Clinical trial NCT04703075
Conditions: Tuberculosis
Sponsor: Johns Hopkins University
Start date: 2022-03-24; Completion date: 2024-06-10
Enrollment: 531 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare treatment success (adherence and completion of treatment) and safety of 1HP with 3HP in HIV-uninfected adults and adolescents at increased risk of TB.

Detailed description:
Tuberculosis (TB) is the leading infectious killer globally and a major cause of illness and suffering. The World Health Organization has prioritized TB preventive therapy (TPT) for people with latent TB infection (LTBI) as a key strategy for controlling the epidemic. Prevention of TB with isoniazid preventive therapy (IPT) is effective and reduces morbidity and mortality, and has been the mainstay of TB prevention for decades. But for an intervention with an excellent evidence of efficacy, global uptake has been abysmal. Completion rates for IPT when it is administered are poor (Gillespie 2008; Durovni 2010), with a large proportion of patients unable to complete treatment (McClintock 2017; Sterling 2011). While uptake is influenced by a variety of factors, a critical element has been the duration of IPT, with adherence falling sharply over time in clinical trials and practice. Shorter course regimens have a much higher completion rate and are more acceptable to patients, clinicians, and programs.

Arms: arm 1: Participants will receive Rifapentine 600 mg daily and isoniazid (INH) 300 mg daily for 4 weeks. arm 2: Participants will receive Rifapentine 900 mg and isoniazid 900 mg weekly for 12 weeks.
Interventions: intervention 1: Rifapentine 600 mg and INH 300 mg intervention 2: Rifapentine 900 mg and INH 900 mg
Intervention descriptions: intervention 1: Participants will receive Rifapentine 600 mg and INH 300 mg intervention 2: Participants will receive Rifapentine 900 mg and INH 900mg

Protocol documents:
Prot_000.pdf: 
Protocol Number IRB00284317 
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1.
TITLE PAGE
Full Title: 
Treatment Success and Safety of 4 Weeks of Daily Rifapentine and Isoniazid 
(1HP) vs. 12 weeks of Weekly Rifapentine and Isoniazid (3HP) for Prevention of 
Tuberculosis in HIV-uninfected Individuals (1v3HP for TPT in HIV-uninfected 
individuals) 
Short Title: 
Ultra Curto TPT 
Clinical Trial Phase: 
Phase IV 
Grant number U01AI152961 TB study in Brazil (DMID 20-0020) 
Protocol number:  
U01AI152961 
Short study name: 
Ultra Curto TPT 
Protocol Version:  
5.0 
Date:   
4 July 2023 
Sponsor:  
JHU 
Funded by: 
 
NIH/DMID 
JHU IRB Identifier: 00284317
NCT04703075
Pharmaceutical and other Study Product Support Provided by: 
Sanofi (Paris, France) 
Chair: Richard E. Chaisson, M.D. 
DMID Medical Officer/Medical Monitor: 
Francisco J. Leyva MD, PhD, ScM 


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2.
SIGNATURE PAGE
I agree to conduct the study in accordance with the current protocol and will 
not make changes to the protocol without permission from DMID and 
CONEP. 
I agree to personally conduct or supervise this study. 
I will ensure that the requirements for obtaining the Informed Consent Form 
and approval by the National Research Ethics Committee (CONEP) or 
Research Ethics Committee (CEP) (Resolution 466 of 2012 of the National 
Brasilian Health Council and complementary resolutions) are attended to. 
I agree to report adverse experiences that occur during this study to the 
sponsor. 
I agree to maintain adequate and accurate study records and to make these 
records available for inspection or monitoring by relevant applicable 
regulatory bodies or at the discretion of the sponsor. 
I also agree to immediately report to the CEP all study modifications and all 
problems and unforeseen events involving risks to humans or others. In 
addition, I will not make any changes to the study without the approval of 
CONEP / CEP and the study sponsor 
I agree to ensure that all team members involved in conducting this study are 
informed of their obligations to fulfill the above commitments and maintain 
confidentiality. 
Signature: 
Date: 07/05/2023 
Principal investigaror 
BETINA DUROVNI 


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3. 
TABLE OF CONTENTS 
Contents 
 
1. 
TITLE PAGE .............................................................................................................................. 1 
2.      SIGNATURE PAGE ……………………………………………………………...………..  2 
 
3. 
TABLE OF CONTENTS ............................................................................................................ 3 
4. 
KEY ROLES ............................................................................................................................... 8 
5. 
LIST OF ABBREVIATIONS ................................................................................................... 10 
6. 
PROTOCOL SUMMARY ........................................................................................................ 12 
6.1 
Study Schema ................................................................................................................... 14 
6.2 
Schedule of Procedures/Evaluations ................................................................................. 14 
6.3 
Study Duration .................................................................................................................. 15 
7. 
INTRODUCTION .................................................................................................................... 18 
7.1 
Background Information ................................................................................................... 18 
7.2 
Rationale ........................................................................................................................... 18 
8. 
OBJECTIVES and Hypotheses ................................................................................................. 18 
8.1 
Primary Objective ............................................................................................................. 18 
8.3 
Secondary Outcomes ......................................................................................................... 19 
9. 
STUDY DESIGN ...................................................................................................................... 19 
9.1 
Study Groups .................................................................................................................... 19 
9.2 
Dosing Structure ............................................................................................................... 19 
9.3 
Trial Period ....................................................................................................................... 20 
9.4 
Site Descriptions ............................................................................................................... 20 
10. 
STUDY POPULATION ....................................................................................................... 21 
10.1 
Inclusion/Exclusion Criteria.............................................................................................. 21 
10.1.1 
 Participant Inclusion Criteria ................................................................................... 21 
10.1.2  Participant Exclusion Criteria ....................................................................................... 21 
10.2 
Recruitment Process .......................................................................................................... 22 
10.3 
Participant Retention ......................................................................................................... 26 
11. 
INTERVENTIONS ............................................................................................................... 26 
11.1 
Biomedical Interventions .................................................................................................. 26 
11.1.1 
Regimen .................................................................................................................... 26 
11.1.2 
Study Product Formulation and Preparation Rifapentine (source: study 31 v.2.0) ... 27 
11.1.3 
Study Product Supply and Accountability .............................................................. 270 
11.1.4  Assessment of Participant Adherence with Study Product(s)/Intervention(s) ……...31  
11.1.5 
Concomitant Medications and Procedures ................................................................ 32 


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11.1.6 Permitted Medications and Procedures .......................................................................... 33 
11.1.7 
Prohibited Medications and Procedures .................................................................... 33 
11.1.8 
Precautionary Medications and Procedures .............................................................. 30 
11.1.9 
Required Medications ............................................................................................... 31 
11.1.10 Rescue Medications ..................................................................................................... 31 
12. 
STUDY PROCEDURES/EVALUATIONS ....................................................................... 314 
12.1 
Clinical Evaluations and Procedures ............................................................................... 314 
12.1.1 Screening ..................................................................................................................... 314 
12.1.2 HIV Counseling and Testing ....................................................................................... 325 
12.1.3     Enrollment................................................................................................................ 336 
12.1.4  Follow-up visits .......................................................................................................... 347 
12.1.5  Treatment Completion and Successful Treatment…………………………………….43 
12.2 
Laboratory Evaluations ................................................................................................... 403 
12.2.1  Specimen Preparation, Handling and Shipping ........................................................... 403 
12.2.2  Total Blood Volume ................................................................................................... 404 
12.3 
Other Study Procedures and Evaluations ........................................................................ 415 
12.3.1  Early Termination Visit ............................................................................................... 415 
12.3.2 
Management of a participant who becomes pregnant during the study .................. 426 
12.3.3 
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 ........................................................................................................ 426 
12.3.4 
Management of a participant who requests premature discontinuation from study 
treatment
 
………………………………………………………………………………………42
6 
12.3.5 
Management of a participant who is incarcerated after enrollment ........................ 437 
12.3.6  Post Early Termination Visit (Visit after Early Termination) for Participants 
Terminating before Completion of their Assigned Study Treatment ........................................ 47 
12.3.7 
Early Termination Visit for Participants Stopping Study Participation after 
Completion of their Assigned Study Treatment ....................................................................... 47 
12.3.8 
 Missed Visit ............................................................................................................. 48 
12.3.9  Unscheduled Visit ......................................................................................................... 48 
12.3.10  Final Study Visit ......................................................................................................... 48 
12.3.11  Time-And-Motion (TAM) Studies…………………………………………………. 48 
13. 
SAFETY ASSESSMENT ..................................................................................................... 49 
13.1 
Safety Assessment Overview ............................................................................................ 49 
13.2 
Adverse Event Procedures and Reporting Requirements .................................................. 50 
13.2.1  Adverse Events ............................................................................................................. 50 


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13.2.2  Study defined AEs ........................................................................................................ 50 
13.3.3  Serious Adverse Events ................................................................................................ 50 
13.3.4  Adverse event (AE) reporting ....................................................................................... 51 
13.3.5  AEs requiring expedited reporting ................................................................................ 51 
13.3.6  AE Reporting period ..................................................................................................... 51 
13.3.7  Recording updated information on SAEs ..................................................................... 51 
13.3.8  Recurrent SAEs ............................................................................................................. 52 
13.3.9  Timeframe for SAE reporting ....................................................................................... 52 
13.3.10  Site investigator assessment and signature ................................................................. 52 
14. 
CLINICAL MANAGEMENT (Source 3HP DTG v5.0) .................................................... 483 
14.1 
Clinical Management of Adverse Events........................................................................ 483 
14.1.1  Toxicity grading tables ............................................................................................... 483 
14.2 
Toxicity management...................................................................................................... 483 
14.2.1  Gastrointestinal ............................................................................................................... 483 
14.2.2  Cutaneous ...................................................................................................................... 53 
14.2.3  Rifamycin hypersensitivity syndrome (RHS)  (Source 3HP DTG v5.0) .................... 493 
14.2.4  Drug-Associated Fever ................................................................................................. 54 
14.2.5.  Liver Toxicity .............................................................................................................. 55 
14.2.6  Peripheral Neuropathy ................................................................................................ 505 
14.2.7  Other Toxicities .......................................................................................................... 516 
14.3  Pregnancy ........................................................................................................................ 516 
14.4 Criteria for Discontinuation ................................................................................................ 516 
14.4.2  Premature study discontinuation ................................................................................. 527 
15. 
STATISTICAL CONSIDERATIONS .................................................................................. 57 
15.1 
Overview and General Design Issues ................................................................................ 57 
15.2  Study Outcomes ................................................................................................................ 58 
15.2.1  Primary Outcome .......................................................................................................... 58 
15.2.2  Secondary Outcome ...................................................................................................... 58 
15.3 
Study Hypotheses ............................................................................................................. 58 
15.4 
Sample Size Considerations .............................................................................................. 59 
15.5 
Enrollment/Stratification/Randomization/Blinding Procedures/Unblinding Procedures ...... 60 
15.6 
Maintaining Trial Treatment Randomization Codes ........................................................ 61 
15.7 
Participant Enrollment and Follow-up .............................................................................. 61 
15.8 
Data and Safety Monitoring .............................................................................................. 61 
15.8.1  Planned Interim Analysis and Stopping Guidelines...................................................... 61 
15.8.2 
  Interim Efficacy Review ......................................................................................... 62 


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15.8.3    Analysis Plan .............................................................................................................. 62 
15.8.4     Economic Analysis 
Plan…………………………………………………………………………………….…...62 
16. 
DATA HANDLING AND RECORDKEEPING ............................................................... 573 
16.1 
Data Management Responsibilities ................................................................................. 573 
16.2 
Essential/Source Documents and Access to Source Data/Documents .............................. 63 
16.3 
Quality Control and Quality Assurance .......................................................................... 584 
17. 
CLINICAL SITE MONITORING ...................................................................................... 584 
18. 
HUMAN SUBJECTS PROTECTIONS ............................................................................. 605 
18.1 
Institutional Review Board/Ethics Committee ............................................................... 605 
18.2 
Vulnerable Participants ................................................................................................... 605 
18.2.1 
Pregnant participants and fetuses ............................................................................ 605 
18.2.2 
Prisoners .................................................................................................................. 605 
18.2.3 
Children .................................................................................................................. 605 
18.2.4 
Illiterate participants ............................................................................................... 606 
18.3 
Informed Consent ........................................................................................................... 616 
18.3.1 
  Informed Consent Process .................................................................................... 616 
18.3.2 
  Assent Process ...................................................................................................... 627 
18.3.3  Documenting Informed Consent ................................................................................. 627 
18.3.4  Stored samples .............................................................................................................. 68 
18.4 
Risks and SARS-CoV-2 
Precautions………………………………………………………………………………..68 
18.5  Social Impact Events............................................................................................................ 70 
18.6 
Benefits ............................................................................................................................. 70 
18.7 
Compensation ................................................................................................................... 70 
18.8 
Participant Privacy and Confidentiality ............................................................................ 71 
18.9  Certificates of Confidentiality ........................................................................................... 71 
18.10  Critical Event Reporting .................................................................................................... 71 
Critical event reporting is described in Section ______ ............................................................... 71 
18.11  Communicable Disease Reporting ..................................................................................... 71 
18.12  New Findings ..................................................................................................................... 71 
18.13  Study Discontinuation ........................................................................................................ 71 
18.14  Post-Trial Access ............................................................................................................... 72 
18.15  Community Advisory Board and Other Relevant Stakeholders ......................................... 72 
19. 
ADMINISTRATIVE PROCEDURES ................................................................................. 72 
19.1   Protocol Registration ........................................................................................................ 72 
19.2   Regulatory Oversight ........................................................................................................ 72 


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19.3 
Study Implementation ....................................................................................................... 72 
19.4 
ClinicalTrials.gov ........................................................................................................... 673 
20. 
PUBLICATION POLICY .................................................................................................. 673 
21. 
REFERENCES ................................................................................................................... 673 
22. 
APPENDICES .................................................................................................................... 728 
I 
Schedule of events and study duration .................................................................................... 729 
II 
Sample study medication & food diary..................................................................................... 82 
III Rifapentine hypersensitivity reaction worksheet ...................................................................... 84 
IV List of Precautionary Medications ............................................................................................ 85 
V 
DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.1 (March 2017) ... 87 
 


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4. 
KEY ROLES 
 
Principal Investigator 
Richard E. Chaisson, MD 
Division of Infectious Diseases 
Johns Hopkins University School of Medicine 
1550 Orleans Street, Room 1M.08 
Baltimore, MD 21287 
Phone: +1-443-955-1755 
Email: rchaiss@jhmi.edu 
 
NIH Program Officer 
Barbara E. Laughon, PhD  
Senior Scientist for TB Drug Development Partnerships 
Tuberculosis Research Section, Respiratory Diseases Branch  
Division of Microbiology and Infectious Diseases, NIAID, NIH 
5601 Fishers Lane, Room 7G78 
Bethesda, MD 20892-9826 
Tel: 240.627.3302 
Fax: 240.627.3114 
BLaughon@niaid.nih.gov 
 
NIH Medical Officer 
Francisco J. Leyva MD, PhD, ScM 
Medical Officer 
Respiratory Diseases Branch - DMID 
NIAID - NIH - HHS 
5601 Fishers Ln., Room 8E27 
Rockville MD 20852-9825 
francisco.leyva@nih.gov 
 
Site Principal Investigators  
Investigators 
Marcelo Cordeiro-Santos, MD, Msc, PhD 
Head of the Clinical Research Center on Mycobacteria - Fundação de Medicina Tropical 
Dr. Heitor Vieira Dourado (FMT-HVD) 
Associate Professor – Universidade do Estado do Amazonas (UEA), Av. Pedro Teixeira, 25 
- Manaus - Amazonas - Brasil - 69040-000 
Phone: +55 92 99119 9199  
E-mail: marcelocordeiro.br@gmail.com 
 
 


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Solange Cesar Cavalcante, MD, MSc, 
PhD 
Senior Researcher - Fundação Oswaldo 
Cruz, Rio de Janeiro 
Infectious Disease Specialist- Municipal 
Health Secretariat of Rio de Janeiro 
Phone: 5521 996318789 
Email:drsocavalcante@yahoo.com.br 
 
Betina Durovni, MD, MPH, PhD 
Infectious Disease Specialist- Municipal 
Health Secretariat of Rio de Janeiro 
Senior Researcher -  Center for Strategic 
Studies - Fundação Oswaldo Cruz, Rio de 
Janeiro 
Phone: 5521 999943122 
E-mail: bdurovni@gmail.com 
 
Statistician 
Larry Moulton, PhD 
Global Disease Epidemiology and 
Control, Johns Hopkins Bloomberg 
School of Public Health 
Wolfe St, Room E5519 
Phone: (410) 955-6370 
E-mail: larrymoulton@gmail.com 
 
Data Manager 
Silvia Cohn, MPH, MSc 
Johns Hopkins Center for TB Research 
Johns Hopkins University School of 
Medicine, 1550 Orleans St, 1M.02 
Baltimore, MD 21287 
Phone: (410) 955-1755 
Email: scohn5@jhmi.edu 
 
Pharmacology Laboratory Director 
Mark Marzinke, PhD, DABCC 
Director, Clinical Pharmacology 
Analytical Laboratory (CPAL) 
Division of Clinical Pharmacology 
Johns Hopkins University 
4940 Eastern Avenue  
Mason F. Lord Center Tower 
Baltimore, MD 21224 
TEL: 410-550-9704 
FAX: 410-502-5598 
Email: mmarzin1@jhmi.edu 
 
Coordenador Central de Estudos 
Beatriz Kohler, RN, MPH, MBA 
Center for Tuberculosis Research 
Escola de Medicina da Universidade 
Johns Hopkins 
1550 Orleans Street, Suite 1M.06 
Baltimore, MD 21287 
Phone: +1 410-614-3812 
Email:  
 
Consultant 
Susan Swindells, MBBS  
Infectious Diseases/Internal Medicine 
University of Nebraska Medical Center 
988106 Nebraska Medical Center 
Omaha, NE 68198-8106  
Phone: (402) 559-5392  
FAX: (402) 553-5527  
Email: sswindells@unmc.edu  
 
Epidemiologists 
David Dowdy, MD, PhD 
Johns Hopkins University 
Bloomberg School of Public Health 
615 N. Wolfe Street, Room E6531 
Baltimore, MD 21205 
Email:  ddowdy1@jhmi.edu 
 
Nicole Salazar-Austin, MD, ScM 
Johns Hopkins School of Medicine 
Bloomberg Children’s Center 
200 N. Wolfe St. 
Baltimore, MD 21287 
Nsalaza1@jhmi.edu 
 
 
 


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5. 
LIST OF ABBREVIATIONS 
AE/AER/EAE 
Adverse Event / Adverse Event Report / Expedited Adverse Event 
AFB 
Acid Fast Bacilli 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT/SGPT 
Alanine Aminotransferase 
ART/ARV 
Antiretroviral Therapy / Antiretroviral 
AST/SGOT 
Aspartate Aminotransferase 
AUC 
Area Under the time-concentration Curve 
CBC 
Complete Blood Count 
CDC 
(US) Centers for Disease Control and Prevention 
Cmax 
Maximum concentration 
CRF 
Case Report Form 
CXR 
Chest X-ray 
DBS 
Dried Blood Spot 
DOT 
Directly Observed Therapy 
DR-TB 
Drug-Resistant Tuberculosis 
DS-TB 
Drug-Susceptible Tuberculosis/Drug-Sensitive Tuberculosis 
DSMB 
Data and Safety Monitoring Board 
DST 
Drug Susceptibility Testing 
EC 
Ethics Committee 
E/CIA 
Chemiluminescence immunoassay  
FDA 
(US) Food and Drug Administration 
H/INH 
Isoniazid 
HBSAG 
Hepatitis B Surface Antigen 
HHC 
Household contact 
HIV 
Human Immunodeficiency Virus 
HP 
Isoniazid and Rifapentine 
IoR 
Investigator of Record 
IPT 
Isoniazid Preventive Therapy 
IRB 
Institutional Review Board 
LFT(s) 
Liver Function Test(s) 
LTBI 
Latent Tuberculosis Infection 
MDR-TB 
Multidrug-Resistant Tuberculosis 
MIC 
Minimum Inhibitory Concentration 
MOP 
Manual of Operations 
M.tb. 
Mycobacterium tuberculosis 
P/RPT 
Rifapentine 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
RIF 
Rifampin/Rifampicin 
SAE 
Serious Adverse Event 
SOC 
Standard Of Care 
SOE 
Schedule of Evaluations 
SOP 
Standard Operating Procedure 


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T1/2 
Half-life 
TB 
Tuberculosis 
TBTC 
Tuberculosis Trials Consortium 
TPT 
TB Preventive Therapy 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
XDR-TB 
Extensively Drug Resistant Tuberculosis 


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6. 
PROTOCOL SUMMARY 
 
 
Protocol Title: 
Treatment Success and Safety of 4 Weeks of Daily Rifapentine 
and Isoniazid (1HP) vs. 12 weeks of Weekly Rifapentine and 
Isoniazid (3HP) for Prevention of Tuberculosis in HIV-uninfected 
Individuals (1v3HP for TPT in HIV-uninfected individuals): Ultra 
Curto 
Treatment 
Indication: 
TB preventive treatment (TPT) in HIV uninfected persons age 
≥15 years with LTBI 
 
Trial Objective: 
To compare treatment success (adherence and completion of 
treatment) and safety of 1HP with 3HP in HIV-uninfected adults 
and adolescents at increased risk of TB.   
 
Trial Design: 
An international, multicenter, randomized, controlled, open-label, 
two arm, Phase IV clinical trial.  
 
Arm A (n=250):  Experimental arm.  Rifapentine 600 mg 
daily and isoniazid 300 mg daily for 4 weeks. 
 
Arm B (n=250): Control arm.  Rifapentine 900 mg and 
isoniazid 900 mg weekly for 12 weeks. 
 
Sample Size 
500 
 
Patient Population: 
The study will enroll HIV-uninfected individuals who are > 15 
years old, and are candidates to receive TB preventive therapy 
(i.e. LTBI with no evidence of active TB). Key exclusion criteria 
include HIV infection, abnormal liver enzymes, neutropenia, 
previous treatment of TB or latent TB infection, or a history of 
study drug intolerance.   
 
Study treatment: 
TB preventive treatment:   
Arm A (n=250):  Experimental arm.  Rifapentine 600 mg daily 
and isoniazid 300 mg daily for 4 weeks. 
 
Arm B (n=250): Control arm.  Rifapentine 900 mg weekly and 
isoniazid 900 mg weekly for 12 weeks. 
 
Trial sites: 
• Health units from Rio de Janeiro Health Secretariat and 
NAPDOT study clinic, Rio de Janeiro, Brazil 
• Fundação de Medicina Tropical (FMT) Dr. Heitor Vieira 
Dourado;  Manaus, Amazonas State, Brazil 


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Criteria for evaluation: 
Primary Objectives: 
To compare treatment success (completion of treatment with >90% adherence) of 1HP 
compared with 3HP in HIV-uninfected adults and adolescents at increased risk of TB. 
 
To compare the safety of 1HP vs 3HP in HIV-uninfected adults and adolescents at 
increased risk of TB. 
 
Primary Outcomes:  
(1)  Successful completion of TPT with >90% adherence documented by self-report, 
pill count, and pharmacologic monitoring. 
 
(2)   Safety of treatment regimens, defined as occurrence of Grade 2 or higher targeted 
safety events while taking study medications or within 14 days of stopping, or 
discontinuation of study medications because of side effects.  
 
Targeted safety events are hypersensitivity syndrome, rash, peripheral neuropathy, 
hepatotoxicity, nausea and vomiting, and drug-related fever. 
 
Secondary Outcome: 
(1) Incremental cost-effectiveness of 1HP and 3HP (compared to each other, 6H, and 
no treatment) using a societal perspective. 
(2) Analyze, in each of the health units in the study, the time needed to provide comprehensive 
care to patients. 
 


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6.1 
Study Schema 
 
 
Figure 1 
  
 
 
 
2, 3, 8,11 


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6.2 
Schedule of Procedures/Evaluations 
See APPENDIX I 
 
 
6.2.1 Laboratory Evaluations 
 
Screening and follow-up 
 
 
Hematology  
 
 
Hemoglobin, hematocrit, red blood cells, white blood cell count, and platelets.  
 
 
 
Blood Chemistry 
 
 
Sodium, potassium, chloride, creatinine, and albumin.  
 
 
 
Liver Function Tests  
 
 
Total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase.  
 
These tests should be performed at any time during the treatment and post-
treatment phase if the participant exhibits signs suggestive of hepatitis (e.g., 
fatigue, weakness, malaise, anorexia, nausea, vomiting, abdominal pain, pale 
stools, dark urine, chills, or jaundice).  
 
 
 
Pregnancy Test 
 
Serum or urine β-HCG  
 
 
 
Dried Blood Spot collection and temporary storage / batch testing 
 
Dried blood spot collection for presence of rifapentine 
 
 
Urine collection  
 
Urine collection and point of care testing for presence of isoniazid 
 
 
 
Sampling for NAT2 metabolizer genotype 
 
 
Dried blood spot or urine as determined by local capacity 
 
 
 
Additional evaluations at Screening only 
 
 
 
HBsAg 
 
 
 
HIV-1 antibody test 
 
 
 
TST or IGRA 
 
6.3 Study duration is in APPENDIX I 
 
 
 
 
 
 


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7. 
INTRODUCTION 
 
7.1 
Background Information 
 
Tuberculosis (TB) is the leading infectious killer globally and a major cause 
of illness and suffering.  The World Health Organization has prioritized TB 
preventive therapy (TPT) for people with latent TB infection (LTBI) as a key 
strategy for controlling the epidemic.  Prevention of TB with isoniazid 
preventive therapy (IPT) is effective and reduces morbidity and mortality, and 
has been the mainstay of TB prevention for decades.  But for an intervention 
with an excellent evidence of efficacy, global uptake has been abysmal.   
Completion rates for IPT when it is administered are poor (Gillespie 2008; 
Durovni 2010), with a large proportion of patients unable to complete 
treatment (McClintock 2017; Sterling 2011). While uptake is influenced by a 
variety of factors, a critical element has been the duration of IPT, with 
adherence falling sharply over time in clinical trials and practice.  Shorter 
course regimens have a much higher completion rate and are more acceptable 
to patients, clinicians, and programs.  
 
7.2 
Rationale 
 
With support from the NIH and the CDC, we have pioneered the development 
of short-course, rifamycin-based TB preventive therapy (TPT) over the past 15 
years. We have evaluated the efficacy of 3 months of weekly rifapentine and 
isoniazid (3HP) in people with and without HIV infection and showed that it is 
non-inferior to longer courses of INH, with better adherence and less toxicity. 
(Schechter 2006; Martinson 2011; Sterling 2011)   
 
This regimen is now recommended as a first-line treatment for latent TB 
infection by the CDC and the World Health Organization, offering the 
potential of substantially increased uptake of TPT as part of the END TB 
Strategy. (WHO 2018)   
 
More recently, supported by NIAID, we have shown that one month of daily 
rifapentine and isoniazid (1HP) is non-inferior to nine months of INH in people 
with HIV infection. (Swindells 2019)  The availability of two innovative, new 
short-course TPT regimens offers a transformative opportunity to global TB 
control and achieving the End TB targets.  However, a major question still 
requiring evidence is the safety of the 1HP regimen in people without HIV 
infection.   
 
While the efficacy of 1HP can be assumed from its success in HIV-positive 
people, safety cannot.  In the 1990s, several studies supported by NIAID and 
the CDC showed that a 2-month TBT regimen of rifampin and  
pyrazinamide (2RZ) was safe and efficacious in HIV-infected 
individuals.(Halsey 1998; Gordin 2000)  However, subsequent research funded 
by NIAID, and experience in clinical practice, demonstrated that 2RZ was not 


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safe in HIV-uninfected people, with high rates of hepatotoxicity and a number 
of deaths.(Schechter 2006; CDC 2001)  No explanation for the difference in 
safety in HIV-infected and –uninfected people has ever been found, but this 
experience underscores the importance of demonstrating safety and tolerability 
in all target populations of new regimens for TBT.  
 
While the 3HP regimen has been proved safe and effective in HIV-positive and 
–negative people, 1HP has only been shown to be safe and efficacious in HIV-
positive people.  An efficacy study in HIV-negatives would be useful for 
purposes of replication of the single study demonstrating the non-inferiority of 
1HP, but such a trial would be extremely costly and time -consuming.  The 
ACTG BRIEF TB trial took 6 years at a cost of >$30 million with its sample 
size of 3000.  It is likely that a non-inferiority efficacy trial in HIV negatives 
would require a sample size of at least 4500.   
 
In the history of TB preventive therapy, a regimen that is efficacious in one 
population has always been efficacious in others.  For 3HP, efficacy was found 
to be quite similar in HIV+ people and HIV-negative, as well as in children.  
What can differ, however, is toxicity and tolerability.  As shown with the 2-
month rifampin and pyrazinamide (2RZ) regimen, safety in people with HIV 
does not ensure safety in HIV-negative people.  Thus, a safety and adherence 
study is both necessary and preferred. 
1HP is now recommended by the WHO as a first-line regimen for treating 
latent TB infection in individuals >12 years of age. (WHO, 2020) To date, this 
regimen has only been studied in people with HIV infection.  Because no 
formal studies of HIV seronegative people have been conducted, this trial will 
provide important information on the safety of the regimen in this population.   
 
Because the 1HP regimen was developed exclusively with NIAID funding and 
sponsorship, the opportunity for the NIH to have full responsibility and credit 
for introducing a highly novel, short-course preventive therapy regimen that 
could radically transform TB control is at hand.  A trial showing that 1HP is 
safe, tolerable, and more likely to be completed than 3HP has the potential to 
fundamentally alter TB control interventions worldwide. 
 
Rationale for self-administered therapy 
 
Directly observed therapy (DOT) has been the standard of care for treatment of 
active TB in clinical trials and clinical practice for many years.  Based on 
WHO guidance that intermittent treatment using rifamycins should be done 
under DOT, the original trials of 3HP provided all treatment under supervision 
of a health care team member.  (Schechter, Martinson, Sterling) Subsequently, 
it became apparent that DOT for TPT was not economically or clinically 
feasible in most settings outside the US, and a trial comparing self-
administered with DOT 3HP was conducted by the TB Trials Consortium.  The 
i-Adhere Study compared treatment completion of 3HP in individuals 
receiving TPT either by DOT or by self-administration, with or without SMS 


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reminders.  The study was a non-inferiority trial with an NI margin of 15% for 
treatment completion.  Adherence in the self-administered arms was measured 
by electronic pill caps.  In the primary analysis, self-administered 3HP failed to 
show non-inferiority to DOT, with rates of 87.2% completion for DOT vs. 
75% (lower 95% CI 68.9%) for self-administered and 76.4% (lower 95% CI 
71.3) for self-administered with SMS reminders. In the pre-planned analysis of 
participants enrolled in the US, however, non-inferiority of self-administration 
was demonstrated.  On the basis of these results, the CDC now endorses self-
administration of 3HP as a treatment option, and the WHO guidelines likewise 
support self-administration.    The BRIEF-TB study used self-administered 
1HP and showed a high treatment completion rate (97%) and excellent 
adherence.  Based on global guidelines and the impracticality of using DOT for 
the millions of patients who require TPT, we will give both 1HP and 3HP by 
self-administration. 
 
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 2008, McKenna 2014). 
Tuberculosis disease characteristics, presentation, diagnosis, and treatment are 
similar for adults and adolescents. Rifapentine currently is approved as TPT in 
the United States for use in persons as young as 2 years old (Priftin® package 
insert 2018). Rifapentine pharmacokinetic results have been found to be 
similar between adults and adolescents down to age 12 (Marshall 1999).  
Rifapentine 900 mg once weekly, with isoniazid for 12 weeks has been used to 
treat children for 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. Daily dosing of rifapentine in children <12 has not been studied, 
however; the IMPAACT network is currently planning a trial of 1HP in 
children.  Inclusion of adolescents is, therefore, appropriate, but inclusion of 
children <12 is not.  
 
8. 
OBJECTIVES and HYPOTHESES 
 
8.1 
Primary Objectives 
To compare treatment success (completion of treatment with >90% adherence) 
of 1HP with 3HP in HIV-uninfected adults and adolescents at increased risk of 
TB. 
 
To compare the safety of 1HP with 3HP in HIV-uninfected adults and 
adolescents at increased risk of TB. 
 
 
 


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8.2 
Primary Outcomes and Hypotheses 
 
 (1) Successful completion of TBT with >90% adherence documented by self-
report, pill count, and pharmacologic monitoring. 
 
Hypothesis: Successful treatment with 1HP will be superior to 3HP, with 90% 
of individuals randomized to 1HP taking >90% of prescribed doses vs 80% of 
those on 3HP.  
 
(2) Safety of treatment regimens, defined as occurrence of Grade 2 or higher 
targeted safety events while taking study medications or within 14 days of 
stopping, or discontinuation of study medications because of side 
effects.Targeted safety events are hypersensitivity syndrome, rash, peripheral 
neuropathy, hepatotoxicity, nausea and vomiting, and drug-related fever. 
Hypothesis: We hypothesize that the safety of 1HP will be superior to 3HP, 
with a rate of targeted adverse events or medication discontinuation of 6% vs. 
13% for 3HP. 
 
8.3 Secondary Outcome and Hypothesis 
 
(1) To compare the cost-effectiveness of 1HP and 3HP using a societal 
approach, modeling the incremental cost-effectiveness of 1HP vs 3HP, 6H, 
and no treatment. 
(2) Analyze, in each of the health units in the study, the time needed to provide 
comprehensive care to patients. 
 
Hypothesis: We hypothesize that 1HP will be cost saving vs 3HP, v modelled 
costs of 6H and v no TPT. 
 
 
 
A separate protocol will be prepared for this component of the study. 
 
9. 
STUDY DESIGN 
 
This is a multicenter, randomized, controlled, open-label, phase IV clinical trial with 
two arms, comparing treatment success and safety of 1HP vs 3HP in HIV-uninfected 
adolescents and adults.   
 
9.1 
Study Groups 
 
Arm A (n=250):  Experimental arm  
Rifapentine and isoniazid once daily for 4 weeks, 28 doses 
 
Arm B (n=250): Control arm  
Rifapentine and isoniazid once weekly for 12 weeks, 12 doses 
 
9.2 
Dosing Structure 
Dosing of rifapentine and INH will be based on the dosages given to individuals >50 


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kg in the BRIEF TB trial for arm A and current CDC guidelines for arm B.  Based on 
a meta-analysis of the pharmacokinetics of rifapentine in nine clinical trials of 
preventive therapy conducted by Hibma and colleagues (Hibma, 2020), weight-
banded dosing will not be used.  This analysis demonstrated that weight-banded 
dosing results in sub-optimal exposures for lower weight patients, as drug clearance is 
not proportional to body weight. An ongoing trial of rifapentine for the treatment of 
active TB is currently underway and is using flat dosing of rifapentine at 1200 
mg/day (TBTC Study 31/ACTG A5349) and no signals of toxicity have been reported 
with this dosage in lower weight individuals.  In 2020, the WHO revised its 
guidelines for treating latent TB and recommended flat dosing of rifapentine for 
adolescents and adults, regardless of weight. (WHO) 
 
Arm A 
Rifapentine:  600 mg once daily for 4 weeks (28 doses) 
Isoniazid:  
300 mg once daily for 4 weeks (28 doses) 
 
Arm B 
Rifapentine:  900 mg once weekly for 12 weeks (12 doses) 
Isoniazid:  
900 mg once weekly for 12 weeks (12 doses) 
 
 
9.3 
Trial Period 
 
The study will take place over a five-year period.  We dedicate the first half-
year to regulatory approvals, site preparation, and training, then will initiate 
participant enrollment in the second half of year 1. Enrollment and follow up 
continues into the fourth year, followed by data analysis, abstract and 
manuscript preparation, and the study’s final report in year five. 
 
Each participant completes 24 weeks on study. 
 
9.4 
Site Descriptions 
 
 
Rio de Janeiro Municipal Health Department 
The Rio de Janeiro Municipal Health Department has an extensive network of 
primary care units that are responsible for caring for tuberculosis patients and 
their contacts.  Primary care clinics in the AP 2.1 region of Rio de Janeiro, 
adjacent to a large favela with high rates of TB, will serve as feeder clinics for 
recruitment.  The study team has extensive experience working in these clinics 
and has conducted previous clinical trials of TB interventions.  Clinical 
activities for the trial will take place at the NAPDOT clinic, located in a public 
building adjacent to the entrance to the favela.  The NAPDOT facility was 
initially established as part of the Gates Foundation-funded THRio Study and 
has served as a research site for subsequent NIH- and CDC- funded studies.  It 
is equipped for active and latent tuberculosis diagnoses, with four exam rooms, 
a patient education area, waiting room, research offices, and a secure file room 
for medical and research records.  


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Fundação de Medicina Tropical (FMT) Dr. Heitor Vieira Dourado and 
Amazonas State University 
Located in Manaus Amazonas State, is a modern research institute addressing 
the most important public health challenges for the people of the equatorial 
jungle.  Areas of expertise include malaria, dengue, Zika, TB, HIV, and 
pharmacology.  The unit collaborates with the State Health Department and 
provides specialty care for TB, HIV, severe malaria, leptospirosis, 
leishmaniasis, and other tropical infections.  The campus includes an inpatient 
unit with 250 beds (including 20 ICU beds) for adults and children with serious 
infections, outpatient clinics, and clinical laboratories with BSL-3 capability 
for M. tuberculosis¸ and biorepository facilities. 
 
10. STUDY POPULATION 
 
The study will enroll HIV-uninfected individuals who are > 15 years old, weight > 40 
kg, and are candidates to receive TB preventive therapy (i.e. LTBI with no evidence 
of active TB).  The primary target population will be household contacts of newly 
diagnosed TB patients, recruited from primary care clinics. 
 
10.1 Inclusion/Exclusion Criteria 
 
 
10.1.1 Participant Inclusion Criteria 
1) Positive tuberculin skin test or interferon-gamma release assay (IGRA) test 
and 
2) Household contact of an infectious TB case within previous 90 days, 
defined as sleeping at least once in a residence with a person diagnosed with 
pulmonary TB, or 
3) Documented conversion of TST/IGRA from negative to positive within 2 
years 
 
10.1.2  Participant Exclusion Criteria 
 
1) Documented HIV infection 
2) Evidence of active tuberculosis on clinical exam or chest x-ray 
3) Known intolerance of any study drug 
4) Treatment for active or latent TB in the past for more than 14 days 
5) Known close contact to someone with INH or rifampin resistant TB 
6) Active liver disease or AST/ALT >3 times ULN 
7) Neutropenia (ANC <1000) 


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8) Peripheral neuropathy >Grade 1 by DAIDS Grading Table 
9) Pregnant or breastfeeding. Women of childbearing potential must agree to 
use non-hormonal contraception during study treatment.    
10) Weight <40 kg  
11) At risk of poor outcome based on clinical judgment and discretion of 
investigator. 
12) Required use of a prohibited medication with a serious drug-drug 
interaction with rifamycins or isoniazid. 
 
10.2 Recruitment Process  
 
 
Rio de Janeiro 
Participants will be recruited from 3 primary health care (PHC) units located in 
Rocinha, a community located in the Municipal Planning Area 2.1 in the city 
of Rio de Janeiro.   
Key steps in the recruitment process include: 
 
• 
Health care workers from the 3 PHC units will evaluate the household 
contacts from pulmonary TB cases clinic to exclude active TB and 
evaluate/diagnosis LTBI.  
• 
The PHC unit´s teams will provide initial information about the study 
and refer those presenting a positive TST or IGRA that express interest 
in the study to the Research Clinical Centre located in one of the 3 
clinics (CF Rinaldo Delamare).  
• 
The research team will receive the potentially eligible participants and 
evaluate for inclusion/exclusion criteria.  
• 
For those eligible patients informed consent will be obtained by the 
study nurse. 
 
 
Manaus 
 
Recruitment will take place at the FMT-HVD ambulatory and hospital unit, 
where an active search of index cases and their close contacts will be carried out 
through the review of medical records and microbiological results.   
Referrals from public clinics in Manaus will also be recruited following 
procedures used in Rio de Janeiro. 
  
Key steps in the recruitment process include: 
• 
Household contacts will be evaluated at the FMT-HVD research clinic. 
• 
Samples will be taken soon after local inclusion procedures, as well as 
chest X-ray.  
• 
All follow-up will be performed at the clinical research clinic.  
• 
The research team will receive the potentially eligible participants and 
evaluate for inclusion/exclusion criteria.  
• 
For those eligible patients informed consent will be obtained by the 


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study nurse. 
 
10.3 Participant Retention 
 
Recruiters and study staff will collect detailed locator information on all 
participants. Staff will test participant mobile and landline phone numbers at 
the screening visit and confirm contact information at every study visit.  
 
Staff will teach participants when and how to notify study staff with questions 
or concerns, to report potential medication side effects and TB symptoms. Staff 
will coordinate unscheduled visits or referral to urgent care to manage signs 
and symptoms.   
 
Staff will call participants who miss a study visit, or call their nominated 
contact if the participant is not reachable, to schedule a follow-up visit. The 
team may conduct a home visit, when necessary and feasible to retain the 
participant on-study. 
 
Study staff will make reminder calls prior to study visits, notifying participants 
of the day/time of the visit, what to bring with them, and any other instructions. 
 
11. INTERVENTIONS  
 
11.1  Biomedical Interventions 
11.1.1 Regimen 
 
Treatment  
Group 
Regimen 
Dose, schedule, route, administration 
 
Duration 
ARM A 
Rifapentine: 600 mg po once daily  
Isoniazid:  300 mg po once daily  
 
All medications will be self-administered 
 
4 weeks 
(28 doses) 
ARM B 
Rifapentine: 900 mg po once weekly 
Isoniazid: 900 mg po once weekly  
 
All medications will be self-administered 
 
12 weeks 
(12 doses) 
 
11.1.2 Study Product Formulation and Preparation   
 
 Rifapentine 
  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 


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DNA-dependent RNA polymerase.  
Rifapentine is well absorbed from the gastrointestinal tract, with 70% 
bioavailability; when taken with food, its Cmax and AUC increase by 40% - 
50% (Priftin package insert 2018).  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 (Priftin, Sanofi) 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 2018).   
Recently, Sanofi has reported the presence of nitrosamine impurities in 
rifapentine lots it has manufactured.  These impurities have also been found in 
rifampin, another TB drug. Low amounts of nitrosamines are common in 
water and foods, including cured and grilled meats, dairy products and 
vegetables. Some types of nitrosamines have been shown to cause cancer in 
tested animals. Nitrosamine impurities may increase the risk of cancer if 
people are exposed to them above acceptable levels and over long periods of 
time (such as many years). The nitrosamine compound found in rifapentine is 
1-cyclopentyl-4-nitrosopiperazine (CPNP). Although there are no data 
available to directly evaluate the carcinogenic potential of CPNP, information 
available on closely related nitrosamine compounds has been used to calculate 
lifetime exposure limits for and CPNP. The US Food and Drug 
Administration (FDA) has established an exposure limit of 0.1 ppm for 


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rifapentine; daily exposures above this level for prolonged periods of times 
(decades) could potentially increase the risk of some cancers.  Short-term use 
is not considered to impose an increased risk of cancer. 
Sanofi has tested all lots of rifapentine and identified levels of CPNP ranging 
from <1 ppm to up to 12 ppm.  The company has proposed a temporary limit 
of 20 ppm of CPNP in rifapentine. To mitigate or avoid shortages and to help 
ensure patients have access to rifamycins, the FDA has agreed that 
manufacturers may temporarily distribute rifapentine containing CPNP levels 
<20 ppm until they can reduce or eliminate the impurities. The World Health 
Organization and the Global Drug Facility of the STOP TB Partnership have 
endorsed this recommendation.  Sanofi will provide rifapentine for the trial, 
and each batch of medication will be tested prior to shipment.  No batch with 
product containing >20 ppm will be used. 
Isoniazid  
Isoniazid is the hydrazide of isonicotinic acid and is one of the primary drugs 
for TB therapy.  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 
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 NAT2 gene-associated phenotypes, slow and fast acetylation, 
which are associated with race, but not sex (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 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 
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 
1985).   


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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. 
 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.   
WHO prequalified, ANVISA-approved isoniazid is available as 300 mg 
tablets and will be obtained from the Brazilian Ministry of Health. 
 
 
 
Safety profile of study regimens  
In June 1998, the US Food and Drug Administration (FDA) approved 
rifapentine (RPT) for the treatment of tuberculosis, the first new drug approved 
for tuberculosis in more than 25 years. In addition, the 3HP regimen is 
registered by the US FDA and is recommended for the prevention of TB disease 
by the US Centers for Disease Control and Prevention (CDC).  The World 
Health Organization recommends 3HP for low burden, middle and high- 
income countries in the integrated guidelines for the programmatic 
management of LTBI. Tolerance of HP regimen was comparable to INH in the 
CPCRA/ACTG trial. 
 
Isoniazid has been used in the treatment and prevention of tuberculosis for over 
50 years, and its adverse event profile is well known. Rash, fever, jaundice, and 
peripheral neuritis are the most common INH-related adverse reactions. 
Concurrent administration of pyridoxine (vitamin B6) prevents INH-related 
peripheral neuropathy as well as nearly all other nervous system disorders 
attributable to INH administration. In this study, if a participant develops 
symptoms of peripheral neuropathy, pyridoxine may be administered at a dose 
of 25 mg with each dose of INH. The dose of pyridoxine may be increased to 
50 mg with each dose of INH if symptoms of peripheral neuropathy persist. 
 
RPT, like other rifamycins, causes red-orange discoloration of body fluids. In 
trials where RPT was combined with INH and other antituberculosis drugs, 
rates of adverse reactions were similar between rifampin and RPT, with 
increased liver aminotransferase activity in about 5% of patients (Priftin 
package insert 2018).  
 
3HP.  In TBTC 26, 3HP was also well-tolerated among study participants 


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compared to 9H. A synopsis of relevant adverse events and their frequencies 
is listed in Table 2.  
 
Table 2. Drug-related adverse events in trials of RPT/INH for LTBI treatment  
 
Study  
Population 
Treatment 
completion 
Adverse Events 
Comment 
Schechter 
2006 
Household contacts in 
Brazil 
3HP 
93% 
3HP 
1% 
DOPT, Trial 
terminated early 
2RZ 
94% 
2RZ 
10% 
Martinson 
2011 
HIV+ not on ART, 
South Africa 
3HP 
96% 
3HP 
8.7/100 PY 
DOPT, Continuous 
INH more toxic  
6H 
84% 
6H 
15.4/100 PY 
Sterling 2011 
Contacts, other high-
risk, >2 yo, US, Can- 
ada, Brazil, Spain 
3HP 
82.1% 
3HP 
8.2% 
DOPT, Toxicity 
related to study drugs 
9H 
69.0% 
9H 
5.5% 
Belknap 2017 
US, S. Africa, Spain 
3HP-DOT 
87.2% 
3HP-DOT 
7.1% 
SAT=self-
administered, SAT+ 
text messages 
3HP-SAT 
74.0% 
3HP-SAT 
8.3% 
3HP-SAT+ 
76.4% 
3HP-SAT+ 
7.9% 
Swindells 
2019 
HIV+, >13 yo, multiple 
countries 
1HP 
97% 
1HP 
2.0/100 PY 
P value for AE rates 
is 0.01 
9H 
90% 
9H 
4.6/100 PY 
Observational Studies 
Chan 2019 
Contacts >12 yo 
Taiwan 
3HP 
83.9% 
3HP 
12.0% 
DOPT used for 3HP 
9H 
78.8% 
9H 
9.4% 
Jo 2019 
Health care workers, 
South Korea 
3HP 
85.0% 
3HP 
15% 
DOPT used for 3HP 
(19% flu-like 
syndrome with 3HP) 
3HR 
81.7% 
3HR 
10% 
Treatment completion rates and occurrence of adverse events in studies of 3HP and 1HP in various populations.  Adverse 
events are reported differently based on published results.  DOPT=directly observed preventive therapy; SAT=self-
administered therapy; numeral=number of months; H=INH; P=rifapentine; R=rifampin; Z=pyrazinamide. 
 
 
 
11.1.3  Study Product Supply and Accountability  
 
Rifapentine will be donated by Sanofi.  The company will provide rifapentine 
(RPT, Priftin®) in boxes containing 3 blister packs of 8 tablets each (24 
tablets of 150 mg each).  
 
Isoniazid will be obtained locally. In the Brazilian national TB program, 
isoniazid is available in 100 or 300 mg tablets.  The study will use 300 mg 
tabs.   
 
Rifapentine and isoniazid will be stored under dry and light-limited conditions 
at temperatures between 15-25° C.  
 
Quality assured pyridoxine will be obtained from a supplier in Brazil, and 
shipped to site along with the isoniazid and rifapentine.  
 
Study medication will be managed and controlled according to the Standard 
Operating Procedures for Distribution, Storage and Accountability. Study sites 
are responsible to maintain records of all study products received, dispensed, 
returned and destroyed (if unused or returned).   
 


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11.1.4  Assessment of Participant Adherence with Study 
Product(s)/Intervention(s)  
Prior to treatment initiation, each participant will receive treatment adherence 
counselling which will include information regarding the treatment, side 
effects, assistance with methods for remembering to take the medication, and 
discussion of any anticipated problems with taking medication. At each study 
visit, participants will be reminded to take all their medication.  HP will be 
taken as self-administered therapy (SAT) in both treatment arms.   
 
In both arms, the study team will use several measures to monitor treatment 
completion, including: 
• Participants will maintain a medication diary for SAT 
• Self-reported dosing at each monitoring visit 
• Pill counts. Participants will bring their unused study medication with 
them. Study staff will count the remaining pills to estimate the number of 
scheduled doses taken 
• Pharmacologic monitoring: 
 
Isoniazid urine testing.  The Isoscreen (GFC Diagnostics) point-of-care 
test, a colorimetric test based on the Arkansas method, (Guerra) will be 
used according to manufacturer-recommended methods that we have 
previously validated in Brazil. (Kendall) In the presence of isoniazid 
metabolites, this test causes urine to change color from yellow to green to 
indicate low levels detected or to blue-black to indicate high levels 
detected; urine remains yellow with no visible color change at five 
minutes if no isoniazid metabolites are detected. The sensitivity of any 
positive result has been estimated as 95-99% at 24 hours and 85% (95% 
binomial confidence interval 76-91%) at 48 hours after the last dose of 
300mg of isoniazid. The sensitivity of a strongly positive result is 
estimated to be >99% at 12 hours, 68-82% at 24 hours, and 5% at 48 
hours. Results are negative 72 hours after the last dose in 87% (78-92%) 
of patients. (Kendall)  
 
Tests will be performed by laboratory technicians at each site but not 
shared with study staff or patients, as the test is not FDA-approved and 
cannot be used for clinical management. 
 
Instructions for specimen collection and processing will be included in the 
study’s Manual of Operations.  
(http://www.gfcdiagnostics.com/isoscreenprocedures.html) 
 
Rifapentine concentrations in dried blood spots (DBS).  Rifapentine has a 
half-life of 14-16 hours and its des-acetyl metabolite has a Tmax of 24 
hours. (Dooley, 2012) At the dosages proposed for this trial, detectable 
levels of both rifapentine (RPT) and des-acetyl rifapentine (des-RPT) can 
be detected in whole blood and plasma for up to 50 hours. Investigators at 


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the Johns Hopkins Clinical Pharmacology Analytic Laboratory (CPAL) 
have validated the accuracy and robustness of DBS measurement of RPT 
and des-RPT. (Parsons) They compared plasma and whole blood-DBS 
levels from healthy volunteers and found acceptable inter-subject 
variability. The mean concentration and lower limit of quantification for 
RPT were 2644 ng/ml and 53.5 ng/ml for DBS and 2475 ng/ml and 56.6 
ng/ml for plasma. Results were reliable after 11 weeks of storage at room 
temperature without light.  
 
We will collect whole blood by venipuncture in EDTA tubes and spot 
25ul on Whatman protein saver 903 cards. After air-drying, cards will be 
stored at ambient temperature in plastic bags away from light. Batches of 
cards will be shipped to Johns Hopkins quarterly and stored at the CPAL. 
RPT and des-RPT analyses will be performed in batches. A 6 mm spot 
will be punched using a Perkin-Elmer DBS puncher and placed in a 96 
deep-well plate. An extraction solvent of 90:10 methanol-to-50 mM 
ammonium formate buffer ratio with 0.5 mg/ml ascorbic acid will be 
added and the plates will be capped and mixed on a titer plate shaker for 1 
h. Aliquots of 400 ul will be withdrawn and analyzed by LC-MS/MS, as 
previously described. (Parsons) 
 
11.1.5 Concomitant Medications and Procedures 
The site investigator will review concomitant medications at screening, the 
enrollment visit, and all clinic visits, tracking start and stop dates, and dose changes on 
the clinical evaluation source document.  Clinical research team members will track 
the list on a dedicated concomitant medication CRF.   
 
Whenever a concomitant medication or study product is initiated or the dose 
changed, investigators should review the concomitant medications’ and 
study products’ most recent package inserts to check for the most current 
information on drug interactions, contraindications, and precautions. 
 
11.1.6 Permitted Medications and Procedures 
All medications and procedures are permitted that comport with inclusion and 
exclusion criteria.   
 
11.1.7  Prohibited Medications and Procedures 
A list of prohibited medications will be included in the MOP; patients requiring 
prohibited medications will not be enrolled.  If use of prohibited drugs is required 
during treatment, study drugs will be stopped and the participant will be considered 
non-adherent thereafter. 
 
11.1.8  Precautionary Medications and Procedures 
Rifapentine is a strong inducer of metabolizing enzymes, so there is a risk of 
drug-drug interactions.  


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All concomitant medications, dosages, frequencies, and routes of 
administration will be recorded and data-entered. Site investigators will consult 
the list of prohibited and precautionary medications (Appendix IV) prior to 
starting any new medication to minimize the potential for drug-drug 
interactions. 
 
11.1.9  Required Medications 
Rifapentine and isoniazid as previously described 
 
11.1.10 Rescue Medications 
The first dose of rifapentine/isoniazid will be administered in the research 
clinic by a licensed health care professional.  The clinic will be equipped with 
standard emergency resuscitation equipment, IV fluids, medications, and 
oxygen. 
 
12.  STUDY PROCEDURES/EVALUATIONS 
 
12.1 Clinical Evaluations and Procedures 
12.1.1 Screening 
Obtain written informed consent or parental permission and assent 
before performing any screening procedures.  
 
1. Verify study entry eligibility criteria are met 
2. Record locator information for contacting participant throughout study 
 
3. Medical history 
 The medical history must include all prior TB and liver disease. In addition, it must 
include all pre-existing and new diagnoses within 30 days prior to study entry. 
Allergies to any medications and their formulations must be documented. Medical 
history and complete physical examination, including concomitant medication history 
4. Medication History 
 A medication history including all prescription and nonprescription medications taken 
within 30 days prior to study entry must be present. Include actual or estimated start 
and stop dates. 
5. Conduct a complete physical exam 
 A complete physical examination at entry is to include at a minimum an examination 
of the skin, head, mouth, and neck; auscultation of the chest; cardiac exam; abdominal 
exam; examination of the lower extremities for edema.  


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6. The complete physical exam will also include signs and symptoms, diagnoses, vital 
signs (temperature, pulse, respiration rate, and blood pressure), height, and weight 
7. TB symptom screen  
Current cough, fever, night sweats, or unintentional weight loss, lymphadenopathy 
and/or other abnormalities on lung examination.  
8. Chest X-ray (CXR) to exclude active TB disease 
9. Persons with symptoms or signs of active TB or an abnormal chest X-ray are ineligible 
to participate in the study, and should be referred for investigation by health clinic 
staff according to local guidelines. Do not proceed with enrollment. 
10. Collect blood for chemistry panel including liver function tests (LFT), complete blood 
count (CBC), hepatitis B surface antigen (HBsAg), and interferon gamma release 
assay (IGRA) or TST if a documented result is not available within 90 days of 
screening.  
11. HIV rapid test to confirm HIV negative status. 
12. For individuals of childbearing potential, collect urine for βHCG. 
Provide counseling and document the need for contraception and the risk of 
rifapentine reducing the effectiveness of oral and injectable hormonal contraception. A 
second barrier method should be used during the 24-week study of the patient's choice 
with medical advice. For those women who for some reason cannot get pregnant or 
who do not have sex, the use of contraceptives is not mandatory. 
 
Screening evaluations must occur prior to the participant’s starting study medications. 
Screening evaluations to determine eligibility must be completed within 7 days prior 
to study enrolment.  
 
 
12.1.2 HIV Counseling and Testing 
 
Counseling prior to and following HIV testing, and reporting 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.  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.  
 
 


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12.1.3     Enrollment (within 7 days of screening) 
 
1. Verify that participant continues to meet study entry eligibility criteria. 
Update locator information for contacting participant throughout study, and 
collect concomitant medication history. 
 
2. Repeat TB symptom screen (current cough, fever, night sweats, or 
unintentional weight loss). Persons with symptoms or signs suggestive of 
TB are ineligible to participate in the study, and should be referred for 
investigation by health clinic staff according to local guidelines.  
 
3. For participants of childbearing potential, collect urine for βHCG, only if a 
result is not available from within 48 hours of enrolment. 
 
4.   Randomize to a treatment arm according to the study’s randomization 
procedure. 
Once randomized and enrolled, study staff will teach participants when and 
how to take their study regimen; including what to do if a dose is late, missed, 
or vomited.  Participants will take their HP at home with a high fat diet to 
promote absorption.   
Study staff will teach examples of common, local, culturally appropriate high 
fat foods that are available within the participant’s socioeconomic status.  
Study staff will administer each participant’s first dose with a standardized 
high fat meal in clinic as an example. 
Participant will record her or his first dose in the medication diary with staff 
guidance. 
 
5. Patient costing survey 
To estimate any additional patient-level and societal costs of 1HP and 3HP 
(e.g., ancillary healthcare visits, transportation to and from the clinic, use of 
formal social support programs, and costs associated with adverse events), we 
will randomly select 50 consenting patients in each arm of the trial to 
administer a patient cost survey. This patient cost survey will ask participants 
to record total duration of clinic visits, travel time to the clinic, and all out-of-
pocket and indirect costs associated with their preventive TB treatment 
care/study participation through completion of treatment. Additional questions 
will be asked to capture information on the amount of time participants spend 
at home completing intervention-related activities (e.g. taking pills, completing 
adherence logs/diaries) and any costs associated with managing TPT-
associated adverse events. The patient costing questionnaire will be integrated 
into existing study surveys and instruments as described in the Manual of 
Operations (MOP). 


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12.1.4  Follow-up visits 
 
  
At all Visits for both treatment arms: 
 
  
Targeted Physical Exam  
 
A targeted physical examination at post-entry visits is to include vital signs 
(temperature, pulse, respiration rate, and blood pressure) and weight. It should 
be driven by any previously identified or new signs or symptoms including 
diagnoses that the participant has experienced since the last visit.  
 
  
Signs and Symptoms  
 
Record all signs and symptoms and grate according to the DAIDS grading 
 
criteria. 
 
Diagnoses  
Record all new diagnoses or worsening of a pre-existing condition, and grade 
according to the DAIDS grading criteria.   
 
Concomitant Medications  
All new concomitant medications taken since the last report and change in 
current concomitant medications since the last report should be recorded, 
including start and stop dates.  
 
 Study Treatment Modifications  
Record all study drug modifications, including initial doses, participant-
initiated and/or protocol-mandated modifications, inadvertent and deliberate 
interruptions (i.e., 3 or more missed doses) at each visit.  
Record permanent discontinuation of treatment. 
 
Patient Costing Survey 
The patient costing questionnaires will be administered to 50 patients who 
were selected at the time of enrolment to complete this survey at two time 
points, namely the completion of treatment and the end of the follow-up 
period.  
 
Arm A:  Rifapentine 600 mg daily and isoniazid 300 mg daily for 4 weeks 
(1HP) 
 
Arm A will have 250 participants. 
 
Weeks 0-4 
All daily doses of rifapentine/isoniazid (HP) will be self-administered at home 
by the participant, except for the initial dose which will be supervised by the 
study staff in clinic. Participants will record their HP dose taking and dose-
related food intake/time on a medication diary card (Appendix II). 


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The research pharmacy at each site will dispense 15 or 16 rifapentine blister 
packs, each with 8 tablets (2 doses per pack, 30-32 doses total) and 30 or 32 
300 mg INH tablets to cover the visit window period.  An extra 2-4 days of 
medication will be provided to allow for vomited doses and to reduce the 
likelihood of medication dumping.  Participants will be told to bring unused 
medication back to clinic for the 2 and 4 week visits. At enrolment, 50 
participants will be selected to complete a patient costing survey and be asked 
to complete this survey two additional times during their follow visits (at 
completion of treatment and at the end of the study participation).  
 
Week 2 (+/- 3 days) 
Day 14 
 
The participant will arrive to clinic at least an hour early, so that everything is 
in place for drug sampling events to begin on time. Check with the participant 
about yesterday’s HP dosing and to be sure that s/he did not take today’s HP 
dose. Check to be sure s/he brought today’s HP dose to clinic. 
 
Record the exact time the sample blood and urine was collected.  
At any time during the events of Day 14 (Week 2 visit) (but before today’s 
dose of HP), conduct the following assessments: 
 
- TB symptom screen 
-  targeted physical exam 
- adverse event assessment 
- adherence questionnaire 
- pill count of HP, review of medication diary card 
- CBC  
- chemistry panel including liver function tests 
- Dried blood spot and urine collection for drug sampling 
- Sampling for NAT2 gene 
- urine pregnancy test for participants of childbearing potential 
 
Week4 (+/- 3 days 
Day 28 
 
The participant will arrive to clinic at least an hour early, so that everything is 
in place for drug sampling events to begin on time. Check with the participant 
about yesterday’s HP dosing and to be sure that s/he did not take today’s HP 
dose. Check to be sure s/he brought today’s HP dose to clinic. 
 
Record the exact time the sample blood and urine was collected.  
At any time during the events of Day 28 (Week 4 visit) (but before today’s 
dose of HP), conduct the following assessments: 
- TB symptom screen 
-  targeted physical exam 


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- adverse event assessment 
- adherence questionnaire 
- patient costing survey 
- pill count of returned HP, review of medication diary card 
- CBC  
- chemistry panel including liver function tests  
- Dried blood spot and urine collection for drug sampling 
- urine pregnancy test for participants of childbearing potential 
 
If participant is assessed to be stable on HP, s/he may take today’s dose. 
 
This is the final dose for the 1HP regimen. 
 
Week 8 (+/- 3 days) 
 
Study team will conduct the following assessments: 
- TB symptom screen 
- targeted physical exam 
- adverse event assessment 
-  urine pregnancy test for participants of childbearing potential 
 
Week 12 (+/- 3 days) 
 
The study team will conduct the following assessments: 
- TB symptom screen 
- targeted physical exam 
- adverse event assessment 
-  urine pregnancy test for participants of childbearing potential 
 
Week 16 (+/- 3 days) 
 
The study team will conduct the following assessments: 
- TB symptom screen 
-  targeted physical exam 
- adverse event assessment 
-  urine pregnancy test for participants of childbearing potential 
 
Week 24 (+/- 3 days) 
 
The study team will conduct the following assessments: 
-TB symptom screen 
-  targeted physical exam 
- adverse event assessment 
- urine pregnancy test for participants of childbearing potential 
- patient costing survey  
 
This is the final study visit 


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Arm B:  Rifapentine 900 mg once-weekly and isoniazid 900 mg once-
weekly for 12 weeks (3HP) 
 
Arm B will have 250 participants. 
 
Weeks 0-4 
All once-weekly doses of rifapentine/isoniazid (HP) will be self-administered 
at home by the participant, except for the initial dose which will be supervised 
by the study staff in clinic. Participants will record their HP dose taking and 
dose-related food intake/time on a medication diary card (Appendix II).   
 
The research pharmacy at each site will dispense 4 rifapentine blister packs, 
each with 8 tablets (1.33 doses per pack, 5.33 doses total) and 12 or 15 300 
mg INH tablets to cover the visit window period.  An extra dose of medication 
will be provide to allow for vomited doses and to reduce the likelihood of 
medication dumping.  Participants will be told to bring unused medication 
back to clinic for the 2, 4, 8 and 12 week visits. 
At enrolment, 50 participants will be selected to complete the patient costing 
survey and be asked to complete this same survey two additional times during 
their follow visits (at completion of treatment and at the end of the study 
participation)  
Week 2 (+/- 3 days) 
 
The study team will conduct the following assessments: 
- TB symptom screen 
- targeted physical exam 
- adverse event assessment 
- adherence questionnaire 
- Pill count of HP, review of medication diary card 
- CBC  
- chemistry panel including liver function tests 
- Urine pregnancy test for participants of childbearing potential 
 
Week 3 (+/- 3 days for visit) 
Day 22 (24 hours after HP dose #4 was taken) 
 
The participant will arrive to clinic at least an hour early, so that everything is 
in place for drug sampling events to begin on time.  
 
Collect the blood and urine for drug sampling and record the exact time the 
sample blood and urine was collected.  
 
The study team will conduct the following assessments: 
- TB symptom screen 
- targeted physical exam 
- adverse event assessment 
- adherence questionnaire 


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- pill count of returned HP, review of medication diary card 
- CBC  
- chemistry panel including liver function tests 
- Dried blood spot and urine collection for drug sampling 
-  Sampling for NAT2 gene 
- urine pregnancy test for participants of childbearing potential 
 
Week 8 (+/- 3 days) 
Study team will conduct the following assessments: 
- TB symptom screen 
- targeted physical exam 
- adverse event assessment 
- adherence questionnaire 
- pill count of returned HP, review of medication diary card 
- CBC  
- chemistry panel including liver function tests  
- urine pregnancy test for participants of childbearing potential 
 
Week 12 (+/- 3 days for visit, but not for drug sampling) 
Day 85  (24 hours after HP dose #12 was taken) 
The participant will arrive to clinic at least an hour early, so that everything is 
in place for drug sampling events to begin on time.  
 
Collect the blood and urine for drug sampling and record the exact time the 
sample blood and urine was collected.  
 
The study team will conduct the following assessments: 
- TB symptom screen 
- targeted physical exam 
- adverse event assessment 
- adherence questionnaire 
- patient costing survey 
- pill count of returned HP, review of medication diary card 
- CBC  
- chemistry panel including liver function tests 
- Dried blood spot and urine collection for drug sampling 
- urine pregnancy test for participants of childbearing potential 
 
This is the final dose for the 3HP regimen. 
 
 
Week 16 (+/- 3 days) 
 
The study team will conduct the following assessments: 
- TB symptom screen 
- targeted physical exam 
- adverse event assessment 


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- urine pregnancy test for participants of childbearing potential 
 
Week 24 (+/- 3 days) 
 
The study team will conduct the following assessments: 
- TB symptom screen 
- targeted physical exam 
- adverse event assessment 
- urine pregnancy test for participants of childbearing potential 
- patient costing survey 
 
This is the final study visit. 
 
 
 
 
 
12.1.5 Treatment completion and successful treatment. 
 
 
 
1HP 
 Completion of therapy is defined as having completed 28 daily doses of 
treatment within 6 weeks.  Treatment success is defined as having taken at 
least 25 doses of medication confirmed by patient report and pill count, and 
having rifapentine or isoniazid detected in urine or DBS specimens. 
 
 
 
3HP 
Completion of therapy is defined as having completed at least 12 weekly doses 
of treatment within 18 weeks.  Treatment success is defined as having taken at 
least 11 doses of medication confirmed by patient report and pill count, and 
having rifapentine or isoniazid detected in urine and DBS specimens. 
 
Figure 2 shows the algorithm that will be used to classify patients as having 
treatment success of failure.  This hierarchical approach begins with self-
reported adherence, then uses pill count, and finally a composite of test results 
for isoniazid in urine and rifapentine and des-RPT in DBS. 
 
Figure 2 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.2 Laboratory Evaluations 
 
12.2.1  Specimen Preparation, Handling and Shipping 
 
Transmission of HIV and other blood borne pathogens can occur through 
contact with contaminated needles, blood, and blood products. Respiratory 
pathogens such as Mycobacterium tuberculosis (MTB) are transmitted by 
inhalation of droplet nuclei.  
 
Appropriate blood, secretion, and respiratory precautions will be employed 
by all personnel in the collection of clinical samples and the shipping and 
handling of all clinical samples and isolates for this study, as currently 
recommended by the Agência Nacional de Vigilância Sanitaria (ANVISA), 
the WHO internationally, and the National Institutes of Health. Human 
biological samples sent to the United States of America will be immediately 
destroyed after performing the test according to the flow of the health unit. 
 
All protocol specimens will be shipped using packaging that meets 
requirements specified by the International Air Transport Association (IATA) 
Dangerous Goods Regulations for UN 3373, Biological Substance, Category 
B, and Packing Instruction 650. Culture isolates, if obtained in this study, are 
to be shipped as specified for UN 2814 Category A Infectious Substances. 
 
12.2.2  Total Blood Volumes per study group 
 
Arm A:  Rifapentine 600 mg daily and isoniazid 300 mg daily for 4 weeks 
 
Laboratory 
Evaluations 
Screening 
Enroll 
Ment 
Week 
2 
Week  
4 
Week  
8 
Week 
12 
Week 
16 
Week 
24 
Hematology 
2ml EDTA 
tube 
 
2 ml 
EDTA 
tube 
2 ml 
EDTA 
tube 
 
 
 
 
Chemistry, incl 
LFTs 
2.5ml SST 
tube 
 
2.5 ml 
SST 
tube 
2.5 ml 
SST 
tube 
 
 
 
 
Hepatitis B 
Surface 
Antigen 
(HBsAg) 
3.5ml SST 
tube 
 
 
 
 
 
 
 
HIV-1 
antibody test 
Rapid test  
 
 
 
 
 
 
 
TB Diagnostics  
 
 
 
 
 
 
 
 
IGRA 
6ml lithium 
heparin 
tube 
 
 
 
 
 
 
 
Pharmacology 
(DBS) 
 
 
0.5ml 
EDTA 
tube 
0.5ml 
EDTA 
tube 
 
 
 
 


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RPT 
monitoring 
 
 
DBS 
DBS 
 
 
 
 
NAT2 gene 
 
 
If DBS 
 
 
 
 
 
TOTAL 
14 ml 
0 
5 ml 
5 ml 
0 
0 
0 
0 
24 ml 
 
 
 
 
 
 
 
 
 
 
Arm B:  Rifapentine 900 mg weekly and isoniazid 900 mg weekly for 12 weeks 
 
Laboratory 
Evaluations 
Screening 
Enrol
l 
Ment 
Week 
2 
Week 
 4 
Week  
8 
Week 
12 
Week  
16 
Week  
24 
Hematology 
2ml EDTA 
tube 
 
2ml 
EDTA 
tube 
2ml 
EDTA 
tube 
2ml 
EDTA 
tube 
2ml 
EDTA 
tube 
 
 
Chemistry, incl 
LFTs 
2.5ml SST 
tube 
 
2.5ml 
SST 
tube 
2.5ml 
SST 
tube 
2.5ml 
SST 
tube 
2.5ml 
SST 
tube 
 
 
Hepatitis B 
Surface 
Antigen 
(HBsAg) 
3.5ml SST 
tube 
 
 
 
 
 
 
 
HIV-1 
antibody test 
Rapid test  
 
 
 
 
 
 
 
TB 
Diagnostics 
 
 
 
 
 
 
 
 
 
IGRA 
6ml lithium 
heparin 
tube 
 
 
 
 
 
 
 
Pharmacology 
(DBS) 
 
 
 
0.5 
EDTA 
tube 
 
0.5 
EDTA 
tube 
 
 
RPT 
monitoring 
 
 
 
DBS 
 
DBS 
 
 
NAT2 gene 
 
 
 
 
If DBS 
 
 
 
 
TOTAL 
14 ml 
0 
4.5 ml 
5 ml 
4.5 ml 
5 ml 
0 
0 
33 ml 
 
 
 
 
 
 
 
 
 
 
12.3 Other Study Procedures and Evaluations 
 
12.3.1  Early Termination Visit 
 
Participants who meet any one or more of the following criteria will be 
discontinued from study treatment: 
• Pregnancy 


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• 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 
A participant who is discontinued from study treatment should still remain on 
study, and continue with follow up visits as described in the schedule of 
evaluations. 
A participant who withdraws consent will not continue to be followed. 
  
12.3.2 Managing a participant who becomes pregnant during the 
study 
 
A participant who becomes pregnant while receiving study therapy will be 
discontinued from study treatment and treated according to National 
Tuberculosis Program or local guidelines. The participant will continue with 
scheduled study follow-up, classified as being on a non-study regimen, and 
will not receive study radiographs.  Pregnancy outcome will be recorded on 
study forms.   
A participant who becomes pregnant while in study follow-up (not on study 
treatment) will continue with scheduled study follow-up and will not receive 
study radiographs.  Pregnancy outcome will be recorded on study forms. 
 
12.3.3 Managing 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 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.  
 
12.3.4 Managing a participant who develops clinical signs of TB 
 
  
 Clinical suspicion of TB is defined as: 
 
 
 Objective evidence of TB (cough, fever, night sweats, weight loss, or  


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 hemoptysis) based on history and/or physical examination PLUS   
 
 radiographic findings, and without concurrent illness that would  
 
 
 explain the findings.  
 
Sputum Acid Fast Bacilli Smear, Gene Xpert, and Sputum Culture X 2  
Whenever active TB is suspected, Gene Xpert, sputum AFB smear and sputum 
culture X 2 should be performed. Positive cultures should undergo speciation, 
and drug susceptibility testing if positive for MTB. A regional or central 
reference laboratory may be used.  
 
12.3.5 Managing 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 in 14 days to assess for any 
late-onset adverse events.  
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.  
 
12.3.6 Managing a participant who is incarcerated after enrollment 
 
This study will not enroll prisoners. However, it is possible that a participant 
could become incarcerated after enrollment. If an enrolled individual is 
incarcerated, then study medications will be stopped and the participant will be 
treated with TPT 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, if timing is within the 
window of all other protocol criteria. 
 
12.3.7  Post Early Termination Visit (Visit after Early Termination) 
for Participants Terminating before Completion of their Assigned 
Study Treatment 
The early termination visit should occur 14 days (+/- 3 days) after stopping 
study drugs, in order to assess for late manifesting adverse events.    
The following should be performed: 
• 
Review contact information 
• 
Symptom assessment 
• 
Adverse event assessment 


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• 
Concomitant medication assessment 
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.   
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 follow-up study 
procedures. 
 
12.3.8  Missed Visit 
A visit is classified as missed if it does not occur within the defined visit 
window of +/- 3 days from the scheduled visit.Register as unscheduled visit, 
detailed below. 
 
12.3.9  Unscheduled Visit 
An unscheduled visit refers to a protocol-required study evaluation that does 
not occur within the defined visit window.   
During an unscheduled visit, all procedures described in the protocol for the 
particular missed visit should be completed, including a study visit that occur 
solely because of an adverse event or a possible poor treatment response.  
 
12.3.10  Final Study Visit 
 
The final study visit is at week 24, for TB symptom screen, AE assessment, 
and targeted physical exam.   
 
12.3.11  Time-and-Motion (TAM) Studies 
 
To assess clinic staff and patient time and resources required for visits specific 
to 1HP and 3HP initiation and follow-up, research staff will conduct time-and-
motion (TAM) studies. TAM studies are designed to capture the amount of 
time needed to provide each unit of clinical and/or laboratory services to the 
patients. Sampling for TAM data collection will be stratified to ensure a broad 
coverage of visits by time of day, day of week, and time of year, plus inclusion 
of participants who require additional clinical evaluation (e.g., for side effects) 
so that the data represents a range of clinical operational conditions in our 
study setting. The TAM data collection requires interaction with clinic staff; 
however, only minimal clinic staff involvement (shadowing/observation of 
staff) is needed, and these studies will not involve collection of protected 


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health information (PHI). The TAM data collection will include a mix of 
directly observed (by study research staff) and self-reported data. All 
participating staff will provide informed consent. The TAM data will capture 
information on the amount of time spent conducting different TB procedures 
(e.g. assessing patient adherence) face-to-face with the patient, and other TB 
clinical tasks that are conducted without the presence of patients (e.g. 
administrative tasks such as review of medical charts). 
 
 
13. SAFETY ASSESSMENT 
 
13.1 Safety Assessment Overview 
 
Responsibilities for ensuring the safety of study participants 
 
National regulatory authorities, the sponsor, participating research institutions, 
Site Principal Investigator and clinical teams, and the study Principal 
Investigator share responsibility for ensuring that participants in this trial are 
exposed to the least possible risk of adverse events that may result from 
participation in this protocol.  
 
The site principal investigator has a personal responsibility to closely monitor 
study participants and an inherent authority to take whatever measures 
necessary to ensure their safety. The principal investigator has the authority to 
terminate, suspend or require changes to the study for safety concerns.  Site 
principal investigators determine severity and causality for each adverse event. 
 
The protocol is approved by all local, national, and Sponsor-affiliated ethics 
committees.  A referral network has been established for referring persons with 
adverse events to the hospital or local clinic.  
 
 
 
 
13.2 Adverse Event Procedures and Reporting Requirements 
 
13.2.1  Adverse Events 
 
An adverse event is any untoward medical occurrence in a patient or clinical 
investigation subject administered a study agent and which does not 
necessarily have a causal relationship with the treatment received. 
 
All Grade 2 or higher clinical or laboratory adverse events will be captured.  
 
13.2.2  Study defined AEs 


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The study will capture study-defined adverse events including hypersensitivity 
syndrome, rash, peripheral neuropathy, hepatotoxicity, nausea and vomiting, 
and drug-related fever. 
 
Participants will be trained to call the study team if they develop symptoms of 
hepatitis or rifamycin hypersensitivity syndrome, and the participant will have 
an unscheduled visit to evaluate as appropriate.  
 
13.3.3  Serious Adverse Events 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence 
that 
• results in death,  
• is life-threatening,  
• requires inpatient hospitalization or prolongation of existing 
hospitalization, 
• results in persistent or significant disability/incapacity, or 
• is a congenital anomaly/birth defect 
• Other medically important conditions. This includes important medical 
events that may not be immediately life- threatening or result in death 
or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the definition 
above.  
 
13.3.4  Adverse event (AE) reporting 
 
Adverse events will be reported according to local and national regulatory 
requirements.  
 
The purpose of AE reporting in this study is to ensure the safety of 
participants, and not to identify new AEs related to isoniazid or rifapentine. 
The 3HP regimen is approved by the US Food and Drug Administration (US 
FDA) and is recommended by WHO as TB preventive therapy. In this study, 
the use of 1HP in HIV-uninfected individuals is considered experimental. 
Investigators will monitor for adverse events in the study.  
 
13.3.5  AEs requiring expedited reporting  
 
The study will report all SAEs, including death from any cause, for any 
participant who had at least one dose of HP, as required by local and national 
regulatory agencies.  
 
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or seizure will also be reported to the Principal Investigator, and Sponsor, and 
Johns Hopkins PI and study coordinator within 72 hours (three days) of site’s 
knowledge.  
 
Reporting a pregnancy will follow similar expedited reporting within 72 hours 
(three days of site’s knowledge) to the Principal Investigator, and Sponsor, 
and Johns Hopkins PI and study coordinator. 
 
13.3.6  AE Reporting period  
 
The reporting period for AEs is from time of participant enrollment to the end 
of trial follow up for that participant. AEs occurring prior to exposure to the 
study agents in this trial do not require reporting.  
 
13.3.7  Recording updated information on SAEs 
 
Sites must follow each SAE until the SAE is resolved or stable if expected to 
remain chronic. Follow up should be according to clinical need, but not more 
than 45 days from the last visit.    
 
Extra, annotated information and/or copies of test results may be provided 
separately.  
 
13.3.8  Recurrent SAEs 
 
If an SAE fully resolves but then re-occurs, the SAE is considered to be a new 
event. 
 
13.3.9  Timeframe for SAE reporting 
 
Clinical research sites must report all events that meet the regulatory agency 
definition of a SAE within 24 hours of awareness of the event.  The event will 
be entered into the clinical database, and in addition, recorded on a SAE form 
and sent to the Johns Hopkins PI and central coordinator, and DMID via 
CROMS PVG. 
 
 SAEs will be submitted to all applicable ethical and regulatory agencies 
according to local and national requirements, or within 72 hours of the site 
becoming aware of the event.  
 
13.3.10  Site investigator assessment and signature 
 
A site physician investigator or sub-investigator must review and verify the 
completed SAE Form for accuracy and completeness and then sign the report. 
In the rare event that such physician(s) are not available for signature, sites 
may submit the SAE requiring reporting without the signature to meet 
reporting timeframe requirements. However, the completed SAE Form with 


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signature and any necessary corrections or additions must be submitted within 
72 hours.  
 
The site Principal Investigator (or designee) is responsible for designating at 
least one other physician at the site who can complete the form and provide 
signature to provide uninterrupted coverage of monitoring of SAEs. 
Procedures 
1. The site PI or designee evaluates the AE and determine whether it 
fulfils the criteria for seriousness. 
2. If the SAE criteria is met, the SAE Form should be completed and 
signed by the responsible investigator.  
3. The completed and signed SAE form should be submitted to 
regulatory authorities, and emailed to the Johns Hopkins PI and study 
coordinator.  
 
 
 
14. CLINICAL MANAGEMENT  
 
14.1 Clinical Management of Adverse Events 
 
14.1.1  Toxicity grading tables 
 
This study will grade toxicity and adverse events according to the Division of 
AIDS (DAIDS) Table for Grading Adult and Pediatric Adverse Events, 
Corrected Version 2.1 (dated July 2017). 
 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
See Appendix V. 
 
14.2 Toxicity management 
 
14.2.1  Gastrointestinal 
 
For nausea/vomiting and/or diarrhea ≥Grade 3 or for Grade 2 toxicity if 
symptoms were not present at the previous visit, all study drugs should be 
withheld until the symptoms have resolved. Reintroduce study drugs with 
caution. Antiemetic and antidiarrheal medication may be used at the site 
investigator's discretion.  Labs should be checked as clinically indicated. 
 
Every effort should be made to reintroduce the study drugs after symptoms 
improve or resolve. 
 
 
 


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14.2.2  Cutaneous 
 
For Grade 2 or Grade 3 cutaneous events that occur after the first dose of HP, 
all study drugs should be withheld until the toxicity resolves. Study drugs 
should be reintroduced with caution.  
 
Grade 4 cutaneous or mucocutaneous rash is a serious toxicity, and all study 
drugs should be permanently discontinued.  
 
Study drugs may be discontinued at the discretion of the site investigator. 
Similarly, study drugs that are temporarily interrupted may be reintroduced at 
the discretion of the site investigator.  
 
14.2.3  Rifamycin hypersensitivity syndrome (RHS)  
 
Signs and symptoms of RHS may include hypotension, urticaria, angioedema, 
acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like 
syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, 
chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, 
cough, syncope, palpitations). There have been reports of anaphylaxis  
 
This syndrome has been associated with intermittent rifampin administration, 
and was reported in a rifapentine and isoniazid regimen study (Langdon 
2004).  In Study 26, flu-like and systemic drug reactions were reported by 
3.5% of 3HP recipients compared to 0.4% of 9h recipients.  More recently, 
among healthy volunteers receiving HP and dolutegravir, 2 of 4 volunteers 
experienced rifamycins hypersensitivity syndrome fever, hypotension, 
elevated transaminases), halting the study.  (Brooks 2018)  No 
hypersensitivity reactions were found with daily HP in the BRIEF TB study.  
We will carefully monitor participants for signs and symptoms of 
hypersensitivity reactions. 
 
For participants who develop signs or symptoms of RHS: 
 
• 
Hold study drug regimen 
 
• 
Assess for RHS through clinical evaluation and laboratory testing, 
including comprehensive metabolic panel, CBC with differential, and 
other tests that are necessary to exclude likely alternative diagnoses. (e.g., 
should symptoms suggest influenza, a nasopharyngeal aspirate for viral 
testing could be sent).  
 
• 
If Grade 3 or higher AE meets the definition for RHS (and symptoms are 
not clearly attributable to an alternative diagnosis), permanently 
discontinue the study drug regimen and notify the Core Team. 
 
See Appendix III for a rifamycin hypersensitivity syndrome worksheet. 


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14.2.4  Drug-Associated Fever 
 
If ≥Grade 3, all study drugs should be held until the participant is afebrile. 
Study drugs should be reintroduced with caution. If fever reoccurs on 
reintroduction, permanently discontinue study drugs.    
 
14.2.5.  Liver Toxicity  
 
All study drugs will be stopped permanently if any of the following liver 
chemistry criteria are met: 
 
• 
ALT ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct bilirubin; 
bilirubin fractionation required) 
• 
NOTE: Serum bilirubin fractionation should be performed if 
testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury. If testing is 
unavailable and a subject meets the criterion of total bilirubin ≥2 
× ULN, then the event meets liver stopping criteria; 
• 
ALT ≥3 × ULN with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, or eosinophilia, or 
• 
ALT ≥5 × ULN; regardless of symptoms 
In the event of liver toxicity, appropriate evaluations for alternative causes may 
be pursued (viral hepatitis, alcohol exposure, etc.). 
  
14.2.6  Peripheral Neuropathy 
 
Peripheral neuropathy associated with INH is less common in HIV-uninfected 
individuals. Individuals who are at risk for developing peripheral neuropathy 
may be started on pyridoxine (vitamin B6) at the Investigator’s discretion. 
 
Participants with baseline peripheral neuropathy <Grade 2 according to the 
DAIDS Grading Table may be entered into the study, but should be monitored 
carefully for progression of the neuropathy. 
 
For Grade 1 or 2, continue the study drugs and follow the participant more 
frequently for progression of peripheral neuropathy. Consider starting or 
increasing vitamin B6 dose.  
 
For Grade 3 or 4, discontinue all study medication until toxicity resolves to 
Grade <2. If peripheral neuropathy does not resolve despite discontinuation of 
study drugs, study drugs may be reintroduced at the site investigator's 
discretion.  
 


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14.2.7  Other Toxicities 
 
For toxicities that do not fall into one of the scenarios above, management will 
be as follows: 
 
Grade 1 and 2: Participants may continue HP at the discretion of the site 
investigator with careful follow-up.  
 
Grade 3 and 4: Study drugs should be held until symptoms have resolved (or 
until ≤Grade 2 or within normal limits). Study drugs may be permanently 
discontinued at the discretion of site investigator.  
 
Site investigators are strongly encouraged to discuss discontinuations and 
reintroductions of study treatment with the core investigators to ensure 
consistency across sites. 
 
If study drugs are suspended for any reason, participants in Arm A will have 8 
weeks from enrollment to complete 28 doses of HP.  Participants in Arm B 
will have 16 weeks from enrollment to complete at least 11 doses of HP. If the 
break in treatment is longer than 4 weeks, the participant will need to be 
rescreened for TB before recommencing HP.  
 
14.3  Pregnancy 
 
Pregnancy is an exclusion criteria for enrollment. An individual who becomes 
pregnant during the study drug treatment phase will be managed according to 
the plan described in Section 12. 
 
14.4 Criteria for Discontinuation of Study Medications 
 
14.4.1  Criteria for Permanent Discontinuation  
•     Discontinuation for an Individual Participant 
•     Drug-related toxicity requiring tx discontinuation 
• 
Pregnancy or breastfeeding. HP will be discontinued and the 
participant will be referred to routine care.  
• 
Diagnosed with active TB disease 
• 
Completion of study events 
• 
Request by participant to terminate treatment 
• 
Clinical reasons believed life threatening by the physician, even if 
not addressed in the toxicity section of the protocol 
• 
Acquires HIV infection while on study 
 


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14.4.2  Premature study discontinuation 
• 
Request by the participant to withdraw 
• 
Pregnancy or breastfeeding 
• 
Request of the primary care provider if s/he thinks the study is no 
longer in the best interest of the participant 
• 
Participant judged by the investigator to be at significant risk of 
failing to comply with the provisions of the protocol as to cause 
harm to self or seriously interfere with the validity of the study 
results 
 
All participants who discontinue therapy will be followed up according to their 
assigned schedule until the end of the study. 
 
15. STATISTICAL CONSIDERATIONS 
 
15.1 Overview and General Design Issues 
 
While the 3HP regimen is proven safe and effective in HIV-positive and –
negative people, 1HP has only been shown to be safe and efficacious in HIV-
positive people.  An efficacy study in HIV-uninfected individuals would be 
useful for purposes of replication of the single study demonstrating the non-
inferiority of 1HP, but such a trial would be extremely costly and time -
consuming.  The ACTG BRIEF TB trial took 6 years at a cost of >$25 million 
with its sample size of 3000.  
 
 It is likely that a non-inferiority efficacy trial in HIV negatives would require a 
sample size of at least 4500.  In the history of TB preventive therapy, a 
regimen that is efficacious in one population has always been efficacious in 
others.  For 3HP, efficacy was found to be quite similar in HIV+ people and 
HIV-negative, as well as in children.  What can differ, however, is toxicity and 
tolerability.  As shown with the 2-month rifampin and pyrazinamide (2RZ) 
regimen, safety in people with HIV does not ensure safety in HIV-negative 
people.  Thus, a safety and adherence study is both necessary and preferred. 
 
1HP is now recommended by the WHO as an alternate first-line regimen for 
treatment of latent TB infection. The USPHS OI Task Force and the CDC have 
indicated that they will likely add language recommending 1HP for HIV 
seropositive adults and adolescents in the near future. 
 
 
 


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15.2  Study Outcomes 
 
15.2.1  Primary Outcomes 
 
(1) Successful completion of TBT with >90% adherence documented by self-
report, pill count, and pharmacologic monitoring. 
 
Definitions: 
 For 1HP, successful completion of TPT is defined as having taken at least 25 
doses of self-administered daily medication within 8 weeks of enrollment 
confirmed by patient report and pill count, and having rifapentine or isoniazid 
detected in urine and DBS specimens. 
 
 
For 3HP, successful completion of TPT is defined as having taken at least 11 
doses of self-administered weekly medication within 16 weeks as confirmed by 
patient report and pill count and having rifapentine or isoniazid detected in 
urine and DBS specimens. 
 
(2) Safety of treatment regimens, defined as occurrence of Grade 2 or higher 
targeted safety events and discontinuation of study medications because of side 
effects.  
 
Targeted safety events are hypersensitivity syndrome, rash, peripheral 
neuropathy, hepatotoxicity, nausea and vomiting, and drug-related fever. 
 
15.2.2  Secondary Outcome 
(1) To compare the cost-effectiveness of 1HP and 3HP using a societal 
approach, modeling the incremental cost-effectiveness of 1HP vs 3HP, 6H, 
and no treatment. This will operate under a separate sub-study protocol. 
(2) Analyze, in each of the health units in the study, the time needed to provide 
comprehensive care to patients. 
 
 
15.3 Study Hypotheses 
(1) Successful completion of TBT with >90% adherence documented by self-
report, pill count, and pharmacologic monitoring. 
 
Hypothesis: Successful treatment with 1HP will be superior to 3HP, with 90% 
of individuals randomized to 1HP taking >90% of prescribed doses vs 80% of 
those on 3HP.  
 
(2) Safety of treatment regimens, defined as occurrence of Grade 2 or higher 
targeted safety events and discontinuation of study medications because of side 
effects. Targeted safety events are hypersensitivity syndrome, rash, peripheral 
neuropathy, hepatotoxicity, nausea and vomiting, and drug-related fever. 
 


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Hypothesis: We hypothesize that the safety of 1HP will be superior to 3HP, 
with a rate of targeted adverse events or medication discontinuation of 6% vs. 
13% for 3HP. 
 
 
15.4 Sample Size Considerations 
 
The sample size target is 500 evaluable adolescents and adults. Having each 
participant complete all of the scheduled drug sampling evaluations will 
provide approximately 1000 rifapentine and isoniazid pharmacological data 
points.  
Assumptions, Outcome 1:  
Successful treatment with 3HP = 80%  
In clinical trials, reported completion rates of 3HP have ranged from 84-92% 
with directly observed therapy.  In the CDC-sponsored iAdhere Trial, 
completion of self-administered 3HP was only 74-76%.  In this study, which 
will use self-administered treatment, we estimate a completion rate of 80%. 
(Belknap 2017)  
Successful treatment with 1HP = 90% 
Completion of self-administered 1HP was 97% in the BRIEF TB Study, which 
was undertaken at research clinics in the ACTG and IMPAACT networks.  We 
estimate that in a more real-world setting adherence will be slightly lower, but 
should still be at least 90%. We believe that demonstrating >90% completion 
for 1HP, significantly greater than with 3HP, will provide compelling evidence 
for clinical practice and treatment guidelines to change. 
Based on these assumptions, with an average cluster (household contacts of the 
index case) size of nearly 2, and an outcome coefficient of variation (CV) of 
0.15, near the mean bound using the maximum entropy distribution (Chatfield 
2020), a sample size of 250 individuals per arm, 500 total, would provide 80% 
power for detecting a significant difference at a two-sided 0.05 significance 
level.  The sample size is not inflated for losses to follow up, as those who fail 
to complete the protocol will have reached a study endpoint. 
 
Assumptions, Outcome 2: 
Proportion of participants experiencing Grade 2 or higher targeted safety 
events with 3HP = 13%. 
In TBTC Study 26 and the iAdhere Study, rates of drug-related adverse events 
with 3HP were 7-8%. In clinical cohort studies, rates of discontinuation for 
adverse events have been higher.  An analysis of patients taking 3HP in 
Taiwan found that treatment discontinuation due to adverse events occurred in 
12%. (Chan, ERJ 2018)  A study of health care workers in South Korea 
reported that 19% of those receiving 3HP had hypersensitivity reactions and 
15% discontinued 3HP due to drug reactions. (Jo, in press)  We conservatively 
assume the rate will be 13%. 


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Proportion of participants experiencing Grade 2 or higher targeted safety 
events with 1HP = 6%. 
In the BRIEF TB trial the rate of targeted safety events was 3%. We would 
want to demonstrate a reduction from 13% to at least as low as 6% in HIV-
negative patients. With a CV of 0.1 (again, in reference to the maximum 
entropy distribution for the corresponding proportions, which are lower here 
than for the previous outcome), and the sample size of 250 individuals (about 
125 households) in each study arm, we will have about 80% power for 
detecting a significant difference at a two-sided 0.05 significance level. We 
would also have 80% power to distinguish between risks of 12% and 5% in the 
two study arms.  Although for convenience we have phrased this in terms of an 
hypothesis test, our goal is to estimate the difference in safety risks. With this 
sample size, and risks of 13% and 6% with 3HP and 1HP, respectively, the 
95% CI for the risk difference will have a half-width of 3 percentage points. 
Reporting this CI will enable readers to make their own conclusions regarding 
non-inferiority of 1HP with respect to 3HP, in addition to superiority. (Dunn 
2018) 
 
15.5 Enrollment/Stratification/Randomization 
This is a randomized trial.  Trial randomization will be computer-generated by 
the study’s central data manager at Johns Hopkins University School of 
Medicine.  Eligible patients who meet all of the inclusion criteria and none of 
the exclusion criteria will be randomized in a 1:1 ratio to the study arms. 
Contacts of the same index case will be considered a cluster and assigned to 
the same treatment arm according to the randomization of the first enrolled 
contact.  Cluster (contacts of an index patient) size is limited to 2 participants 
per index case due to the diminishing returns in terms of power per enrollee 
within a household.  
Randomization will be stratified by study site. After household contacts have 
signed informed consent forms, they will be randomized as a cluster to the 
same study arm, i.e. all receiving the same regimen. Other household members 
subsequently identified will not be eligible for the study.  
The study is unblinded for practical reasons owing to differing pill counts 
between the arms and adherence being essential to the primary outcome. 
 
15.6 Maintaining Trial Treatment Randomization Codes 
The Johns Hopkins data manager will create a randomization sequence using 
STATA.  
To prevent selection bias in the assignment to treatment the allocation 
sequence will be concealed from those assigning participants to intervention 
groups, until the moment of assignment. 
 
15.7 Participant Enrollment and Follow-up 


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See Section 12.1.3 
 
15.8 Data and Safety Monitoring 
 
A Data and Safety Monitoring Board (DSMB) will review the study protocol 
and oversee progress of the trial at least annually.  DSMB representatives will 
be determined by JHU who will manage the DSMB, but will include an 
independent statistician and at least one clinician who is experienced in the 
field of TB care.  
 
The DSMB will meet at the following time points:  Organizational Meeting, 
scheduled review meeting for interim analysis, annually, ad hoc meeting to 
address a specific safety concern, and a final meeting.      
 
15.8.1 Planned Interim Analysis and Stopping Guidelines 
 
 
 
After 25 participants in Arm A have completed 4 weeks treatment (28th HP 
dose), and 25 participants from ARM B have completed 4 weeks treatment 
(their 4th HP dose), we will conduct an interim safety and adherence 
assessment to ensure that 1HP is safe and well tolerated by HIV-negative 
participants, as compared with 3HP. 
 
 
No early stopping rules will be formally adopted for this Phase IV trial. 
 
Enrollment will not pause during the interim analysis.  However, when 
participants from 80 households have completed 16 weeks on-study, a masked 
assessment of the within-household correlation will be made to verify sample 
size assumptions.  
 
   
 
 
15.8.2  Interim Efficacy Review 
 
 
No interim analysis for efficacy is planned. 
 
 
 
15.8.3    Analysis Plan 
Analyses will be intention-to-treat for both primary outcomes of successful 
completion and safety. For the successful completion outcome, losses to follow 
up (at 4 weeks for Arm 1HP and 12 weeks for Arm 3HP) will be considered as 
unsuccessful; a sensitivity analysis will be conducted among those not lost in 
both arms as of 12 weeks. For the safety outcome as of 24 weeks, losses will 
be considered as failures (safety events).  
For the primary outcomes, if fewer than 5% of failures occur in households 
with 2 or more failures, p-values will be calculated using Fisher’s exact test, 
and 95% confidence intervals (CI) for risk differences will be calculated using 
the standard asymptotic formula. 
Otherwise, within-household correlation will be accounted for using 


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generalized estimating equations with logit link (for p-value) or identity link 
(for risk difference CI) and exchangeable correlation structure. If there are 
convergence problems, a log link function will be used, with delta-method-
constructed confidence intervals. 
Incidence of active tuberculosis will only be assessed during six months 
following enrollment but will be evaluated as an exploratory outcome. 
Incidence will be compared using Kaplan-Meier estimates at 24 weeks and 
Greenwood’s variance formula. This will be a sufficiently rare event that 
within-household correlation will be ignorable. Censoring will be at last study 
visit or death. As a sensitivity analysis, TB-free survival will also be analyzed.  
TAM studies for the Ultra Curto study are designed to capture the amount of 
time needed to provide each unit of clinical and/or laboratory services to the 
patients. Sampling for TAM data collection will be stratified to ensure a broad 
coverage of visits by time of day, day of week, and time of year, plus inclusion 
of participants who require additional clinical evaluation (e.g., for side effects) 
so that the data represents a range of clinical operational conditions in our 
study setting. The data from TAM study will be analyzed and reported as unit 
time per 1) each discrete activity specified (clinical, laboratory, and treatment 
management) in Table 1 and 2) assessed as total health care staff person-time 
required (reported by types of personnel) for one patient throughout his/her 
LTBI care cascade (from initial diagnosis and clinical evaluations to treatment 
completion, inclusive of management of side effects). These time estimates 
will include both the direct (e.g. patient’s face-to-face interaction with health 
care staff)  and indirect (e.g. administrative efforts such as chart reviews and 
data reporting) efforts relevant for programmatic component of the patient 
event schedules of the Ultra Curto trial.” 
 
 
15.8.4 Economic Analysis Plan 
 
The economic analysis plan will be submitted as a separate companion study to 
this main trial. 
 
 
 
16. DATA HANDLING AND RECORDKEEPING 
 
16.1 Data Management Responsibilities 
 
 
Data handling and record keeping will be performed by the site, under the 
supervision of the site PI in accordance with procedures that are documented in 
the site’s detailed Data Management Operations Manual.  
 
Each participant will be assigned a unique study ID number. This number will 
be recorded on each data collection form and clinical specimen. Personally 


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identifiable information including names will not be used on data collection 
forms. All study records will be stored in locked files in a secure area and 
access will be limited to study personnel and designated regulatory personnel. 
All forms will be reviewed prior to data entry for accuracy, consistency, and 
completeness by designated study staff.   
 
Statistical analysis will be done as a joint effort between JHU Investigators and 
the site PI, using JHU statisticians. 
 
16.2 Essential/Source Documents and Access to Source Data/Documents 
 
Appropriate records will be maintained for this trial, in compliance with ICH 
E6 GCP, and regulatory and institutional requirements for the protection of 
confidentiality of participants. Study records (source documents, signed 
informed consent forms, IRB/IEC correspondence and approval letters, and 
screening logs) will be kept in a secure location accessible only to authorized 
study staff. The following will have access to study records: members of the 
study team; IRBs that review the study, the Office of Human Research 
Protections, the US FDA, EMEA, the NIAID, and other local, US, and 
international regulatory entities. Authorized representatives of the Sponsor and 
regulatory agencies will be permitted to examine study records for QA 
reviews, audits, and evaluation of the study safety and progress. 
 
Secure archives are available on-site for preliminary storage after study 
closure, before moving them to an off-site, secure storage facility. Study 
records will be maintained by the investigator following study discontinuation 
in accordance with all applicable NIH and local regulatory requirements in 
Brazil. 
 
 
16.3 Quality Control and Quality Assurance 
 
Sites will submit a detailed quality management plan prior to study-start. QC 
and QA will be conducted according to site-specific SOPs.  
 
Data will be validated on entry, using range and consistency checks. Quality 
control procedures will include review of CRFs for completion and correctness 
and source data verification. The study will be monitored by internal and 
external monitors. The study site will provide direct access to all trial-related 
facilities, source documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and inspection by regulatory authorities. Following 
written procedures, study monitors will verify that the clinical trial is 
conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol and the applicable regulatory requirements. 
 
 
 


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17. CLINICAL SITE MONITORING 
 
 
Site Monitoring will be conducted to ensure that human subject protection, 
study procedures, laboratory procedures, study intervention administration, and 
data collection processes are of high quality and meet Sponsor, JHU, Health 
Department (Rio de Janeiro)/FMT(Manaus) and regulatory guidelines, and that 
the study is conducted in accordance with the protocol and site SOPs. Site 
monitoring will be performed according to details in a written monitoring plan. 
 
The study will be monitored internally at regular intervals according to site 
specific SOPs.  Westat will conduct periodic external monitoring.  
 
The following will be monitored by internal and external reviewers: 
 
100% Source Data Verification for all enrolled participants.  
For these participants, the following will be conducted:  
• 
Informed Consent Form (ICF) review for 100% of participants.  
• 
On-site source data verification (SDV) of source documents: paper 
source versus electronic Case Report Form (eCRF) 
• 
Eligibility criteria (full eligibility will be assessed for 100% of enrolled 
participants) 
• 
Review of randomization documentation and verification of correct 
treatment arm allocation 
• 
Monitoring of Investigational Product (IP) accountability and pharmacy 
documentation for all enrolled participants. 
• 
Monitoring of safety laboratory results, requisition forms and shipping 
documentation 
• 
Verifying that all biological samples have been collected and stored 
(e.g. urine, blood, and dried blood spot samples) as per protocol 
•        Sites’ pharmacies to review product storage and management 
 
 
 


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18. HUMAN SUBJECTS PROTECTIONS 
 
18.1 Institutional Review Board/Ethics Committee 
This protocol, the informed consent document (Appendix VI), and any subsequent 
modifications must be reviewed and approved by the IRB or Ethics Committee (s) (EC) 
responsible for overseeing the study.  
 
18.2 Vulnerable Participants 
 
18.2.1 Pregnant participants and fetuses 
This trial excludes pregnant participants 
 
18.2.2 Prisoners 
This trial excludes prisoners and individuals with known impending 
incarceration. 
 
18.2.3 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. 
Participants who reach age 18 will be consented on the adult ICF at their next 
visit. 
 
18.2.4 Illiterate participants 
Illiterate participants will be consented by a trained research team member in 
the presence of an independent adult third party witness who is chosen by the 
participant, and is not a member of the research team. 
 
The participant will make her or his mark or thumbprint as signature, and the 
witness will sign in the informed consent document, noting date and time of 
signature. 
 


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18.3 Informed Consent 
 
Informed written consent and assent, where applicable, using IRB-approved consent 
forms, will be obtained by trained study personnel prior to performing study-specific 
procedures.  Potential participant’s and/or their parent/guardian will receive 
information about risks and possible benefits of study participation, study objectives 
and procedures, potential toxicities, and the informed consent process.   
 
Informed consent requires the signature or mark of the participant and/or parent/ 
guardian if the participant is under age 18 years.  A copy of the signed and dated 
informed consent document will be offered to participants for their records.   
 
The rights and welfare of the subjects will be protected by emphasizing that the quality 
of the participant’s medical care will not be adversely affected if they decline to 
participate in this study, and that they may withdraw consent at any time.  If the choice 
is made not to participate in the study, the patient will be referred to local sources of 
TB care.  
 
18.3.1  Informed Consent Process 
This study will be conducted according to the ethical principles set forth in the 
Declaration of Helsinki, ICH-GCP, and local regulatory requirements as 
applicable. 
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.   
In an area of the facility that preserves confidentiality, trained study staff will 
explain the conditions of the study 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’ or 
thumbprint 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 to participate.  A 
copy of the signed informed consent document will be given to the participant 
for his/her records.   
 


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18.3.2  Assent Process 
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. 
A participant who reaches age 18 during the study will be consented on the 
adult ICF at the next study visit. 
 
 
 
 
18.3.3 Documenting Informed Consent 
 
The informed consent and assent process will be documented in a narrative 
source note as described in the MOP. 
 
Original, signed informed consent documents will be stored in an informed 
consent master binder, with a copy filed in each participant’s source document 
binder. A third copy will be given to the participant or held separately in a 
secured area for the participant. 
 
18.3.4 Stored samples 
 
 
This study does not create a biobank or contribute to an existing biobank.  
Dried blood spots for qualitative drug levels and urine specimens will be stored 
on site temporarily for batched runs in Brazil and the USA. 
 
18.4 Risks and SARS-CoV-2 Precautions 
 
 
The 3HP regimen has been approved by the US FDA and is recommended by 
WHO for TB preventive therapy. The potential benefits of taking 3HP is a 
reduced risk of developing TB disease. The 3HP regimen has been found to be 
safe in other studies. In a recent DTG-3HP PK study, 2 of 3 participants 
developed a hypersensitivity syndrome. The potential harm to participants may 
include developing drug induced adverse reaction, particularly hypersensitivity 
reactions due to RPT. 
 
1HP has demonstrated safety and tolerability during a trial in PLWH.  This is 
the first trial of 1HP in HIV un-infected individuals.  
 


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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 following measures will minimize risk to participants: individual 
participants will be closely monitored clinically, and a Data and Safety 
Monitoring Board will review trial progress at scheduled and ad hoc intervals.   
The investigational regimens could prove to have greater toxicity than the 
standard regimen.  This is unlikely given that toxicity data collected in the  
BRIEF TB/A5279 clinical trial showed that 1HP administered to PLWH at a 
once daily weight-stratified dose of rifapentine plus isoniazid for four weeks 
was well tolerated.  However, this is the first 1HP trial to include HIV- 
uninfected participants.    
Confidentiality risks will be minimized through the measures described in 
Section 18.  
 
SARS-CoV-2 Precautions 
 
As of July 2020, Brazil is experiencing widespread community transmission of 
SARS-CoV-2, the cause of COVID-19 disease.  The study team will take steps 
necessary to protect study participants and staff from the risk of becoming 
infected with SARS-CoV-2 because of participation in this protocol.  The 
study will provide personal protective equipment to the study staff, if needed. 
 
 
I. 
Opening and closing of the protocol 
a. The trial will be opened to accrual when specific permission is 
obtained from local IRBs in Rio de Janeiro and Manaus, and when 
local and national health guidelines allow clinical research to be 
undertaken. 
 
b. The study team will suspend recruitment into the trial when advised 
by local and national health authorities, or when the study team 
determines that recruitment of participants could jeopardize the 
health of study staff and participants.  Reopening of the trial would 
occur when the conditions in part I.a., above, have been met.   
 
II. 
Management of enrolled participants should a shutdown be necessary. 
a. Participants receiving study medications would be advised to 
continue treatment until complete.  Medication refills would be 
delivered to participants either at the study clinic or by mail. 
 
b. Safety monitoring would be conducted through telephone, 
WhatsApp, or other remote methods.  Safety labs would be 


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collected, if possible, either by allowing participants to visit study 
clinics or by home visits by phlebotomists.  In both circumstances 
strict infection control guidelines would be followed, including use 
of personal protective equipment by both staff and participants.  If 
safety and monitoring labs could not be carried out, participants 
could continue medication with remote monitoring only, given that 
both study regimens are WHO-approved and known to be generally 
safe. 
 
c. In the absence of SARS-CoV-2 testing it is conceivable that AEs 
that are due to COVID-19 could be wrongly attributed to study 
interventions (especially fever, nausea, and increased LFTs).  In the 
event that a study participant developed such symptoms, study staff 
would facilitate access to SARS-CoV-2 testing as part of evaluating 
the possible AE. 
 
18.5  Social Impact Events 
Individuals enrolled in this study may experience personal problems resulting 
from the study participation. Such problems are termed social impact events. 
Although study sites will make every effort to protect participant privacy and 
confidentiality, it is possible that participants' involvement in the study could 
become known to others, and that participants may experience stigmatization 
or discrimination as a result of being perceived as being HIV- infected or at risk 
for HIV infection. For example, participants could be treated unfairly, or could 
have problems being accepted by their families and/or communities. Problems 
may also occur in circumstances in which study participation is not disclosed, 
such as impact on employment related to time taken for study visits. 
In the event that a participant reports a social impact event, every effort will be 
made by study staff to provide appropriate assistance, and/or referrals to 
appropriate resources.  Social impact events are documented and reviewed on 
a scheduled basis by the protocol team leadership with the goal of reducing 
their incidence and enhancing the ability of study staff to mitigate them when 
possible. 
Social impact events that are judged by the IoR/designee to be serious, 
unexpected, or more severe or frequent than anticipated, will be reported to the 
responsible site’s EC/IRB promptly, or otherwise in accordance with the 
EC/IRB’s requirements. 
 
18.6 Benefits 
 
Both treatment regimens are offered with therapeutic warrant, meaning that it 
is reasonable to expect that these TPT treatments will be safe and tolerated.  
The study is not powered for efficacy of preventing tuberculosis.  
 


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Study participants will benefit indirectly as it is well established that outcomes 
for participants in LTBI trials are better than those for patients receiving 
routine care.  This study will benefit society by contributing to the 
understanding of optimal strategies for preventing tuberculosis.   
 
18.7 Compensation 
 
Participants in the study, regardless of treatment arm, will receive 
compensation for time and travel expenses required to attend scheduled study 
visits. Compensation will be in compliance with the local regulation. 
 
18.8 Participant Privacy and Confidentiality 
All participant-related information including case report forms, laboratory 
specimens, evaluation forms, reports, etc., will be kept strictly confidential. All 
records will be kept in a secure, double locked location and only research staff 
will have access to the records.  
Participants will be identified only by means of a coded number specific to each 
participant. All computerized databases will identify participants by numeric 
codes only, and will be password-protected. Upon request, participant records 
will be made available to the study sponsor, the sponsor’s monitoring 
representative, representatives of a participating pharmaceutical sponsor and 
applicable regulatory entities. 
 
18.9  Certificates of Confidentiality 
Certificates of Confidentiality protect the privacy interests of research 
participants and are limited to information that is sent to the U.S. The NIH 
issues Certificates of Confidentiality are part of NIH funded grant awards, such 
as this trial. 
 
 
18.10  Critical Event Reporting 
          Critical event reporting is described in Section 13. 
 
18.11  Communicable Disease Reporting 
Any findings involving a communicable disease will be reported to the 
appropriate health authorities per Brazil’s local and national requirements. 
 
18.12  New Findings 
New findings will be reported in the DSMB report, if applicable, and/or in 
subsequent reports, abstracts, and publications.  Participants will be informed 
of any new findings that could affect their willingness to join the study or 
continue participating. 
 
 
 


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18.13  Study Discontinuation 
The study may be discontinued at any time by the sponsor, investigators, 
DSMB, or by any of the relevant local, national, and international regulatory 
authorities. 
 
18.14  Post-Trial Access 
Post trial access is not applicable, because complete TPT regimens are 
provided in the study period. 
 
18.15  Community Advisory Board and Other Relevant Stakeholders 
The protocol will be reviewed and approved by the local institutions Research 
Ethics Committee (CEP) in Rio de Janeiro and Manaus and the National 
Health Research Commission (CONEP)  and the Johns Hopkins School of 
Medicine (IRB). 
 
19. ADMINISTRATIVE PROCEDURES 
 
19.1   Protocol Registration 
 
The study will be registered with the DMID Protocol Registration Office, if 
applicable.  
 
19.2   Regulatory Oversight 
The study will not operate under an IND. 
 
19.3 Study Implementation 
 
 
 
19.3.1  Investigator team  
 
 
The investigator team of collaborators will meet at least semi-monthly  
 
 
by teleconference to discuss implementation progress. The meetings  
 
 
will be chaired by the PI. 
 
 
19.3.2  Project and site implementation teams  
The core project management team will oversee project implementation. The 
team will include the PI, Project Manager, Site Investigators, Study 
Coordinator, and Data Manager. The project management team will meet every 
2 weeks by teleconference or face to face.  
 
The Site implementation team will be comprised of the site  investigators, clinic 
coordinators, and recruiters responsible for the implementation of the project at 
trial sites. The site implementation team will oversee the day-to-day 
operational aspects of the study at the trial site.   
 


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19.4 ClinicalTrials.gov 
This protocol is subject to the Food and Drug Administration Amendments 
Act of 2007 (FDAAA) and will be registered in ClinicalTrials.gov. 
 
20. PUBLICATION POLICY  
Publication of the results of this trial will occur during the project, if appropriate, or at 
the end of the project, consistent with normal scientific practices. The results of the 
study will be submitted for publication in peer-reviewed scientific journals. 
Publication will occur in accordance with International Committee of Medical Journal 
Editors and Indian Council of Medical Research guidance, among others. 
 
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22. APPENDICES 
 
I 
Schedule of events and study duration 
II 
Sample study medication & food diary 
III 
Rifapentine hypersensitivity reaction worksheet 
IV 
List of Precautionary Medications 
V 
Division of AIDS (DAIDS) Table for Grading Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (dated July 2017) 
 
 
 
 
 


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APPENDIX I 
Table 1A: Schedule of evaluations (SOE) for Arm A  
1HP 
Screening  Enrolment 
On-study period* 
Study week 
*** 
0 
2 
4 
8 
12 
16 
24 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
History 
X 
X 
 
 
 
 
 
 
Concomitant med list 
X 
X 
X 
X 
X 
X 
X 
X 
TB symptom screen 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
X 
 
 
 
 
 
 
 
Physical exam (targeted) 
 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
 
 
X 
X 
X 
X 
X 
X 
Adherence Questionnaire 
 
 
X 
X 
 
 
 
 
Pill count 
 
 
X 
X 
 
 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
X 
 
 
 
 
Chemistry, including LFTs 
X 
 
X 
X 
 
 
 
 
Hepatitis B surface antigen (HBsAg) 
X 
 
 
 
 
 
 
 
Pregnancy test 
X 
X** 
X 
X 
X 
X 
X 
X 
HIV-1 antibody test (Documented) 
X 
 
 
 
 
 
 
 
TB DIAGNOSTICS 
 
 
 
 
 
 
 
 
Chest x-ray 
X 
 
 
 
 
 
 
 
TST or Interferon gamma release assay 
(IGRA) 
X 
 
 
 
 
 
 
 
PHARMACOLOGY 
 
 
 
 
 
 
 
 
Sampling for rifapentine (dried blood 
spot) 
 
 
X 
X 
 
 
 
 
Sampling for isoniazid  (urine) 
 
 
X 
X 
 
 
 
 
Sampling for NAT2 gene 
 
 
X 
 
 
 
 
 
STUDY DRUG DOSING 
 
 
 
 
 
 
 
 
Isoniazid/rifapentine (once daily for 4 
weeks)*  
 
X 
X 
X 
 
 
 
 
COSTING EVALUATIONS 
 
 
 
 
 
 
 
 
Patient Costing Survey (50 patients) 
 
X 
 
 
 
X 
 
X 
Clinic Staff Time-and-Motion**** 
 
X 
X 
X 
X 
X 
X 
X 
*All study visits will have a visit window of +/-3 days     **for individuals of childbearing 
potential (repeat at enrollment if screening pregnancy test was more than 48 hours prior to 
enrolment)  *** Up to 7 days prior to enrolment     **** All visits are eligible, but time-and-
motion (TAM) assessments will be conducted at a randomly selected sample of study visits. 
The TAM assessment involves clinic staff, not study participants.    † Within 90 days of 
screening 
 
 
 


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Table 1B: Schedule of evaluations (SOE) for Arm B 
 
3HP 
Screening  Enrolment 
On-study period* 
Study week dose (dose 1 given at week 0)_ 
*** 
1 
2 
3 
8 
11 
16 
24 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
History 
X 
X 
 
 
 
 
 
 
Concomitant med list 
X 
X 
X 
X 
X 
X 
X 
X 
TB symptom screen 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
X 
 
 
 
 
 
 
 
Physical exam (targeted) 
 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
 
 
X 
X 
X 
X 
X 
X 
Adherence Questionnaire 
 
 
X 
X 
X 
X 
 
 
Pill count 
 
 
X 
X 
X 
X 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
X 
X 
X 
 
 
Chemistry, including LFTs 
X 
 
X 
X 
X 
X 
 
 
Hepatitis B surface antigen (HBsAg) 
X 
 
 
 
 
 
 
 
Pregnancy test 
X 
X** 
X 
X 
X 
X 
X 
X 
HIV-1 antibody test (Documented) 
X 
 
 
 
 
 
 
 
TB DIAGNOSTICS 
 
 
 
 
 
 
 
 
Chest x-ray 
X 
 
 
 
 
 
 
 
TST or Interferon gamma release assay 
(IGRA) 
X 
 
 
 
 
 
 
 
PHARMACOLOGY 
 
 
 
 
 
 
 
 
Sampling for rifapentine (dried blood 
spot) 
 
 
 
X 
 
X 
 
 
Sampling for isoniazid (urine) 
 
 
 
X 
 
X 
 
 
NAT2 gene 
 
 
 
X 
 
 
 
 
STUDY DRUG DOSING 
 
 
 
 
 
 
 
 
Isoniazid/rifapentine (once weekly for 12 
weeks)*  
 
X 
X 
X 
X 
X 
 
 
COSTING EVALUATIONS 
 
 
 
 
 
 
 
 
Patient Costing Survey (50 patients) 
 
X 
 
 
 
X 
 
X 
Clinic Staff Time-and-Motion**** 
 
X 
X 
X 
X 
X 
X 
X 
*All study visits will have a visit window of +/-3 days     **for individuals of childbearing 
potential (repeat at enrollment if screening pregnancy test was more than 48 hours prior to 
enrolment)   *** Up to 7 days prior to enrolment     **** All visits are eligible, but time-and-
motion (TAM) assessments will only be conducted at a randomly selected sample of study 
visits. The TAM assessment involves clinic staff, not study participants.    † Within 90 days of 
screening 
 
 
 


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STUDY DURATION 
 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
IRB aproval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study site preparation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trainning 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health, Economics 
and Social  Data 
Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Manuscript 
preparation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final report 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX II 
 
1HP Medication Diary 
ARM A 
 
PID ____(sticker)________                           Month___________________ 
 
ose # 
Date of 
dose 
Time of 
dose 
Food and drink taken with HP 
Initials 
example 1 Jan 
2020 
7:30 am 
Rice, beans, 1 egg, coffee with milk 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
Notes: 
 
 
 
 


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3HP Medication Diary 
ARM B 
 
PID ____(sticker)________ 
 
Dose # 
Date of 
dose 
Time of 
dose 
Food and drink taken with HP 
Initials 
example 1 Jan 
2020 
7:30 am 
Rice, beans, 1 egg, coffee with milk 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
Notes: 
 
 
 
 
 
 
 
 
 
 
Participants will need a dosing source document for their home TPT doses. 
 
Print medication diary on heavy card stock. 
Fold, staple, or tape a blank cover on top to keep the record private. 
 
Distribute the card with the first TPT dose. 
Ask/remind participants to bring the card to every visit. 
 
Have the participant fill the card during the first TPT DOT dose in clinic as practice for when s/he will 
fill the card for home doses. 
 
 
 
 
 


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APPENDIX III  
 
Hypersensitivity Symptom Checklist  
 
Date HP Given: _____/____/_____              Dose #: ________              Time: ____h_____ 
 
1.  Any symptom/ sign to be followed by a comment and reported to the Investigator on duty 
who will complete a Hypersensitivity Checklist form 
 
2.  Any event recorded on this form MUST also be recorded on the Adverse Event Log 
 
Date 
Time 
Medical event 
Tick if 
Present 
Initial and 
Comment 
 
 
Hypotension 
 
 
 
 
Urticaria (Hives) 
 
 
 
 
Angioedema  
(swelling around lips/ eyes) 
 
 
 
 
Acute bronchospasm 
 
 
 
 
Conjunctivitis (Red, itchy eyes) 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
Neutropenia 
 
 
 
 
Anaphylaxis 
 
 
 
 
Flu-like syndrome: 
 
 
 
 
          Weakness 
 
 
 
 
          Fatigue 
 
 
 
 
          Muscle Pain 
 
 
 
 
 
          Nausea 
 
 
 
 
          Vomiting 
 
 
 
 
          Headache 
 
 
 
 
          Fever/ Chills 
 
 
 
 
          Body Aches 
 
 
 
 
          Rash 
 
 
 
 
          Itching 
 
 
 
 
          Sweats 
 
 
 
 
          Dizziness 
 
 
 
 
 
          Shortness of breath 
 
 
 
 
           Chest pain 
 
 
 
 
          Cough 
 
 
 
 
          Syncope 
 
 
 
 
          Palpitations  
 
 
 
 
 
 


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APPENDIX IV 
List of Precautionary Medications 
 
Precautionary Agents with INH 
 
Carbamazepine 
Chlorzoxazone 
Disulfiram 
Ketoconazole  
 
 
Phenytoin 
Warfarin 
Theophylline 
Selective serotonin re-uptake inhibitor antidepressants (e.g. citalopram, fluoxetine, paroxetine, 
sertraline) 
 
Precautionary Agents with RPT 
Medication Class 
Precautionary Medications 
Antiarrhythmics 
Disopyramide 
Mexiletine 
Quinidine 
Tocainide 
Antibiotics 
Chloramphenicol 
Clarithromycin 
Dapsone 
Doxycycline 
Fluoroquinolones 
Anticoagulants 
Warfarin 
Anticonvulsants 
Phenytoin 
Antimalarials 
Quinine 
Antipsychotics 
Haloperidol 
Azole Antifungals 
Fluconazole 
Itraconazole 
Ketoconazole 


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Medication Class 
Precautionary Medications 
Barbiturates 
Phenobarbital 
Benzodiazepines 
Diazepam 
Beta-Blockers 
Propranolol 
Calcium Channel 
Blockers 
Diltiazem 
Nifedipine 
Verapamil 
Cardiac Glycoside 
Preparations 
Digoxin 
Corticosteroids 
Prednisone 
Fibrates 
Clofibrate 
Oral hypoglycemic 
agents 
Sulfonylureas 
Hormonal 
Contraceptives/ 
Progestins 
Ethinyl estradiol 
Levonorgestrel 
Immunosuppressants 
Cyclosporine 
Tacrolimus 
Methylxanthines 
Theophylline 
Narcotic analgesics 
Methadone 
Phosphodiesterase-5 
(PDE-5) Inhibitors 
Sildenafil 
Thyroid preparations 
Levothyroxine 
Tricyclic Antidepressants 
Amitriptyline 
Nortriptyline 
 
 
 
APPENDIX V 
DAIDS Grading Table v 2.1 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 

SAP_001.pdf: 
20February 2023 
Page 1 
 
STATISTICAL ANALYSIS PLAN 
Full Title: 
Treatment Success and Safety of 4 Weeks of Daily Rifapentine and Isoniazid (1HP) 
vs. 12 weeks of Weekly Rifapentine and Isoniazid (3HP) for Prevention of 
Tuberculosis in HIV-uninfected Individuals (1v3HP for TPT in HIV-uninfected 
individuals) 
Short Title: 
Ultra Curto TPT 
 
Clinical Trial Phase: 
Phase IV 
 
 
___________________________________________________________________________ 
ClinicalTrials.gov Identifier: NCT04703075 
 
Version 1.    20 February 2023    L. Moulton & R. Chaisson & R. Thompson 
 
__________________________________________________________________________________ 
 
 
Grant number U01A152961 TB study in Brazil (DMID 20-0020) 
 
Pharmaceutical and other Study Product Support Provided by: 
 
Sanofi (Paris, France) 
 
Study Chair and Principal Investigator:  
Richard E. Chaisson, MD 
 
Site Principal Investigators:  
Betina Durovni, MD, MPH, PhD 
Marcelo Cordeiro dos Santos, MD, MSc, PhD 
Solange Cavalcante, MD, MSc, PhD 
 
Study Biostatisticians: 
 
Lawrence Moulton, PhD 
 
Silvia Cohn, MS 
 
 
 
 
 


20February 2023 
Page 2 
 
 
1. INTRODUCTION 
 
This document contains the statistical analysis plan for the Ultra Curto TPT study. The 
goal is to avoid data-driven analyses during and at the end of the study to the extent 
possible.  Much of the content of this Statistical Analysis Plan (SAP) is taken directly from 
the Ultra Curto TPT Study Protocol, version 3.1 of 24 November 2021.   
 
2. BACKGROUND 
 
2.1.  Study Overview 
 
 
This multi-center study compares the treatment success and safety of 3 months of 
weekly rifapentine and isoniazid (3HP) to one month of daily rifapentine and 
isoniazid (1HP) in HIV-uninfected adolescents and adults.   
  
3. OBJECTIVES and HYPOTHESES 
 
3.1 Primary Objectives 
 
To compare treatment success of 1HP with 3HP in HIV-uninfected adults and 
adolescents at increased risk of TB. 
To compare the safety of 1HP with 3HP in HIV-uninfected adults and 
adolescents at increased risk of TB. 
 
3.2  Primary Outcomes and Hypotheses 
 
 (1) Treatment success of TBT with >90% adherence documented by self-
report, pill count, and pharmacologic monitoring. 
 
Hypothesis: Successful treatment with 1HP will be superior to 3HP, with 90% 
of individuals randomized to 1HP taking >90% of prescribed doses vs 80% of 
those on 3HP.  
 
(2) Safety of treatment regimens, defined as occurrence of Grade 2 or higher 
targeted safety events and discontinuation of study medications because of 
side effects. Targeted safety events are hypersensitivity syndrome, rash, 
peripheral neuropathy, hepatotoxicity, nausea and vomiting, and drug-related 
fever. 
Hypothesis: We hypothesize that the safety of 1HP will be superior to 3HP, 
with a rate of targeted adverse events or medication discontinuation of 6% vs. 
13% for 3HP. 
 
3.3  Secondary Outcome and Hypothesis 
 
(1) Incremental cost-effectiveness of 1HP and 3HP (compared to each other, 
6H, and no treatment) using a societal perspective. 


20February 2023 
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(2) Analyze, in each of the health units in the study, the time needed to provide 
comprehensive care to patients.  
 
Hypothesis: We hypothesize that 1HP will be cost saving vs 3HP, vs modelled 
costs of 6H and vs no TPT. 
 
 
 
 
3.4 Exploratory Aims 
Incidence of active tuberculosis will be assessed during the six months 
following enrollment. 
4. 
STUDY DESIGN 
 
This is a multicenter, randomized, controlled, open-label, phase IV clinical trial with 
two arms, comparing treatment success and safety of 1HP vs 3HP in HIV-uninfected 
adolescents and adults.   
 
4.1 
Study Groups 
 
TB preventive treatment:   
Arm A (n=250):  Experimental arm.  Rifapentine 600 mg daily and isoniazid 300 mg daily 
for 4 weeks. 
 
Arm B (n=250): Control arm.  Rifapentine 900 mg weekly and isoniazid 900 mg weekly for 
12 weeks. 
 
Patient Population: 
 
The study will enroll HIV-uninfected individuals who are > 15 years old, and are candidates 
to receive TB preventive therapy (i.e. LTBI with no evidence of active TB). Key exclusion 
criteria include HIV infection, abnormal liver enzymes, neutropenia, previous treatment of 
TB or latent TB infection, or a history of study drug intolerance.   
 
 
Study sites: 
 
• Health units from Rio de Janeiro Health Secretariat and NAPDOT study 
clinic, Rio de Janeiro, Brazil 
• Fundação de Medicina Tropical (FMT) Dr. Heitor Vieira Dourado;  Manaus, 
Amazonas State, Brazil 
 
 
 
Figure 1. Study Schema 


20February 2023 
Page 4 
 
 
 
                 
 
 
5. RANDOMIZATION  
The Stata randomization code was run and saved in a file by S. Cohn, 
stratified by the two sites, with randomly permuted blocks of several random 
block sizes (details not given here for reasons of masking security). Eligible 
patients who meet all of the inclusion criteria and none of the exclusion 
criteria will be randomized in a 1:1 ratio to the study arms. Contacts of the 


20February 2023 
Page 5 
 
same index case will be considered a cluster and assigned to the same 
treatment arm according to the randomization of the first enrolled contact.  
Cluster (contacts of an index patient) size is limited to 2 participants per index 
case due to the diminishing returns in terms of power per enrollee within a 
household.  
Randomization will be stratified by study site. After household contacts have 
signed informed consent forms, they will be randomized as a cluster to the 
same study arm, i.e. all receiving the same regimen. Other household members 
subsequently identified will not be eligible for the study.  
The study is unblinded for practical reasons owing to differing pill counts 
between the arms and adherence being essential to the primary outcome. 
 
 
6. SAMPLE SIZE CONSIDERATIONS 
 
The sample size target is 500 evaluable adolescents and adults. Having each 
participant complete all of the scheduled drug sampling evaluations will 
provide approximately 1000 rifapentine and isoniazid pharmacological data 
points.  
Assumptions, Outcome 1:  
Successful treatment with 3HP = 80%  
In clinical trials, reported completion rates of 3HP have ranged from 84-92% 
with directly observed therapy.  In the CDC-sponsored iAdhere Trial, 
completion of self-administered 3HP was only 74-76%.  In this study, which 
will use self-administered treatment, we estimate a completion rate of 80%. 
(Belknap 2017)  
Successful treatment with 1HP = 90% 
Completion of self-administered 1HP was 97% in the BRIEF TB Study, which 
was undertaken at research clinics in the ACTG and IMPAACT networks.  
We estimate that in a more real-world setting adherence will be slightly lower, 
but should still be at least 90%. We believe that demonstrating >90% 
completion for 1HP, significantly greater than with 3HP, will provide 
compelling evidence for clinical practice and treatment guidelines to change. 
Based on these assumptions, with an average cluster (household contacts of 
the index case) size of nearly 2, and an outcome coefficient of variation (CV) 
of 0.15, near the mean bound using the maximum entropy distribution 
(Chatfield 2020), a sample size of 250 individuals per arm, 500 total, would 
provide 80% power for detecting a significant difference at a two-sided 0.05 
significance level. The sample size is not inflated for losses to follow up, as 
those who fail to complete the protocol will have reached a study endpoint.  
 
Assumptions, Outcome 2: 
Proportion of participants experiencing Grade 2 or higher targeted safety 
events with 3HP = 13%. 
In TBTC Study 26 and the iAdhere Study, rates of drug-related adverse events 
with 3HP were 7-8%. In clinical cohort studies, rates of discontinuation for 
adverse events have been higher.  An analysis of patients taking 3HP in 


20February 2023 
Page 6 
 
Taiwan found that treatment discontinuation due to adverse events occurred in 
12%. (Chan, ERJ 2018)  A study of health care workers in South Korea 
reported that 19% of those receiving 3HP had hypersensitivity reactions and 
15% discontinued 3HP due to drug reactions. (Jo 2019)  We conservatively 
assume the rate will be 13%. 
 
Proportion of participants experiencing Grade 2 or higher targeted safety 
events with 1HP = 6%. 
In the BRIEF TB trial the rate of targeted safety events was 3%. We would 
want to demonstrate a reduction from 13% to at least as low as 6% in HIV-
negative patients. With a CV of 0.1 (again, in reference to the maximum 
entropy distribution for the corresponding proportions, which are lower here 
than for the previous outcome), and the sample size of 250 individuals (about 
125 households) in each study arm, we will have about 80% power for 
detecting a significant difference at a two-sided 0.05 significance level. We 
would also have 80% power to distinguish between risks of 12% and 5% in 
the two study arms.  Although for convenience we have phrased this in terms 
of an hypothesis test, our goal is to estimate the difference in safety risks. 
With this sample size, and risks of 13% and 6% with 3HP and 1HP, 
respectively, the 95% CI for the risk difference will have a half-width of 3 
percentage points. Reporting this CI will enable readers to make their own 
conclusions regarding non-inferiority of 1HP with respect to 3HP, in addition 
to superiority. (Dunn 2018) 
 
7. STUDY POPULATION 
 
The study will enroll HIV-uninfected individuals who are > 15 years old, weight > 
40 kg, and are candidates to receive TB preventive therapy (i.e. LTBI with no 
evidence of active TB).  The primary target population will be household contacts of 
newly diagnosed TB patients, recruited from primary care clinics. Analyses of the 
primary adherence and safety outcomes will be made using data from all enrollees 
collected through 24 weeks on study. 
 
7.1 
Inclusion/Exclusion Criteria 
 
7.1.1 Participant Inclusion Criteria 
1) Positive tuberculin skin test or interferon-gamma release assay (IGRA) test 
and 
2) Household contact of an infectious TB case within previous 90 days, 
defined as sleeping at least once in a residence with a person diagnosed with 
pulmonary TB; or 
3) Documented conversion of TST/IGRA from negative to positive within 2 
years 
 


20February 2023 
Page 7 
 
7.1.2  Participant Exclusion Criteria 
 
 1) Documented HIV infection 
2) Evidence of active tuberculosis on clinical exam or chest x-ray 
3) Known intolerance of any study drug 
4) Treatment for active or latent TB in the past for more than 14 days 
5) Known close contact to someone with INH or rifampin resistant TB 
6) Active liver disease or AST/ALT >3 times ULN 
7) Neutropenia (ANC <1000) 
8) Peripheral neuropathy >Grade 1 by DAIDS Grading Table 
9) Pregnant or breastfeeding. Women of childbearing potential must agree to 
use non-hormonal contraception during study treatment.    
10) Weight <40 kg  
11) At risk of poor outcome based on clinical judgment and discretion of 
investigator. 
12) Required use of a prohibited medication with a serious drug-drug 
interaction with rifamycins or isoniazid. 
 
 
8. ANALYSIS POPULATION 
 
Analyses will be intention-to-treat for both primary outcomes of successful 
completion and safety, slightly modified in that outcomes will begin being counted 
from the time of the initial study article dose, which will be supervised by the study 
staff in clinic.  
 
  
9. FORMAL INTERIM ANALYSIS 
No formal interim analysis for treatment success or safety is planned. 
 
 
10. STATISTICAL METHODS 
 
10.1 General Considerations 
 
Stata 16.1, R 4.0, and SAS 9.4 or later versions will be used for conducting the main study 
analyses.   
 
 
10.2 Outcome Definitions 
 


20February 2023 
Page 8 
 
10.2.1 Treatment completion and successful treatment 
 
 
 
1HP 
 Completion of therapy is defined as having completed 28 daily doses of 
treatment within 6 weeks.  Treatment success is defined as having taken at 
least 25 doses of medication confirmed by patient report and pill count, and 
having rifapentine or isoniazid detected at least once in urine or DBS 
specimens. 
 
 
 
3HP 
Completion of therapy is defined as having completed at least 12 weekly 
doses of treatment within 18 weeks.  Treatment success is defined as having 
taken at least 11 doses of medication confirmed by patient report and pill 
count, and having rifapentine or isoniazid detected at least once in urine or 
DBS specimens. 
 
Figure 2 shows the algorithm that will be used to classify patients as having 
treatment success of failure.  This hierarchical approach begins with self-
reported adherence, then uses pill count, and finally a composite of test results 
for isoniazid in urine and rifapentine and des-RPT in DBS. 
 
             Figure 2  Treatment Success 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the treatment success outcome, note that when loss to follow up precludes being able to 
demonstrate the requisite number of doses having been taken, the outcome is classified as 
“unsuccessful.” A sensitivity analysis will be conducted among those who complete their last 
scheduled visit after 23 weeks on study.  


20February 2023 
Page 9 
 
 
 
 
10.2.2 Safety: Numbers of participants with at least one occurrence of Grade 2 or higher 
targeted safety events and/or discontinuation of study medications because of side effects 
attributed to study medications. 
 
Targeted safety events are hypersensitivity syndrome, rash, peripheral neuropathy, 
hepatotoxicity, nausea and vomiting, and drug-related fever. 
 
This study will grade toxicity and adverse events according to the Division of 
AIDS (DAIDS) Table for Grading Adult and Pediatric Adverse Events, 
Corrected Version 2.1 (dated July 2017). 
 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
See Appendix V of the study protocol. 
 
For the primary safety outcome as of 24 weeks, those who do not complete their last 
scheduled visit after 23 weeks on study will be considered as failures (safety events).  
 
 
10.3 Aim-specific analyses 
 
Tests of statistical significance will not be undertaken for baseline characteristics; rather, the 
clinical importance of any imbalance will be noted. 
 
10.3.1 Treatment Success and Safety 
 
  A superiority framework will be used for these analyses, with statistical significance defined 
as p<0.05 for each of the two primary outcomes. No multiplicity correction will be employed. 
For each of the primary outcomes, if fewer than 5% of failures (unsuccessful treatment; 
specified Grade 2 event) occur in households with 2 or more failures, p-values will be 
calculated using Fisher’s exact test, and 95% confidence intervals (CI) for risk 
differences will be calculated using the standard asymptotic formula. 
Otherwise, within-household correlation will be accounted for using generalized estimating 
equations with logit link (for p-value) or identity link (for risk difference CI) and 
exchangeable correlation structure. If there are convergence problems with the risk difference 
estimation, a log link function will be used, with delta-method-constructed confidence 
intervals for risk differences. 
 
Subgroup analyses will be performed by: 
 
   Site 
   Sex 
   Age (dichotomized at overall median) 
   Weight (dichotomized at overall median) 
 
Interaction tests will assess differential effects. 


20February 2023 
Page 10 
 
 
10.3.2 Cost-Effectiveness 
The primary outcome for the cost-effectiveness analysis will be the incremental cost-
effective ratio (ICER) per disability-adjusted life-year (DALY) averted by 1HP versus 
3HP. The incremental cost-effectiveness ratio is defined as (total cost 1HP – total cost 
3HP) / (total DALYs averted 1HP – total DALYs averted 3HP). Similar ICER estimates 
will be calculated to compare incremental DALYs averted by 1HP and 3HP versus 6H 
and no treatment. Additionally, the cost per treatment completed and cost per adverse 
event averted will be calculated for 1HP and 3HP, alongside estimates of the ICER 
values for each of these secondary cost-effectiveness outcomes comparing all treatment 
strategies. 
Cost-effectiveness will be estimated using a Markov model to simulate a population of 
individuals eligible for TPT under each treatment strategy. Cost and effectiveness 
parameters (e.g. treatment costs, adherence, treatment completion) for the model will be 
taken from empiric values observed at each health unit participating in the Curto study. 
One-way and multi-way sensitivity analysis will be used to evaluate cost-effectiveness 
on specific model parameters, including but not limited to: discount rate, currency 
conversion rate, cadre of staff providing services, price of rifapentine, 1HP and 3HP 
completion rates, and 1HP and 3HP efficacy. A probabilistic sensitivity analysis using 
Monte Carlo simulation will be used to simulate the Markov model across ranges of all 
input parameters and build estimates of uncertainty around each cost and cost-
effectiveness outcome. For each iteration, the Monte Carlo simulation will sample with 
replacement from a beta distribution for all model parameters empirically observed 
across Curto health units, with the mode at the median value observed. Uncertainty will 
be presented as 95% uncertainty intervals, defined as the observed value at the 2.5th and 
97.5th percentiles for each outcome across the Monte Carlo iterations.  
Using the results of the Monte Carlo simulation, we will construct incremental cost-
effectiveness ratio planes and cost-effectiveness acceptability curves (CEACs) to 
demonstrate the probability of each strategy being cost-effective at different willingness-
to-pay (WTP) thresholds. While we will consider a range of WTP thresholds in the 
primary analysis, we will use as our primary WTP threshold the most recent objective 
data on Brazil’s country-specific WTP threshold. We will further report the probability 
of being cost-effective at WTP thresholds in $500 increments ($500, $1000, etc). The 
ICER per DALY averted comparing 1HP to 3HP will be used for the primary ICER 
plane and CEAC.  
Costs will be evaluated from the societal perspective, incorporating both costs to patients and 
to the healthcare system. Research costs will be excluded. Estimates of DALYs will be 
derived by combining literature values (TPT long-term effectiveness (Sterling, 2011), 
disability weights (Salomon, 2015)) with trial-based observations. We will use an analytic 
horizon of 5 years for tuberculosis events, with a lifetime horizon for TB-related sequelae, 
including death. The primary analysis will annuitize costs linearly using a 3% annual 
discount rate based on estimated life-years. In the analysis, costs will be presented in the 
latest year in which costs are measured during the trial, with costs collected in earlier years 
inflated using the World Bank’s gross domestic product deflator for Brazil 
(https://data.worldbank.org/indicator/NY.GDP.DEFL.KD.ZG?locations=BR). All costs will 
then be converted to United States Dollars using the median World Bank conversion rate for 
that year (https://data.worldbank.org/indicator/PA.NUS.FCRF?locations=BR). 
 


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Time needed for care 
As a part of economic data collection, time-and-motion (TAM) studies will be used to 
evaluate the time needed to provide comprehensive care for patients at each health unit. 
Sampling for TAM data collection will be stratified to ensure a broad coverage of visits 
by time of day, day of week, and time of year, plus inclusion of participants who require 
additional clinical evaluation (e.g., for side effects) so that the data represents a range of 
clinical operational conditions in our study setting. The TAM data will be analyzed and 
reported as median unit time with inter-quartile ranges (IQRs) per 1) discrete activity and 
2) total health care staff person-time required (reported by types of personnel) for one 
patient throughout his/her LTBI care cascade (from initial diagnosis and clinical 
evaluations to treatment completion, inclusive of management of side effects). These 
time estimates will include both the direct (e.g. patient’s face-to-face interaction with 
health care staff) and indirect (e.g. administrative efforts such as chart reviews and data 
reporting) efforts relevant for programmatic component of the patient event schedules of 
the Ultra Curto trial. 
 
Time estimates will be presented separately for each health unit participating in the Ultra 
Curto trial. Differences in time requirements and cadre of staff completing activities 
across sites will be noted descriptively, but no formal statistical analysis will be 
performed to evaluate differences in time requirements across sites. 
 
 
10.3.3 Tuberculosis 
Incidence of active tuberculosis will be evaluated as an exploratory outcome. Incidence 
will be compared using Kaplan-Meier estimates at 24 weeks after enrolment and 
Greenwood’s variance formula. This will be a sufficiently rare event that within-
household correlation will be ignorable. Censoring will be at earliest of last study visit or 
death. As a sensitivity analysis, TB-free survival will also be analyzed.  
 
 
 
REFERENCES 
 
Belknap R, Holland D, Feng PJ, et al., TB Trials Consortium iAdhere Study Team. Self-
administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine  Treatment 
of Latent Tuberculosis Infection: A Randomized Trial. Ann Intern Med. 2017;167:689-697. 
 
Chan PC, Lee PH, Lu MJ, Huang YC, Feng TY, Chen WW, Lee CC, Huang YF, Chiang CY. 
Tolerability of rifapentine-based regimens in latent tuberculosis infection treatment in the 
elderly. Eur Respir J. 2019 Mar 18;53(3):1802396.  
 
Chatfield MD, Farewell DM. Understanding between-cluster variation in prevalence, and 
limits for how much variation is plausible. Stat Meth Med Res. 2021;30(1):286-298. 
Dunn DT, Copas AJ, Brocklehurst P. Superiority and non-inferiority: two sides of the same 
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Kyung-Wook Jo 1, Ju Sang Kim 2, Hyouk-Soo Kwon 3, Yea Eun Park 1, Ja Young 
Kim 4, Min Jee Hong 4, Tae Sun Shim  Adverse event and treatment completion rates of a 
12-dose weekly isoniazid and rifapentine course for South Korean healthcare workers Respir 
Med 2019 Oct-Nov;158:42-48. 
 
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Sterling TR, Villarino ME, Borisov AS, et a l. Three Months of Rifapentine and Isoniazid for 
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Sun HY, Huang YW, Huang WC, Chang LY, Chan PC, Chuang YC, Ruan SY, Wang JY, 
Wang JT. Twelve-dose weekly rifapentine plus isoniazid for latent tuberculosis infection: A 
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