scheduled visit 
then repeated efforts must be made to contact the participant, until six weeks after the Month 18 visit of 


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the Last Participant In.  If these attempts are unsuccessful then the participant should be considered lost 
to follow-up and reported as such.  
8.6 
Management of a participant with a positive sputum culture for M. 
tuberculosis at or after week 17 but before week 26  
In the event of a positive culture confirmed as M. tuberculosis from a sputum specimen obtained at or 
after week 17 but before week 26, at least 3 repeat sputum samples should be obtained and sent for 
smear and culture.  If M. tuberculosis is isolated in culture, drug susceptibility testing should be performed 
on one of the isolates.   
The participant’s case will be referred to the central study clinician for classification as either at risk for 
unfavorable outcome or not at risk for unfavorable outcome based on review of previous microbiology 
results and clinical information. Any participant determined to be at risk for an unfavorable outcome will 
be taken off of assigned study treatment and treated in accordance with local guidelines. The participant’s 
treatment will not be changed without central study clinician consultation unless the site investigator 
determines that a change is needed for emergency circumstances. The central study clinician will be 
blinded with respect to treatment assignment. 
8.7 
Management of a participant with a positive sputum smear at or after week 
17 
In the event of a positive sputum smear from a specimen obtained at or after week 17, a repeat sputum 
sample should be obtained and sent for smear and culture. If M. tuberculosis is isolated in culture, drug 
susceptibility testing should be performed on one of the isolates.   
Sputum smear results should not be used for clinical decision-making during the study.  Participants with 
a positive sputum smear at or after week 17 will be referred to the central study clinician for further 
evaluation, including additional action if indicated, and follow-up, as outlined in section 8.6.   
8.8 
Management of a participant with a positive sputum culture for M. 
tuberculosis at or after week 26 
In the event of a positive sputum culture for M. tuberculosis from a specimen obtained at or after week 26, 
a repeat sputum sample should be obtained and sent for smear and culture. If M. tuberculosis is isolated 
in culture, drug susceptibility testing should be performed on one of the isolates.   
TB treatment change (including restarting treatment) is usually not indicated by a single positive culture, 
and is usually not considered unless there is worsening of clinical signs/symptoms and/or chest X-ray 
findings. If the participant remains well clinically (i.e. there is no clinical or radiological evidence of failure 
or relapse), then the clinician may consider requesting additional sputum samples and reviewing the 
participant’s progress in two to four weeks depending on the clinical condition of the participant.   


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8.9 
Management of a participant in whom a treatment change is being 
considered 
If a treatment change is being considered, perform all of the following: 
• 
Collect at least three additional sputum samples.  These sputa should be sent to the study 
laboratory for smear and culture.  If M. tuberculosis is isolated in culture, drug susceptibility 
testing should be performed on one of the isolates.   
• 
Two (2) of these sputum specimens must be obtained prior to changing or re-initiating TB 
treatment and collected at least 4 hours apart. 
• 
Discuss the proposed treatment change with the central study clinician before implementing the 
treatment change.  
• 
For participants consenting to storage of specimens, obtain blood for plasma, sputum and urine 
for frozen storage. 
Treatment extension or re-initiation of treatment in a participant should never be implemented prior to 
reviewing the participant’s case with the central study clinician. 
Treatment of participants in whom TB treatment is changed or re-initiated should be according to local 
guidelines.  
8.10 Management of a participant who is discontinued from study treatment 
8.10.1 Management of a participant who is discontinued from study treatment 
because s/he is determined to be ineligible after enrollment (‘late 
exclusions’) 
These individuals should have study drugs discontinued, and undergo an early termination visit 
approximately 14 days after discontinuation of study drugs.  The assessments to be performed at 
the early termination visit are in Section 9.  Individuals should be referred to local sources of 
medical care.   
8.10.2 Management of participants who become pregnant during the study 
Women who become pregnant while receiving study therapy will be taken off of study treatment 
and treated according to National Tuberculosis Program or local guidelines.  The women will 
continue to receive scheduled study follow-up, will be classified as being on a non-study regimen, 
and will not receive study radiographs.  The outcome of the pregnancy will be reported on study 
forms.   
Women who become pregnant while in study follow-up (not on study treatment) will continue to 
receive scheduled study follow-up, and will not receive study radiographs.  The outcome of the 
pregnancy will be reported on study forms.  


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8.10.3 Management of participants who are discontinued from study treatment in 
the setting of an adverse event or the investigator judges that 
discontinuation of study treatment is in the participant’s best interest 
The site investigator may discontinue a participant from treatment in the event of a severe or 
serious adverse event, or at any time if the investigator thinks discontinuation is in the 
participant’s best interest.  Discontinuation from study treatment should be discussed with the 
central study clinician prior to discontinuation, unless discontinuation is considered an emergency 
by the site investigator.  For study purposes, the participant should continue to be followed in the 
study per the study schedule and remain under the supervision of the site investigator, unless the 
participant withdraws consent.   The participant should be referred to appropriate local sources of 
care for management of medical problems that cannot reasonably be managed by the study 
team.  
8.10.4 Management of a participant who requests premature discontinuation from 
study treatment 
A participant may request premature discontinuation from study treatment.  An early termination 
visit should be performed and the participant should continue to be followed in the study per the 
study schedule, unless the participant withdraws consent.   The participant should be referred to 
appropriate local sources of care for management of tuberculosis. 
8.10.5 Management of a participant who is incarcerated after enrollment 
This study will not enroll prisoners. However, it is possible that a participant will be incarcerated 
after enrollment. If an enrolled individual is incarcerated, then study medications will be stopped 
and the participant will be treated for active TB according to the standards of the institution in 
which s/he is incarcerated. While incarcerated, individuals will not be followed in the study. When 
the individual is no longer incarcerated, study treatment and/or study follow-up may continue, at 
the discretion of the investigator. 
 
8.11 Premature termination of the study or closure of a study stratum or a study 
site 
The study or a study stratum can be terminated by the sponsor on the advice of the Data and Safety 
Monitoring Board.  The sponsor has the right to close the study and the sponsor has a right to close a 
site, although this should occur only after consultation between involved parties.  In the event of study 
termination or site termination, the central and local ethics committees/institutional review boards must be 
informed.  If the study or a study site is closed before the planned end of the study, all study materials 
(except documents required to be retained and stored on site) must be returned to the sponsor.  The site 
investigator will retain all other documents until notification is given by the sponsor and/or as required by 
the local regulatory authorities.  If the study or a study site is closed prematurely, participants should 
undergo an Early Termination Visit unless otherwise directed by the sponsor.  


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9 
STUDY SCHEDULE 
Activities to be conducted at study visits are also shown in Appendix A.   
9.1 
Screening  
The following will be performed after written informed consent: 
• 
Assessment of inclusion and exclusion criteria  
• 
Interview for demographic and contact information 
• 
Medical history 
• 
Height and weight will be measured 
• 
Chest radiograph unless results of a chest radiograph done within the previous fourteen 
(14) days are available.  
• 
An HIV test will be obtained when any one or more of the following apply: a) HIV 
serostatus is unknown; b) the last documented negative HIV test was > 3 months prior to 
screening; c) written documentation of HIV-1 infection at any time prior to study entry is 
not available for confirmation of HIV-infected status.  
• 
For individuals known or suspected to be HIV-infected, CD4 T cell enumeration should be 
performed unless the results are available for a test performed within 30 days prior to 
screening. 
• 
For individuals known to be HIV-infected, an HIV viral load should be performed unless 
results are available for a test performed within 30 days prior to screening.  
• 
Urine or serum pregnancy test for women of child-bearing potential, unless results of a 
negative are available for a test performed within seven (7) days prior to screening. 
• 
A sputum sample will be obtained and sent to the study laboratory for mycobacterial 
smear and culture. 
• 
Sputum for rapid molecular test, if available at site  
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
• 
Diabetes screening. 
• 
Blood will be obtained for a complete blood count (including white blood cell differential, 
hemoglobin, and platelet count), and serum or plasma will be tested for alanine 
aminotransferase (ALT), total bilirubin, creatinine, albumin, and potassium, unless results 
from those tests performed within fourteen (7) days prior to screening are available.   
9.2 
Baseline  
The baseline visit is defined as the visit at which study drug treatment is initiated.  A baseline visit will be 
performed for individuals who meet study eligibility criteria and are willing to participate in the study.  The 


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baseline visit should be performed as soon as possible and up to 7 days after screening.  If applicable the 
screening and baseline activities may be performed in the same visit, with two sputa sent to the study 
laboratory.  The baseline visit is defined as the visit during which study drug treatment is initiated.  
Participants who no longer meet eligibility criteria will be referred to a local source of tuberculosis care, 
and to other appropriate sources of clinical care as applicable.  A log will be maintained of individuals who 
are screened but not enrolled. 
The following will be performed at baseline: 
• 
Review of interval tuberculosis treatment to assess whether the participant continues to 
meet eligibility criteria 
• 
Review of concomitant medications to assess whether the participant continues to meet 
eligibility criteria 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
Visual acuity and color perception testing  
• 
A sputum sample will be obtained and sent to the study laboratory for smear and culture. 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
• 
For participants consenting to storage of specimens for future identification of potential 
biomarkers of TB treatment response: a sputum specimen will be obtained and stored 
frozen; a urine specimen will be obtained and stored frozen; blood will be obtained for 
frozen storage of plasma.  
• 
For HIV-infected participants on efavirenz and rifapentine treatment: plasma for efavirenz 
quantification 
• 
Randomization 
9.3 
Study Visits at Weeks 2, 4, 8, and 12 
Study visits should be performed within a window of +/- three (3) days.  The following will be performed at 
each study visit: 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Blood creatinine, ALT, total bilirubin, and complete blood count (including WBC 
differential and platelets) 
• 
ONE SPUTUM obtained for mycobacterial smear and culture 
• 
Measurement of weight 


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• 
In addition, at week 4 for all participants: testing of visual acuity and color perception 
should be performed. 
• 
In addition at weeks 4 and 8 for HIV-infected participants on efavirenz: plasma for 
efavirenz quantification and HIV viral load testing at week 8 
• 
For participants consenting to storage of specimens for future identification of potential 
biomarkers of TB treatment response: a sputum specimen will be obtained and stored 
frozen; a urine specimen will be obtained and stored frozen; blood will be obtained for 
frozen storage of plasma.  
• 
In addition, any time after completion of 14 study drug doses and no later than the week 
8 study visit for all participants: PK sampling for TB drug 
• 
In addition, once any time after enrollment for all participants: blood for 
pharmacogenomic testing 
 
9.4 
Week 17 
This visit should be performed within a window of +/- three (3 days).  The following will be performed: 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Blood creatinine, ALT, total bilirubin, and complete blood count (including WBC 
differential and platelets) 
• 
TWO SPUTA will be obtained for mycobacterial smear and culture 
• 
Measurement of weight 
• 
For HIV-infected participants on efavirenz: plasma for efavirenz quantification, HIV viral 
load testing. For participants consenting to storage of specimens for future identification 
of potential biomarkers of TB treatment response: a sputum specimen will be obtained 
and stored frozen; a urine specimen will be obtained and stored frozen; blood will be 
obtained for frozen storage of plasma.  
• 
For all participants (if not already done): blood for pharmacogenomics testing 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
 
9.5 
Week 22 
This visit should be performed within a window of +/- three (3) days.  The following will be performed: 
• 
Review of participant personal contact information 


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• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
TWO SPUTA obtained for mycobacterial smear and culture 
• 
Measurement of weight 
• 
Blood creatinine, ALT, total bilirubin, and complete blood count including WBC differential 
and platelets 
• 
In addition, for all participants (if not already done): blood for pharmacogenomics testing 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
 
9.6 
Week 26 
This visit should be performed within a window of +/- seven (7) days.  The following will be performed: 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
TWO SPUTA obtained for mycobacterial smear and culture 
• 
Chest radiograph 
• 
Measurement of weight 
• 
For participants consenting to storage of specimens for future identification of potential 
biomarkers of TB treatment response who in addition have been assigned to the 26-week 
treatment arm: a sputum specimen will be obtained and stored frozen; a urine specimen 
will be obtained and stored frozen; blood will be obtained for frozen storage of plasma.  
• 
In addition, for all participants (if not already done): blood for pharmacogenomics testing 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
 
9.7 
Study Visits At Months 9, 12, 15, and 18 
Study visits should be performed at months 9, 12, 15, and 18.  Visits should be performed within a 
window of +/- seven (7) days.  The following will be performed at each study visit: 
• 
Review of participant personal contact information 
• 
Symptom assessment 
• 
Review of interval medical history 


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• 
Concomitant medication assessment 
• 
Measurement of weight 
• 
TWO SPUTA obtained for mycobacterial smear and culture.  For participants whose 
Month 18 sputa are both contaminated, two additional sputa should be obtained. 
• 
In addition, for all participants (if not already done): blood for pharmacogenomics testing 
• 
Storage of M. tuberculosis bacterial isolate (if culture positive) 
 
9.8 
Early Termination Visit for Participants Terminating Before Completion of 
their Assigned Study Treatment 
The early termination visit should occur approximately 14 days after stopping study drugs, in order to 
assess for late manifesting adverse events.   The following should be performed: 
• 
Symptom assessment 
• 
Adverse event assessment 
• 
Concomitant medication assessment 
• 
Blood creatinine, ALT, total bilirubin, and complete blood count (including WBC 
differential and platelets) 
• 
One sputum obtained for mycobacterial smear and culture 
• 
Chest radiograph 
• 
Measurement of weight 
Participants experiencing an adverse event at the time of early termination should be followed until 
resolution or stabilization of the event (see Section 12).  Participants who were receiving study treatment 
at the time of early termination will be referred to local sources for tuberculosis care.   
A participant who withdraws consent will not have to undergo follow-up study procedures. 
9.9 
Early Termination Visit for Participants Terminating After Completion of 
their Assigned Study Treatment 
Procedures for visits at Month 9 should be followed.  In addition, for participants consenting to storage of 
specimens for future identification of potential biomarkers of TB treatment response: a sputum specimen 
will be obtained and stored frozen; a urine specimen will be obtained and stored frozen; blood will be 
obtained for frozen storage of plasma. 
Participants experiencing an adverse event at the time of early termination should be followed until 
resolution or stabilization of the event (see Section 12).  
A participant who withdraws consent will not have to undergo follow-up study procedures. 


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9.10 Unscheduled Visit 
Any visit conducted in addition to those required as per the study schedule will be considered to be 
unscheduled regardless of the reason for the visit. A sputum sample should be collected for 
mycobacterial culture if that participant is capable of producing sputum.  Other assessments that are 
undertaken should be as clinically indicated.  
9.11 Early/Late Visit 
Any visit that a patient attends outside of the specified window but not in addition to those required as per 
the study schedule will be considered as an early/late visit and marked as such on study forms.  
Assessments undertaken should be those for the scheduled visit that has been missed or will be missed.  
Other assessments should be undertaken as clinically indicated.  


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10 
STUDY INTERVENTION/INVESTIGATIONAL DRUGS 
10.1 Study Drugs 
The study drugs are rifampin, rifapentine, pyrazinamide, ethambutol, isoniazid, moxifloxacin, and 
pyridoxine (vitamin B6).  Each of the study products is described in section 3.  
The study products will be combined into the following study treatment regimens: 
 
Regimen 1 (control regimen): 2RHZE/4RH 
• Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed 
by  
• Eighteen weeks of daily treatment with rifampin and isoniazid 
 
 
Regimen 2 (investigational regimen): 2PHZE/2PH 
• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, 
followed by  
• Nine weeks of daily treatment with rifapentine and isoniazid  
 
 
 
Regimen 3 (investigational regimen): 2PHZM/2PHM 
• Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, 
followed by  
• Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin  
Rifampin, isoniazid, pyrazinamide, and ethambutol are the current first-line anti-tuberculosis drugs used 
worldwide for treatment of drug-susceptible tuberculosis.  Pyridoxine (vitamin B6) decreases the risk of 
isoniazid-related peripheral neurotoxicity and is commonly co-administered with isoniazid during 
tuberculosis therapy.  Each of these agents will be used at conventional doses and dosage schedules 
during this clinical trial.   
Rifapentine, a rifamycin antibiotic, is approved in the United States by the Food and Drug Administration 
for the treatment of pulmonary tuberculosis; the approved dose is 600 mg twice weekly for two months 
followed by 600 mg once weekly for four months, in combination with other anti-tuberculosis drugs.  As 
detailed above, pre-clinical and clinical studies indicate that maximal anti-tuberculosis activity is achieved 
at rifapentine doses higher than 600 mg and intervals shorter than twice weekly.  During this clinical trial 
rifapentine will be administered at a dose of 1200 mg, once daily for 17 weeks in Regimens 2 and 3.   
Moxifloxacin is a broad-spectrum fluoroquinolone antibiotic active against M. tuberculosis.  It is used 
worldwide for treatment of drug-resistant tuberculosis.  During this clinical trial moxifloxacin will be 
administered at the conventional adult dose of 400 mg once daily, and it will be administered for 
seventeen weeks in Regimen 3.    


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10.2 Study Drug Acquisition 
All study drugs, except for vitamin B6 for the full duration of study therapy will be provided by Sanofi.  
Vitamin B6 supplies will be obtained locally.  Study drugs will be distributed in bulk to study site 
pharmacies, which will dispense indicated supplies for individual participants according to individual 
pharmacy plans that will be approved by the sponsor or the sponsor’s designee. Treatment of participants 
who discontinue study treatment will be with locally supplied drugs. 
10.3 Study Drug Storage and Stability 
Study drugs will be stored in accordance with the written MOOP, and may not be used after their 
expiration date.    
10.4 Administration and Dosage of Study Drugs 
All drugs will be administered orally, seven days per week, throughout treatment.  Five of seven doses 
per week will be given as DOT by study personnel, or by a healthcare worker or lay treatment supervisor 
who is aware of the study protocol and trained regarding the study protocol.  Doses on weekends and on 
holidays up to three consecutive days may be either DOT or self-administered. Participants receiving a 
rifapentine-containing investigational regimen should take study drugs within one hour after ingesting 
food.  Participants receiving a rifampin-containing investigational regimen should take study drugs on an 
empty stomach; for participants on rifampin who have difficulty tolerating study drugs on an empty 
stomach, then administration with food is reasonable. Information about ingestion of food will be recorded 
for every study drug dose. 
Doses of study medications will be determined by body weight, as follows: 
Drug 
Dose 
Isoniazid 
300 mg 
Vitamin B6 
25 or 50 mg 
 
 
Pyrazinamide 
 
     < 55 kg 
1000 mg 
     ≥ 55-75 kg 
1500 mg 
     > 75 kg 
2000 mg 
 
 
Ethambutol 
 
     < 55 kg 
800 mg 
     ≥ 55-75 kg 
1200 mg 
     > 75 kg 
1600 mg 
 
 
Rifampin 
600 mg 
 
 
Rifapentine 
1200 mg 
 
 
Moxifloxacin 
400 mg 
Drugs and doses used to initiate treatment will be assigned by the enrollment application, based on 
weight reported at enrollment.  


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10.5 Dose Modifications for a Participant 
10.5.1 Dose Modifications for a Change in Participant’s Weight 
Study drug doses for pyrazinamide and ethambutol should be adjusted for the participant’s weight 
that was recorded at the most recent study visit.  
10.5.2 Drug Re-challenges 
In a participant experiencing side effects, whether to initiate a drug re-challenge as well as the 
drugs, dosages, and schedule for a drug re-challenge are at the discretion of the treating 
clinician.  General recommendations for consideration are provided within the MOOP.   
10.6 Criteria for Discontinuation of Study Drugs 
Participants who meet any one or more of the following criteria will be discontinued from study treatment: 
• 
Pregnancy 
• 
Any clinical adverse event, laboratory abnormality, intercurrent illness, other medical condition or 
situation occurs such that continued administration of study treatment is not in the best interest of 
the participant 
• 
Participant request for premature discontinuation of study treatment 
• 
Participants classified as ‘late exclusions’ 
Procedures for study follow-up are described in Section 9.  Except in emergency situations, the decision 
to discontinue a participant from treatment should be first discussed with the central study clinician or 
his/her designee.  
10.7 Accountability Procedures for the Study Drugs 
Study drugs will be shipped periodically to the study sites.  The investigator or designee will acknowledge 
receipt of and keep an inventory of study drugs.  Unused product should be stored at the site until 
directed by the study sponsor.  
10.8 Assessment of Subject Compliance with Study Treatment 
Each dose of study drugs given by DOT will be recorded by the healthcare worker.  Participants will be 
asked to record doses of study drugs not administered by DOT.  Adherence will be reviewed at each 
study visit.  Non-adherence should prompt an investigation into the cause of non-adherence and 
measures to address the non-adherence.  


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11 
ASSESSMENT OF EFFICACY 
11.1 Summary of Bacteriological Methods 
Detailed laboratory procedures for laboratory staff performing mycobacteriological tests are in the MOOP.  
The following brief description is intended to provide guidance to clinical study staff.   
All study sputa (expectorated or induced) should be sent to the designated study site laboratory.  Any 
anticipated changes in the designated site laboratory (i.e. to a different laboratory) and/or a change in the 
type of solid or liquid media used must be communicated in writing to the TBTC Project Officer prior to 
executing the change(s). 
The following will be performed for all study sputa:  Nalc-NaOH decontamination followed by culture using 
both solid medium and the Becton Dickinson Mycobacterial Growth Indicator Tube (MGIT) liquid culture 
automated system.  Bacterial load will be determined and recorded for all specimens using the time to 
positivity output automatically provided by the MGIT system. 
For all cultures showing growth of acid-fast bacilli, the acid fast bacilli will be species identified at least to 
the level of M. tuberculosis complex vs. not M. tuberculosis complex.   
For each participant, the first study isolate of M. tuberculosis will have culture-based phenotypic drug 
susceptibility testing performed at the study site-designated laboratory for isoniazid, rifampin, and 
fluoroquinolones.  In addition, phenotypic drug susceptibility testing should be performed for the first of 
any M. tuberculosis isolates obtained at/after the Week 17 study visit.  
For each participant, the first study isolate of M. tuberculosis as well as any M. tuberculosis isolates 
cultured from sputum obtained at/after the Week 17 study visit should be stored frozen.  The first study 
isolate of M. tuberculosis should be sent to the CDC laboratory.  Additional M. tuberculosis isolates 
pertinent to the participant’s treatment assignment should be sent to the CDC laboratory if requested by 
the CDC Data Center. 
  
 
 


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12 
ASSESSMENT OF SAFETY 
12.1 Specification of Safety Parameters 
12.1.1 Primary Outcome Measure 
Proportion of participants with grade 3 or higher adverse events during study drug treatment 
12.1.2 Secondary Outcome Measure 
Discontinuation of assigned treatment for a reason other than microbiological ineligibility 
12.2 Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
12.2.1 Adverse Events and Serious Adverse Events 
At each study visit participants will be asked about adverse events that have occurred since their 
previous visit.  Solicited events will include symptoms, hospitalizations, and new medical 
diagnoses.  Participants will also be asked to describe other signs, symptoms, and events not 
captured by the solicited event listing.   
Monitoring of laboratory parameters will be performed as described in Section 9 and Appendix A.   
12.2.1.1 Definition of Adverse Event  
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and that does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product.   
Any adverse events detected will be graded according to the Common Toxicity Criteria for 
Adverse Events (CTC) toxicity tables and coded using MedDRA.   
12.2.1.2 Serious Adverse Event  
A Serious Adverse Event (SAE) is any adverse event that results in any of the following 
outcomes: 
• 
Death 
• 
Life-threatening (subject at immediate risk of death) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in congenital anomaly/birth defect 
• 
Results in a persistent or significant disability or incapacity 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon appropriate 


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medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
12.3 Recording and Reporting Procedures 
12.3.1 Overview 
A sign or symptom should be reported as an adverse event if it meets either (or both) of the 
following criteria: a) reaches severity of grade 3 or higher; b) represents a new diagnosis.  
Laboratory findings should be recorded as adverse events only if clinically significant.   
12.3.2 Reporting Procedures 
Any SAE or grade 4 toxicity must be reported by the site to the TBTC on an Adverse Event 
Report within 48 hours of the site’s awareness of the event. 
SAEs, death, or life-threatening problems that may reasonably be regarded as caused by or 
associated with the administration of the study drug regimen (defined as at least ‘possibly 
associated’ with the study drug regimen) must be reported by the site to the Sponsor (TBTC) and 
the local IRB within 48 hours of the site’s awareness of the event. For participants who die, as 
much information as possible on cause of death and details of the final illness will be obtained 
from relevant sources.   
Any adverse event that meets the definition of being a suspected unexpected serious adverse 
reaction (SUSAR) will be reported promptly by the Sponsor (TBTC) to the FDA, international 
regulatory agencies, the CDC IRB, and all clinical investigators.   A SUSAR is defined as an 
adverse reaction that is unexpected (i.e. not consistent with the applicable product information) 
AND also meets the definition of a serious adverse event.  
12.3.3 Pregnancy 
For study purposes, pregnancy must be recorded on an Adverse Event Report form.  
Management of women who become pregnant during the study is described in Section 8. 
12.4 Management of adverse events 
For AEs that in the investigator’s judgment may be due to study drugs, the following general 
approach to management should be applied.  In general, for grade 1 toxicities, the patient will be 
followed carefully and the study drugs will be continued.  For grade 2 toxicities, the patient will be 
followed more carefully, with additional laboratory and/or clinic visits as necessary, and the study 
drugs may be temporarily held if in the investigator’s judgment continuation of study drugs would 
be unsafe.  
 
Grade 3 and 4 AEs should be carefully assessed.  The site clinician should consider other 
possible causes for toxicity before discontinuing study medicines.  When possible, concomitant 
medicines should be withheld first at the discretion of the site clinician if it is suspected that 
concomitant medicines are contributing to the toxicity.  If after careful assessment and in the site 
investigator’s judgment the event is at least possibly attributable to study drug(s), then the 


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causative study drug(s) may be withheld; the participant should be permanently discontinued 
from study drugs if it is in their best interest.   
 
For all toxicities that are treatment-emergent and that require the study therapy to be temporarily 
or permanently discontinued, relevant clinical and laboratory tests will be obtained as clinically 
indicated and repeated as needed until final resolution or stabilization of the toxicity.  Any 
participant for whom study drugs are temporarily held will be resumed on study medication as 
soon as possible.   
12.4.1 Type and Duration of the Follow-up of Subjects After Adverse Events 
Participants who experience adverse events that necessitate temporary or permanent 
discontinuation of study drugs will still be considered to be part of the study and will continue to 
be followed in the study until completion of follow-up.  If study drugs are permanently 
discontinued, further anti-tuberculosis therapy may be administered at the clinic staff’s discretion 
according to local or National Tuberculosis Program guidelines.   
12.5 Data and Safety Monitoring Board 
The TBTC Data and Safety Monitoring Board (DSMB) will review the study protocol and oversee progress 
of the trial.  The TBTC DSMB is comprised of a clinical TB expert, an epidemiologist with extensive 
experience with TB and HIV, and an internationally recognized clinical trialist/statistician, all of whom are 
not otherwise involved in the study. The DSMB will convene approximately annually, or more often as 
needed. 
12.6 Interim Monitoring and Analyses by the Data and Safety Monitoring Board 
The DSMB will have access to data and interim results and may recommend early closure of any 
experimental arm or the trial if, in their judgment, interim evidence is sufficiently strong that one of the trial 
interventions is clearly indicated or clearly contraindicated because of a net difference in efficacy, safety, 
or tolerability as defined by the corresponding primary endpoints for the trial, with a difference between 
arms that is statistically significant at the 0.1% level, according to the Haybittle-Peto statistical criterion for 
monitoring interim efficacy data. The analysis sequence described in section 13.5 will be followed for 
interim analysis. It is possible that arm 3 could be inferior to arm 1 (e.g., due to less adherence, drug 
interactions), but arm 2 not inferior to arm 1. If this is occurs, the study team will discuss implications with 
the DSMB.   
 


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13 
STATISTICAL CONSIDERATIONS 
13.1 Study Hypotheses 
This study has two main hypotheses and consists of two comparisons: 
A) In previously untreated individuals with drug-susceptible pulmonary tuberculosis treated with eight 
weeks of rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by nine weeks of 
rifapentine, isoniazid, and moxifloxacin (2PHZM/2PHM), all given daily throughout, the proportion 
of participants who experience absence of cure (unfavorable outcome) will not be inferior to that 
observed in participants who are treated with the standard regimen (eight weeks of rifampin, 
isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid) all 
given daily throughout. 
B) In previously untreated individuals with drug-susceptible pulmonary tuberculosis treated with eight 
weeks of rifapentine, isoniazid, pyrazinamide, and ethambutol followed by nine weeks of 
rifapentine plus isoniazid (2PHZE/2PH), all given daily throughout, the proportion of participants 
who experience absence of cure (unfavorable outcome) will not be inferior to that observed in 
participants who are treated with the standard regimen (eight weeks of rifampin, isoniazid, 
pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given 
daily throughout. 
13.2 Study Outcome Measures 
 
Primary Efficacy Endpoint: 
• 
TB disease-free survival at twelve months after study treatment assignment 
Primary Safety Endpoint: 
• 
Proportion of participants with grade 3 or higher adverse events during study drug treatment 
 
Secondary Efficacy Endpoints: 
• 
TB disease-free survival at eighteen months after study treatment assignment 
• 
Proportion of participants who are culture negative at eight weeks (solid and liquid media considered 
separately) 
• 
Time to stable sputum culture conversion (solid and liquid media considered separately) 
• 
Speed of decline of sputum viable bacilli by automated MGIT days to detection 
• 
Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have an 
unfavorable outcome 
• 
Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have a favorable 
outcome 
• 
Discontinuation of assigned treatment for a reason other than microbiological ineligibility 
• 
Estimated steady state efavirenz PK parameters including mid-dosing interval concentration 


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13.3 Definition of primary outcome status 
The primary analysis will be conducted using culture results from solid media and liquid media. 
Each participant will be classified into one of the following 3 outcome categories of Absence of 
Cure (Unfavorable Outcome), Cure (Favorable Outcome), or Not Assessable.  An independent 
Endpoint Committee will be formed and be responsible for determining final outcome status. The 
primary efficacy endpoint will be assessed at 12 months after treatment assignment; a secondary 
efficacy endpoint will consider the follow-up period to be 18 months after treatment assignment. 
Absence of Cure (Unfavorable Outcome) meeting any one or more of the following: 
• 
Absence of bacteriological cure.  A participant will be considered to have absence of 
bacteriological cure if he/she has a sputum sample, obtained at or after Week 17, that is 
culture positive for an M. tuberculosis strain that is indistinguishable from the initial isolate, 
and this is confirmed by a second sample that is culture positive for M. tuberculosis. A 
second confirmatory sample is required as a single positive sputum culture in isolation will not 
be considered absence of bacteriological cure.   
• 
Participants who die from any cause during study treatment, except from violent or accidental 
cause (e.g. road traffic accident). 
• 
Participants failing to complete treatment and not assessable at the end of the follow-up 
period. 
• 
Participants who had a positive culture for M. tuberculosis when last seen, whether confirmed 
by a second sample or not, unless determined to have been re-infected 
• 
Participants receiving any one or more of the following: a) extension of treatment beyond that 
permitted by the protocol; b) a re-start of treatment; c) a change in treatment for any reason 
except re-infection, pregnancy, or temporary drug challenge 
Cure (Favorable Outcome) meeting any one of the following and not already classified as having 
an unfavorable outcome 
• 
Participants with negative cultures at the end of the follow-up period  
• 
Participants who at the end of the follow-up period are clinically without symptoms/signs of 
ongoing active TB and are unable to produce a sputum specimen 
• 
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 without evidence of 
M. tuberculosis 
Not Assessable (meeting any one or more of the following and not already classified as having an 
unfavorable outcome) 
• 
Participants who completed assigned treatment and then default from follow-up, with their 
last culture being negative for M. tuberculosis 


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• 
Women who become pregnant during their assigned active treatment and stop their assigned 
treatment  
• 
Participants who die during the follow-up phase (≥ 15 days after completion of study 
treatment) 
• 
Participants who die from a violent (e.g. homicide) or accidental (e.g. road traffic) cause 
during their assigned active treatment.  As above, suicide will be considered an unfavorable 
outcome  
• 
Participants re-infected with a new strain of M. tuberculosis, demonstrated to be different 
from that identified at study entry through genotyping methods 
13.4 Analysis Groups 
There will be 4 analysis groups, as follows: 
Intention-to-Treat (ITT) 
Includes all enrolled participants who receive a treatment assignment. 
Microbiologically Eligible 
Includes the subset of Intention-to-Treat participants who, in addition, have culture confirmation of 
drug-susceptible tuberculosis at study entry. Participants classified as ‘not assessable’ will be 
considered to have an unfavorable outcome.   
Assessable 
Includes the subset of Microbiologically Eligible participants who, in addition, are not classified as 
‘not assessable’.   
Adherent Per-Protocol 
Includes the subset of Assessable participants who, in addition, complete assigned study 
treatment and follow-up.   
13.5 Analysis Plan 
13.5.1 Co-Primary efficacy analyses 
There will be two co-primary efficacy analyses.  One will consider the Microbiologically Eligible 
analysis population, and the other will consider the Assessable population. The assessable group 
is defined by exclusions that do not introduce selection bias. For each, the comparison of 
Regimen 1 (control regimen) versus Regimen 3 (2PHZM/2PHM) will be considered first, and, if 
non-inferiority criteria are met then the comparison of Regimen 1 versus Regimen 2 
(2PHZE/2PH) will be considered.   In each comparison, non-inferiority will be assessed by 
comparing the upper bound of a 95%, 2-sided confidence interval for the difference between the 
proportion of participants who are classified as having an unfavorable outcome on the control 
regimen (Regimen 1) and the intervention regimen to the predefined non-inferiority margin of 
6.6%.  


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13.5.2 Primary safety analysis 
There will be two comparisons: for comparison 1, Regimen 1 (control regimen) will be compared 
against Regimen 2 (2PHZE/2PH); for comparison 2, Regimen 1 (control regimen) will be 
compared against Regimen 3 (2PHZM/2PHM).  The primary safety endpoint is proportion of 
participants with grade 3 or higher adverse events.  The primary safety analysis will include the 
Intention-to-Treat group. 
13.5.3 Secondary efficacy analyses 
In secondary efficacy analyses, the primary efficacy endpoint will be assessed in the Adherent 
Per-Protocol analysis population, and secondary efficacy endpoints will be assessed for the 
Microbiologically Eligible, the Assessable, and the Adherent Per-Protocol analysis populations.  
Regimen 1 (control regimen) will be compared against Regimen 2 (2PHZE/2PH), and Regimen 1 
will also be compared against Regimen 3 (2PHZM/2PHM).  
13.5.4 Secondary safety analyses 
Tolerability will be assessed as discontinuation of the assigned treatment for a reason other than 
microbiological ineligibility.  Regimen 1 (control regimen) will be compared against Regimen 2 
(2PHZE/2PH) and Regimen 1 will also be compared against Regimen 3 (2PHZM/2PHM).  This 
analysis will include the Intention-to-Treat group. 
13.5.5 Secondary Efavirenz PK analysis 
Efavirenz pharmacokinetics will be evaluated in the first 31 and then a total of 90 patients from 
each of two groups of participants randomized to treatment regimen 2 or 3 of the study and 
receiving efavirenz based ART. Participants receiving efavirenz will fall into one of two groups for 
the PK evaluation: 1) HIV-infected participants on efavirenz with virologic suppression at the time 
of study enrollment (Group 1), or 2) HIV-infected participants started on efavirenz after initiation 
but before or at week 8 of study tuberculosis drugs (Group 2).  Individual-level measurements of 
efavirenz mid-dosing interval concentrations and estimates of efavirenz apparent oral clearance 
using a model-based post-hoc Bayesian approach will be performed. The efavirenz PK data will 
be judged acceptable if we have evidence that >80% of participants have estimated efavirenz 
mid-dosing interval concentrations ≥1 mg/L. 
 
13.6 Sample Size Considerations 
The primary objective of the trial is to evaluate whether rifapentine containing regimens can produce 
outcomes at least as favorable as standard therapy, but with a shorter treatment course.  Therefore, the 
trial is structured as a non-inferiority study.   
Key assumptions: 
• 
Primary endpoint rate: 15% absence of cure (unfavorable) in the standard regimen arm 
(Microbiologically Eligible population).   This rate is based on observed results for the control arm 
(MITT analysis group) in two recently completed phase 3 clinical trials (27/161 [14%] in the 
Rifaquin trial [Jindani et al., 2013] and 100/743 [13.5%] at 18 months post randomization and 
114/679 [16.8%] at 24 months after the end of treatment in the Oflotub trial [Merle et al., 2013].)    


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• 
Margin to define inferiority: 6.6% (δ = 0.066) 
• 
95% confidence (type 1 error, α = 0.05). The sequential testing of regimen 3 and regimen 2 
protects the type 1 error rate, as follows: If the statistical test for regimen 3 fails at 95% 
confidence, then conclude that both experimental regimens are not noninferior. If and only if 
regimen 3 is noninferior, then proceed to test regimen 2 at 95% confidence. A type 1 error occurs 
if either regimen is incorrectly deemed noninferior; the sequential approach limits the probability 
of this error to 5% overall. 
• 
Power: 80% (type 2 error, β = 0.20) for primary analysis among Microbiologically Eligible 
subgroup, with power recalculated for the restriction to Assessable subgroup (see below) 
• 
Proportion of enrolled patients who would be found to be late exclusions due to microbiological 
ineligibility – 12% (based on observed results in recent TBTC phase 2 studies) 
• 
Proportion of enrolled patients who would be found to be ‘not assessable’: 12% (based on 
observed results in the Rifaquin trial [Jindani et al., 2013]) 
With 816 per arm, we expect 612 assessable. With the expected 15% unfavorable outcomes among 
those who are assessable, then with the same noninferiority margin and type 1 error rate, we have 90% 
power to test the primary hypotheses among the Assessable subgroup. The 6.6% margin to define 
inferiority (6.6%) takes into consideration the following issues: (1) the rates in historical trials of inpatient 
TB treatment for 6-month and 4-month regimens conducted by the British Medical Research Council 
support a difference in relapse up to 6% (East African/British Medical Research Council 1976, 1977, 
1981; East and Central Africa/British Medical Research Council 1986; Singapore Tuberculosis 
Service/British Medical Research Council 1986; Nunn and Crook 2013); (2) recent trials in contemporary 
outpatient populations suggest a higher baseline proportion (15%) of unfavorable outcomes likely to be 
observed based on phase 3 trials and definitions; (3) the investigators in this trial and others perceive that 
the benefits of reducing treatment duration to 3 or 4 months would have advantages not outweighed by a 
possible increase in the relapse rate of up to 6%; and (4) the 6.6% margin does not imply that the 
experimental regimen may result in as much as 6.6% more unfavorable outcomes, but rather, for a fixed 
design, the maximum difference consistent with a non-inferior conclusion decreases as the proportion of 
unfavorable outcomes in the control arm increases. 


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14 
QUALITY CONTROL AND QUALITY ASSURANCE 
Study staff will be trained in Good Clinical Practice and in performance of study procedures.  The sponsor 
or the sponsor’s delegate will conduct a meeting with each site prior to the trial opening at the site in order 
to ensure that everything is in place for the trial to start, the study file contains all the essential 
documents, and study staff understand procedures and their roles and responsibilities.  The study will be 
conducted in accordance with the protocol and study-specific procedures manuals.   
14.1 Local quality control 
Each site will have a written plan for local quality control including data quality management.  
14.2 External monitoring 
External monitoring will be conducted to ensure the safety and conduct of this study, which involves 
patients with a serious illness (i.e. tuberculosis), uses an investigational drug treatment, will take place in 
multiple international sites, and may be used to modify the license for rifapentine and moxifloxacin.   
External monitoring will be conducted periodically by a contract research organization (CRO).  Direct 
access to data at each site will be required for the purposes of monitoring and audit, and this will be made 
explicit in the consent form.  Local investigators and their institutions will provide direct access to source 
documents and data for trial-related monitoring, audit, and regulatory inspections, in the clinic, the 
pharmacy, and the mycobacteriology laboratory.  
External monitoring will be conducted according to a written manual of procedures.  Monitoring will focus 
on ensuring that the following study activities are conducted per the protocol and associated documents: 
consent procedures, enrollment, dispensing of trial medications, correct implementation of treatment and 
follow-up procedures, accurate recording and reporting of adverse events and appropriate reporting of 
adverse events, correct implementation and reporting of mycobacteriology laboratory testing, accurate 
completion of case report forms, and timely and accurate data entry.  Additional activities or study 
elements may be monitored as needed.   
 


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15 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
This study will be conducted in conformity with the ethical standards set out in the latest version of the 
Declaration of Helsinki.   
15.1 Institutional Review Board 
Each participating institution will provide for the review and approval of this protocol and the associated 
informed consent documents by an appropriate institutional ethics committee (IEC) or Institutional Review 
Board (IRB).  Any amendments to the protocol or consent materials must also be approved before they 
are placed into use. 
15.2 Informed Consent Process 
Adults:  Only individuals who provide written informed consent will be enrolled in this study.  Written 
informed consent is required before any study-specific procedures are performed.  Potential participants 
will have the conditions of the study explained to them, including potential harms and benefits, the nature 
and timing of study procedures, alternatives to study participation, that study participation is voluntary, 
that a decision to not participate in the study will not affect the quality of their future medical care, and that 
they may withdraw from participation at any time.  The information in the Informed Consent document will 
be translated into relevant local languages.  Literate individuals will be provided with a language-
appropriate document to read; illiterate individuals (i.e. individuals who speak and understand, but do not 
read and write, the language in which the consent discussion is conducted) will have the contents of the 
document explained to them by a trained study staff member; such individuals can be enrolled by ‘making 
their mark’ on the consent document.  Potential participants will have the opportunity to ask questions of 
the site investigator or delegate, and to discuss participation with their family and/or friends or think about 
the study prior to deciding whether or not to participate.  A copy of the signed informed consent document 
will be given to the participant for his/her records.   
Children:  For potential participants under 18 years of age, the assent of the child as well as the written 
informed consent of the child’s legal guardian will be required for enrollment in this study.  The child will 
receive, in language appropriate to the age and maturity of the child, an explanation of the research 
procedures; a description of the risks, discomforts, or inconveniences that the child might experience; and 
assurance that the child can withdraw from the study at any time.  The assent process will be conducted 
by a study staff member who is experienced in consent and assent procedures, and in accordance with 
IRB/IEC requirements.  All study participants age < 18 years will provide oral or written assent and written 
consent by the participant’s legal guardian, in accordance with national and/or local IRB/IEC 
requirements. 
15.3 Subject Confidentiality 
All records identifying the participant will be kept confidential and, to the extent permitted by the 
applicable laws and regulations, will not be made publicly available without sufficient de-identification 
procedures.   


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Participant names will not be supplied to the sponsor.  All study documents and forms will be identified by 
a code only.  All paper study records will be stored in a locked office and electronic study records will be 
stored on password-protected computers; only designated trained study staff will have access to study 
records.  Transmission of electronic records to the sponsor will occur through a web-based data entry 
application that conforms to the Federal Information Security Management Act, or using a secure CDC 
File Transfer Protocol (FTP).   
The study monitors, other authorized representatives of the sponsor, and regulatory authorities may 
inspect all documents and records required to be maintained by the Investigator, including but not limited 
to, medical records, primary laboratory data, and pharmacy records for study participants; this information 
will be provided to participants during the Informed Consent process.  The clinical study site will permit 
access to such records. 
15.4 Study Discontinuation 
The Data and Safety Monitoring Board may recommend study termination or the termination of a study 
arm.  In addition, after consultation with involved parties, the Sponsor has the right to close the study and 
the right to close a study site.  If the study is closed, all involved ethics committees should be notified.  If a 
site is closed, then the local IEC/IRB and the CDC IRB should be notified.  In the event that the study is 
discontinued or a study site is closed, participants will undergo an early termination study visit.  
Participants experiencing an adverse event at the time of early termination should be followed until 
resolution or stabilization of the event.  Participants who were receiving study treatment at the time of 
early termination will be referred to local sources for tuberculosis care.   


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16 
DATA HANDLING AND RECORD KEEPING 
ICH-GCP requirements for data documentation will be followed.   
Data handling and record keeping will be performed in accordance with a study MOOP.  Briefly, 
information from source documents will be recorded on study-specific case report forms, which will be 
entered into the study electronic information system.  The study electronic information system will be 
programmed to maintain an audit trail, perform consistency checks, and generate reports of 
missing/inconsistent data. After study completion, de-identified data that can be legally released to the 
public may be released through a public-use data set after the data are evaluated for quality and 
confidentiality and shared with any partners, per CDC’s policy on data sharing. 
The study file and source documents should be retained until the sponsor gives notification.   
 


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17 
PUBLICATIONS AND DISSEMINATION OF STUDY RESULTS 
The study lead investigators and the TBTC Publications and Presentations committee must approve the 
use of any coded study data for the purposes of publication or presentation in advance.  Any proposal for 
collection of additional data or analysis of study data must be agreed to in advance by the study lead 
investigators and the protocol team.  The preparation of and authorship of publications arising from this 
study will be in accordance with the TBTC Bylaws.   
These criteria will not apply to public-use data that have been made available in accordance with CDC’s 
policy on data sharing. Persons who use publicly available data will be asked to acknowledge the TBTC 
and the S31 Protocol Team.  
Updates on the progress of the trial will be presented at the twice-yearly TBTC meetings. Additional 
dissemination of results will be through the press, national governments at meetings and international 
organizations at conferences. Overall (aggregate) study results will be shared with study participants 
through mechanisms and materials reviewed and approved by the TBTC Community Research Advisors 
Group.  


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18 
LITERATURE REFERENCES 
Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr., Dye C, Halloran ME.  
Epidemiological benefits of more-effective tuberculosis vaccines, drugs, and diagnostics. Proc Natl Acad 
Sci USA 2009;106:13980-5. 
Aung KJ, Declercq E, Ali MA, Naha S, Datta Roy SC, Taleb MA, Hossain MA, Rigouts L, Gumusboga A, 
Van Deun A. Extension of the intensive phase reduces relapse but not failure in a regimen with rifampicin 
throughout. Int J Tuberc Lung Dis. 2012 Apr;16(4):455-61. 
Avelox (moxifloxacin) package insert.  Bayer HealthCare Pharmaceuticals, Inc, 2012. 
Ball P, Stahlmann R, Kubin R, Choudhri S, Owens R. Safety profile of oral and intravenous moxifloxacin: 
cumulative data from clinical trials and postmarketing studies. Clin Ther 2004;26:940-50. 
Baciewicz AM, Self TH. Isoniazid interactions. South Med J. Jun 1985;78(6):714-718. 
Bemer-Melchior P, Bryskier A, Drugeon HB. Comparison of the in vitro activities of rifapentine and 
rifampicin against Mycobacterium tuberculosis complex. J Antimicrob Chemother. 2000;46:571-6. 
Blakemore R, Nabeta P, Davidow AL, Vadwai V, Tahirli R, Munsamy V, Nicol M, Jones M, Persing DH, 
Hillemann D, Ruesch-Gerdes S, Leisegang F, Samudio C, Rodrigues C, Boehme CC, Perkins MD, Alland 
D. A multisite assessment of the quantitative capabilities of the Xpert MTB/RIF assay. Am J Respir Crit 
Care Med. 2011;184:1076-84. 
Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control 
and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care 
Med. Feb 15 2003;167(4):603-662. 
Bradley JS, Jackson MA; Committee on Infectious Diseases; American Academy of Pediatrics. The use 
of systemic and topical fluoroquinolones. Pediatrics. 2011;128:e1034–e1045. 
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, Choudhri S, Daley CL, Munsiff 
SS, Zhao Z, Vernon A, Chaisson RE. Moxifloxacin versus ethambutol in the first 2 months of treatment for 
pulmonary tuberculosis. Am J Respir Crit Care Med. 2006;174:331-8. 
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SUPPLEMENTS/APPENDICES 
 


TBTC S31:  Rifapentine-containing tuberculosis treatment shortening regimens 
Version 1.1 
 
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 ____________________________________________________________________________________________ 
 
 
Appendix A: Schedule of Procedures/Evaluations 
 
 ____________________________________________________________________________________________ 
76 
Visit Window 
 
Up to 7 
days after 
screen 
+/- three (3) days 
+/- seven (7) days 
Early Term. 
during tx. 
Early Term.  
after tx. 
Visit 
Screen 
Baseline 
WK 
2 
WK 
4 
WK 
8 
WK 
12 
WK 
17 
WK 
22 
WK 
26 
MO 
9 
MO 
12 
MO 
15 
MO 
18 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms 
 
X 
X 
X 
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 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
Interval medical history 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest radiograph 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Visual tests 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 T cell count (if HIV-
pos) 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Viral load (if HIV-pos) 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum for smear and 
cultureb 
X 
X 
X 
X 
X 
X 
XX 
XX 
XX 
XX 
XXc 
XX 
XX 
X 
XX 
Sputum for rapid molecular 
test, if available at site 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Storage of Mtb bacterial 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 


 
 ____________________________________________________________________________________________ 
77 
isolate 
Diabetes screend 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Bilirubin 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Creatinine 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Hemoglobin 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
WBC with differential 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Platelets 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Albumin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Potassium 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling for TB drugs 
 
 
Obtain within this 
interval 
 
 
 
 
 
 
 
 
 
 
Blood sampling for 
pharmacogenomics testing 
 
 
Obtain any time after enrollment 
 
 
Plasma for EFV PK and 
viral load (only for HIV-
infected participants on RPT 
and efavirenz or startinge 
efavirenz 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Sputum, plasma, and urine 
specimens for storage 
(consenting participant only) 
 
X 
X 
X 
X 
 
Xf 
Xf 
 
 
 
 
 
 
X 
 
NOTES 
a Unless results of a test performed at or within 30 days prior to screening are available. 
 
b All sputa should be sent to the designated study laboratory with the exception of the screening specimen, which may be evaluated at any locally 
acceptable laboratory.  Two specimens (i.e. one at screening and one at baseline) are required prior to initiation of study treatment. Two (2) sputa should 
be obtained at each of weeks 17, 22, 26 and at each of months 9, 12, 15, and 18.   
 
c If both of the month 12 or month 18 sputa are contaminated, then the participant should be asked to provide two (2) additional sputa. 
 
d Hemoglobin A1C is the preferred test.  If such testing is not available, then fasting or random blood glucose can be measured. 
 
e Collect 1st specimen at screening or baseline, not both. Participants starting efavirenz while on study TB treatment should have plasma obtained (for 
storage) within 7 days before starting efavirenz (window is immediately prior to 1st efavirenz dose to a maximum of 7 days prior to 1st efavirenz dose).  
 
f To be collected at the end-of-study treatment visit (i.e. either week 17 or week 26). 
 
 


 
 ____________________________________________________________________________________________ 
78 
Appendix B:  Abbreviations 
 
Abbreviation 
Full-length identification 
ACTG 
AIDS Clinical Trials Group 
AE 
Adverse event 
ALT 
Alanine aminotransferase (alternative term is serum glutamic-
pyruvic transaminase [SGPT]) 
AUC 
Area under the concentration-time curve 
CDC 
Centers for Disease Control and Prevention (United States) 
CFR 
Code of Federal Regulations (United States) 
CRO 
Contract research organization 
DOT 
Directly observed therapy 
DSMB 
Data and Safety Monitoring Board 
E 
Ethambutol 
EFV 
Efavirenz 
FDA 
Food and Drug Administration (United States) 
G 
Gatifloxacin 
GCP 
Good Clinical Practice 
H 
Isoniazid 
ICH 
International Conference on Harmonisation 
INH 
Isoniazid 
IEC 
Institutional ethics committee 
IRB 
Institutional review board 
ITT 
Intention-to-treat 
M 
Moxifloxacin 
MDR 
Multidrug-resistant 
MGIT 
Mycobacterial Growth Indicator Tube 
MIC 
Minimum inhibitory concentration 
MITT 
Modified intention-to-treat 
MOOP 
Manual of Operating Procedures 
MTB 
Mycobacterium tuberculosis 


 
 ____________________________________________________________________________________________ 
79 
P 
Rifapentine 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PZA 
Pyrazinamide 
R 
Rifampin (alternative term is rifampicin) 
SAE 
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse reaction 
TBTC 
Tuberculosis Trials Consortium 
WHO 
World Health Organization 
XDR 
Extensively drug resistant 
Z 
Pyrazinamide 
 
 
 


1 
 
 
Rifapentine-containing treatment shortening regimens for pulmonary 
tuberculosis:  
A randomized, open-label, controlled phase 3 clinical trial 
 
 
 
Consortium Identifiers: 
Tuberculosis Trials Consortium Study 31 
AIDS Clinical Trials Group A5349 
 
 
ClinicalTrials.gov Identifier: NCT02410772 
 
 
 
Statistical Analysis Plan 
 
Version Number: 2.0 
9 July 2019 
 
 
CONFIDENTIAL 
PLEASE DO NOT SHARE 
 
 
Approval:  
Patrick Phillips, Trial Statistician 
 
 
7/10/2019


2 
 
General Information 
 
This document describes and substantiates the statistical principles and methods used for the 
analysis of data from TBTC S31/A5349. This document is designed to support the trial protocol. 
This Statistical Analysis Plan (SAP) supersedes previous versions of the SAP. Every care was 
taken in the drafting of this SAP, but corrections or amendments may be necessary.  
 
Version 1.0 of the SAP was signed off prior to the database extract for the first interim efficacy 
analysis.  
 
 
Statement of Compliance 
 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice E6 (ICH-GCP), U.S. Code of Federal Regulations 45 CFR 
46 and 21 CFR, and applicable site-specific regulatory requirements.   
 
 
 


3 
 
Contents 
 
1 
Introduction .......................................................................................................................................... 6 
 
Protocol Summary ........................................................................................................................ 6 
 
Schematic of study design ............................................................................................................ 8 
 
Sample size considerations ........................................................................................................... 9 
 
Margin of non-inferiority .............................................................................................................. 9 
2 
Objectives............................................................................................................................................ 12 
 
Primary Objectives ...................................................................................................................... 12 
 
Secondary Objectives .................................................................................................................. 12 
3 
Endpoints ............................................................................................................................................ 13 
 
Primary Endpoints ....................................................................................................................... 13 
 
Secondary Endpoints .................................................................................................................. 13 
4 
Study definitions ................................................................................................................................. 14 
 
Definition of primary outcome ................................................................................................... 14 
 
Absence of Cure (Unfavorable) ........................................................................................... 14 
 
Cure (Favorable) .................................................................................................................. 15 
 
Not Assessable .................................................................................................................... 15 
 
Participants Randomized in Error ............................................................................................... 15 
 
Exclusion criteria after enrollment (‘Late Exclusion’) ................................................................. 15 
 
Adequate treatment ................................................................................................................... 17 
 
Visit windows .............................................................................................................................. 18 
 
Treatment and follow-up phases ................................................................................................ 18 
 
Microbiologic classification ......................................................................................................... 19 
 
Inoculation results............................................................................................................... 19 
 
Culture results ..................................................................................................................... 19 
5 
Efficacy Analyses ................................................................................................................................. 21 
 
Study Populations ....................................................................................................................... 21 
 
Intention-to-Treat (ITT) ....................................................................................................... 21 
 
Microbiologically Eligible .................................................................................................... 21 
 
Assessable ........................................................................................................................... 21 
 
Adherent Per-Protocol (PP95)............................................................................................. 21 


4 
 
 
Adherent Per-Protocol (PP75)............................................................................................. 21 
 
Analysis plan for the primary efficacy outcome ......................................................................... 21 
 
Co-primary efficacy analyses .............................................................................................. 21 
 
Non-inferiority test ............................................................................................................. 22 
 
Superiority test .................................................................................................................... 22 
 
Secondary efficacy analyses ................................................................................................ 22 
 
Tabulation of the primary outcome classification .............................................................. 23 
 
Sub-group analyses ............................................................................................................. 23 
 
Independent Endpoint Review Committee ........................................................................ 23 
 
Additional sensitivity analyses ............................................................................................ 24 
 
Bayesian analysis of non-inferiority .................................................................................... 25 
 
Analysis plan for secondary efficacy outcomes .......................................................................... 25 
 
TB disease-free survival at eighteen months after study treatment assignment .............. 25 
 
Time to stable culture conversion ...................................................................................... 25 
 
Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to 
detection 26 
 
Time to unfavorable efficacy outcome ............................................................................... 26 
6 
Safety Analyses ................................................................................................................................... 28 
 
Analysis population ..................................................................................................................... 28 
 
Primary safety analysis ................................................................................................................ 28 
 
Secondary safety analyses .......................................................................................................... 28 
 
Treatment-related grade 3 or higher adverse events ......................................................... 28 
 
Tolerability .......................................................................................................................... 28 
 
All-cause mortality during treatment or follow-up ............................................................. 28 
 
Serious adverse events (SAEs) ............................................................................................ 29 
 
All grade adverse events (AEs) ............................................................................................ 29 
 
Laboratory safety parameters ............................................................................................ 29 
 
Acquired drug resistance .................................................................................................... 29 
7 
Data summaries .................................................................................................................................. 30 
 
Recruitment and baseline characteristics ................................................................................... 30 
 
Recruitment, screening, & eligibility ................................................................................... 30 
 
Exclusions from analysis ...................................................................................................... 30 


5 
 
 
Baseline characteristics ....................................................................................................... 30 
 
Adherence to study medications ................................................................................................ 30 
 
Concomitant medications ........................................................................................................... 30 
 
Retention, participant disposition, and description of follow-up ............................................... 30 
8 
Other Analyses .................................................................................................................................... 31 
 
Risk Factor Analysis ..................................................................................................................... 31 
 
Efavirenz Pharmacokinetics Analysis .......................................................................................... 31 
9 
Interim monitoring by the Data and Safety Monitoring Board (DSMB) ............................................. 32 
 
Monitoring for efficacy ............................................................................................................... 32 
 
Monitoring for safety .................................................................................................................. 32 
10 Version history .................................................................................................................................... 34 
 
List of changes from version 1.0 ................................................................................................. 34 
11 References .......................................................................................................................................... 35 
 
 
 
 
 
 
 
 
 
 
 
 
 


6 
 
1 
Introduction 
 
 
Protocol Summary  
 
Title: Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a 
randomized, open-label, controlled, phase 3 clinical trial 
 
Hypotheses: 
A) Seventeen (17) week rifapentine-based regimen 
 
In previously untreated individuals with active drug-susceptible pulmonary 
tuberculosis treated with eight weeks of rifapentine (P), isoniazid (H), 
pyrazinamide (Z) and ethambutol (E) followed by nine weeks of 
rifapentine plus isoniazid, all given daily throughout, the proportion of 
participants who experience absence of cure (unfavorable outcome) will 
not be inferior to that observed in participants who are treated with a 
standard regimen (eight weeks of rifampin (R), isoniazid, pyrazinamide 
and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all 
given daily throughout.  
 
B) Seventeen (17) week rifapentine- plus moxifloxacin-containing regimen 
 
In previously untreated individuals with active drug-susceptible pulmonary 
tuberculosis treated with eight weeks of rifapentine, isoniazid, 
pyrazinamide and moxifloxacin (M), followed by nine weeks of rifapentine, 
isoniazid, and moxifloxacin, all given daily throughout, the proportion of 
participants who experience absence of cure (unfavorable outcome) will 
not be inferior to that observed in participants who are treated with a 
standard regimen (eight weeks of rifampin, isoniazid, pyrazinamide and 
ethambutol followed by eighteen weeks of rifampin plus isoniazid), all 
given daily throughout. 
 
Phase: 
3 
Design: 
This will be an international, multicenter, randomized, controlled, open-
label, 3-arm, phase 3 non-inferiority trial. 
Population: 
Participants with newly diagnosed, previously untreated pulmonary 
tuberculosis.  
Number of Sites: 
Multiple international sites, primarily sites of the Tuberculosis Trials 
Consortium and the AIDS Clinical Trials Group.   
Study Duration: 
Duration per participant is approximately 18 months. 
 
 
 


7 
 
Description of Agent or Intervention: 
After written informed consent, participants will be 
randomly assigned to receive one of the following oral regimens: 
 
 
Regimen 1 (control regimen): 2RHZE/4RH 
 Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, 
followed by  
 Eighteen weeks of daily treatment with rifampin and isoniazid 
 
 
Regimen 2 (investigational regimen): 2PHZE/2PH 
 Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and 
ethambutol, followed by  
 Nine weeks of daily treatment with rifapentine and isoniazid  
 
 
 
Regimen 3 (investigational regimen): 2PHZM/2PHM 
 Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and 
moxifloxacin, followed by  
 Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin 
 
 
 


8 
 
 
Schematic of study design 
 
Figure 1 Schematic of study design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screen for eligibility 
Enroll
Randomize 1:1:1
Regimen 1 
(control regimen) 
2RHZE/4RH 
(26 weeks) 
Regimen 2 
(investigational) 
2PHZE/2PH 
(17 weeks) 
Regimen 3 
(investigational) 
2PHZM/2PHM 
(17 weeks) 
Participant follow-up: 
18 months after treatment assignment 
Analysis of Outcome Measures 
Primary at 12 months; secondary at 18 months 


9 
 
 
Sample size considerations 
The primary objective of the trial is to evaluate whether rifapentine containing regimens can 
produce outcomes at least as favorable as standard therapy, but with a shorter treatment 
course.  Therefore, the trial is structured as a non-inferiority study. 
 
Key assumptions: 
• 
Primary endpoint rate: 15% absence of cure (unfavorable) in the standard regimen arm 
(Microbiologically Eligible population).   This rate is based on observed results for the 
control arm (MITT analysis group) in two recently completed phase 3 clinical trials 
(27/161 [14%] in the Rifaquin trial1 and 100/743 [13.5%] at 18 months post 
randomization and 114/679 [16.8%] at 24 months after the end of treatment in the 
Oflotub trial2.)    
• 
Margin to define inferiority: 6.6% (δ = 0.066) 
• 
95% confidence (type 1 error, α = 0.05). The sequential testing of regimen 3 and 
regimen 2 protects the type 1 error rate, as follows: If the statistical test for regimen 3 
fails at 95% confidence, then conclude that both experimental regimens are not 
noninferior. If and only if regimen 3 is noninferior, then proceed to test regimen 2 at 95% 
confidence. A type 1 error occurs if either regimen is incorrectly deemed noninferior; the 
sequential approach limits the probability of this error to 5% overall. 
• 
Power: 80% (type 2 error, β = 0.20) for primary analysis among Microbiologically Eligible 
subgroup, with power recalculated for the restriction to Assessable subgroup (see 
below) 
• 
Proportion of enrolled participants who would be found to be late exclusions due to 
microbiological ineligibility – 12% (based on observed results in recent TBTC phase 2 
studies) 
• 
Proportion of enrolled participants who would be found to be ‘not assessable’: 12% 
(based on observed results in the Rifaquin trial1) 
 
With 816 per arm, we expect 612 assessable. With the expected 15% unfavorable outcomes 
among those who are assessable, then with the same noninferiority margin and type 1 error 
rate, we have 90% power to test the primary hypotheses among the Assessable subgroup.  
 
 
Margin of non-inferiority 
 
The 6.6% margin to define inferiority (6.6%) takes into consideration the following issues:  
(1) the rates in historical trials of inpatient TB treatment for 6-month and 4-month regimens 
conducted by the British Medical Research Council support a difference in relapse up to 
6% (East African/British Medical Research Council 1976, 1977, 1981; East and Central 
Africa/British Medical Research Council 1986; Singapore Tuberculosis Service/British 
Medical Research Council 1986; Nunn and Crook 2013);  
(2) recent trials in contemporary outpatient populations suggest a higher baseline proportion 
(15%) of unfavorable outcomes likely to be observed based on phase 3 trials and 
definitions;  
(3) the investigators in this trial and others perceive that the benefits of reducing treatment 
duration to 3 or 4 months would have advantages not outweighed by a possible increase 
in the relapse rate of up to 6%; and  
(4) the 6.6% margin does not imply that the experimental regimen may result in as much as 
6.6% more unfavorable outcomes, but rather, for a fixed design, the maximum difference 
consistent with a non-inferior conclusion decreases as the proportion of unfavorable 
outcomes in the control arm increases. 
 


10 
 
A 6% margin of non-inferiority trials has been used in other recent trials of single-drug 
substitution treatment shortening trials (e.g. REMoxTB). The justification of this margin is 
published in the online supplements with these papers (Gillespie et al, 2014 NEJM). We have 
attached the justification from that study as an attachment to support a 6% margin.   
 
We believe an extension from 6% to 6.6% is justified for the following reasons: 
 
1) The justification for a 4.8% margin in the FDA Guidance for Industry for Pulmonary 
Tuberculosis Trials is based on previous trials under ‘per protocol’ type analyses with 
many post-randomization exclusions, in a largely in-patient population; we observe 
larger proportions of unfavorable outcomes today than was seen in these relapse-
only analyses from previous trials. We feel this provides a justification for a larger 
margin than 4.8%, and also the 6% that was justified for the REMoxTB trial.  Recent 
trials in contemporary outpatient populations suggest a higher proportion (16% in 
REMoxTB MITT) of unfavorable outcomes, even than that anticipated in the 
REMoxTB trial sample size calculations (10%). 
 
Furthermore, the rationale for a 4.8% margin is based on the situation where a single 
drug that has an unknown contribution to the regimen is replaced by a new drug (the 
replacement of ethambutol, for example). In our study, rifampicin is replaced by 
rifapentine (in addition to the substitution of moxifloxacin for ethambutol in one arm). 
It is known that rifampicin is the most important drug in the current regimen. It might 
therefore be appropriate to consider not just the removal of the final two months of 
therapy (following the argument in lines 829-832 in the FDA Guidance) to estimate 
M1, but also the consider the removal of rifampicin from the regimen. This would 
require consideration of a comparison of six months of HRZE (2HRZE/4HR) with four 
months of HZE (2HZE/2H) when estimating M1. We are not aware of any trials that 
evaluated a 4-month regimen without rifampicin, so providing a comprehensive 
rationale similar to that which underpins the 4.8% would be challenging but would 
lead to a larger M1 and therefore support a margin of non-inferiority larger than 4.8%. 
2) Considering the clinical argument (from FDA Guidance and Nunn, Phillips, Gillespie 
2008) we, and in broader consultation within our two large publicly-funded 
international consortia of TB stakeholders (CDC TB Trials Consortium and NIH AIDS 
Clinical Trials Group), consider the benefits of a 4-month rifapentine-based regimen 
justify the margin of 6.6%. Our consortia consider 600 patients per arm sufficiently 
large to provide adequate precision on the difference in efficacy between the 
regimens to determine whether an intervention regimen might be considered not 
inferior to the control regimen.  
The following graph was used to describe the maximum observable difference (solid 
line) from in the point estimate from the line of equality (plotted as dashed line) with a 
6.6% margin under the stated assumptions.  
 


11 
 
 
 
 
The FDA Guidance for Industry Pulmonary Tuberculosis: Developing Drugs for Treatment 
identifies two studies comparing four and six months of TB therapy that provide data to estimate 
M1 for providing a rationale for the margin of non-inferiority. Study 2 (data from the 4th and 5th 
EA/BMRC trials) also included two four-month regimens without a rifamycin in the continuation 
phase, 2SHRZ/2HZ and 2SHRZ/2H. The combined relapse rate in these two arms was 63 
(31%) / 203. Using the figures quoted in the FDA guidance document for the 2SHRZ/4HR 
regimen from this study (4.7% (8/172)), the treatment effect (4-month regimen minus 6-month 
regimen) is 26.4%, 95% CI (19.3%, 33.5%) for the unstratified risk difference. This lower bound 
of 19.3% provides an estimate of M1 for the removal of the final 2 months of HR therapy, and 
the removal of R in months 3 and 4. We want to preserve a reasonable proportion of this 
treatment effect and have therefore selected a 6.6% margin of non-inferiority which preserves 
more than 50% of M1.  
 
For these reasons it is our perspective that a margin of 6.6% is justified.  


12 
 
2 
Objectives 
 
 
Primary Objectives 
 
To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single 
substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the 
duration of treatment for drug-susceptible pulmonary tuberculosis 
 
To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes 
moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to 
determine whether it is possible to reduce to seventeen weeks the duration of treatment for 
drug-susceptible pulmonary tuberculosis   
 
 
Secondary Objectives 
 
To evaluate the safety of the investigational regimens 
 
To evaluate the tolerability of the investigational regimens 
 
To collect and assess biospecimens from consenting participants for the purpose of 
research on discovery and validation of TB biomarkers 
 
To determine the correlation of mycobacterial and clinical markers with time to culture 
conversion, treatment failure, and relapse. 
 
To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs. The main 
objectives of the PK/PD study are to characterize study drug PK parameters and to 
determine relationships between treatment outcomes and PK parameters.  
 
To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among 
participants with TB/HIV co-infection taking efavirenz-based combination antiretroviral 
therapy and TB treatment with rifapentine. 
 
 


13 
 
3 
Endpoints 
 
 
Primary Endpoints 
 
Efficacy: TB disease-free survival at twelve months after study treatment assignment.   
 
Safety: Proportion of participants with grade 3 or higher adverse events during study drug 
treatment 
 
 
Secondary Endpoints 
 
TB disease-free survival at eighteen months after study treatment assignment 
 
Time to stable sputum culture conversion (solid and liquid media considered separately)  
 
Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection 
 
Proportion of participants who are culture negative at completion of eight weeks of treatment 
(solid and liquid media considered separately) 
 
Sensitivity analyses assuming all participants classified as ‘not assessable’ have a favorable 
outcome 
 
Discontinuation of assigned treatment for a reason other than microbiological ineligibility 
 
Estimated steady state efavirenz PK parameters including mid-dosing interval concentration 
 


14 
 
4 
Study definitions 
 
 
Definition of primary outcome  
Each participant will be classified into one of the following three outcome categories: 
1. Absence of Cure (Unfavorable Outcome) 
2. Cure (Favorable Outcome), or  
3. Not assessable. 
The primary outcome is defined as twelve months after study treatment assignment. Actual visit 
dates, rather than scheduled visit names (e.g. Week 26, or Month 9), will be used for all 
analyses. See section 4.5 for visit windows that define the time periods. In particular, Month 12 
includes data from visits up to 442 days from treatment initiation. 
Only data up to the end of the Month 12 analysis visit window will be included in the primary 
analysis of the primary efficacy outcome. 
 
 Absence of Cure (Unfavorable) 
A participant will be classified as having an unfavorable outcome if any one of the following 
conditions is met: 
1. A participant will be considered to have absence of bacteriological cure if he/she has a 
sputum sample, obtained at or after Week 17 and no later than the end of the Month 12 
analysis visit window, that is Mtb Culture Positive (see section 4.7 for definitions of culture 
results) that is indistinguishable from the initial isolate (see separate sequencing plan for 
definitions), and this is confirmed by a second sample that is Mtb culture positive. A second 
confirmatory sample, on a different day without an intervening Mtb Negative culture result, is 
required, as a single positive sputum culture result in isolation will not be considered 
absence of bacteriological cure. If results from strain analysis are inconclusive or 
unavailable, it will be assumed that strains were indistinguishable.  
2. Participants who die from any cause during study treatment (‘study treatment phase’ is 
defined in section 4.6), except from violent or accidental cause (e.g. road traffic accident). 
Suicide during study treatment will be classified as an unfavorable outcome.  
3. Participants who are withdrawn from follow-up or lost to follow-up prior to the scheduled end 
of treatment of study treatment, except for pregnancies and violent or accidental death that 
are instead classified as having a Not Assessable outcome (see section 4.1.3). 
4. Participants who had an Mtb Positive culture result when last seen during or prior to the 
Month 12 analysis visit window, whether confirmed by a second sample or not, unless 
determined to have been re-infected. 
5. Participants receiving any one or more of the following, except when given for failure or 
recurrence subsequently shown to be a reinfection with a strain of M. tuberculosis, different 
from that or those identified at study entry through genotyping methods):  
a) Extension of treatment beyond that permitted by the protocol; excepting 
a. Temporary drug re-challenge; 
b. Over-treatment with drugs from assigned study kits; 
c. Twenty-one days or fewer of non-study anti-TB medications given for 
treatment of active TB; or 
d. Secondary isoniazid preventative therapy in HIV infected participants. 
b) Re-start of treatment for active TB;  
c) Change in treatment (including frequency or dosage) for any reason except re-
infection, pregnancy, or temporary drug challenge. 
6. Participants who die during the follow-up phase (as defined in section 4.6) where the cause 
of death is considered related to tuberculosis. 
 


15 
 
 Cure (Favorable)  
A participant will be classified as having a favorable outcome if any one of the following 
conditions is met and an unfavorable outcome has not occurred: 
1. Participants whose last culture result during the Month 12 analysis visit window is Mtb 
Negative (See Section 4.7).  
2. Participants who are seen during the Month 12 analysis visit window and are clinically 
without symptoms/signs of ongoing active TB (indicated by absence of initiation of possible 
poor treatment response evaluation or PPTR that does not indicate presence of 
symptoms/signs of ongoing active TB), and have achieved culture conversion prior to Month 
12, and  
1. Are unable to produce a sputum specimen at any point during the Month 12 analysis 
visit window; or 
2. Produce a sputum specimen that is contaminated or unevaluable without evidence of 
M. tuberculosis, and no sputum specimens yield positive or negative culture results 
during the Month 12 analysis visit window. 
 
 Not Assessable 
A participant will be classified as having a Not Assessable outcome if any one of the following 
conditions is met and an unfavorable outcome has not occurred: 
1. Participants not otherwise classified as unfavorable, but do not attend a visit within the 
Month 12 analysis visit window, and their last culture result is negative for M. tuberculosis. 
2. Women who become pregnant during assigned study treatment (see section 4.6 for 
definition of study treatment phase). 
3. Participants who die during the follow-up phase (as defined in section 4.6) of any cause that 
is not considered related to tuberculosis. 
4. Participants who die from a violent (e.g. homicide) or accidental (e.g. road traffic) cause 
during their assigned study treatment (see section 4.6 for definition of study treatment 
phase).  As above, suicide will be considered an unfavorable outcome.  
5. Participants who are: 
a) Retreated, or have treatment changed or extended; and  
b) Demonstrated to be re-infected with a strain of M. tuberculosis, different from 
that or those identified at study entry through genotyping methods. 
A participant classified as having a Not Assessable outcome will be excluded from the 
Assessable and Adherent Per-Protocol analyses, but considered as Unfavorable for other 
analyses.  
 
 
Participants Randomized in Error 
Participants who were randomized in error are those who were found to not meet eligibility 
criteria after enrollment, other than criteria in Section 4.3, relating to microbiology.  
 
Determination of whether eligibility criteria was violated and subsequent classification as 
‘randomized in error’ will be based only on data that was collected prior to randomization. All 
participants who are found to be in violation of any eligibility criteria (other than the criteria in 
Section 4.3 relating to microbiology) will be classified as randomized in error, irrespective of 
whether the participant was withdrawn from treatment or not.  
 
 
Exclusion criteria after enrollment (‘Late Exclusion’) 
Microbiological confirmation of drug-susceptible tuberculosis is not expected always to be 
available at the time of enrollment.  Enrolled individuals who are subsequently determined to 


16 
 
meet either of the following criteria will be classified as ‘late exclusions’ and study treatment will 
be discontinued: 
1. None of screening, baseline, and Week 2 study visit sputum cultures are Mtb Positive  
2. M. tuberculosis cultured or detected through molecular assays (Cepheid Xpert MTB/RIF or 
Hain MTBDRplus assays) from any sputum obtained at screening, baseline, or week two 
study visit is determined subsequently to be resistant to one or more of isoniazid, rifampin, 
or fluoroquinolones.  
 
 
 


17 
 
 
Adequate treatment 
Only participants having completed an adequate number of study doses will be included in the 
Per Protocol (PP) analysis populations. Two PP analysis populations are defined. PP75 
excludes participants who have received less than approximately 75% of study doses (see 
Table below for exact doses required) using the definitions consistent with previous phase III TB 
trials, in particular the REMoxTB trial3 and in the original trials which determined the 
effectiveness of the control 6 month isoniazid-rifampin regimen4. The TB-REFLECT analyses5 
have shown that even participants with less than 95% adherence have poorer outcomes than 
those with perfect adherence, and consecutive missed doses is associated with poorer 
outcomes than occasional missed doses6. For these reasons, the PP95 analysis population 
excludes participants who have received less than approximately 95% of study doses (see 
Table 1 below for exact doses required). PP95 will be the primary per protocol analysis 
population with PP75 being supportive.  
 
Table 1. Two definitions of adequate treatment 
 
 
75% Adherence (PP75) 
Approximately 75% of doses 
within 125% of the intended 
duration. 
95% Adherence (PP95) 
Approximately 95% of doses within 
125% of the intended duration.  
 
Doses 
Days  
Doses 
Days since 
treatment 
initiation 
Regimen 1 
At least 42 
intensive phase 
doses 
No more 
than 70 
days since 
treatment 
initiation 
At least 54 
intensive phase 
doses 
No more than 
70 days since 
treatment 
initiation 
At least 84 
continuation phase 
doses 
No more 
than 168 
days since 
completing 
intensive 
phase 
At least 120 
continuation phase 
doses 
No more than 
168 days since 
completing 
intensive 
phase 
No more than 42 doses missed 
No more than 5 consecutive DOT 
doses missed 
Regimens 2 or 3 
At least 42 
intensive phase 
doses 
No more 
than 70 
days since 
treatment 
initiation 
At least 54 
intensive phase 
doses 
No more than 
70 days since 
treatment 
initiation 
At least 42 
continuation phase 
doses 
No more 
than 84 
days since 
completing 
intensive 
phase 
At least 60 
continuation phase 
doses 
No more than 
84 days since 
completing 
intensive 
phase 
No more than 28 doses missed 
No more than 5 consecutive DOT 
doses missed 


18 
 
 
 
Visit windows 
Participants are assessed at screening, baseline (Week 0), Week 2, Week 4, Week 8, Week 12, 
Week 17, Week 22, Week 26, Month 9 and 3-monthly to Month 18 with visit dates scheduled 
from the date of treatment initiation.  
 
For the purpose of analysis, each scheduled visit will have a window before and after the target 
date, calculated from date of first dose of study medication. The only exception is the visit 
window for Baseline which is from date of screening consent to date of randomization 
(inclusive). Any visits after randomization up to 24 days after treatment initiation are included in 
the Week 2 visit window.  
 
When referring to a visit in this analysis plan (e.g. ‘Week 17’), this implies within the defined visit 
window as specified below in Table 2. 
 
Table 2. Analysis visit windows 
Visit 
Target date (days from date 
of first dose of treatment) 
Analysis window 
Baseline (including screening 
period) 
Date of randomization 
Date of screening consent – 
Date of randomization 
Week 2 
14 
Day after randomization-24 
Week 4 
28 
25-52 
Week 8 
56 
53-80 
Week 12 
84 
81-115 
Week 17 
119 
116-150 
Week 22 
154 
151-178 
Week 26 
182 
179-262 
Month 9 
270 
263-352 
Month 12 
360 
353-442 
Month 15 
450 
443-523 
Month 18 
540 
533-no upper bound  
(an upper bound of 570 will 
be used for reporting safety 
analyses)  
 
Any visit, scheduled or unscheduled (including possible poor treatment response or post early 
termination visits), that falls into the analysis window will be assigned to that visit for the purpose 
of analysis. If two visits fall within the same interval, the one closest to the target date will be 
used for analyses by visit, or the highest value, depending on the analysis, so that there is only 
one unique visit for each participant and analysis time-point. However, all critical endpoint 
determining data will be used (e.g. culture results). 
 
 
Treatment and follow-up phases 
For the purposes of analysis, the screening, treatment and follow-up phases are defined as 
follows: 
 
 
Pre-treatment phase 
o Start: date informed consent signed. 
o End: day before start of study treatment. 
 


19 
 
 
Study treatment phase 
o Start: date of start of study treatment. 
o End: date of last dose of allocated treatment regimen, plus 14 days. 
 
 
Follow-up phase 
o Start: the day after the end of the study treatment phase. 
o End: date of the last participant contact (scheduled or unscheduled, or other contact 
e.g. phone call). 
 
 
Microbiologic classification 
 
 Inoculation results 
Each sputum specimen is inoculated onto solid and liquid media. The result of each inoculation 
is classified as Mtb Positive, Mtb Negative, Contaminated, or Unevaluable (Table 3). It is 
expected that one sputum specimen will produce two inoculation results, one for each media 
type. Inoculation results reported as Mtb alone, Mtb with other mycobacteria (e.g., NTM), or Mtb 
with contamination will be classified as Mtb Positive. Inoculations reported as no growth or other 
mycobacteria without identification of Mtb will be classified as Mtb Negative. Inoculations 
reported as contaminated without identification of Mtb will be classified as Contaminated.  
 
Table 3. Classification of culture results per inoculum 
Inoculation 
Result 
Classification 
Definition 
Mtb Positive 
Definitive identification of Mtb with or without the presence of contaminants 
or other mycobacteria. 
Mtb Negative 
No Mtb or contaminants detected at least 42 days after inoculation. Growth 
of other mycobacteria (NTM) in the absence of Mtb or contaminants.   
Contaminated 
Growth of contaminants with or without other mycobacteria, but with no 
identification of Mtb.   
Unevaluable 
Includes any of the following: 
 
Sputum processed at non-lab of record. 
 
Media inoculated more than 4 days after sputum received in the lab. 
 
Missing culture result. 
 
Mtb identification was presumptive with no definitive identification. 
 
Result of no growth determined fewer than 42 days after inoculation. 
 
 Culture results 
The primary analysis will be conducted using results from inoculation onto solid and liquid 
media. For each sputum specimen, results from solid and liquid media inoculations will be 
combined into a single Culture Result, see Table 4.  When multiple sputa are collected on a 
single day, all results of each inoculation are used to establish the Culture Result. 
 


20 
 
For some analyses, solid and liquid culture will be analyzed separately. For these analyses, 
definitions in Table 4 will be used, considering only inoculations from that culture media.  
.   
 
Table 4. Specimen Culture Result Classification for all inoculation results 
Culture Result 
Classification  
Definition for visits when a 
single specimen (multiple 
media) is collected 
Definition for visits when 
multiple specimens (multiple 
media) are collected 
Mtb Culture 
Positive 
Any inoculation from a single 
specimen is Mtb Positive 
Any inoculation from any 
specimen collected on a single 
day is Mtb Positive 
Mtb Culture 
Negative 
All inoculations are Mtb 
Negative for a single specimen 
When at least one inoculation 
from a specimen is Mtb 
Negative and additional 
inoculation(s) is Contaminated 
When at least one inoculation 
from a specimen is Mtb Negative 
and additional inoculation(s) is 
Unevaluable 
All inoculations from all 
specimens collected on a single 
day are Mtb Negative 
When at least one inoculation 
from all specimens collected on 
a single day is Mtb Negative and 
additional inoculation(s) is 
Unevaluable or Contaminated 
 
Culture 
Contaminated 
All inoculation results are 
Contaminated for a single 
specimen 
When at least one inoculation 
from a single specimen is 
Contaminated and additional 
inoculation(s) is Unevaluable 
All inoculations from all 
specimens collected on a single 
day are Contaminated 
When at least one inoculation 
from all specimens collected on 
a single day is Contaminated 
and additional inoculation(s) is 
Unevaluable 
Culture 
Unevaluable 
All inoculation results from a 
single specimen are 
Unevaluable 
All inoculations from all 
specimens collected on a single 
day are Unevaluable 
Unable to 
produce sputum 
Attempt to collect sputum is 
unsuccessful as participant is 
unable to produce sputum 
All attempts to collect sputum is 
unsuccessful as participant is 
unable to produce sputum 
  


21 
 
5 
Efficacy Analyses 
 
 
Study Populations 
There will be five analysis groups, as follows: 
 
 Intention-to-Treat (ITT) 
Includes all randomized participants. 
 
 Microbiologically Eligible 
Includes the subset of Intention-to-Treat participants who, in addition, have culture confirmation 
of drug-susceptible tuberculosis as defined by section 4.3, and were not randomized in error as 
defined by section 4.2. Participants classified as ‘not assessable’ will be considered to have an 
unfavorable outcome in this analysis. 
 
 Assessable 
Includes the subset of Microbiologically Eligible participants who, in addition, are not classified 
as ‘not assessable’. 
 
 Adherent Per-Protocol (PP95) 
Includes the subset of Assessable participants who, receive 95% of assigned treatment as 
defined in Section 4.4. Participants in the Assessable study population that do not complete 
adequate treatment for the reason of death or bacteriological treatment failure will be included in 
the PP95 analysis population provided they receive 95% of doses up to the time of treatment 
withdrawal. This will be the primary PP analysis population. 
 
 Adherent Per-Protocol (PP75) 
Includes the subset of Assessable participants who, receive 75% of assigned treatment as 
defined in Section 4.4. Participants in the Assessable study population that do not complete 
adequate treatment for the reason of death or bacteriological treatment failure will be included in 
the PP75 analysis population provided they receive 75% of doses up to the time of treatment 
withdrawal. This is a supportive PP analysis population and is included for comparability with 
previous trials (particularly REMoxTB) 
 
 
Analysis plan for the primary efficacy outcome 
 
 Co-primary efficacy analyses 
The primary analyses of efficacy is based on the modified ITT populations: the Microbiologically 
Eligible and Assessable study populations. While an ITT analysis is commonly used for a 
superiority trial, it may not be sufficiently conservative for a non-inferiority trial since ITT analysis 
can bias toward no treatment difference. Both the International Conference on Harmonisation 
(ICH) E9 document of Statistical Principles for Clinical Trials7 and the FDA document of 
Guidance for Industry Non-Inferiority Clinical Trials (REF) suggest looking at the ITT analysis 
cautiously for a non-inferiority trial and recommend considering PP analysis as equally 
important for a non-inferiority trial8. A PP analysis, however, does introduce bias through 
exclusions based on post-randomization exclusions9 which is particularly problematic in a study 
that is not placebo-controlled. The PP analyses (PP95 and PP75) will therefore be considered 
secondary in the primary efficacy analyses.  
 


22 
 
There will be two co-primary efficacy analyses, one for the Microbiologically Eligible population 
and another for Assessable population. Non-inferiority must be demonstrated in both 
populations in order to declare non-inferiority for an intervention regimen. 
 
For each, the comparison of unfavorable outcome as defined by protocol at primary efficacy 
endpoint for Regimen 1 (control regimen) versus Regimen 3 (2PHZM/2PHM) will be considered 
first, and, if non-inferiority criteria are met, then the comparison of Regimen 1 versus Regimen 2 
(2PHZE/2PH) will be considered.  
In the event that the arm of Regimen 3 is terminated for safety concerns in the interim 
monitoring, the comparison of Regimen1 versus Regimen 2 (2PHZE/2PH) will be carried out for 
co-primary efficacy analyses. 
If Regimen 3 is not terminated for safety concerns in the interim monitoring and the non-
inferiority criteria for Regimen 1 versus Regimen 3 at the primary endpoint are not met (see 
5.2.1), then the comparison of Regimen 1 versus Regimen 2 at the primary endpoint will be 
considered as an exploratory efficacy analysis. 
 
 Non-inferiority test  
The proportion of participants with unfavorable outcome can be estimated thus:   if 
ar  and br   
are the proportions of unfavorable outcome for the two study arms (a = Regimen 1 and b = 
Regimen 2 or Regimen 3) and if is the non-inferiority margin (= 6.6%), then the statistical 
hypothesis is: 



a
b
r
r
H :
0
     vs.   



a
b
r
r
H :
1
 
For a significance level of 0.05, the statistical test is equivalent to obtaining the two-sided 95% 
confidence interval for the difference of  𝒓𝒃−𝒓𝒂 .  If the upper bound of the confidence 
interval is less than, then the non-inferiority of Regimen 2 or Regimen 3 to Regimen 1 with a 
significance level of 0.05 is established (equivalent to one-sided α=0.025). 
The difference in proportion unfavorable will be calculated using a stratified analysis using 
Cochran-Mantel-Haenszel weights10. Randomization is stratified by site, HIV status and 
presence of cavitation. The analysis will be stratified by HIV status and presence of cavitation 
only. Inclusion of site as a factor in the stratified analysis will result in some groups with too few 
participants. The unstratified difference in proportions will also be presented, although the 
stratified difference will be considered primary.  
 
 Superiority test     
Regimens that are shown to be non-inferior to control will also be assessed for superiority 
compared to control using a two-sided significance level of 0.05. 
 
 Comparison of intervention arms 
If the intervention regimen 3 (containing moxifloxacin and rifapentine) is shown to be non-
inferior to control, the two intervention regimens will be compared to each other in the primary 
efficacy outcome to assess the added effect of moxifloxacin to the regimen in a superiority 
comparison using a two-sided significance level of 0.05. This is an exploratory comparison as 
the study is not powered for this comparison.  
 
 Secondary efficacy analyses 
In additional secondary efficacy analyses, the primary efficacy endpoint will be assessed in the 
PP95 and PP75 populations, in addition to the full ITT population. 
 


23 
 
 Tabulation of the primary outcome classification  
Since the primary efficacy outcome is a composite of various components, the actual reason 
(component) for outcome will also be tabulated by treatment arm. 
Participants will be classified by the first event (chronologically) that made the participant 
unfavorable and further sub-classified by the bacteriological status at the time that this outcome 
occurred (culture converted, never culture converted, bacteriological reversion, or 
bacteriological relapse).  
 
 Sub-group analyses 
This primary efficacy analysis will be repeated in subgroups according to the following baseline 
factors (i.e. those present at enrollment or from study-specific samples collected for screening 
and baseline visits). For factors reliant on results from sputum samples, the results must be 
from the study laboratory of record. Categorical variables will be split by tertiles except where 
there is previous clinical justification for a different cut-off.  
 
HIV status 
 
Presence of cavitation on baseline chest radiograph 
 
Extent of cavitation on baseline chest radiograph 
 
Sex 
 
Weight  
 
BMI  
 
WHO scale smear quantification  
 
Solid culture colony count 
 
MGIT days to detection 
 
GeneXpert MTB/RIF Cycle Threshold 
 
Age  
 
Country of study center 
 
Smoking history 
 
History of diabetes  
 
Ethnicity and race 
 
The test for an interaction between the covariate and treatment will be done using logistic 
regression comparing the model including the interaction term and the model with only marginal 
terms using the likelihood ratio test to evaluate the statistical significance of inclusion of the 
interaction term in the model.  
 
 Independent Endpoint Review Committee 
An independent blinded endpoint review committee (ERC) will be formed to review individual 
primary efficacy outcome classification at the end of the trial in the event that the assessment of 
non-inferiority is marginal for one or both regimens.  
Members of the ERC will be identified prior to the end of the trial, and will include a small 
number of experts with experience in conducting clinical trials for new treatments for TB who are 
not otherwise involved in the trial. The ERC may not be needed, but may be convened and 
asked to review individual primary efficacy outcome classification for a subset of patients under 
the following scenarios:  
 
if the upper bound of the 95% confidence interval of the difference in the proportion of 
unfavorable outcomes is within 2% of the non-inferiority margin of 6.6%, in other words 
between 4.6% and 8.6%, for either regimen as compared to control provided the 
regimen is shown to safe and well tolerated. This range includes scenarios when non-
inferiority has been demonstrated (<6.6%) or just missed (>6.6%).  


24 
 
 
if there are large number of outcomes (10% or more) that are based on limited 
bacteriology or limited data and the review by the ERC would be considered valuable in 
interpreting the results.  
The ERC may be asked to review outcome classification in other situations.  
The ERC will review the full bacteriological, clinical and baseline data for participants, while 
staying blinded to treatment allocation. The ERC will review all participants classified as 
unfavorable or not assessable in the primary efficacy outcome, although they would be 
expected to focus on the more complex cases and more straightforward cases (e.g. clear 
bacteriological relapse) might be presented in summary form. The ERC will be asked to 
determine whether, based on the entirety of the data available, they would consider this 
participant to have had an unfavorable outcome of treatment or be in the process of having an 
unfavorable outcome of treatment and to quantify their confidence using a scale from 1 (very 
unlikely) to 4 (very likely). The ERC will be encouraged to come to consensus in each case.  
Any re-classification by the ERC will not replace the primary efficacy outcome defined based on 
the algorithm described in this analysis plan, but will be a sensitivity analysis used to 
supplement the primary efficacy results and provide further insight into whether the intervention 
regimens should be considered to have non-inferior efficacy.  
 
A document further describing the terms of reference of the endpoint review committee will be 
prepared prior to the end of the trial. 
 
 Additional sensitivity analyses 
The following additional sensitivity analyses will be conducted: 
1. The primary efficacy analysis will be repeated in the Microbiologically Eligible study 
population where all participants classified as not assessable will be classified as 
favorable rather than unfavorable. 
2. The primary efficacy analysis will be repeated in the Microbiologically Eligible and 
Assessable study populations where participants taking any non-study anti-TB 
medications for more than 21 days for any reason (including secondary isoniazid 
preventative therapy) will instead be classified as unfavorable.  
3. The primary efficacy analysis will be repeated in the Microbiologically Eligible and 
Assessable study populations where participants taking any non-study anti-TB 
medications for more than 5 days for any reason (including secondary isoniazid 
preventative therapy) will instead be classified as unfavorable.  
4. The primary efficacy analysis will be repeated with a modification to the definitions of 
‘Absence of Cure’ using the following text to replace the paragraph numbered 1 in 
section 4.1.1. so that intervening negative cultures are ignored in the determination 
of absence of bacteriological cure: 
A participant will be considered to have absence of bacteriological cure if 
he/she has a sputum sample, obtained at or after Week 17 and no later 
than the end of the Month 12 analysis visit window, that is Mtb Culture 
Positive (see section 4.7 for definitions of culture results) that is 
indistinguishable from the initial isolate (see separate sequencing plan for 
definitions), and this is confirmed by a second sample that is Mtb culture 
positive. A second confirmatory sample, on a different day (irrespective 
of intervening Mtb Negative culture results), is required, as a single 
positive sputum culture result in isolation will not be considered absence 
of bacteriological cure. If results from strain analysis are inconclusive or 
unavailable, it will be assumed that strains were indistinguishable.  


25 
 
5. The primary efficacy analysis will be repeated reclassifying all exogenous 
reinfections as unfavorable. 
6. The primary efficacy analysis will be repeated considering only culture inoculation 
results from MGIT liquid media and ignoring any culture inoculation results from solid 
media.  
7. The primary efficacy analysis will be repeated considering only culture inoculation 
results from solid media and ignoring any culture inoculation results from MGIT liquid 
media. 
8. The primary efficacy analysis will be repeated in the Microbiologically Eligible and 
Assessable study populations excluding additionally participants for whom none of 
screening or baseline study visit sputum cultures are Mtb Positive (week 2 sputum 
cultures will not be used for determining late exclusions).  
9. The primary efficacy analysis will be repeated in the Microbiologically Eligible and 
Assessable study populations including all participants classified as randomized in 
error. For such patients, the classification of the outcome will follow the algorithm in 
section 4.1. 
 
 
 Bayesian analysis of non-inferiority 
A Bayesian analysis of non-inferiority provides a more informative interpretation of the trial 
results by providing an estimate of the probability that the interventions regimens have efficacy 
not much worse than the control regimen for different thresholds of what might be considered 
‘not much worse’. Following methods described previously11, Bayesian binomial regression will 
be used to estimate the distribution of the difference in the proportion of unfavorable outcomes 
between each intervention arm and the control arm, in each analysis population considering 
both non-informative and informative priors. These methods have also been used in secondary 
analyses of the STREAM Stage 1 trial (NCT02409290).  
 
 
Analysis plan for secondary efficacy outcomes 
 
 TB disease-free survival at eighteen months after study treatment 
assignment 
The primary efficacy endpoint for the trial is TB disease-free survival twelve months after study 
treatment assignment. For that primary analysis (described above), only data up to and 
including the 12 month visit window will be used, see section 4.1 above. Participants are 
followed for eighteen months from start of treatment and an important secondary efficacy 
outcome is therefore TB disease-free survival eighteen months after study treatment 
assignment.  
For this analysis (TB disease-free survival eighteen months after study treatment assignment), 
the same definitions for the primary efficacy outcome in section 4.1 will be used with the 
exception that the Month 18 visit will be used in the definitions in place of the Month 12 visit. All 
the same analyses for the primary efficacy analysis described in section 5.2 will be repeated 
using this Month 18 endpoint. 
 
 Time to stable culture conversion  
Time to stable culture conversion is defined as the time from randomization to the first of two 
consecutive Mtb Culture Negative results, collected on separate days without an intervening 
Mtb Culture Positive, and processed at the study lab of record. Participants that never achieve 
culture conversion will be censored at the date of collection of sputum that yielded their last 
negative or positive culture result. 


26 
 
Time to stable culture conversion will be analyzed separately for cultures from solid and liquid 
culture media. The Microbiologically Eligible study population will be used for these analyses.  
Median time to stable culture conversion will be calculated for each regimen. A hazard ratio with 
corresponding two-sided 95% confidence intervals and p-value will be estimated using a Cox 
Proportional Hazards model will be used, adjusted for the stratification factors of HIV status and 
presence of cavitation. 
The equality of survivor functions for time to stable culture conversion will be compared using a 
(Wilcoxon) Log rank test, stratified by HIV status and presence of cavitation. Regimen 2 and 
Regimen 3 will each be compared with the control Regimen 1.  
The assumption of proportional hazards will be tested using the proportional hazards test based 
on the Schoenfeld residuals and by reviewing the log minus log survival plot (against log time) 
after fitting the Cox Proportional Hazards model.  
Even when Kaplan-Meier curves of time to culture conversion have been shown to diverge in 
the presence of an effective drug (such as bedaquiline), they tend to converge later in followup 
potentially violating the assumption of proportional hazards. In the case where there is adequate 
evidence that the proportional hazard assumptions are violated at the 5% level (i.e. p<0.05), 
methods where proportional hazards is not a necessary assumption will be used, such as 
restricted mean survival time. 
The analyses above of time to sputum culture conversion will be repeated as follows: 
1. With the alternative definition as time from randomisation to the first Mtb Negative 
culture from sputa processed at the study lab of record (without the need for a 
second negative culture to confirm). 
2. Including only participants for whom 75% of more of culture results from sputum 
samples collected between randomization and week 12 are evaluable. 
The Kaplan-Meier estimator will be used to calculate the proportion of participants with 95% 
confidence interval who are culture negative after 8 weeks and after 12 weeks.  
 
 Speed of decline of sputum viable bacilli by automated liquid MGIT culture 
days to detection  
The Microbiologically Eligible study population will be used for these analyses.  
Speed of decline of MGIT days to detection will be analyzed using mixed effect non-linear 
regression comparing different parametric models, and taking account of the latest research and 
other relevant published studies. Parametric models for modelling the quantitative decline in 
viable bacilli used to date have included bi-exponential12, hyperbolic tangent function13 and 
surge functions14. 
 
 Time to unfavorable efficacy outcome 
Time to unfavorable efficacy outcome is defined as the time from randomization to the first 
event that results in the definition of an unfavorable efficacy outcome for that participant. 
The time will be analyzed first using the primary efficacy outcome (using data from 
randomization to 12 months) and also using the secondary efficacy outcome at 18 months (as 
defined in section 5.3.1) 
Participants that do not achieve culture conversion (i.e. fail to have 2 consecutive culture 
negative results), and have not otherwise been called unfavorable, will be called unfavorable at 
the date of the last visit when a culture positive result was obtained. 
These analyses will be repeated for the Microbiologically Eligible, PP95 and PP75 study 
populations.  
Participants classified as favorable or not assessable will be censored in this analysis at the 
date of collection of sputum that yielded their last negative culture result. 


27 
 
Median time to unfavorable outcome will be calculated for each regimen. A hazard ratio with 
corresponding two-sided 95% confidence intervals and p-value will be estimated using a Cox 
Proportional Hazards model will be used, adjusted for the stratification factors of HIV status and 
presence of cavitation. 
The equality of survivor functions will be compared using a (Wilcoxon) Log rank test, stratified 
by HIV status and presence of cavitation. Regimen 2 and Regimen 3 will each be compared 
with the control Regimen 1.  
The assumption of proportional hazards will be tested using the proportional hazards test based 
on the Schoenfeld residuals and by reviewing the log minus log survival plot (against log time) 
after fitting the Cox Proportional Hazards model.  
 


28 
 
6 
Safety Analyses 
 
 
Analysis population 
All safety analyses will be conducted using the Safety Analysis Population which includes all 
participants randomized that took at least one dose of the allocated study regimen.  
 
 
Primary safety analysis 
The primary safety outcome is the proportion of participants with grade 3 or higher adverse 
events during the study treatment phase (defined above in section 4.6). 
The difference in proportion of participants with a grade 3 or higher adverse event during study 
treatment phase between each of Regimens 2 and 3 compared to Regimen 1 with 
corresponding two-sided 95% confidence intervals will be estimated using the same methods as 
for the primary efficacy analysis (section 5.2.2).  
It is hypothesized that the rifapentine regimens will have safety at least as good as the control 
regimen, but no non-inferiority margin has been pre-specified. The objective is to estimate the 
difference between regimens and describe the precision in this estimate (using 95% confidence 
intervals).  
The primary safety analysis will also be repeated in the Microbiologically Eligible and 
Assessable analysis populations. 
 
 
Secondary safety analyses 
 
 Treatment-related grade 3 or higher adverse events 
The primary safety analysis will be repeated considering only the subset of grade 3 or higher 
adverse events during study treatment phase that are considered at least possibly related to 
study treatment. 
 
 Tolerability 
Tolerability of the regimen is evaluated using the outcome of discontinuation of assigned 
treatment for a reason other than microbiological ineligibility. For this reason, participants 
excluded from the microbiologically eligible study population will also be excluded from this 
analysis.  
The proportion of participants discontinuing assigned treatment will be tabulated by regimen, by 
week of discontinuation after date of start of treatment, and by cause of discontinuation (e.g. 
adverse event, withdrawal of consent, treatment failure).  
 
 All-cause mortality during treatment or follow-up 
All-cause mortality includes all deaths from any cause during treatment or follow-up up to the 
end of the Month 18 visit window.  
The number of participants who die during treatment and follow-up will be tabulated by regimen 
with listings of primary cause of death.  
Median survival time will be calculated for each regimen. Participants that do not die will be 
censored at the date last known to be alive. A hazard ratio with corresponding two-sided 95% 
confidence intervals and p-value will be estimated using a Cox Proportional Hazards model will 
be used, adjusted for the stratification factors of HIV status and presence of cavitation. 
The equality of survivor functions will be compared using a (Wilcoxon) Log rank test, stratified 
by HIV status and presence of cavitation. Regimen 2 and Regimen 3 will each be compared 
with the control Regimen 1.  


29 
 
The assumption of proportional hazards will be tested using the proportional hazards test based 
on the Schoenfeld residuals and by reviewing the log minus log survival plot (against log time) 
after fitting the Cox Proportional Hazards model.  
 
 Serious adverse events (SAEs) 
The proportion of participants with an SAE during study treatment phase will be tabulated by 
regimen, MedDRA system organ class (SOC), MedDRA preferred term (PT) and severity grade.  
The proportion of participants with a Serious Adverse Reactions (SARs) and Suspected 
Unexpected SARs (SUSARs) during study treatment phase will also be tabulated by regimen 
and severity grade.  
 
 All grade adverse events (AEs) 
The proportion of participants with any AE during study treatment phase will be tabulated by 
regimen, and relatedness to allocated regimen, MedDRA system organ class, MedDRA 
preferred term and severity grade.  
 
 Laboratory safety parameters 
Laboratory safety parameters will be summarized by regimen and study visit (scaled by upper or 
lower limit of normal, ULN) including a summary of the highest (or lowest) measurement 
recorded at any visit. Summaries of drug induced liver injury (DILI) will be included using the 
published definition from secondary analyses of the REMoxTB trial15 (ALT > 5x ULN and ALT > 
3x ULN and total bilirubin >2 x ULN), ATS definitions and using Hy's law. 
These summaries will be repeated limiting to measurements only during the study treatment 
phase.  
 
 Acquired drug resistance 
Acquired drug resistance will be summarized by regimen, distinguishing between resistance 
acquired at time of treatment failure or relapse following study treatment and resistance 
acquired while on a non-study retreatment regimen.  
 
 
 


30 
 
7 
Data summaries 
 
 
Recruitment and baseline characteristics 
 
 Recruitment, screening, & eligibility 
The number of participants screened and randomized will be tabulated by center and regimen. 
The number of participants who were not enrolled will be presented by center. 
 
 Exclusions from analysis 
The number of participants excluded from each of the study populations will be tabulated by 
regimen and by reason for exclusion. 
 
 Baseline characteristics 
Baseline characteristics will be tabulated by regimen. Characteristics will include sex, age, 
ethnicity, weight, BMI, whether underweight (BMI <18.5 kg/m2), race, ethnicity, cavitation, 
radiographic severity of disease, Karnofsky score, and laboratory parameters such as, HIV 
status, CD4 count (if applicable), smoking status, smear and culture grading, serum albumin, 
hemoglobin, and time to positivity on MGIT. The baseline characteristics table will be repeated 
for each of study populations.  
 
 
Adherence to study medications 
The protocol requires at least 5 weekly doses to be provided by directly observed therapy (DOT) 
(i.e. participants should receive ~71% of study doses as DOT). The rest of doses are allowed to 
be self-administered (SAT). 
Treatment adherence will be summarized by regimen first considering only DOT doses and also 
considering DOT and SAT doses.  
 
 
Concomitant medications 
Use of concomitant medications will be summarized by treatment arm considering separately 1. 
Non-TB and Non-antiretroviral medications, 2. Anti-retroviral medications, and 3. Additional non-
study TB medications.  
 
 
Retention, participant disposition, and description of follow-up 
Completion of treatment and completion of scheduled follow-up will be summarized by regimen 
including reasons for failure to complete treatment and follow-up. 


31 
 
8 
Other Analyses 
 
 
Risk Factor Analysis 
Univariate and multivariate analyses will be carried out to assess the association of unfavorable 
outcomes and clinical and demographic variables using Cox regression (time to event 
endpoints) and logistic regression (binary endpoints). Variables included as potential risk factors 
include baseline data in addition to on-treatment data such as time to culture conversion and 
weight gain. The most parsimonious model that contains significant variables with p<0.05 will be 
used to identify risk factors.  The interactions between risk factors and treatment regimens will 
be examined to evaluate variations of different risk factors among treatment regimens. 
 
 
Efavirenz Pharmacokinetics Analysis  
Efavirenz pharmacokinetics will be evaluated in the first 31 and then a total of 90 participants 
from each of two groups of participants randomized to treatment regimen 2 or 3 of the study and 
receiving efavirenz based ART. The analysis plan for this is described in a separate statistical 
analysis plan (TBTC Study 31 Efavirenz Pharmacokinetic Statistical Analysis Plan). 
 


32 
 
9 
Interim monitoring by the Data and Safety Monitoring Board (DSMB) 
 
Interim analyses will be provided to the DSMB for monitoring the efficacy and safety and for the 
DSMB to review other matters occurring during the trial. Based on the interim results, the DSMB 
may recommend early closure of any experimental arm or the trial if the interim evidence is 
sufficiently strong that one of the trial interventions is clearly indicated or clearly contraindicated 
because of a net difference in efficacy, safety, or tolerability. 
 
If the evidence provides proof beyond reasonable doubt that there is a clear and meaningful 
benefit or harm of a given regimen, the DSMB may recommend termination of one of the 
treatment arms or termination of the study.  
 
 
Monitoring for efficacy 
Two interim analyses for the primary efficacy outcome are planned. To provide guidance to 
continue, adjust or stop the trial, the two interim analyses will be carried out after 40% and 60% 
of participants, respectively, reach 12 months post-randomization, and allowing for up to an 
additional four months for reporting of all culture results. The primary efficacy outcome will be 
conducted according to the statistical analysis plan described in section 5.2 with the analysis 
populations described therein. 
 
Specifically, the primary analysis of the primary outcome will be conducted for both MITT and 
per protocol analysis populations. Non-inferiority hypotheses will not be evaluated, only 
superiority hypothesis – whether either intervention is superior to control. It is generally not 
recommended to stop a trial early for early evidence of non-inferiority as obtaining more 
information is usually beneficial, unless superiority has been demonstrated16. 
 
There will be no ordering of hypotheses in the interim analyses.  
 
The Haybittle-Peto stopping boundaries are to be used for the interim analyses. Following the 
Haybittle-Peto rule in monitoring the efficacy, the statistical criterion for the differences between 
arms is set at the 0.1% level of statistical significance in each of the two interim analyses. If any 
arm is shown to have superior efficacy to the control arm at the 0.1% level of statistical 
significance (i.e. using 99.9% confidence intervals), the DSMB should consider whether it would 
be appropriate to terminate some arms or the whole trial, taking into account other efficacy and 
safety analyses. The overall type I error rate for testing non-inferiority and superiority is 
unaffected by the addition of these interim analyses using the Haybittle-Peto stopping 
boundaries due to the high level of evidence required (99.9% confidence intervals)17.  
 
 
Monitoring for safety  
The DSMB will convene approximately annually, or more often as needed, to review safety 
data. The safety monitoring in the interim analyses will focus on the comparison of the 
proportion of participants with adverse events in each treatment arm, with a particular focus on 
the primary safety endpoint. Concerns about the extent and type of adverse events observed 
may lead to early termination of the trial when the DSMB judges that the potential benefits of the 
new regimens are unlikely to outweigh the risks. In other cases, the DSMB may recommend 
measures short of termination that may reduce the risk of adverse events. For example, 
modifying the inclusion criteria if the risks are concentrated in a particular subgroup or instituting 
screening procedures that could identify those at increased risk of a particular adverse event. 
 


33 
 
 
Unblinded statistician   
If the primary trial unblinded statistician takes on the responsibility for the interim analysis and 
reporting to the DSMB, this statistician will not participate in any discussions about further 
changes to the trial protocol, and statistical input from a blinded statistician will be sought as 
necessary. 
 
 


34 
 
10 Version history 
Version 1.0 
12 December 2018 
Version 1.1 
16 April 2019 
Version 2.0 
09 July 2019 
 
 
 
List of changes from version 1.0 to version 2.0 
 
Added expanded justification for margin of non-inferiority in section 1.4. 
Added section 5.2.4 ‘Comparison of intervention arms’ to describe exploratory comparison of the two 
intervention regimens.  
Added in section 9.1 further clarification of procedures at interim analyses, namely superiority 
hypothesis testing for superiority only not non-inferiority and clarifying that overall type I error is not 
affected by Haybittle-Peto stopping rules. 
Added section 9.3. Unblinded study statistician describing the role of the unblinded trial statistician 
and their absence from any protocol design changes.   
 
 
 


35 
 
11 References 
1. 
Jindani A, Harrison TS, Nunn AJ, et al. High-dose rifapentine with moxifloxacin for 
pulmonary tuberculosis. N Engl J Med 2014; 371(17): 1599-608. 
2. 
Merle CS, Fielding K, Sow OB, et al. A Four-Month Gatifloxacin-Containing Regimen for 
Treating Tuberculosis. N Engl J Med 2014; 371(17): 1588-98. 
3. 
Gillespie SH, Crook AM, McHugh TD, et al. Four-Month Moxifloxacin-Based Regimens 
for Drug-Sensitive Tuberculosis. N Engl J Med 2014; 371(17): 1577-87. 
4. 
Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by 
the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent 
publications. Int J Tuberc Lung Dis 1999; 3(10 Suppl 2): S231-79. 
5. 
Imperial MZ, Nahid P, Phillips PPJ, et al. A patient-level pooled analysis of treatment-
shortening regimens for drug-susceptible pulmonary tuberculosis. Nature Medicine 2018; 
24(11): 1708-15. 
6. 
Bastard M, Sanchez-Padilla E, Hewison C, et al. Effects of treatment interruption 
patterns on treatment success among patients with multidrug-resistant tuberculosis in armenia 
and abkhazia. J Infect Dis 2015; 211(10): 1607-15. 
7. 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. Statistical Principles for Clinical Trials (E9). 1998. 
8. 
Rehal S, Morris TP, Fielding K, Carpenter JR, Phillips PP. Non-inferiority trials: are they 
inferior? A systematic review of reporting in major medical journals. BMJ Open 2016; 6(10): 
e012594. 
9. 
Mauri L, D'Agostino RB, Sr. Challenges in the Design and Interpretation of Noninferiority 
Trials. N Engl J Med 2017; 377(14): 1357-67. 
10. 
Mohamed K, Embleton A, Cuffe RL. Adjusting for covariates in non-inferiority studies 
with margins defined as risk differences. Pharmaceutical statistics 2011; 10(5): 461-6. 
11. 
Laptook AR, Shankaran S, Tyson JE, et al. Effect of Therapeutic Hypothermia Initiated 
After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic 
Encephalopathy: A Randomized Clinical Trial. JAMA 2017; 318(16): 1550-60. 
12. 
Sloan DJ, Mwandumba HC, Garton NJ, et al. Pharmacodynamic Modeling of Bacillary 
Elimination Rates and Detection of Bacterial Lipid Bodies in Sputum to Predict and Understand 
Outcomes in Treatment of Pulmonary Tuberculosis. Clin Infect Dis 2015; 61(1): 1-8. 
13. 
Burger DA, Schall R. A Bayesian Nonlinear Mixed-Effects Regression Model for the 
Characterization of Early Bactericidal Activity of Tuberculosis Drugs. J Biopharm Stat 2015; 
25(6): 1247-71. 
14. 
Svensson EM, Svensson RJ, Te Brake LHM, et al. The Potential for Treatment 
Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in 
Patients With Pulmonary Tuberculosis. Clin Infect Dis 2018; 67(1): 34-41. 
15. 
Tweed CD, Wills GH, Crook AM, et al. Liver toxicity associated with tuberculosis 
chemotherapy in the REMoxTB study. BMC Med 2018; 16(1): 46. 
16. 
Korn EL, Freidlin B. Interim monitoring for non-inferiority trials: minimizing patient 
exposure to inferior therapies. Ann Oncol 2018; 29(3): 573-7. 
17. 
Pocock SJ. When (not) to stop a clinical trial for benefit. JAMA 2005; 294(17): 2228-30. 
 


1 
 
Addendum to the Statistical Analysis Plan for TBTC 
Study 31 / ACTG A5349 
 
Version: 1.0 
22 Jul 2020 
 
Approved: Patrick Phillips, Trial Statistician 
 
 
 
 
 
1 
Purpose  
This document is an addendum to the Statistical Analysis Plan (SAP) of the TBTC Study 31 / 
ACTG A5349, is version 2.0, 9 July 2019. 
The purpose of this document is two-fold:  
1. to provide further clarification on specific definitions in the SAP where the wording was 
unclear, and 
2. to describe further sensitivity analyses of the primary efficacy endpoint.  
This document does not propose any modifications or changes to the analysis plan for the trial 
beyond wording clarification and specification of further sensitivity analyses.  
2 
Clarification of Analysis Plan Definitions 
 
Pregnancy during assigned study treatment 
Section 4.1.3 of the SAP describes criteria for classification of study participants as having a Not 
Assessable outcome. The second item in the list specifies that ‘Women who become pregnant 
during assigned study treatment’ are classified as Not Assessable. This item is intended to refer 
specifically to women who become pregnant and for whom treatment is changed due to 
pregnancy. This item therefore does not apply to women who become pregnant during assigned 
study treatment where treatment is not changed due to pregnancy. 
7/22/2020


2 
 
3 
Additional Sensitivity Analyses 
Section 5.2.9 of the SAP describes nine additional sensitivity analyses. The following five 
sensitivity analyses will also be conducted: 
10. The primary efficacy analysis will be repeated relaxing the criteria for evaluable cultures 
by removing the inoculation result classification of ‘Unevaluable’ so that inoculations are 
reclassified as positive, negative, contaminated, or missing.  
11. The primary efficacy analysis will be repeated reclassifying participants classified as Not 
Assessable because they did not attend a visit within the Month 12 analysis visit window 
based on the immediate next data available for the participant after the Month 12 
analysis visit window. If the patient is culture negative at the next visit after the Month 12 
visit window, they will be classified in this analysis as favorable, if they are culture 
positive at the next visit at the Month 12 visit window, they will be classified in this 
analysis as unfavorable. This sensitivity analysis will be interpreted with caution as, at 
the time of the 12-month primary analysis when all participants will not have completed 
18 months of follow-up, it will include a mix of month 15 and month 18 data. 
12. The primary efficacy analysis will be repeated reclassifying patients that have two 
positive cultures but do not have subsequent restart of treatment as favorable rather 
than unfavorable. 
13. The primary efficacy analysis will be repeated with modified analysis visit windows for 
visits after Month 9 according to the following table: 
Visit 
Target date (days 
from date of first 
dose of treatment) 
SAP v2.0 Analysis 
window for primary 
analysis  
Analysis window for 
sensitivity analysis  
Month 9 
270 
263-352 
263-345 
Month 12 
360 
353-442 
346-442 
Month 15 
450 
443-523 
443-509 
Month 18 
540 
533-no upper bound  
(an upper bound of 
570 will be used for 
reporting safety 
analyses)  
510-no upper bound  
(an upper bound of 
570 will be used for 
reporting safety 
analyses)  
The analysis visit windows for the primary Month 12 visit and the end of follow-up Month 
18 visit extend to 14 and 30 days prior to the target date of visit respectively (rather than 
7 days for other study visits) since these are critical visits for the primary and end of 
follow-up efficacy analyses. 
14. The primary efficacy analysis will be repeated reclassifying as Cure (Favorable) those 
participants who have not achieved culture conversion prior to Month 12, but are 
otherwise seen during the Month 12 analysis visit window and are clinically without 
symptoms/signs or ongoing active TB and fulfill all the other criteria under the second 
item under section 4.1.2. 


 
Rifapentine-containing treatment shortening regimens for pulmonary 
tuberculosis: 
A randomized, open-label, controlled phase 3 clinical trial 
 
 
Consortium Identifiers: 
Tuberculosis Trials Consortium Study 31 
AIDS Clinical Trials Group A5349 
 
ClinicalTrials.gov Identifier: NCT02410772 
 
Whole Genome Sequencing 
 Analysis Plan  
(WGSAP) 
 
Version Number: 1.0 
7 July 2020 
CONFIDENTIAL 
PLEASE DO NOT SHARE 
 
 
Approval:  Jamie Posey, TB Research Lab Team Lead 
 
Patrick Phillips, Trial Statistician  
 
 
 


2 
 
General Information 
This document describes and substantiates principles and methods used for the analysis of whole-
genome sequencing (WGS) data from trial TBTC S31/ACTG A5349. This document is designed to 
support the trial protocol and the trial statistical analysis plan (SAP). 
Version 1.0 of this Whole Genome Sequencing Analysis Plan (WGSAP) was signed off prior to the 
inclusion of WGS data to the database extract for the primary efficacy analysis. 
 
 
 
 
 


3 
 
1. Introduction 
1.1 
Purpose 
Culture results that occur after randomization are important for classification of the primary efficacy 
outcomes for the primary analysis. Furthermore, whether the strain of M. tuberculosis complex (MTBC) 
is the same or different from the baseline isolate, also affects classification. The trial statistical analysis 
plan (SAP) describes in detail how the primary efficacy outcome is defined but does not include 
information on rules for when two strains can be considered indistinguishable versus not 
indistinguishable.  
 
2. Methods and Procedures 
1.2 
Definitions and classification for reporting WGS 
Indistinguishable isolates: Difference of <10 single-nucleotide polymorphism (SNPs) between paired 
isolates. 
Not indistinguishable isolates: Difference of ≥10 single-nucleotide polymorphism (SNPs) between 
paired isolates. 
Inconclusive: Sequence was not obtained or did not meet quality threshold from at least one isolate of 
the isolates pair. 
Unavailable isolates: At least one of the isolates from the pair was not shipped from the site or was 
not received at the CDC Laboratory. 
 
1.3 
Handling of Mixed infections 
The following approach will be applied if mixed infection is detected using current methods. 
- 
WGS of MTBC culture obtained at or after week 17 suggests a mix of the baseline isolate and a 
different isolate: will be classified as Indistinguishable. 
- 
Baseline MTBC culture has mix of two isolates. WGS of MTBC culture obtained at or after week 
17 suggests a mix of the baseline isolates (or one of the baseline isolates) and a different 
isolate: will be classified as Indistinguishable. 
- 
WGS of MTBC culture obtained at or after week 17 suggests a mix of two different strains as 
compared to baseline isolate: will be classified as a Not indistinguishable. 
- 
WGS of MTBC culture obtained at or after week 17 suggests a mixed infection, but we are 
unable to determine in the baseline strain or close variant (<10 SNPs) Inconclusive. 
Cut-off for 10 SNPs is based on CDC’s experience using wgSNP analysis from routine WGS for all US 
strains for transmission analysis and used in the standard WGS molecular epidemiology done as part 
of domestic TB surveillance.  


4 
 
 
 
1.4 
Selection of isolates to be sequenced 
The following isolates will be sequenced: 
- 
The first isolate available per participant (or isolate linked in time to TB resurgence) that is 
obtained at week 17 or after post-randomization 
- 
A corresponding baseline isolate to the participant above 
- 
Further isolates if study team requests WGS to provide help differentiate relapse vs. reinfection, 
decided on a case by case basis 
Exclusion criteria: 
- 
Visibly contaminated isolates will not be sequenced 
- 
Isolates that did not produce enough growth on subculture will not be sequenced 
- 
Isolates for which sequences obtained contain <90% MTB DNA will be excluded from analysis 
- 
Isolates for which sequences obtained include <50x coverage on repeated extraction 
 
1.5 
Sample shipment and isolate banking 
Samples are shipped from laboratories serving all sites and are received and processed by the 
Laboratory Branch at CDC (LB-CDC). LB-CDC will request reshipment of grossly contaminated 
samples and will attempt decontamination and subculture in cases where TB colonies are isolated. The 
use and banking of the isolates from Study 31/A5349 is guided by material transfer agreements (MTAs) 
with each of the sites and may have differing clauses for storage and sharing. 
 
1.6 
DNA extraction and WGS 
Chromosomal DNA will be extracted from 200 uL of a frozen stock using the Zymo Quick DNA 
Fungal/Bacterial kit and quantified using the Qubit 3.0 high sensitivity assay.  Sequencing libraries will 
be generated using the Nextera XT library prep kit following standard protocols. The libraries will be 
sequenced (2 x 250bp reads) on the Miseq platform using Miseq Reagent Kit v3 600 cycle chemistry. 
Samples with a sequence read set Q30 frequency <80% will be repeated. 
 
1.7 
WGS data processing and analysis 
The presence of DNA not from MTBC organisms will be detected with the microbial classification 
engine Centrifuge. Samples containing less than 90% MTBC will be excluded from further analysis.  


5 
 
Reference guided assemblies will be created using Bionumerics 7.6 Reference Mapper v 1.2.3 using 
M. tuberculosis strain H37Rv (NC00962.3) as the reference with the following settings for base calling: 
Minimum total coverage=3, Minimum forward coverage=1, Minimum reverse coverage=1, Single base 
threshold=0.75, double base threshold=0.85, triple base threshold=0.95, gap threshold=0.5. Bowtie 
based algorithm described in reference. Samples with an average genome coverage less than 50 will 
be resequenced. 
Reference guided assemblies for baseline sample and for the first sample available sample collected at 
or after 17 weeks (or isolate linked in time to TB resurgence) will be compared using Bionumerics V7.6 
SNP analysis filters. For a SNP to be retained in the comparison, the base in both samples must have a 
total coverage of 5 reads, must not contain ambiguous bases, must not contain unreliable bases, must 
not contain gaps, and must not be within 12 basepairs of another SNP. SNPs that are non-informative 
(identical in both samples) were also excluded. The number of high-quality SNPs between the two 
samples will be recorded as the SNP distance.  
Paired isolates with <10 SNPs will be considered indistinguishable and not further analyzed. Paired 
isolates with a SNP distance >25 SNPs will be considered not indistinguishable. In cases when SNP 
distance is between 10 and 25 SNPs a manual curation will be used to look at every SNP location and 
verify that all the calls have appropriate coverage and sequence meets quality threshold. The purpose 
of manual curation to ascertain that difference is ≥10 SNPs (or not) and to confirm SNP quality. If the 
difference is ≥10 true SNPs isolates will be considered not indistinguishable.    
To rule out the presence of a mixed infection in a single sample, variant call files will be analyzed for 
the presence of multiple phylogenetic SNPs. The detection of greater than one phylogenetic SNP will 
suggest mixed infections. To rule out the presence of a mixed infection in either one of the paired 
samples where one sample contains both the strain in the first sample as well as a second strain, 
variant call files will be examined. SNPs fixed in one sample (identified in >90% of the reads) but mixed 
in the corresponding sample (present in 25-75% of the reads) are identified and counted. Difference 
greater than 25 SNPs will suggest that the sample contains two strains.  
 
1.8 
Incorporation of WGS data into Study S31/A5349 database 
A spreadsheet containing a line list per participant with SNPs difference between the paired baseline 
isolate and positive isolate(s) from week 17 or after will be shared with Clinical Research Branch (CRB) 
and merged with the main TBTC2 study database. 
 
1.9 
Software used 
Bionumerics V7.6 (Applied Maths, Belgium) 
Centrifuge v1.0.3 (https://github.com/infphilo/centrifuge/releases) 
 


6 
 
1.10 
References  
1 
Witney, A.A., Bateson, A.L.E., Jindani, A. et al. Use of whole-genome sequencing to 
distinguish relapse from reinfection in a completed tuberculosis clinical trial. BMC Med 15, 71 
(2017). 
2 
José Afonso Guerra-Assunção, Rein M. G. J. Houben, Amelia C. Crampin, Themba Mzembe, 
Kim Mallard, Francesc Coll, Palwasha Khan, Louis Banda, Arthur Chiwaya, Rui P. A. Pereira, 
Ruth McNerney, David Harris, Julian Parkhill, Taane G. Clark, Judith R. Glynn, Recurrence 
due to Relapse or Reinfection With Mycobacterium tuberculosis: A Whole-Genome 
Sequencing Approach in a Large, Population-Based Cohort With a High HIV Infection 
Prevalence and Active Follow-up, The Journal of Infectious Diseases, Volume 211, Issue 7, 1 
April 2015, Pages 1154–1163, https://doi.org/10.1093/infdis/jiu574. 
3 
Pouseele H and Supply P. 2015.  Accurate Whole-Genome Sequencing-Based 
Epidemiological Surveillance of Mycobacterium. Tuberculosis. Data Methods in Microbiology, 
ISSN: 0580-9517, Vol: 42, 359-394 
4 
Kim D, Song L, Breitwieser FP, and Salzberg SL. 2016. Centrifuge: rapid and sensitive 
classification of metagenomic sequences. Genome Research 26 (12): 1721-9.2016. 
5 
Bryant JM, Harris SR, Parkhill J, Dawson R, Diacon AH, van Helden P, et al. Whole-genome 
sequencing to establish relapse or re-infection with Mycobacterium tuberculosis: a 
retrospective observational study. Lancet Respir Med. 2013;1(10):786-92.  
 
5.1 
Contact info 
Lab Branch: Jamie Posey (hzp9@cdc.gov) 
Clinical Research Branch: Jessica Ricaldi (mpi7@cdc.gov) 
 
6 
Version history 
Version 1.0 
7 July 2020 
 
 
 
 
 




 
1 
 
 
Rifapentine-containing treatment shortening regimens for pulmonary 
tuberculosis:  
A randomized, open-label, controlled phase 3 clinical trial 
 
 
 
Consortium Identifiers: 
Tuberculosis Trials Consortium Study 31 
AIDS Clinical Trials Group A5349 
 
 
ClinicalTrials.gov Identifier: NCT02410772 
 
 
 
Statistical Analysis Plan 
 
Version Number: 1.0 
12 December 2018 
 
 
CONFIDENTIAL 
PLEASE DO NOT SHARE 
 
 
Approval:  
Patrick Phillips, Trial Statistician 
 
 


 
2 
 
General Information 
 
This document describes and substantiates the statistical principles and methods used for the 
analysis of data from TBTC S31/A5349. This document is designed to support the trial protocol. 
This Statistical Analysis Plan (SAP) supersedes previous versions of the SAP. Every care was 
taken in the drafting of this SAP, but corrections or amendments may be necessary.  
 
Version 1.0 of the SAP will be signed off prior to the database extract for the first interim efficacy 
analysis.  
 
 
Statement of Compliance 
 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice E6 (ICH-GCP), U.S. Code of Federal Regulations 45 CFR 
46 and 21 CFR, and applicable site-specific regulatory requirements.   
 
 
 


 
3 
 
Contents 
 
1 
Introduction .......................................................................................................................................... 6 
 
Protocol Summary......................................................................................................................... 6 
 
Schematic of study design ............................................................................................................ 8 
 
Sample size considerations ........................................................................................................... 9 
 
Margin of non‐inferiority .............................................................................................................. 9 
2 
Objectives............................................................................................................................................ 12 
 
Primary Objectives ...................................................................................................................... 12 
 
Secondary Objectives .................................................................................................................. 12 
3 
Endpoints ............................................................................................................................................ 13 
 
Primary Endpoints ....................................................................................................................... 13 
 
Secondary Endpoints .................................................................................................................. 13 
4 
Study definitions ................................................................................................................................. 14 
 
Definition of primary outcome ................................................................................................... 14 
 
Absence of Cure (Unfavorable) ........................................................................................... 14 
 
Cure (Favorable) .................................................................................................................. 15 
 
Not Assessable .................................................................................................................... 15 
 
Participants Randomized in Error ............................................................................................... 15 
 
Exclusion criteria after enrollment (‘Late Exclusion’) ................................................................. 15 
 
Adequate treatment ................................................................................................................... 17 
 
Visit windows .............................................................................................................................. 18 
 
Treatment and follow‐up phases ................................................................................................ 18 
 
Microbiologic classification ......................................................................................................... 19 
 
Inoculation results ............................................................................................................... 19 
 
Culture results ..................................................................................................................... 19 
5 
Efficacy Analyses ................................................................................................................................. 21 
 
Study Populations ....................................................................................................................... 21 
 
Intention‐to‐Treat (ITT) ....................................................................................................... 21 
 
Microbiologically Eligible .................................................................................................... 21 
 
Assessable ........................................................................................................................... 21 
 
Adherent Per‐Protocol (PP95) ............................................................................................. 21 


 
4 
 
 
Adherent Per‐Protocol (PP75) ............................................................................................. 21 
 
Analysis plan for the primary efficacy outcome ......................................................................... 21 
 
Co‐primary efficacy analyses .............................................................................................. 21 
 
Non‐inferiority test ............................................................................................................. 22 
 
Superiority test .................................................................................................................... 22 
 
Secondary efficacy analyses ................................................................................................ 22 
 
Tabulation of the primary outcome classification .............................................................. 22 
 
Sub‐group analyses ............................................................................................................. 23 
 
Independent Endpoint Review Committee ........................................................................ 23 
 
Additional sensitivity analyses ............................................................................................ 24 
 
Bayesian analysis of non‐inferiority .................................................................................... 25 
 
Analysis plan for secondary efficacy outcomes .......................................................................... 25 
 
TB disease‐free survival at eighteen months after study treatment assignment .............. 25 
 
Time to stable culture conversion ...................................................................................... 25 
 
Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to 
detection 26 
 
Time to unfavorable efficacy outcome ............................................................................... 26 
6 
Safety Analyses ................................................................................................................................... 28 
 
Analysis population ..................................................................................................................... 28 
 
Primary safety analysis ................................................................................................................ 28 
 
Secondary safety analyses .......................................................................................................... 28 
 
Treatment‐related grade 3 or higher adverse events ......................................................... 28 
 
Tolerability .......................................................................................................................... 28 
 
All‐cause mortality during treatment or follow‐up ............................................................. 28 
 
Serious adverse events (SAEs) ............................................................................................ 29 
 
All grade adverse events (AEs) ............................................................................................ 29 
 
Laboratory safety parameters ............................................................................................ 29 
 
Acquired drug resistance .................................................................................................... 29 
7 
Data summaries .................................................................................................................................. 30 
 
Recruitment and baseline characteristics ................................................................................... 30 
 
Recruitment, screening, & eligibility ................................................................................... 30 
 
Exclusions from analysis ...................................................................................................... 30 


 
5 
 
 
Baseline characteristics ....................................................................................................... 30 
 
Adherence to study medications ................................................................................................ 30 
 
Concomitant medications ........................................................................................................... 30 
 
Retention, participant disposition, and description of follow‐up ............................................... 30 
8 
Other Analyses .................................................................................................................................... 31 
 
Risk Factor Analysis ..................................................................................................................... 31 
 
Efavirenz Pharmacokinetics Analysis .......................................................................................... 31 
9 
Interim monitoring by the Data and Safety Monitoring Board (DSMB) ............................................. 32 
 
Monitoring for efficacy ............................................................................................................... 32 
 
Monitoring for safety .................................................................................................................. 32 
10  Version history .................................................................................................................................... 33 
 
List of changes from version 1.0 ................................................................................................. 33 
11  References .......................................................................................................................................... 34 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
6 
 
1 
Introduction 
 
 
Protocol Summary  
 
Title: Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a 
randomized, open-label, controlled, phase 3 clinical trial 
 
Hypotheses: 
A) Seventeen (17) week rifapentine-based regimen 
 
In previously untreated individuals with active drug-susceptible pulmonary 
tuberculosis treated with eight weeks of rifapentine (P), isoniazid (H), 
pyrazinamide (Z) and ethambutol (E) followed by nine weeks of 
rifapentine plus isoniazid, all given daily throughout, the proportion of 
participants who experience absence of cure (unfavorable outcome) will 
not be inferior to that observed in participants who are treated with a 
standard regimen (eight weeks of rifampin (R), isoniazid, pyrazinamide 
and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all 
given daily throughout.  
 
B) Seventeen (17) week rifapentine- plus moxifloxacin-containing regimen 
 
In previously untreated individuals with active drug-susceptible pulmonary 
tuberculosis treated with eight weeks of rifapentine, isoniazid, 
pyrazinamide and moxifloxacin (M), followed by nine weeks of rifapentine, 
isoniazid, and moxifloxacin, all given daily throughout, the proportion of 
participants who experience absence of cure (unfavorable outcome) will 
not be inferior to that observed in participants who are treated with a 
standard regimen (eight weeks of rifampin, isoniazid, pyrazinamide and 
ethambutol followed by eighteen weeks of rifampin plus isoniazid), all 
given daily throughout. 
 
Phase: 
3 
Design: 
This will be an international, multicenter, randomized, controlled, open-
label, 3-arm, phase 3 non-inferiority trial. 
Population: 
Participants with newly diagnosed, previously untreated pulmonary 
tuberculosis.  
Number of Sites: 
Multiple international sites, primarily sites of the Tuberculosis Trials 
Consortium and the AIDS Clinical Trials Group.   
Study Duration: 
Duration per participant is approximately 18 months. 
 
 
 


 
7 
 
Description of Agent or Intervention: 
After written informed consent, participants will be 
randomly assigned to receive one of the following oral regimens: 
 
 
Regimen 1 (control regimen): 2RHZE/4RH 
 Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, 
followed by  
 Eighteen weeks of daily treatment with rifampin and isoniazid 
 
 
Regimen 2 (investigational regimen): 2PHZE/2PH 
 Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and 
ethambutol, followed by  
 Nine weeks of daily treatment with rifapentine and isoniazid  
 
 
 
Regimen 3 (investigational regimen): 2PHZM/2PHM 
 Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and 
moxifloxacin, followed by  
 Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin 
 
 
 


 
8 
 
 
Schematic of study design 
 
Figure 1 Schematic of study design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screen for eligibility
Enroll
Randomize 1:1:1
Regimen 1 
(control regimen) 
2RHZE/4RH 
(26 weeks) 
Regimen 2 
(investigational) 
2PHZE/2PH 
(17 weeks)
Regimen 3 
(investigational) 
2PHZM/2PHM 
(17 weeks)
Participant follow-up: 
18 months after treatment assignment 
Analysis of Outcome Measures 
Primary at 12 months; secondary at 18 months 


 
9 
 
 
Sample size considerations 
The primary objective of the trial is to evaluate whether rifapentine containing regimens can 
produce outcomes at least as favorable as standard therapy, but with a shorter treatment 
course.  Therefore, the trial is structured as a non-inferiority study. 
 
Key assumptions: 
• 
Primary endpoint rate: 15% absence of cure (unfavorable) in the standard regimen arm 
(Microbiologically Eligible population).   This rate is based on observed results for the 
control arm (MITT analysis group) in two recently completed phase 3 clinical trials 
(27/161 [14%] in the Rifaquin trial1 and 100/743 [13.5%] at 18 months post 
randomization and 114/679 [16.8%] at 24 months after the end of treatment in the 
Oflotub trial2.)    
• 
Margin to define inferiority: 6.6% (δ = 0.066) 
• 
95% confidence (type 1 error, α = 0.05). The sequential testing of regimen 3 and 
regimen 2 protects the type 1 error rate, as follows: If the statistical test for regimen 3 
fails at 95% confidence, then conclude that both experimental regimens are not 
noninferior. If and only if regimen 3 is noninferior, then proceed to test regimen 2 at 95% 
confidence. A type 1 error occurs if either regimen is incorrectly deemed noninferior; the 
sequential approach limits the probability of this error to 5% overall. 
• 
Power: 80% (type 2 error, β = 0.20) for primary analysis among Microbiologically Eligible 
subgroup, with power recalculated for the restriction to Assessable subgroup (see 
below) 
• 
Proportion of enrolled participants who would be found to be late exclusions due to 
microbiological ineligibility – 12% (based on observed results in recent TBTC phase 2 
studies) 
• 
Proportion of enrolled participants who would be found to be ‘not assessable’: 12% 
(based on observed results in the Rifaquin trial1) 
 
With 816 per arm, we expect 612 assessable. With the expected 15% unfavorable outcomes 
among those who are assessable, then with the same noninferiority margin and type 1 error 
rate, we have 90% power to test the primary hypotheses among the Assessable subgroup.  
 
 
Margin of non-inferiority 
 
The 6.6% margin to define inferiority (6.6%) takes into consideration the following issues:  
(1) the rates in historical trials of inpatient TB treatment for 6-month and 4-month regimens 
conducted by the British Medical Research Council support a difference in relapse up to 
6% (East African/British Medical Research Council 1976, 1977, 1981; East and Central 
Africa/British Medical Research Council 1986; Singapore Tuberculosis Service/British 
Medical Research Council 1986; Nunn and Crook 2013);  
(2) recent trials in contemporary outpatient populations suggest a higher baseline proportion 
(15%) of unfavorable outcomes likely to be observed based on phase 3 trials and 
definitions;  
(3) the investigators in this trial and others perceive that the benefits of reducing treatment 
duration to 3 or 4 months would have advantages not outweighed by a possible increase 
in the relapse rate of up to 6%; and  
(4) the 6.6% margin does not imply that the experimental regimen may result in as much as 
6.6% more unfavorable outcomes, but rather, for a fixed design, the maximum difference 
consistent with a non-inferior conclusion decreases as the proportion of unfavorable 
outcomes in the control arm increases. 
 


 
10 
 
A 6% margin of non‐inferiority trials has been used in other recent trials of single‐drug substitution 
treatment shortening trials (e.g. REMoxTB). The justification of this margin is published in the online 
supplements with these papers (Gillespie et al, 2014 NEJM). We have attached the justification from 
that study as an attachment to support a 6% margin.   
 
We believe an extension from 6% to 6.6% is justified for the following reasons: 
 
1) The justification for a 4.8% margin in the FDA Guidance for Industry for Pulmonary 
Tuberculosis Trials is based on previous trials under ‘per protocol’ type analyses with many 
post‐randomization exclusions, in a largely in‐patient population; we observe larger 
proportions of unfavorable outcomes today than was seen in these relapse‐only analyses 
from previous trials. We feel this provides a justification for a larger margin than 4.8%, and 
also the 6% that was justified for the REMoxTB trial.  Recent trials in contemporary 
outpatient populations suggest a higher proportion (16% in REMoxTB MITT) of unfavorable 
outcomes, even than that anticipated in the REMoxTB trial sample size calculations (10%). 
 
Furthermore, the rationale for a 4.8% margin is based on the situation where a single drug 
that has an unknown contribution to the regimen is replaced by a new drug (the 
replacement of ethambutol, for example). In our study, rifampicin is replaced by rifapentine 
(in addition to the substitution of moxifloxacin for ethambutol in one arm). It is known that 
rifampicin is the most important drug in the current regimen. It might therefore be 
appropriate to consider not just the removal of the final two months of therapy (following 
the argument in lines 829‐832 in the FDA Guidance) to estimate M1, but also the consider 
the removal of rifampicin from the regimen. This would require consideration of a 
comparison of six months of HRZE (2HRZE/4HR) with four months of HZE (2HZE/2H) when 
estimating M1. We are not aware of any trials that evaluated a 4‐month regimen without 
rifampicin, so providing a comprehensive rationale similar to that which underpins the 4.8% 
would be challenging but would lead to a larger M1 and therefore support a margin of non‐
inferiority larger than 4.8%. 
2) Considering the clinical argument (from FDA Guidance and Nunn, Phillips, Gillespie 2008) 
we, and in broader consultation within our two large publicly‐funded international consortia 
of TB stakeholders (CDC TB Trials Consortium and NIH AIDS Clinical Trials Group), consider 
the benefits of a 4‐month rifapentine‐based regimen justify the margin of 6.6%. Our 
consortia consider 600 patients per arm sufficiently large to provide adequate precision on 
the difference in efficacy between the regimens to determine whether an intervention 
regimen might be considered not inferior to the control regimen.  
The following graph was used to describe the maximum observable difference (solid line) 
from in the point estimate from the line of equality (plotted as dashed line) with a 6.6% 
margin under the stated assumptions.  
 


 
11 
 
 
 
For these reasons it is our perspective that a margin of 6.6% is justified.  


 
12 
 
2 
Objectives 
 
 
Primary Objectives 
 
To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single 
substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the 
duration of treatment for drug-susceptible pulmonary tuberculosis 
 
To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes 
moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to 
determine whether it is possible to reduce to seventeen weeks the duration of treatment for 
drug-susceptible pulmonary tuberculosis   
 
 
Secondary Objectives 
 
To evaluate the safety of the investigational regimens 
 
To evaluate the tolerability of the investigational regimens 
 
To collect and assess biospecimens from consenting participants for the purpose of 
research on discovery and validation of TB biomarkers 
 
To determine the correlation of mycobacterial and clinical markers with time to culture 
conversion, treatment failure, and relapse. 
 
To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs. The main 
objectives of the PK/PD study are to characterize study drug PK parameters and to 
determine relationships between treatment outcomes and PK parameters.  
 
To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among 
participants with TB/HIV co-infection taking efavirenz-based combination antiretroviral 
therapy and TB treatment with rifapentine. 
 
 


 
13 
 
3 
Endpoints 
 
 
Primary Endpoints 
 
Efficacy: TB disease-free survival at twelve months after study treatment assignment.   
 
Safety: Proportion of participants with grade 3 or higher adverse events during study drug 
treatment 
 
 
Secondary Endpoints 
 
TB disease-free survival at eighteen months after study treatment assignment 
 
Time to stable sputum culture conversion (solid and liquid media considered separately)  
 
Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection 
 
Proportion of participants who are culture negative at completion of eight weeks of treatment 
(solid and liquid media considered separately) 
 
Sensitivity analyses assuming all participants classified as ‘not assessable’ have a favorable 
outcome 
 
Discontinuation of assigned treatment for a reason other than microbiological ineligibility 
 
Estimated steady state efavirenz PK parameters including mid-dosing interval concentration 
 


 
14 
 
4 
Study definitions 
 
 
Definition of primary outcome  
Each participant will be classified into one of the following three outcome categories: 
1. Absence of Cure (Unfavorable Outcome) 
2. Cure (Favorable Outcome), or  
3. Not assessable. 
The primary outcome is defined as twelve months after study treatment assignment. Actual visit 
dates, rather than scheduled visit names (e.g. Week 26, or Month 9), will be used for all 
analyses. See section 4.5 for visit windows that define the time periods. In particular, Month 12 
includes data from visits up to 442 days from treatment initiation. 
Only data up to the end of the Month 12 analysis visit window will be included in the primary 
analysis of the primary efficacy outcome. 
 
 Absence of Cure (Unfavorable) 
A participant will be classified as having an unfavorable outcome if any one of the following 
conditions is met: 
1. A participant will be considered to have absence of bacteriological cure if he/she has a 
sputum sample, obtained at or after Week 17 and no later than the end of the Month 12 
analysis visit window, that is Mtb Culture Positive (see section 4.7 for definitions of culture 
results) that is indistinguishable from the initial isolate (see separate sequencing plan for 
definitions), and this is confirmed by a second sample that is Mtb culture positive. A second 
confirmatory sample, on a different day without an intervening Mtb Negative culture result, is 
required, as a single positive sputum culture result in isolation will not be considered 
absence of bacteriological cure. If results from strain analysis are inconclusive or 
unavailable, it will be assumed that strains were indistinguishable.  
2. Participants who die from any cause during study treatment (‘study treatment phase’ is 
defined in section 4.6), except from violent or accidental cause (e.g. road traffic accident). 
Suicide during study treatment will be classified as an unfavorable outcome.  
3. Participants who are withdrawn from follow-up or lost to follow-up prior to the scheduled end 
of treatment of study treatment, except for pregnancies and violent or accidental death that 
are instead classified as having a Not Assessable outcome (see section 4.1.3). 
4. Participants who had an Mtb Positive culture result when last seen during or prior to the 
Month 12 analysis visit window, whether confirmed by a second sample or not, unless 
determined to have been re-infected. 
5. Participants receiving any one or more of the following, except when given for failure or 
recurrence subsequently shown to be a reinfection with a strain of M. tuberculosis, different 
from that or those identified at study entry through genotyping methods):  
a) Extension of treatment beyond that permitted by the protocol; excepting 
a. Temporary drug re-challenge; 
b. Over-treatment with drugs from assigned study kits; 
c. Twenty-one days or fewer of non-study anti-TB medications given for 
treatment of active TB; or 
d. Secondary isoniazid preventative therapy in HIV infected participants. 
b) Re-start of treatment for active TB;  
c) Change in treatment (including frequency or dosage) for any reason except re-
infection, pregnancy, or temporary drug challenge. 
6. Participants who die during the follow-up phase (as defined in section 4.6) where the cause 
of death is considered related to tuberculosis. 
 


 
15 
 
 Cure (Favorable)  
A participant will be classified as having a favorable outcome if any one of the following 
conditions is met and an unfavorable outcome has not occurred: 
1. Participants whose last culture result during the Month 12 analysis visit window is Mtb 
Negative (See Section 4.7).  
2. Participants who are seen during the Month 12 analysis visit window and are clinically 
without symptoms/signs of ongoing active TB (indicated by absence of initiation of possible 
poor treatment response evaluation or PPTR that does not indicate presence of 
symptoms/signs of ongoing active TB), and have achieved culture conversion prior to Month 
12, and  
1. Are unable to produce a sputum specimen at any point during the Month 12 analysis 
visit window; or 
2. Produce a sputum specimen that is contaminated or unevaluable without evidence of 
M. tuberculosis, and no sputum specimens yield positive or negative culture results 
during the Month 12 analysis visit window. 
 
 Not Assessable 
A participant will be classified as having a Not Assessable outcome if any one of the following 
conditions is met and an unfavorable outcome has not occurred: 
1. Participants not otherwise classified as unfavorable, but do not attend a visit within the 
Month 12 analysis visit window, and their last culture result is negative for M. tuberculosis. 
2. Women who become pregnant during assigned study treatment (see section 4.6 for 
definition of study treatment phase). 
3. Participants who die during the follow-up phase (as defined in section 4.6) of any cause that 
is not considered related to tuberculosis. 
4. Participants who die from a violent (e.g. homicide) or accidental (e.g. road traffic) cause 
during their assigned study treatment (see section 4.6 for definition of study treatment 
phase).  As above, suicide will be considered an unfavorable outcome.  
5. Participants who are: 
a) Retreated, or have treatment changed or extended; and  
b) Demonstrated to be re-infected with a strain of M. tuberculosis, different from 
that or those identified at study entry through genotyping methods. 
A participant classified as having a Not Assessable outcome will be excluded from the 
Assessable and Adherent Per-Protocol analyses, but considered as Unfavorable for other 
analyses.  
 
 
Participants Randomized in Error 
Participants who were randomized in error are those who were found to not meet eligibility 
criteria after enrollment, other than criteria in Section 4.3.  
 
Determination of whether eligibility criteria was violated and subsequent classification as 
‘randomized in error’ will be based only on data that was collected prior to randomization. All 
participants who are found to be in violation of any eligibility criteria (other than the criteria in 
Section 4.3 relating to microbiology) will be classified as randomized in error, irrespective of 
whether the participant was withdrawn from treatment or not.  
 
 
Exclusion criteria after enrollment (‘Late Exclusion’) 
Microbiological confirmation of drug-susceptible tuberculosis is not expected always to be 
available at the time of enrollment.  Enrolled individuals who are subsequently determined to 


 
16 
 
meet either of the following criteria will be classified as ‘late exclusions’ and study treatment will 
be discontinued: 
1. None of screening, baseline, and Week 2 study visit sputum cultures are Mtb Positive  
2. M. tuberculosis cultured or detected through molecular assays (Cepheid Xpert MTB/RIF or 
Hain MTBDRplus assays) from any sputum obtained at screening, baseline, or week two 
study visit is determined subsequently to be resistant to one or more of isoniazid, rifampin, 
or fluoroquinolones.  
 
 
 


 
17 
 
 
Adequate treatment 
Only participants having completed an adequate number of study doses will be included in the 
Per Protocol (PP) analysis populations. Two PP analysis populations are defined. PP75 
excludes participants who have received less than approximately 75% of study doses (see 
Table below for exact doses required) using the definitions consistent with previous phase III TB 
trials, in particular the REMoxTB trial3 and in the original trials which determined the 
effectiveness of the control 6 month isoniazid-rifampin regimen4. The TB-REFLECT analyses5 
have shown that even participants with less than 95% adherence have poorer outcomes than 
those with perfect adherence, and consecutive missed doses is associated with poorer 
outcomes than occasional missed doses6. For these reasons, the PP95 analysis population 
excludes participants who have received less than approximately 95% of study doses (see 
Table 1 below for exact doses required). PP95 will be the primary per protocol analysis 
population with PP75 being supportive.  
 
Table 1. Two definitions of adequate treatment 
 
 
75% Adherence (PP75) 
Approximately 75% of doses 
within 125% of the intended 
duration. 
95% Adherence (PP95) 
Approximately 95% of doses within 
125% of the intended duration.  
 
Doses 
Days  
Doses 
Days since 
treatment 
initiation
Regimen 1 
At least 42 
intensive phase 
doses 
No more 
than 70 
days since 
treatment 
initiation
At least 54 
intensive phase 
doses 
No more than 
70 days since 
treatment 
initiation 
At least 84 
continuation phase 
doses 
No more 
than 168 
days since 
completing 
intensive 
phase
At least 120 
continuation phase 
doses 
No more than 
168 days since 
completing 
intensive 
phase 
No more than 42 doses missed 
No more than 5 consecutive DOT 
doses missed
Regimens 2 or 3 
At least 42 
intensive phase 
doses 
No more 
than 70 
days since 
treatment 
initiation
At least 54 
intensive phase 
doses 
No more than 
70 days since 
treatment 
initiation 
At least 42 
continuation phase 
doses 
No more 
than 84 
days since 
completing 
intensive 
phase
At least 60 
continuation phase 
doses 
No more than 
84 days since 
completing 
intensive 
phase 
No more than 28 doses missed 
No more than 5 consecutive DOT 
doses missed


 
18 
 
 
 
Visit windows 
Participants are assessed at screening, baseline (Week 0), Week 2, Week 4, Week 8, Week 12, 
Week 17, Week 22, Week 26, Month 9 and 3-monthly to Month 18 with visit dates scheduled 
from the date of treatment initiation.  
 
For the purpose of analysis, each scheduled visit will have a window before and after the target 
date, calculated from date of first dose of study medication. The only exception is the visit 
window for Baseline which is from date of screening consent to date of randomization 
(inclusive). Any visits after randomization up to 24 days after treatment initiation are included in 
the Week 2 visit window.  
 
When referring to a visit in this analysis plan (e.g. ‘Week 17’), this implies within the defined visit 
window as specified below in Table 2. 
 
Table 2. Analysis visit windows 
Visit 
Target date (days from date 
of first dose of treatment) 
Analysis window 
Baseline (including screening 
period) 
Date of randomization 
Date of screening consent – 
Date of randomization
Week 2 
14
Day after randomization-24
Week 4 
28
25-52 
Week 8 
56
53-80 
Week 12 
84
81-115 
Week 17 
119
116-150 
Week 22 
154
151-178 
Week 26 
182
179-262 
Month 9 
270
263-352 
Month 12 
360
353-442 
Month 15 
450
443-523 
Month 18 
540 
533-no upper bound  
(an upper bound of 570 will 
be used for reporting safety 
analyses)  
 
Any visit, scheduled or unscheduled (including possible poor treatment response or post early 
termination visits), that falls into the analysis window will be assigned to that visit for the purpose 
of analysis. If two visits fall within the same interval, the one closest to the target date will be 
used for analyses by visit, or the highest value, depending on the analysis, so that there is only 
one unique visit for each participant and analysis time-point. However, all critical endpoint 
determining data will be used (e.g. culture results). 
 
 
Treatment and follow-up phases 
For the purposes of analysis, the screening, treatment and follow-up phases are defined as 
follows: 
 
 
Pre-treatment phase 
o Start: date informed consent signed. 
o End: day before start of study treatment. 
 


 
19 
 
 
Study treatment phase 
o Start: date of start of study treatment. 
o End: date of last dose of allocated treatment regimen, plus 14 days. 
 
 
Follow-up phase 
o Start: the day after the end of the study treatment phase. 
o End: date of the last participant contact (scheduled or unscheduled, or other contact 
e.g. phone call). 
 
 
Microbiologic classification 
 
 Inoculation results 
Each sputum specimen is inoculated onto solid and liquid media. The result of each inoculation 
is classified as Mtb Positive, Mtb Negative, Contaminated, or Unevaluable (Table 3). It is 
expected that one sputum specimen will produce two inoculation results, one for each media 
type. Inoculation results reported as Mtb alone, Mtb with other mycobacteria (e.g., NTM), or Mtb 
with contamination will be classified as Mtb Positive. Inoculations reported as no growth or other 
mycobacteria without identification of Mtb will be classified as Mtb Negative. Inoculations 
reported as contaminated without identification of Mtb will be classified as Contaminated.  
 
Table 3. Classification of culture results per inoculum 
Inoculation 
Result 
Classification 
Definition 
Mtb Positive 
Definitive identification of Mtb with or without the presence of contaminants 
or other mycobacteria. 
Mtb Negative 
No Mtb or contaminants detected at least 42 days after inoculation. Growth 
of other mycobacteria (NTM) in the absence of Mtb or contaminants.   
Contaminated 
Growth of contaminants with or without other mycobacteria, but with no 
identification of Mtb.   
Unevaluable 
Includes any of the following: 
 
Sputum processed at non-lab of record. 
 
Media inoculated more than 4 days after sputum received in the lab. 
 
Missing culture result. 
 
Mtb identification was presumptive with no definitive identification. 
 
Result of no growth determined fewer than 42 days after inoculation. 
 
 Culture results 
The primary analysis will be conducted using results from inoculation onto solid and liquid 
media. For each sputum specimen, results from solid and liquid media inoculations will be 
combined into a single Culture Result, see Table 4.  When multiple sputa are collected on a 
single day, all results of each inoculation are used to establish the Culture Result. 
 


 
20 
 
For some analyses, solid and liquid culture will be analyzed separately. For these analyses, 
definitions in Table 4 will be used, considering only inoculations from that culture media.  
.   
 
Table 4. Specimen Culture Result Classification for all inoculation results 
Culture Result 
Classification  
Definition for visits when a 
single specimen (multiple 
media) is collected 
Definition for visits when 
multiple specimens (multiple 
media) are collected 
Mtb Culture 
Positive 
Any inoculation from a single 
specimen is Mtb Positive 
Any inoculation from any 
specimen collected on a single 
day is Mtb Positive 
Mtb Culture 
Negative 
All inoculations are Mtb 
Negative for a single specimen 
When at least one inoculation 
from a specimen is Mtb 
Negative and additional 
inoculation(s) is Contaminated 
When at least one inoculation 
from a specimen is Mtb Negative 
and additional inoculation(s) is 
Unevaluable 
All inoculations from all 
specimens collected on a single 
day are Mtb Negative 
When at least one inoculation 
from all specimens collected on 
a single day is Mtb Negative and 
additional inoculation(s) is 
Unevaluable or Contaminated 
 
Culture 
Contaminated 
All inoculation results are 
Contaminated for a single 
specimen 
When at least one inoculation 
from a single specimen is 
Contaminated and additional 
inoculation(s) is Unevaluable 
All inoculations from all 
specimens collected on a single 
day are Contaminated 
When at least one inoculation 
from all specimens collected on 
a single day is Contaminated 
and additional inoculation(s) is 
Unevaluable 
Culture 
Unevaluable 
All inoculation results from a 
single specimen are 
Unevaluable 
All inoculations from all 
specimens collected on a single 
day are Unevaluable 
Unable to 
produce sputum 
Attempt to collect sputum is 
unsuccessful as participant is 
unable to produce sputum 
All attempts to collect sputum is 
unsuccessful as participant is 
unable to produce sputum 
  


 
21 
 
5 
Efficacy Analyses 
 
 
Study Populations 
There will be five analysis groups, as follows: 
 
 Intention-to-Treat (ITT) 
Includes all randomized participants. 
 
 Microbiologically Eligible 
Includes the subset of Intention-to-Treat participants who, in addition, have culture confirmation 
of drug-susceptible tuberculosis as defined by section 4.3, and were not randomized in error as 
defined by section 4.2. Participants classified as ‘not assessable’ will be considered to have an 
unfavorable outcome in this analysis. 
 
 Assessable 
Includes the subset of Microbiologically Eligible participants who, in addition, are not classified 
as ‘not assessable’. 
 
 Adherent Per-Protocol (PP95) 
Includes the subset of Assessable participants who, receive 95% of assigned treatment as 
defined in Section 4.4. Participants in the Assessable study population that do not complete 
adequate treatment for the reason of death or bacteriological treatment failure will be included in 
the PP95 analysis population provided they receive 95% of doses up to the time of treatment 
withdrawal. This will be the primary PP analysis population. 
 
 Adherent Per-Protocol (PP75) 
Includes the subset of Assessable participants who, receive 75% of assigned treatment as 
defined in Section 4.4. Participants in the Assessable study population that do not complete 
adequate treatment for the reason of death or bacteriological treatment failure will be included in 
the PP75 analysis population provided they receive 75% of doses up to the time of treatment 
withdrawal. This is a supportive PP analysis population and is included for comparability with 
previous trials (particularly REMoxTB) 
 
 
Analysis plan for the primary efficacy outcome 
 
 Co-primary efficacy analyses 
The primary analyses of efficacy is based on the modified ITT populations: the Microbiologically 
Eligible and Assessable study populations. While an ITT analysis is commonly used for a 
superiority trial, it may not be sufficiently conservative for a non-inferiority trial since ITT analysis 
can bias toward no treatment difference. Both the International Conference on Harmonisation 
(ICH) E9 document of Statistical Principles for Clinical Trials7 and the FDA document of 
Guidance for Industry Non-Inferiority Clinical Trials (REF) suggest looking at the ITT analysis 
cautiously for a non-inferiority trial and recommend considering PP analysis as equally 
important for a non-inferiority trial8. A PP analysis, however, does introduce bias through 
exclusions based on post-randomization exclusions9 which is particularly problematic in a study 
that is not placebo-controlled. The PP analyses (PP95 and PP75) will therefore be considered 
secondary in the primary efficacy analyses.  
 


 
22 
 
There will be two co-primary efficacy analyses, one for the Microbiologically Eligible population 
and another for Assessable population. Non-inferiority must be demonstrated in both 
populations in order to declare non-inferiority for an intervention regimen. 
 
For each, the comparison of unfavorable outcome as defined by protocol at primary efficacy 
endpoint for Regimen 1 (control regimen) versus Regimen 3 (2PHZM/2PHM) will be considered 
first, and, if non-inferiority criteria are met, then the comparison of Regimen 1 versus Regimen 2 
(2PHZE/2PH) will be considered.  
In the event that the arm of Regimen 3 is terminated for safety concerns in the interim 
monitoring, the comparison of Regimen1 versus Regimen 2 (2PHZE/2PH) will be carried out for 
co-primary efficacy analyses. 
If Regimen 3 is not terminated for safety concerns in the interim monitoring and the non-
inferiority criteria for Regimen 1 versus Regimen 3 at the primary endpoint are not met (see 
5.2.1), then the comparison of Regimen 1 versus Regimen 2 at the primary endpoint will be 
considered as an exploratory efficacy analysis. 
 
 Non-inferiority test  
The proportion of participants with unfavorable outcome can be estimated thus:   if ar  and br  
are the proportions of unfavorable outcome for the two study arms (a = Regimen 1 and b = 
Regimen 2 or Regimen 3) and if is the non-inferiority margin (= 6.6%), then the statistical 
hypothesis is: 


a
b
r
r
H :
0
     vs.   



a
b
r
r
H :
1
 
For a significance level of 0.05, the statistical test is equivalent to obtaining the two-sided 95% 
confidence interval for the difference of  𝒓𝒃െ𝒓𝒂 .  If the upper bound of the confidence 
interval is less than, then the non-inferiority of Regimen 2 or Regimen 3 to Regimen 1 with a 
significance level of 0.05 is established (equivalent to one-sided α=0.025). 
The difference in proportion unfavorable will be calculated using a stratified analysis using 
Cochran-Mantel-Haenszel weights10. Randomization is stratified by site, HIV status and 
presence of cavitation. The analysis will be stratified by HIV status and presence of cavitation 
only. Inclusion of site as a factor in the stratified analysis will result in some groups with too few 
participants. The unstratified difference in proportions will also be presented, although the 
stratified difference will be considered primary.  
 
 Superiority test     
Regimens that are shown to be non-inferior to control will also be assessed for superiority 
compared to control using a two-sided significance level of 0.05. 
 
 Secondary efficacy analyses 
In additional secondary efficacy analyses, the primary efficacy endpoint will be assessed in the 
PP95 and PP75 populations, in addition to the full ITT population. 
 
 Tabulation of the primary outcome classification  
Since the primary efficacy outcome is a composite of various components, the actual reason 
(component) for outcome will also be tabulated by treatment arm. 
Participants will be classified by the first event (chronologically) that made the participant 
unfavorable and further sub-classified by the bacteriological status at the time that this outcome 
occurred (culture converted, never culture converted, bacteriological reversion, or 
bacteriological relapse).  
 


 
23 
 
 Sub-group analyses 
This primary efficacy analysis will be repeated in subgroups according to the following baseline 
factors (i.e. those present at enrollment or from study-specific samples collected for screening 
and baseline visits). For factors reliant on results from sputum samples, the results must be 
from the study laboratory of record. Categorical variables will be split by tertiles except where 
there is previous clinical justification for a different cut-off.  
 
HIV status 
 
Presence of cavitation on baseline chest radiograph 
 
Extent of cavitation on baseline chest radiograph 
 
Sex 
 
Weight  
 
BMI  
 
WHO scale smear quantification  
 
Solid culture colony count 
 
MGIT days to detection 
 
GeneXpert MTB/RIF Cycle Threshold 
 
Age  
 
Country of study center 
 
Smoking history 
 
History of diabetes  
 
Ethnicity and race 
 
The test for an interaction between the covariate and treatment will be done using logistic 
regression comparing the model including the interaction term and the model with only marginal 
terms using the likelihood ratio test to evaluate the statistical significance of inclusion of the 
interaction term in the model.  
 
 Independent Endpoint Review Committee 
An independent blinded endpoint review committee (ERC) will be formed to review individual 
primary efficacy outcome classification at the end of the trial in the event that the assessment of 
non-inferiority is marginal for one or both regimens.  
Members of the ERC will be identified prior to the end of the trial, and will include a small 
number of experts with experience in conducting clinical trials for new treatments for TB who are 
not otherwise involved in the trial. The ERC may not be needed, but may be convened and 
asked to review individual primary efficacy outcome classification for a subset of patients under 
the following scenarios:  
 
if the upper bound of the 95% confidence interval of the difference in the proportion of 
unfavorable outcomes is within 2% of the non-inferiority margin of 6.6%, in other words 
between 4.6% and 8.6%, for either regimen as compared to control provided the 
regimen is shown to safe and well tolerated. This range includes scenarios when non-
inferiority has been demonstrated (<6.6%) or just missed (>6.6%).  
 
if there are large number of outcomes (10% or more) that are based on limited 
bacteriology or limited data and the review by the ERC would be considered valuable in 
interpreting the results.  
The ERC may be asked to review outcome classification in other situations.  
The ERC will review the full bacteriological, clinical and baseline data for participants, while 
staying blinded to treatment allocation. The ERC will review all participants classified as 
unfavorable or not assessable in the primary efficacy outcome, although they would be 
expected to focus on the more complex cases and more straightforward cases (e.g. clear 


 
24 
 
bacteriological relapse) might be presented in summary form. The ERC will be asked to 
determine whether, based on the entirety of the data available, they would consider this 
participant to have had an unfavorable outcome of treatment or be in the process of having an 
unfavorable outcome of treatment and to quantify their confidence using a scale from 1 (very 
unlikely) to 4 (very likely). The ERC will be encouraged to come to consensus in each case.  
Any re-classification by the ERC will not replace the primary efficacy outcome defined based on 
the algorithm described in this analysis plan, but will be a sensitivity analysis used to 
supplement the primary efficacy results and provide further insight into whether the intervention 
regimens should be considered to have non-inferior efficacy.  
 
A document further describing the terms of reference of the endpoint review committee will be 
prepared prior to the end of the trial. 
 
 Additional sensitivity analyses 
The following additional sensitivity analyses will be conducted: 
1. The primary efficacy analysis will be repeated in the Microbiologically Eligible study 
population where all participants classified as not assessable will be classified as 
favorable rather than unfavorable. 
2. The primary efficacy analysis will be repeated in the Microbiologically Eligible and 
Assessable study populations where participants taking any non-study anti-TB 
medications for more than 21 days for any reason (including secondary isoniazid 
preventative therapy) will instead be classified as unfavorable.  
3. The primary efficacy analysis will be repeated in the Microbiologically Eligible and 
Assessable study populations where participants taking any non-study anti-TB 
medications for more than 5 days for any reason (including secondary isoniazid 
preventative therapy) will instead be classified as unfavorable.  
4. The primary efficacy analysis will be repeated with a modification to the definitions of 
‘Absence of Cure’ using the following text to replace the paragraph numbered 1 in 
section 4.1.1. so that intervening negative cultures are ignored in the determination 
of absence of bacteriological cure: 
A participant will be considered to have absence of bacteriological cure if 
he/she has a sputum sample, obtained at or after Week 17 and no later 
than the end of the Month 12 analysis visit window, that is Mtb Culture 
Positive (see section 4.7 for definitions of culture results) that is 
indistinguishable from the initial isolate (see separate sequencing plan for 
definitions), and this is confirmed by a second sample that is Mtb culture 
positive. A second confirmatory sample, on a different day (irrespective 
of intervening Mtb Negative culture results), is required, as a single 
positive sputum culture result in isolation will not be considered absence 
of bacteriological cure. If results from strain analysis are inconclusive or 
unavailable, it will be assumed that strains were indistinguishable.  
5. The primary efficacy analysis will be repeated reclassifying all exogenous 
reinfections as unfavorable. 
6. The primary efficacy analysis will be repeated considering only culture inoculation 
results from MGIT liquid media and ignoring any culture inoculation results from solid 
media.  
7. The primary efficacy analysis will be repeated considering only culture inoculation 
results from solid media and ignoring any culture inoculation results from MGIT liquid 
media. 


 
25 
 
8. The primary efficacy analysis will be repeated in the Microbiologically Eligible and 
Assessable study populations excluding additionally participants for whom none of 
screening or baseline study visit sputum cultures are Mtb Positive (week 2 sputum 
cultures will not be used for determining late exclusions).  
9. The primary efficacy analysis will be repeated in the Microbiologically Eligible and 
Assessable study populations including all participants classified as randomized in 
error. For such patients, the classification of the outcome will follow the algorithm in 
section 4.1. 
 
 
 Bayesian analysis of non-inferiority 
A Bayesian analysis of non-inferiority provides a more informative interpretation of the trial 
results by providing an estimate of the probability that the interventions regimens have efficacy 
not much worse than the control regimen for different thresholds of what might be considered 
‘not much worse’. Following methods described previously11, Bayesian binomial regression will 
be used to estimate the distribution of the difference in the proportion of unfavorable outcomes 
between each intervention arm and the control arm, in each analysis population considering 
both non-informative and informative priors. These methods have also been used in secondary 
analyses of the STREAM Stage 1 trial (NCT02409290).  
 
 
Analysis plan for secondary efficacy outcomes 
 
 TB disease-free survival at eighteen months after study treatment 
assignment 
The primary efficacy endpoint for the trial is TB disease-free survival twelve months after study 
treatment assignment. For that primary analysis (described above), only data up to and 
including the 12 month visit window will be used, see section 4.1 above. Participants are 
followed for eighteen months from start of treatment and an important secondary efficacy 
outcome is therefore TB disease-free survival eighteen months after study treatment 
assignment.  
For this analysis (TB disease-free survival eighteen months after study treatment assignment), 
the same definitions for the primary efficacy outcome in section 4.1 will be used with the 
exception that the Month 18 visit will be used in the definitions in place of the Month 12 visit. All 
the same analyses for the primary efficacy analysis described in section 5.2 will be repeated 
using this Month 18 endpoint. 
 
 Time to stable culture conversion  
Time to stable culture conversion is defined as the time from randomization to the first of two 
consecutive Mtb Culture Negative results, collected on separate days without an intervening 
Mtb Culture Positive, and processed at the study lab of record. Participants that never achieve 
culture conversion will be censored at the date of collection of sputum that yielded their last 
negative or positive culture result. 
Time to stable culture conversion will be analyzed separately for cultures from solid and liquid 
culture media. The Microbiologically Eligible study population will be used for these analyses.  
Median time to stable culture conversion will be calculated for each regimen. A hazard ratio with 
corresponding two-sided 95% confidence intervals and p-value will be estimated using a Cox 
Proportional Hazards model will be used, adjusted for the stratification factors of HIV status and 
presence of cavitation. 


 
26 
 
The equality of survivor functions for time to stable culture conversion will be compared using a 
(Wilcoxon) Log rank test, stratified by HIV status and presence of cavitation. Regimen 2 and 
Regimen 3 will each be compared with the control Regimen 1.  
The assumption of proportional hazards will be tested using the proportional hazards test based 
on the Schoenfeld residuals and by reviewing the log minus log survival plot (against log time) 
after fitting the Cox Proportional Hazards model.  
Even when Kaplan-Meier curves of time to culture conversion have been shown to diverge in 
the presence of an effective drug (such as bedaquiline), they tend to converge later in followup 
potentially violating the assumption of proportional hazards. In the case where there is adequate 
evidence that the proportional hazard assumptions are violated at the 5% level (i.e. p<0.05), 
methods where proportional hazards is not a necessary assumption will be used, such as 
restricted mean survival time. 
The analyses above of time to sputum culture conversion will be repeated as follows: 
1. With the alternative definition as time from randomisation to the first Mtb Negative 
culture from sputa processed at the study lab of record (without the need for a 
second negative culture to confirm). 
2. Including only participants for whom 75% of more of culture results from sputum 
samples collected between randomization and week 12 are evaluable. 
The Kaplan-Meier estimator will be used to calculate the proportion of participants with 95% 
confidence interval who are culture negative after 8 weeks and after 12 weeks.  
 
 Speed of decline of sputum viable bacilli by automated liquid MGIT culture 
days to detection  
The Microbiologically Eligible study population will be used for these analyses.  
Speed of decline of MGIT days to detection will be analyzed using mixed effect non-linear 
regression comparing different parametric models, and taking account of the latest research and 
other relevant published studies. Parametric models for modelling the quantitative decline in 
viable bacilli used to date have included bi-exponential12, hyperbolic tangent function13 and 
surge functions14. 
 
 Time to unfavorable efficacy outcome 
Time to unfavorable efficacy outcome is defined as the time from randomization to the first 
event that results in the definition of an unfavorable efficacy outcome for that participant. 
The time will be analyzed first using the primary efficacy outcome (using data from 
randomization to 12 months) and also using the secondary efficacy outcome at 18 months (as 
defined in section 5.3.1) 
Participants that do not achieve culture conversion (i.e. fail to have 2 consecutive culture 
negative results), and have not otherwise been called unfavorable, will be called unfavorable at 
the date of the last visit when a culture positive result was obtained. 
These analyses will be repeated for the Microbiologically Eligible, PP95 and PP75 study 
populations.  
Participants classified as favorable or not assessable will be censored in this analysis at the 
date of collection of sputum that yielded their last negative culture result. 
Median time to unfavorable outcome will be calculated for each regimen. A hazard ratio with 
corresponding two-sided 95% confidence intervals and p-value will be estimated using a Cox 
Proportional Hazards model will be used, adjusted for the stratification factors of HIV status and 
presence of cavitation. 
The equality of survivor functions will be compared using a (Wilcoxon) Log rank test, stratified 
by HIV status and presence of cavitation. Regimen 2 and Regimen 3 will each be compared 
with the control Regimen 1.  


 
27 
 
The assumption of proportional hazards will be tested using the proportional hazards test based 
on the Schoenfeld residuals and by reviewing the log minus log survival plot (against log time) 
after fitting the Cox Proportional Hazards model.  
 


 
28 
 
6 
Safety Analyses 
 
 
Analysis population 
All safety analyses will be conducted using the Safety Analysis Population which includes all 
participants randomized that took at least one dose of the allocated study regimen.  
 
 
Primary safety analysis 
The primary safety outcome is the proportion of participants with grade 3 or higher adverse 
events during the study treatment phase (defined above in section 4.6). 
The difference in proportion of participants with a grade 3 or higher adverse event during study 
treatment phase between each of Regimens 2 and 3 compared to Regimen 1 with 
corresponding two-sided 95% confidence intervals will be estimated using the same methods as 
for the primary efficacy analysis (section 5.2.2).  
It is hypothesized that the rifapentine regimens will have safety at least as good as the control 
regimen, but no non-inferiority margin has been pre-specified. The objective is to estimate the 
difference between regimens and describe the precision in this estimate (using 95% confidence 
intervals).  
The primary safety analysis will also be repeated in the Microbiologically Eligible and 
Assessable analysis populations. 
 
 
Secondary safety analyses 
 
 Treatment-related grade 3 or higher adverse events 
The primary safety analysis will be repeated considering only the subset of grade 3 or higher 
adverse events during study treatment phase that are considered at least possibly related to 
study treatment. 
 
 Tolerability 
Tolerability of the regimen is evaluated using the outcome of discontinuation of assigned 
treatment for a reason other than microbiological ineligibility. For this reason, participants 
excluded from the microbiologically eligible study population will also be excluded from this 
analysis.  
The proportion of participants discontinuing assigned treatment will be tabulated by regimen, by 
week of discontinuation after date of start of treatment, and by cause of discontinuation (e.g. 
adverse event, withdrawal of consent, treatment failure).  
 
 All-cause mortality during treatment or follow-up 
All-cause mortality includes all deaths from any cause during treatment or follow-up up to the 
end of the Month 18 visit window.  
The number of participants who die during treatment and follow-up will be tabulated by regimen 
with listings of primary cause of death.  
Median survival time will be calculated for each regimen. Participants that do not die will be 
censored at the date last known to be alive. A hazard ratio with corresponding two-sided 95% 
confidence intervals and p-value will be estimated using a Cox Proportional Hazards model will 
be used, adjusted for the stratification factors of HIV status and presence of cavitation. 
The equality of survivor functions will be compared using a (Wilcoxon) Log rank test, stratified 
by HIV status and presence of cavitation. Regimen 2 and Regimen 3 will each be compared 
with the control Regimen 1.  


 
29 
 
The assumption of proportional hazards will be tested using the proportional hazards test based 
on the Schoenfeld residuals and by reviewing the log minus log survival plot (against log time) 
after fitting the Cox Proportional Hazards model.  
 
 Serious adverse events (SAEs) 
The proportion of participants with an SAE during study treatment phase will be tabulated by 
regimen, MedDRA system organ class (SOC), MedDRA preferred term (PT) and severity grade.  
The proportion of participants with a Serious Adverse Reactions (SARs) and Suspected 
Unexpected SARs (SUSARs) during study treatment phase will also be tabulated by regimen 
and severity grade.  
 
 All grade adverse events (AEs) 
The proportion of participants with any AE during study treatment phase will be tabulated by 
regimen, and relatedness to allocated regimen, MedDRA system organ class, MedDRA 
preferred term and severity grade.  
 
 Laboratory safety parameters 
Laboratory safety parameters will be summarized by regimen and study visit (scaled by upper or 
lower limit of normal, ULN) including a summary of the highest (or lowest) measurement 
recorded at any visit. Summaries of drug induced liver injury (DILI) will be included using the 
published definition from secondary analyses of the REMoxTB trial15 (ALT > 5x ULN and ALT > 
3x ULN and total bilirubin >2 x ULN), ATS definitions and using Hy's law. 
These summaries will be repeated limiting to measurements only during the study treatment 
phase.  
 
 Acquired drug resistance 
Acquired drug resistance will be summarized by regimen, distinguishing between resistance 
acquired at time of treatment failure or relapse following study treatment and resistance 
acquired while on a non-study retreatment regimen.  
 
 
 


 
30 
 
7 
Data summaries 
 
 
Recruitment and baseline characteristics 
 
 Recruitment, screening, & eligibility 
The number of participants screened and randomized will be tabulated by center and regimen. 
The number of participants who were not enrolled will be presented by center. 
 
 Exclusions from analysis 
The number of participants excluded from each of the study populations will be tabulated by 
regimen and by reason for exclusion. 
 
 Baseline characteristics 
Baseline characteristics will be tabulated by regimen. Characteristics will include sex, age, 
ethnicity, weight, BMI, whether underweight (BMI <18.5 kg/m2), race, ethnicity, cavitation, 
radiographic severity of disease, Karnofsky score, and laboratory parameters such as, HIV 
status, CD4 count (if applicable), smoking status, smear and culture grading, serum albumin, 
hemoglobin, and time to positivity on MGIT. The baseline characteristics table will be repeated 
for each of study populations.  
 
 
Adherence to study medications 
The protocol requires at least 5 weekly doses to be provided by directly observed therapy (DOT) 
(i.e. participants should receive ~71% of study doses as DOT). The rest of doses are allowed to 
be self-administered (SAT). 
Treatment adherence will be summarized by regimen first considering only DOT doses and also 
considering DOT and SAT doses.  
 
 
Concomitant medications 
Use of concomitant medications will be summarized by treatment arm considering separately 1. 
Non-TB and Non-antiretroviral medications, 2. Anti-retroviral medications, and 3. Additional non-
study TB medications.  
 
 
Retention, participant disposition, and description of follow-up 
Completion of treatment and completion of scheduled follow-up will be summarized by regimen 
including reasons for failure to complete treatment and follow-up. 


 
31 
 
8 
Other Analyses 
 
 
Risk Factor Analysis 
Univariate and multivariate analyses will be carried out to assess the association of unfavorable 
outcomes and clinical and demographic variables using Cox regression (time to event 
endpoints) and logistic regression (binary endpoints). Variables included as potential risk factors 
include baseline data in addition to on-treatment data such as time to culture conversion and 
weight gain. The most parsimonious model that contains significant variables with p<0.05 will be 
used to identify risk factors.  The interactions between risk factors and treatment regimens will 
be examined to evaluate variations of different risk factors among treatment regimens. 
 
 
Efavirenz Pharmacokinetics Analysis  
Efavirenz pharmacokinetics will be evaluated in the first 31 and then a total of 90 participants 
from each of two groups of participants randomized to treatment regimen 2 or 3 of the study and 
receiving efavirenz based ART. The analysis plan for this is described in a separate statistical 
analysis plan (TBTC Study 31 Efavirenz Pharmacokinetic Statistical Analysis Plan). 
 


 
32 
 
9 
Interim monitoring by the Data and Safety Monitoring Board (DSMB) 
 
Interim analyses will be provided to the DSMB for monitoring the efficacy and safety and for the 
DSMB to review other matters occurring during the trial. Based on the interim results, the DSMB 
may recommend early closure of any experimental arm or the trial if the interim evidence is 
sufficiently strong that one of the trial interventions is clearly indicated or clearly contraindicated 
because of a net difference in efficacy, safety, or tolerability. 
 
If the evidence provides proof beyond reasonable doubt that there is a clear and meaningful 
benefit or harm of a given regimen, the DSMB may recommend termination of one of the 
treatment arms or termination of the study.  
 
 
Monitoring for efficacy 
Two interim analyses for the primary efficacy outcome are planned. To provide guidance to 
continue, adjust or stop the trial, the two interim analyses will be carried out after 40% and 60% 
of participants, respectively, reach 12 months post-randomization, and allowing for up to an 
additional four months for reporting of all culture results. The primary efficacy outcome will be 
conducted according to the statistical analysis plan described in section 5.2 with the analysis 
populations described therein. 
 
There will be no ordering of hypotheses in the interim analyses.  
 
The Haybittle-Peto stopping boundaries are to be used for the interim analyses. Following the 
Haybittle-Peto rule in monitoring the efficacy, the statistical criterion for the differences between 
arms is set at the 0.1% level of statistical significance in each of the two interim analyses. If any 
arm is shown to have superior efficacy to the control arm at the 0.1% level of statistical 
significance (i.e. using 99.9% confidence intervals), the DSMB should consider whether it would 
be appropriate to terminate some arms or the whole trial, taking into account other efficacy and 
safety analyses.  
 
 
Monitoring for safety  
The DSMB will convene approximately annually, or more often as needed, to review safety 
data. The safety monitoring in the interim analyses will focus on the comparison of the 
proportion of participants with adverse events in each treatment arm, with a particular focus on 
the primary safety endpoint. Concerns about the extent and type of adverse events observed 
may lead to early termination of the trial when the DSMB judges that the potential benefits of the 
new regimens are unlikely to outweigh the risks. In other cases, the DSMB may recommend 
measures short of termination that may reduce the risk of adverse events. For example, 
modifying the inclusion criteria if the risks are concentrated in a particular subgroup or instituting 
screening procedures that could identify those at increased risk of a particular adverse event. 
 


 
33 
 
10 Version history 
Version 1.0 
12 December 2018
 
 
 
 
 
 
List of changes from version 1.0 


 
34 
 
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