Clinical trial NCT01404312
Conditions: Tuberculosis HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2012-05-23; Completion date: 2017-11-14
Enrollment: 3000 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
HIV-infected people have an increased risk of developing active tuberculosis (TB). At the time the study was designed, the standard course of treatment for TB was 6 to 9 months of isoniazid (INH).This study compared the safety and effectiveness of a 4-week regimen of rifapentine (RPT) plus INH versus a standard 9-month regimen of INH in HIV-infected people who are at risk of developing active TB.

Detailed description:
The World Health Organization (WHO) estimated that in 2017 there were 10 million new cases of TB, and 1.6 million people died as a result of TB. Among new TB cases, it is estimated that 920,000 occurred in people who were HIV-coinfected, and 23% of TB deaths were among HIV-coinfected individuals. In Africa, TB is the leading AIDS-related opportunistic infection. Latent TB infection occurs when people are infected with the bacteria that cause TB, but they do not have any symptoms of TB infection. Latent TB can develop into active TB, and HIV-infected people have an increased risk of progressing from latent TB to active TB. INH is a medication that is prescribed for people with latent TB to help prevent active TB from developing. The standard INH treatment regimen is 6 to 9 months; a shorter treatment regimen of 3 months of once-weekly RPT plus INH has proven to be as effective and improved adherence. The purpose of this study was to compare the safety and effectiveness of a 4-week daily regimen of RPT plus INH to a standard 9-month daily INH regimen for TB prevention in HIV-infected individuals.

This study enrolled HIV-infected people who did not have evidence of active TB but who were at high risk of developing active TB. Participants were randomly assigned to receive RPT and INH once a day for 4 weeks or INH once a day for 9 months. All participants received pyridoxine (vitamin B6) with each dose of INH to help prevent possible side effects. Study visits occurred at baseline and Weeks 2, 4, 8, 12, 16, 20, 24, and 36. At select study visits, participants had a physical exam, clinical assessment, blood collection, and a chest radiograph or chest computed tomography (CT) scan (if needed). Some participants had their blood stored for future testing. Follow-up study visits occurred every 12 weeks starting at Week 48 and continued for 3 years after the last participant enrolled.

Arms: arm 1: Participants received RPT (dosage based on their weight), 300 mg of INH, and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 4. During Weeks 5 to 36, participants did not receive any study medications. arm 2: Participants received 300 mg of INH and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 36.
Interventions: intervention 1: Rifapentine (RPT) intervention 2: Isoniazid (INH) intervention 3: Pyridoxine (Vitamin B6)
Intervention descriptions: intervention 1: RPT dosing was be based on participants' weight:

Participants who weighed 30 kg to less than 35 kg received 300 mg once daily (administered as two 150-mg tablets).

Participants who weighed 35 kg to less than 45 kg received 450 mg once daily (administered as three 150-mg tablets).

Participants who weighed greater than 45 kg received 600 mg once daily (administered as four 150-mg tablets). intervention 2: Participants received one 300-mg tablet or three 100-mg tablets of INH once daily. intervention 3: Participants received 25 mg or 50 mg of pyridoxine, based on the current local, national, or international dosing guidelines.

Participants who received 25 mg of pyridoxine took one 25-mg tablet once daily with INH.

Participants who received 50 mg of pyridoxine took two 25-mg tablets once daily with INH.

Protocol documents:
Prot_001.pdf: 
 
 
 
 
 
A5279 
 
Phase III Clinical Trial of Ultra-Short-Course Rifapentine/Isoniazid for the 
Prevention of Active Tuberculosis in HIV-Infected Individuals with Latent 
Tuberculosis Infection 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
The National Institute of Allergy 
and Infectious Diseases 
 
 
Pharmaceutical Support Provided by: 
sanofi-aventis 
 
 
IND #: 112,339 
 
 
 
The ACTG Tuberculosis  
Transformative Science Group: 
 
Richard E. Chaisson, MD, Chair 
 
Protocol Co-Chairs: 
Richard E. Chaisson, MD  
 
Susan Swindells, MBBS 
 
 
Protocol Vice Chair:  
 
 
 
Amita Gupta, MD, MHS 
 
 
DAIDS Clinical Representative: 
 
 
Daniel H. Johnson, MD 
 
Clinical Trials Specialist: 
Laura E. Moran, MPH 
 
 
 
 
 
 
FINAL Version 2.0 
August 28, 2014 


A5279 
 
 
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CONTENTS 
 
 
Page 
 
SITES PARTICIPATING IN THE STUDY .................................................................................... 4 
PROTOCOL TEAM ROSTER ..................................................................................................... 5 
STUDY MANAGEMENT ............................................................................................................. 9 
GLOSSARY OF TERMS ........................................................................................................... 11 
SCHEMA .................................................................................................................................. 13 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 15 
1.1 
Hypothesis ......................................................................................................... 15 
1.2 
Primary Objective ............................................................................................... 15 
1.3 
Secondary Objectives ........................................................................................ 15 
1.4 
Supportive/Exploratory Objectives ..................................................................... 15 
2.0 
INTRODUCTION ........................................................................................................... 16 
2.1 
Background ........................................................................................................ 16 
2.2 
Rationale ........................................................................................................... 23 
3.0 
STUDY DESIGN ........................................................................................................... 29 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 30 
4.1 
Inclusion Criteria ................................................................................................ 30 
4.2 
Exclusion Criteria ............................................................................................... 32 
4.3 
Study Enrollment Procedures............................................................................. 33 
4.4 
Coenrollment Guidelines .................................................................................... 34 
5.0 
STUDY TREATMENT ................................................................................................... 34 
5.1 
Regimens, Administration, and Duration ............................................................ 35 
5.2 
Study Product Formulation and Preparation ....................................................... 36 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 36 
5.4 
Concomitant Medications ................................................................................... 37 
5.5 
Adherence Assessment ..................................................................................... 38 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 39 
6.1 
Schedule of Events ............................................................................................ 39 
6.2 
Timing of Evaluations ......................................................................................... 42 
6.3 
Instructions for Evaluations ................................................................................ 43 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 47 
7.1 
Toxicity .............................................................................................................. 48 
7.2 
Pregnancy.......................................................................................................... 49 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 49 
8.1 
Permanent Treatment Discontinuation ............................................................... 49 
8.2 
Premature Study Discontinuation ....................................................................... 49 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 50 
9.1 
General Design Issues ....................................................................................... 50 


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CONTENTS (Cont’d) 
Page 
 
9.2 
Endpoints ........................................................................................................... 50 
9.3 
Randomization and Stratification ........................................................................ 51 
9.4 
Sample Size and Accrual ................................................................................... 51 
9.5 
Monitoring .......................................................................................................... 53 
9.6 
Analyses ............................................................................................................ 54 
9.7 
Cost-Effectiveness Analysis ............................................................................... 56 
10.0 
PHARMACOLOGY PLAN .............................................................................................. 56 
10.1 
Pharmacology Objectives .................................................................................. 56 
10.2 
Pharmacology Study Design .............................................................................. 57 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis .............................. 61 
10.4 
Anticipated Outcomes ........................................................................................ 65 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 65 
11.1 
Records to Be Kept ............................................................................................ 65 
11.2 
Role of Data Management ................................................................................. 65 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 66 
11.4 
Expedited Adverse Event (EAE) Reporting ........................................................ 66 
12.0 
HUMAN PARTICIPANTS .............................................................................................. 67 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 67 
12.2 
Participant Confidentiality ................................................................................... 67 
12.3 
Study Discontinuation ........................................................................................ 67 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 68 
14.0 
BIOHAZARD CONTAINMENT ...................................................................................... 68 
15.0 
REFERENCES .............................................................................................................. 69 
 
APPENDIX I:   
SAMPLE INFORMED CONSENT 
 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
A5279 is a multicenter study open to all US and non-US ACTG clinical research sites (CRSs). 
 
 
 
 
 


 
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PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Richard E. Chaisson, MD  
Division of Infectious Diseases  
Johns Hopkins University 
1503 E. Jefferson Street  
Baltimore, MD 21231  
Phone: (410) 955-1755  
FAX: (410) 955-0740  
E-mail: rchaiss@jhmi.edu  
 
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  
E-mail: sswindells@unmc.edu  
 
Vice Chair 
Amita Gupta, MD, MHS  
Division of Infectious Diseases  
Johns Hopkins University 
Jefferson Street Building, Room 2-121B 
600 North Wolfe Street  
Baltimore, MD 21287  
Phone: (410) 502-7696  
FAX: (443) 287-6440  
E-mail: agupta25@jhmi.edu  
 
DAIDS Clinical Representative  
Daniel H. Johnson, MD 
TCRB/TRP/DAIDS/NIAID/NIH  
5601 Fishers Lane 
Room 9E39, MSC 9830 
Rockville MD 20852 
Phone: 240-627-3066 
E-mail: daniel.johnson@nih.gov 
 
Clinical Trials Specialist 
Laura E. Moran, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: (301) 628-3373 
FAX: (301) 628-3302 
E-mail: lmoran@s-3.com 
 
Statisticians 
Janet Andersen, ScD  
Statistical & Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 621 
651 Huntington Avenue  
Boston, MA 02115-6017  
Phone: (617) 432-2814  
FAX: (617) 432-2843  
E-mail: andersen@sdac.harvard.edu  
 
Yajing Bao, MS   
Statistical and Data Analysis Center 
Harvard School of Public Health  
FXB Building, Room 601  
651 Huntington Avenue 
Boston, MA 02115-6017  
Phone: (617) 432-1115  
FAX: (617) 432-2843  
E-mail: ybao@sdac.harvard.edu 
 
Site Support Specialist 
Christina Blanchard-Horan, PhD, MA, 
CCRP 
ACTG Network Coordinating Center 
Social & Scientific Systems Inc. 
8757 Georgia Avenue, 12th floor  
Silver Spring, MD 20910  
Phone: (301) 628-3339 
FAX: (301) 628-3302  
E-mail: cblanchardhoran@s-3.com 
 
 


 
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Data Manager 
Ann Walawander, MA  
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road  
Amherst, NY 14226-1056  
Phone: (716) 834-0900 x7290  
FAX: (716) 834-8432  
E-mail: walawander.ann@fstrf.org 
 
DAIDS Pharmacist 
Katherine Shin, PharmD 
Pharmaceutical Affairs Branch  
DAIDS/NIAID/NIH 
Pharmaceutical Affairs Branch 
5601 Fishers Lane. 
Room 9D30A 
Rockville MD 20852 
Phone: 240-627-3047 
FAX: 301-402-1506 
E-mail: kashin@niaid.nih.gov 
 
Pharmacologists 
Courtney V. Fletcher, PharmD  
University of Nebraska Medical Center 
College of Pharmacy 
986000 Nebraska Medical Center  
Omaha, NE 68198-6000  
Phone: (402) 559-4333  
FAX: (402) 449-5060  
E-mail: cfletcher@unmc.edu 
 
Anthony T. Podany, PharmD 
University of Nebraska Medical Center 
College of Pharmacy 
986045 Nebraska Medical Center 
Omaha, NE 68198-1945 
Phone: (402) 559-1346 
E-mail: apodany@unmc.edu 
 
 
 
 
 
 
 
 
 
Investigators 
Constance A. Benson, MD  
University of California, San Diego 
Antiviral Research Center 
220 Dickinson Street, Suite A #8208 
San Diego, CA 92103-8208 
Phone: (619) 543-8080  
FAX: (619) 543-5066  
E-mail: cbenson@ucsd.edu 
 
David P. Holland, MD 
Division of Infectious Diseases  
Duke University Medical Center 
Box 102359 
Durham, NC 27710 
Phone: (919) 613-5160 
FAX: (919) 684-8902 
E-mail: david.p.holland@duke.edu 
 
Marc Antoine Jean Juste, MD 
GHESKIO Centers 
33, Boulevard Harry Truman 
Port-au-Prince 
HAITI 
Phone: (509) 3408-4091 
E-mail: mjeanjuste@gheskio.org 
 
Eric Nuermberger, MD 
Division of Infectious Diseases  
Johns Hopkins University  
Center for TB Research 
1550 Orleans St., Room 107 
Baltimore, MD 21231 
Phone: (410) 502-0580 
FAX: (410) 614-8173 
E-mail: enuermb@jhmi.edu 
 
Sandy Pillay, MB ChB  
Nelson R. Mandela School of Medicine 
University of KwaZulu-Natal 
302 DDMRI Building 
719 Umbilo Road  
Durban , 4001  
SOUTH AFRICA 
Phone: 27 31 260 4668  
FAX: 27 82 602 3872  
E-mail: pillay@ukzn.ac.za  


 
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Investigators (Cont'd) 
Ian M. Sanne, MD, FCP, DTM&H  
Wits Health Consortium 
Clinical HIV Research Unit 
Helen Joseph Hospital 
Themba Lethu Clinic 
Perth Road Westdene  
Johannesburg, 2193  
SOUTH AFRICA  
Phone: 27 11 276 8801 
FAX: 27 11 482 2130  
E-mail: isanne@witshealth.co.za  
 
Field Representative 
Janet Nicotera, RN, BSN 
Vanderbilt University Medical Center 
Institute for Global Health 
2525 West End Ave, Suite 750 
Nashville, TN 37203-1738 
Phone: (615) 343-6556 
FAX: (615) 343-7797 
E-mail: janet.nicotera@vanderbilt.edu 
 
Laboratory Technologist 
David L. Shugarts, MA 
University of Colorado Denver  
Mail Stop B-168, Room P15-11006 
12700 E. 19th Avenue 
Aurora, CO  80045 
Phone: (303) 724-2981 
FAX: (303) 724-4926 
E-mail: David.Shugarts@ucdenver.edu 
 
CSS Representative 
Amina M. Shali  
Moi University International 
Clinical Trials Unit  
P.O. Box 2066  
Eldoret, 30100  
KENYA 
Phone: 011 254 720 858 553 
E-Mail: aminashali@yahoo.co.uk
Laboratory Data Coordinator 
Jimi Tutko, BS 
Frontier Science & Technology Research 
Foundation, Inc.  
4033 Maple Road  
Amherst, NY 14226 
Phone: (716) 834-0900 x7382 
FAX: (716) 833-0655 
E-mail: tutko@fstrf.org 
 
Industry Representative 
Marilyn Maroni, MD 
sanofi-aventis 
9, rue du Président ALLENDE 
94256 Gentilly Cedex 
FRANCE 
Phone: 33 (0) 1 41 24 59 48 or 33 (0) 6.86 
38 86 06  
E-mail: marilyn.maroni@sanofi.com 
 
Site Investigators 
Site 11301: 
Jorge L. Sanchez, MD, MPH 
E-mail: jsanchez@impactaperu.org 
 
Site 11302: 
Javier R. Lama, MD, MPH  
E-mail: jrlama@impactaperu.org 
 
Site 12001: 
Mitch Matoga, MBBS 
E-mail: mmatoga@unclilongwe.org.mw 
 
Site 12101: 
Guilherme do Amaral Calvet, MD, MSc 
E-mail: guilherme.calvet@ipec.fiocruz.br 
 
Site 12301: 
Lerato Mohapi, MD 
E-mail: mohapil@phru.co.za 
 
Site 12601: 
Ronald Kibet Tonui, MB ChB  
E-mail: rktonui@mu.ac.ke  
 


 
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Site Investigators (Cont’d) 
Site 12701: 
Taolo Modise, GNM 
E-mail: tmodise@bhp.org.bw 
 
Site 12801:  
Margaret Kasaro, MB ChB 
E-mail: Error! Hyperlink reference not 
valid. 
 
Site 31422: 
Kogieleum Naidoo, MB ChB 
E-mail: naidook45@ukzn.ac.za 
 
Site 31441: 
Deelip Kadam, MD  
E-mail: dileep.kadam@gmail.com 
 
Site 31470: 
William Burman, MD 
E-mail: bburman@dhha.org 
 


 
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STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.coreA5279@fstrf.org via e-mail. 
The appropriate team member will respond with a "cc" to the team. A response should generally 
be received within 24 hours (Monday-Friday). 
 
Protocol e-mail Group  
Sites planning to register to this study must contact the Computer Support Group at the Data 
Management Center (DMC) to have the relevant personnel at the site added to the 
actg.protA5279 e-mail group. Include the protocol number in the email subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org  
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the protocol Co-Chairs/Vice Chair. Send an e-mail message to 
actg.coreA5279@fstrf.org (ATTN: Richard Chaisson, MD; Susan Swindells, MBBS; Amita 
Gupta, MD, MHS). Include the protocol number, patient identification number (PID), and a brief 
relevant history. 
 
Laboratory 
For questions specifically related to pharmacologic laboratory tests, contact the protocol 
Pharmacologist. Send an e-mail message to actg.coreA5279@fstrf.org (ATTN: Courtney 
Fletcher, PharmD, Anthony Podany, PharmD). 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRFs), 
the CRF schedule of events, randomization/registration, delinquencies, and other data 
management issues, contact the Data Manager.  
• 
For transfers, reference the Patient Transfer from Site to Site SOP 119, and contact Ann 
Walawander, MA directly.  
• 
For other questions, send an e-mail message to actg.coreA5279@fstrf.org (ATTN: Ann 
Walawander, MA).   
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration 
For randomization/participant registration questions or problems and study identification number 
(SID) lists.  
• 
Send an e-mail message to rando.support@fstrf.org  
• 
or call the Statistical and Data Analysis Center (SDAC)/DMC Randomization Desk at (716) 
898-7301.    
 
Computer and Screen Problems  
Contact the SDAC/DMC programmers: 
• 
Send an e-mail message to actg.support@fstrf.org   
• 
or call (716) 834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist. Send an 
e-mail message to actg.coreA5279@fstrf.org (ATTN: Laura Moran, MPH). 


 
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Copies of the Protocol 
To request hard copies of the protocol, send a message to ACTGNCC@s-3.com (ATTN: Diane 
Delgado) via e-mail. Electronic copies can be downloaded from the ACTG Web site 
(https://www.actgnetwork.org). 
 
Product Package Inserts 
To request copies of product package inserts, contact the DAIDS Regulatory Support Center 
(RSC): 
• 
Send an e-mail message to RIC@tech-res.com  
• 
or call (301) 897-1708. 
 
Protocol Registration 
For protocol registration questions: 
• 
Send an e-mail message to Protocol@tech-res.com  
• 
or call (301) 897-1707.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, 
contact Katherine Shin, PharmD, Protocol Pharmacist:  
• 
Send an e-mail message to kashin@niaid.nih.gov 
• 
or call (301) 594-1517.  
 
IND (Investigational New Drug) Number or Questions  
For any questions about the IND, contact the DAIDS RSC:  
• 
Send an e-mail message to Regulatory@tech-res.com  
• 
or call (301) 897-1706. 
 
Study Product Orders 
Call the Clinical Research Products Management Center at (301) 294-0741. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
To report an EAE or for questions related to EAE reporting, contact DAIDS through the RSC 
Safety Office:  
• 
Send an e-mail message to DAIDSRSCSafetyOffice@tech-res.com  
• 
or call 1-800-537-9979 or 301-897-1709 or fax 1-800-275-7619 or 301-897-1710.  
 
Phone Calls 
Sites are responsible for documenting any phone calls made to protocol team members. Send 
an e-mail to actg.coreA5279@fstrf.org 
 
Protocol-Specific Web Page 
Additional information about the study may be found on the A5279 protocol-specific web page 
(PSWP).


 
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GLOSSARY OF TERMS 
 
AE 
 
Adverse Event 
ALT 
 
Alanine Aminotransferase 
ANC 
 
Absolute Neutrophil Count 
ART 
 
Antiretroviral Therapy 
AST 
 
Aspartate Aminotransferase 
ATS 
 
American Thoracic Society  
AUC 
 
Area under the Concentration-Time Curve 
BCG 
 
Bacille Calmette-Guerin (TB vaccine) 
CDC   
Centers for Disease Control and Prevention 
CFU 
 
Colony-forming Units 
CI 
 
Confidence Interval 
COD  
Cause of Death 
CLIA  
Clinical Laboratory Improvement Amendments 
CMV  
Cytomegalovirus 
CRF 
 
Case Report Form 
CRPMC  
Clinical Research Products Management Center  
CRS 
 
Clinical Research Site 
CSS 
 
Community Scientific Subcommittee 
DAERS 
DAIDS Adverse Event Reporting System 
DAIDS  
Division of AIDS 
DMC  
Data Management Center 
DOT 
 
Directly Observed Therapy 
DSMB  
Data and Safety Monitoring Board 
EAE 
 
Expedited Adverse Event 
EC 
 
Ethics Committee 
E/CIA  
Enzyme or chemiluminescence 
EMB 
 
Ethambutol 
EFV 
 
Efavirenz 
FDA 
 
Food and Drug Administration 
HBM  
Human Biological Materials  
IATA  
International Air Transport Association 
ICF 
 
Informed Consent Form 
ICH  
 
International Conference on Harmonisation 
IDSA  
Infectious Diseases Society of America 
IGRA  
Interferon Gamma Release Assay 
IND 
 
Investigational New Drug 
INH 
 
Isoniazid 
IPT 
 
INH Preventive Therapy 
IRB 
 
Institutional Review Board 
ITT 
 
Intention-to-Treat 
LTBI 
 
Latent Tuberculosis Infection 
LFU 
 
Loss to Follow-Up 
MAC  
Mycobacterium Avium Complex 
MDR TB 
Multi-Drug-Resistant Tuberculosis 
MTB 
 
Mycobacterium tuberculosis 
NIAID  
National Institute of Allergy and Infectious Diseases 


 
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NNRTI  
Non-Nucleoside Reverse Transcriptase Inhibitor 
NRTI  
Nucleoside Reverse Transcriptase Inhibitor 
NVP 
 
Nevirapine 
NWCS  
New Work Concept Sheet 
OHRP  
Office for Human Research Protections 
PBMC  
Peripheral Blood Mononuclear Cell 
PD  
 
Pharmacodynamic 
PI 
 
Protease Inhibitor 
PID 
 
Patient Identification Number 
PK 
 
Pharmacokinetic 
PPD 
 
Purified Protein Derivative 
PRO 
 
Protocol Registration Office 
PSWP  
Protocol-Specific Web Page 
PY 
 
Person-Year 
PZA 
 
Pyrazinamide 
RE 
 
Regulatory Entity 
RFB   
Rifabutin  
RIF 
 
Rifampin 
RPT 
 
Rifapentine 
RR 
 
Relative Risk 
RSC 
 
Regulatory Support Center 
SAE 
 
Serious Adverse Event 
SGOT  
Serum Glutamic Oxaloacetic Transaminase 
SGPT  
Serum Glutamic Pyruvic Transaminase 
SID 
 
Study Identification Number 
SOC 
 
Standard of Care 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TB 
 
Tuberculosis 
TBTC  
Tuberculosis Trials Consortium 
TST 
 
Tuberculin Skin Test 
ULN 
 
Upper Limit of Normal 
U.S. 
 
United States 
WHO  
World Health Organization 
XDR TB 
Extensively Drug-Resistant Tuberculosis 
 
 


 
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SCHEMA 
 
 
A5279 
 
Phase III Clinical Trial of Ultra-Short-Course Rifapentine/Isoniazid for the Prevention of Active 
Tuberculosis in HIV-Infected Individuals with Latent Tuberculosis Infection 
 
DESIGN 
This study is a multicenter, randomized, open-label, phase III clinical trial 
comparing a 4-week daily rifapentine (RPT)/isoniazid (INH) regimen to a 
standard 9-month daily INH regimen for the prevention of tuberculosis (TB) 
in HIV-infected participants without evidence of active TB. The primary 
objective will be efficacy of TB prevention. The study will also assess safety 
and tolerability of the regimens, adherence to the treatments, and patterns 
of antibiotic resistance among Mycobacterium tuberculosis (MTB) isolates 
in participants who fail on these prophylactic regimens. 
 
DURATION 
Each participant will be followed for 3 years (156 weeks) after the last 
participant is enrolled. 
 
SAMPLE SIZE 
3000 participants 
 
POPULATION 
HIV-1 infected men and women ≥13 years old and ≥30 kg without evidence 
of active TB who: 
1. Have tuberculin skin test (TST) reactivity ≥5 mm or a positive interferon 
gamma release assay (IGRA), OR  
2. Live in high TB burden areas, defined as areas with an estimated or 
reported TB prevalence of 60/100,000, according to the WHO or 
national or local health authorities. (Please refer to the A5279 
protocol-specific web page [PSWP] for the WHO link to TB 
prevalence information by country. The protocol core team 
[actg.corea5279@fstrf.org] should be consulted if a site has data 
to suggest that the local TB burden differs significantly from the 
WHO country estimates and, therefore, should be considered in 
the application of this inclusion criterion.) 
 
If taking antiretroviral therapy (ART) at study entry, only approved 
nucleoside reverse transcriptase inhibitors (NRTIs) with efavirenz (EFV) or 
nevirapine (NVP) for at least 4 weeks are permitted. A list of approved 
antiretroviral drugs is located on the A5279 PSWP. Participants on 
NVP must be dosed at 200 mg twice daily (BID).   
 
NVP trough levels will be evaluated in the first 90 participants in Arm 
A who are receiving NVP at entry and who meet other criteria in 
section 10.0, after which enrollment for participants on NVP may be 
temporarily halted. NVP pharmacokinetic (PK) data will be evaluated 
to determine whether standard NVP dosing results in adequate PK 
drug exposure in the presence of RPT treatment. If the A5279 team 


 
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determines that concomitant dosing of NVP and RPT results in 
adequate drug exposure, the study may continue enrollment of 
participants receiving NVP.   
 
EFV concentrations and pharmacogenetics will be evaluated in the 
first 90 participants who enroll in Arm B under Version 2.0 who are 
receiving EFV at entry and who meet other criteria in section 10.0.  
Additionally, under Version 2.0, EFV concentrations and 
pharmacogenetics will be evaluated in an additional 30 participants 
from Arm A who will undergo PK sampling at weeks 0, 2, 4, and 16. 
 
NOTE: Participants randomized to Arm A may initiate any ART 
regimen after completing 4 weeks of RPT/INH. Participants 
randomized to Arm B may initiate any ART regimen after study entry. 
 
STRATIFICATION Participants will be stratified based on (1) the most recent CD4+ cell count 
obtained within 180 days prior to entry (<100, 100-250, and >250 
cells/mm3) and (2) ART use at entry (Yes/No). 
 
REGIMEN 
Participants will be randomized within strata in a 1:1 ratio to receive either: 
 
Arm A: 4-week daily regimen of weight-based RPT and INH, plus 
pyridoxine (vitamin B6) 
OR 
Arm B: 9-month (36-week) daily INH regimen, plus pyridoxine (vitamin B6) 
 


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
Ultra-short-course (4-week) daily rifapentine (RPT)/isoniazid (INH) is not inferior to a 
standard 9-month (36-week) daily INH regimen for the prevention of tuberculosis (TB) in 
HIV-infected individuals. 
 
1.2 
Primary Objective 
 
To compare the efficacy of a 4-week daily regimen of weight-based RPT/INH to a 
standard 9-month (36 week) daily INH regimen for TB prevention in HIV-infected 
individuals.  
 
1.3 
Secondary Objectives 
 
1.3.1 To compare safety and tolerability of the regimens 
 
1.3.2 To compare overall and non-TB mortality rates among participants receiving the 
two regimens 
 
1.3.3 To compare adherence rates in the two regimens 
 
1.3.4 To investigate patterns of antibiotic resistance among Mycobacterium 
tuberculosis (MTB) isolates in participants failing prophylaxis  
 
1.4 
Supportive/Exploratory Objectives 
 
The following objectives will be defined in detail in separate analysis plans. 
 
1.4.1 To inform public health policy by comparing estimated costs and cost-
effectiveness of the two regimens in various populations 
 
1.4.2 To investigate the effect of RPT/INH on efavirenz (EFV) and nevirapine (NVP) 
plasma concentrations   
 
1.4.3 To describe exposure-outcome relationships among EFV and NVP 
pharmacokinetic (PK) parameters and virologic failure, and safety and tolerance 
related to EFV and NVP  
 
1.4.4 To investigate relationships among genetic characteristics of drug metabolizing 
enzymes and drug transporters and the PK characteristics of EFV, NVP, and 
RPT.   
 
1.4.5 To determine the PK characteristics of EFV and its 7-OH-EFV and 8-OH-EFV 
metabolites when given in combination with RPT+INH (Arm A) and when 
given with INH alone (Arm B).   
 


 
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1.4.6 To compare EFV PK data obtained from combination therapy with RPT+INH 
and INH alone with a control group consisting of a set of plasma samples 
with participants receiving ART containing EFV but not RPT or INH, which 
will be collected from individuals in Arm A who have completed RPT/INH 
therapy and have allowed for a washout period. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
The World Health Organization (WHO) estimates that in 2009, the last full year for which 
data collection is complete, there were 9.4 million new incident cases of TB, and 1.68 
million deaths [1]. Among new incident cases of TB, 1.1 million were HIV-coinfected, and 
35% of TB deaths were among HIV-coinfected individuals. In Africa, where AIDS is the 
leading cause of death (COD) from any disease, TB is the leading AIDS-related 
opportunistic infection [2]. South Africa has the highest national HIV burden in the world, 
with an estimated 1 of every 6 of the world’s cases occurring there; South Africa also 
has the second highest estimated TB incidence rate per capita globally [3]. 
 
INH Treatment of Latent TB Infection (LTBI) 
INH has been the cornerstone of treatment for LTBI to prevent active TB for more than 
30 years; the first report of successful prevention of TB with INH was published in 1956 
[4, 5]. In placebo-controlled trials of INH treatment of LTBI in persons in contact with 
persons with active TB who converted their tuberculin skin tests (TST) from negative to 
positive, the rate of developing active TB in the placebo groups was 12.9 cases/1000 
person-years (PY) in the first year of follow-up, and 1.6 cases/1000 PY in the 
subsequent 7 years of follow-up [6]. Other placebo-controlled studies have further 
elucidated the background rates of developing active TB. Among British schoolchildren 
enrolled in a vaccine trial, placebo recipients who converted their TST from negative to 
positive during follow-up, the incidence of TB in the 15 years of follow-up was 4.7%, with 
the highest risk in the first 3 years after TST conversion [7]. Numerous randomized, 
placebo-controlled studies of the efficacy of INH given for 12 months were conducted in 
the 1950s and 1960s in countries with both high and low TB prevalence and across a 
broad spectrum of patient populations at risk for active TB. The efficacy based on the 
overall reduction in the incidence of active TB in these studies ranged from 25% to 92%; 
the protective efficacy when measured among those who completed a full course of 
treatment was approximately 90% [5]. Five-year TB incidence in the placebo groups of 
these trials ranged from 11.6 to 21.3/1000 PY. The effectiveness of INH preventive 
therapy (IPT) in non-HIV-infected populations is directly associated with duration of 
treatment with a reduction in development of active TB of 21% after 3 months, 65% after 
6 months, and 75% after 12 months, although completion rates for 6-9 months of INH 
are unacceptably low, ranging from 20% to 70% [8]. Despite high levels of success and 
strong recommendations for use of INH for LTBI in high-resource countries where TB 
risk is low to moderate, uptake and completion of treatment remains less than optimal. In 
a recent study in the United States (US) and Canada, 17.1% of persons at risk who were 
offered INH after a positive TST declined treatment; persons recently in contact with 
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started INH treatment, 52.7% failed to complete the recommended course, with the 
recommendation of a 9-month regimen, residence in congregate settings, and injection 
drug use being among the strongest predictors of failure to complete LTBI treatment [9].  
 
INH Treatment of LTBI in HIV-Infected Individuals 
HIV infection contributes significantly to an increased risk of progression of LTBI to 
active TB. Published rates of progression based on data from a variety of studies range 
from 35 to 162 cases/1000 PY of observation, with an annual risk among HIV-infected 
persons with a positive TST of 45 cases/1000 PY [5, 10]. Debate also continues 
regarding the efficacy of LTBI treatment among HIV-infected individuals. In a Cochrane 
Database review of 12 randomized clinical trials of LTBI treatment in 8578 randomized 
HIV-infected persons, preventive therapy with any anti-TB drugs administered for 6-12 
months versus placebo resulted in an overall 32% reduction in the incidence of active TB 
(relative risk [RR] 0.68; 95% confidence interval [CI] 0.54, 0.85) [11]. The effect was 
greater for those with a positive TST (62% reduction; RR 0.38; [95% CI 0.25, 0.57]) than 
for those with a negative TST (11% reduction; RR 0.89; [95% CI 0.64, 1.24]).  
 
The efficacy was similar for all regimens but waned over time regardless of regimen. 
There was no reduction in all-cause mortality, but a favorable trend for mortality 
reduction among those with a positive TST. Among those studies reporting incidence 
rates for HIV-infected individuals in the placebo arm, they varied by population as 
indicated below: 
 
Study 
TST Status 
TB Rate/ 
100 person-
years 
Haiti, 1986-92 
Purified Protein 
Derivative (PPD)+ 
10.0 
 
PPD- 
5.7 
Uganda, 1993-97 
PPD+ 
3.4 
 
Anergic 
3.06 
Kenya, 1992-96 
PPD+ 
8.03 
 
PPD- 
2.73 
Zambia, 1992-96 
PPD+/- 
8.06 
U.S., 1991-96 
Anergic 
0.9 
Zambia, 1998 
PPD+/- 
4.94 
Haiti, 2001 
PPD- 
1.5 
Spain, 2003 
Anergic 
3.1 
South Africa, 2007 
Anergic 
11.6 
 
Antiretroviral therapy (ART) was not available to participants followed in the majority of 
these trials. While more recent studies have indicated that INH administered for 6 
months reduced the relative rate of TB by 55% to 67% when compared to placebo, the 
effect waned substantially within 6 months to 2.5 years after discontinuing INH [12, 13]. 
In a recently published study from South Africa, two clinical cohorts were evaluated in 
the context of incident TB during exposure to IPT and/or ART [14]. There were 267 
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with an incident rate ratio of 6.2/100 PY. Compared to ART-naïve patients, those who 
received ART alone had a 64% decreased hazard for development of TB, and patients 
who received ART after receiving IPT had an 89% reduced hazard. In another recently 
reported study conducted in Botswana, 2000 HIV-infected patients were randomized to 
receive either 6 months or 36 months of INH to evaluate whether a longer duration of 
INH might have a more durable effect in reducing the incidence of TB [15]. The TB 
incidence rate was 2.22/100 PY in the 6-month INH arm and 0.57/100 PY in the 36-
month arm, representing a 57% reduction overall in the 36-month INH arm. The percent 
reduction was largely driven by those who entered with a positive TST; those 
participants with a positive TST had a 92% reduction in the incidence of active TB after 
36 months of INH. When evaluated according to the use of ART, those with a positive 
TST at entry who received both 36 months of INH and ART had an overall reduction of 
96% in the annual incidence of TB. The effect of 6 months of INH began to wane 
immediately after discontinuation; the TB rate in this arm for those with a positive TST 
rose to 6.5/100 PY within approximately 1.5 years after stopping INH; the annual 
incidence in this arm was 2.5%. Conversely, in a randomized, controlled trial of 6 months 
of INH/ethambutol (EMB) versus 36 months of INH alone in 712 HIV-infected patients 
without evidence of active TB, the incidence rate of TB in the INH/EMB arm was 2.4/100 
PY versus 1.6/100 PY for INH alone [16]. The historical background rate of TB in the 
population in the absence of INH was reported to be 7/100 PY. Similar to the Botswana 
study, the benefit for either arm was lost within 6 months after stopping preventive 
therapy. In both of these studies, there was no significant difference in TB rates between 
arms for those with a negative TST, and overall adverse event (AE) rates were low and 
not significantly different among the treatment arms, suggesting that all regimens tested 
were relatively safe.  
 
Despite the favorable findings of these and previous studies, there has been little uptake 
of preventive therapy in regions of the world where it is most needed. Although longer 
courses of up to 36 months of IPT may further reduce the incidence rates of TB among 
HIV-infected individuals, the poor rates of uptake and the high proportion of individuals 
who fail to complete even 6 months of IPT highlight the need for alternative, more 
effective short-course approaches for treatment of LTBI. The TB rate per annum in 
persons living with HIV in high prevalence areas is still estimated to range from 2-7% 
depending on the geographic region, the coverage of ART, and the uptake of IPT.  
 
Shortened Courses of LTBI Treatment 
Alternative shortened courses of LTBI treatment have been evaluated in HIV-infected 
individuals. In a randomized clinical trial conducted prior to the advent of highly active 
ART [17] evaluated a 2-month regimen of daily rifampin (RIF) and pyrazinamide (PZA) 
compared with a 12-month regimen of daily INH in 1583 HIV-infected persons with a 
positive TST. Only 69% of patients completed 12 months of INH versus 80% for those 
randomized to RIF/PZA. However, there were no differences in rates for confirmed or 
probable TB, HIV disease progression, or death, although drug discontinuation rates 
were slightly higher in the RIF/PZA arm. This study was conducted in the US, Mexico, 
Haiti, and Brazil, and more than 70% of the patients were enrolled in the US; thus, it was 
not a test of short-course LTBI treatment in resource-limited settings with high endemic 
rates of TB. However, despite showing comparable results to IPT, there has been little 
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ongoing uncertainty based on two other studies that evaluated short-course RIF/PZA in 
high TB endemic regions; one in Zambia where the regimen was administered twice 
weekly for 3 months, and one in Haiti where the regimen was administered twice weekly 
for 2 months [18, 19]. In both studies, the overall rate of TB was higher in the short-
course LTBI treatment arms compared to the INH arms, although both studies used 
intermittent RIF/PZA. It is also possible that the lack of uptake reflects cases of severe 
liver injury associated with a 2-month regimen of RIF/PZA (albeit mostly in HIV-negative 
participants) after more widespread implementation of American Thoracic Society 
(ATS)/Centers for Disease Control and Prevention (CDC)/Infectious Diseases Society of 
America (IDSA) guidelines in 2000 [5].    
 
Although these data support the benefit of LTBI treatment in HIV-infected individuals, 
including with the use of short-course RIF/PZA, data from large randomized clinical trials 
in HIV-infected patients exposed to TB in high TB prevalence resource-limited settings 
have only recently emerged. In a recently completed phase III clinical trial comparing 12 
weeks of weekly RPT/INH (900 mg/ 900 mg) to 6 months of daily INH (300 mg) in South 
Africans with HIV and LTBI, the hazard of TB or death in the RPT/INH arm was 14% 
lower than for INH (HR=0.86, 95% CI 0.5-1.3, p=0.35) [20]. Although the difference was 
not statistically significant, the study was only powered to detect a 50% difference, and it 
is encouraging that RPT/INH given only once-weekly for 12 weeks could have similar 
efficacy to daily INH for 6 months. ACTG 5259/TBTC Study 26: “A Study of the 
Effectiveness and Tolerability of Weekly Rifapentine/Isoniazid for Three Months Versus 
Daily Isoniazid for Nine Months for the Treatment of Latent Tuberculosis Infection” has 
recently completed its preliminary analysis of more than 7500 patients at high risk for TB 
who were randomized to either 12 weekly doses of RPT 900 mg and INH 900 mg or 9 
months of daily INH. The study found that RPT/INH was noninferior to standard INH and 
had significantly higher rates of treatment completion and lower rates of adverse events. 
The rates of TB in TBTC Study 26 were 0.13 cases per 100 PY in the INH arm and 0.07 
cases per 100 PY in the RPT/INH arm. Only about 200 HIV-infected patients were 
included in this analysis, but a preliminary Cox proportional hazards analysis indicates 
that HIV was associated with an 8-fold increase in the hazard of TB, regardless of 
treatment arm. The ACTG has enrolled an additional approximately 200 HIV/TB-
coinfected patients whose outcomes will be analyzed in several years; data from this trial 
will further inform the field. However, the HIV substudy is powered for tolerability rather 
than efficacy in the coinfected cohort. People receiving or planning to receive ART within 
90 days of enrollment are excluded because of the lack of PK/safety data with RPT and 
antiretroviral agents. Therefore, the study will provide limited information about this 
regimen in HIV-infected patients in resource-limited settings with high TB burden. At this 
point, the TB Trials Consortium (TBTC) is not planning more trials for LTBI. Building on 
this work, an efficacy trial by the ACTG in areas of high TB burden and in patients 
requiring ART is the next logical step. 
 
Pre-clinical models of TB disease suggest that more frequent administration of RPT can 
lead to higher cure rates and shorter treatment duration. Although mice do not develop 
LTBI, a model in which mice are aerosol-immunized with Bacille Calmette-Guerin (BCG) 
vaccine prior to low-dose aerosol challenge with MTB produces an infection similar to 
human LTBI, based on the relatively small population (ie, 104 CFU [colony-forming 
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[21]. A 3-month regimen of weekly RPT/INH in this model was shown to be equivalent to 
daily INH for 6-9 months and was subsequently demonstrated to have similar efficacy in 
humans [22, 23]. In the murine model of active TB, daily dosing of RPT was associated 
with substantially higher rifamycin exposure when compared with RIF, and reduced the 
duration of treatment needed to prevent relapse [24, 25]. Current experiments using a 
refined murine model of LTBI that reliably produces a lower bacterial burden by 
immunizing with recombinant BCG vaccine provide early evidence of the superior 
activity of daily RPT as compared to daily INH or other therapies. In the first experiment, 
mice received RPT 10 mg/kg administered 5 days/week (5/7), in doses comparable to 
humans, alone and with INH, PZA, or both, for 8 weeks. Control mice received RIF 10 
mg/kg (5/7) alone and with INH, PZA, or both, for 8 weeks. The RPT-based regimens 
were significantly more active than their corresponding RIF-based controls. These 
regimens sterilized cultures more rapidly, with the exception of the comparison of the 
RPT/PZA and RIF/PZA, for which the trend favored RPT, but did not quite reach 
statistical significance after adjusting for multiple comparisons (p=0.06 for that 
comparison). All mice became culture negative by weeks 4-6 [26]. In a second 
experiment, RPT 10 mg/kg (5/7), with or without INH, was superior to INH alone, RIF 
alone, and RIF/INH control regimens. One month of RPT/INH (5/7) resulted in relapse 
rates similar to 4 months of RIF (5/7), 3 months of RIF/INH (5/7), and 3 months of 
RPT/INH (1/7) [E. Nuermberger, unpublished data]. Comparison to 6 months of INH 
(5/7) is pending. Treatment of mice in this model suggests that daily high-dose RPT 
should eliminate LTBI more quickly than conventional regimens.  
 
These pre-clinical experiments serve as the basis for the ultra-short-course of RPT-
based therapy proposed in this clinical trial, since the murine model of LTBI was 
previously found predictive of efficacy for the 2-month course RIF/PZA [27, 19, 17]. 
Furthermore, rifamycin PK is comparable between humans and mice. As indicated in the 
tables below, the 10 mg/kg dose in mice results in drug exposures that are remarkably 
similar to the exposures observed in healthy volunteers after the recommended human 
dose of 600 mg (ie, ~10 mg/kg). Steady-state RPT exposures observed in Ugandan TB 
patients receiving RPT 10 mg/kg (5/7) in combination with INH, PZA, and EMB in TBTC 
Study 29 were lower than exposures previously observed in mice and healthy volunteers 
(mean RPT AUC0-24 = 179 µg-h/mL) [28]. A substantial portion of this difference could be 
due to the expected autoinduction of rifamycin metabolism with repeated dosing; 
although no autoinduction could be demonstrated after 7 consecutive daily 
administrations of 600 mg RPT [29], more recent investigations documented changes 
consistent with RPT autoinduction after 7 thrice weekly administrations of 900 mg RPT 
concomitant with daily moxifloxacin [30]. More importantly, RPT bioavailability being 
greatly increased (from 33 % to up to 86%) by food intake, fasting prior to drug 
administration in Study 29 is expected to have had a significant impact [Priftin package 
insert 2009, 31]. In addition, these fasting conditions may have enhanced the RPT and 
INH physico-chemical interaction expected to occur in acid conditions [32]. 
Pharmacogenetic differences also may underlie reduced RPT exposures among African 
patients, as recently observed for RIF [33]. An ongoing RPT dose escalation study 
among healthy volunteers (TBTC Study 29B) will determine safety, tolerability, and RPT 
exposures in fed patients receiving 7/7 dosing and should confirm the RPT dose 
necessary to produce in LTBI patients the same RPT exposures observed in mice 
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so a higher mg/kg dose is necessary to achieve similar area under the concentration-
time curve (AUC) values. The 10 mg/kg dose in mice most closely represents the INH 
exposures observed in humans who are rapid acetylators of INH. Compared to INH 
exposures in humans who are slow acetylators, the Cmax in mice at this dose is 50% 
higher, but the AUC is 50-60% lower.   
 
Mean PK parameter value in serum after a single RPT dose 
Species 
Humans [34] 
Mice [24] 
Dose 
600 mg 
10 mg/kg 
PK parameter 
 
 
      Cmax (µg/ml) 
15.8 
13.0 
      AUC* (µg-h/ml) 
386 
417 
 *AUC0-∞ for humans, AUC0-48h for mice 
 
Mean PK parameter value in serum after a single RIF dose 
Species 
Humans [35] 
Mice [36] 
Dose 
600 mg 
10 mg/kg 
PK parameter 
 
 
      Cmax (µg/ml) 
14.9 
12.1 
      AUC0-24h (µg-h/ml) 
118 
116 
 
Mean PK parameter value in serum after a single INH dose 
Species 
Humans* [37] 
Mice  [38] 
Dose 
300 mg 
10 mg/kg 
PK parameter 
 
 
      Cmax (µg/ml) 
5.3-6.2 
7.5 
      AUC0-24h (µg-h/ml) 
11.4-23.7 
9.3 
 *Range shown is for rapid and slow acetylators of INH. 
 
TB/HIV Drug Interactions 
Rifamycin drugs such as RPT have the potential to cause drug-drug interactions 
of clinical importance. Rifampin (RIF), the most commonly-used rifamycin, is a 
potent inducer of multiple metabolizing enzymes, including cytochrome P450 
enzymes, as well as P-glycoprotein and phase 2 enzymes [39]. Since most 
protease inhibitors (PI) and non-nucleoside reverse transcriptors (NNRTIs) are 
metabolized by cytochrome P450 3A4 isoenzyme (CYP3A4), induction of CYP3A4 
by RIF can lead to reduced serum concentrations of antiretrovirals (ARVs) with a 
risk for treatment failure or emergence of resistance to ARVs. NVP and EFV are 
both subject to drug-drug interactions with RIF. EFV is cleared by CYP2B6 and 
CYP3A4 metabolizing enzymes, and EFV may act as a 3A4 inhibitor or inducer. 
NVP is eliminated via CYP3A4 and CYP2B6 and induces CYP3A4. 
 
 
In patients who must be treated with RIF-based therapy for TB and require 
concurrent HAART, EFV is the NNRTI of choice. Since the PK of EFV 600 mg daily 
is similar to that of EFV 800 mg daily when coadministered with RIF in HIV/TB 
coinfected patients [40, 41], some recommend that EFV dosing should be 


 
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increased in patients taking RIF; the US Food and Drug Administration (FDA) has 
recently approved a change in the label for EFV to increase dosage to 800 mg 
daily for patients weighing >50 kg when taking RIF. Despite somewhat diminished 
plasma concentrations of EFV in PK studies in patients taking RIF, however, 
pharmacodynamic (PD) studies in Brazil, South Africa, Thailand, and India in 
HIV/TB-coinfected patients receiving RIF have shown durable virologic and 
immunologic responses at the standard EFV dose of 600 mg daily [41--46]. These 
study findings suggest that a daily dose of 600 mg of EFV is safe and likely to be 
efficacious in patients being treated concurrently for HIV and TB with a RIF-based 
regimen. The effect of the physiological changes of pregnancy combined with RIF-
based therapy on EFV concentrations and treatment outcomes among pregnant 
women is unknown. 
 
NVP is frequently used in pregnancy and is widely available in fixed-dose 
combinations. When the standard dose of 200 mg twice daily is coadministered 
with RIF, serum concentrations of NVP are decreased by 20-30% [47]. One group 
found that coadministration of RIF with NVP caused significant decreases in the 
Cmax (42%), trough concentration (53%), and AUC (46%) of NVP as well as 
significant increases in NVP oral clearance (Cl/F) [48]. However, studies 
evaluating the consequences of reduced NVP concentrations when given with RIF 
have yielded variable results. In one study, long-term CD4+ T-cell and HIV viral 
load values were similar in patients on NVP who had received a RIF-based 
regimen compared to those who had not. [47]. Conversely, two other studies have 
shown higher risk of virologic failure in patients taking NVP together with RIF [49]; 
The Thai Red Cross evaluated the efficacy of 600 mg NVP coadministered with 
RIF-containing TB regimen. They found the efficacy at 48 weeks to be similar to 
standard 400 mg dose, but there was a higher rate of NVP hypersensitivity in the 
higher dose group [50]. A recent study by Swaminathan and colleagues found 
higher rates of treatment failure and death in patients treated with RIF-based TB 
therapy and a NVP-based HIV regimen compared to patients receiving EFV-based 
HAART [51]. At this point, the optimal NVP dose when NVP is given together with 
a RIF-containing TB regimen is unclear.  
 
It has long been thought that RPT causes less induction of P450 enzymes than 
RIF, but a new study in healthy volunteers by Dooley et al. has found that daily 
dosing of RPT is a more potent inducer than daily RIF [52]. Using midazolam (a 
CYP3A4-metabolized drug) as a substrate, these investigators found that RPT at 
doses of 5-20 mg/kg daily reduced AUCs by >90%, compared to a 75% reduction 
with RIF. Thus, coadministration of RPT with CYP3A4-metablized drugs such as 
PIs, raltegravir, and NNRTIs could result in clinically significant reductions in 
these agents. 
 
INH inhibits CYP 2C19, 3A4 and, weakly, 2D6 [53]. INH is primarily metabolized via 
n-acetyl-transferase 2 (NAT2) to the inactive metabolite acetylisoniazid. The rate at 
which acetylisoniazid is formed is highly dependent on individual NAT2 genetics. 
INH is not currently recognized as having an interaction with EFV. However, 
studies performed in human liver microsomes have shown INH to inhibit CYP 1A2 
and 2A6 [54]. Additionally, data recently presented by Bertrand et al. from patients 


 
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taking RIF and INH have shown there to be a concentration dependent inhibition 
effect of INH on EFV clearance, particularly evident in individuals with the CYP 
2B6 516TT genotype and NAT2 slow acetylators [55]. These data allow the 
hypothesis that when EFV is coadministered with RIF (or RPT) and INH, then the 
inductive effect of RIF or RPT may be offset in some patients by the inhibitory 
effect of INH. This provides a plausible explanation for the contradictory results, 
seen largely between EFV-RIF PK studies in healthy volunteers and PK 
evaluations of EFV-RIF-INH coadministration in patients [56]. Whether or not the 
interaction between INH and the secondary metabolizing pathway of EFV 
(CYP2A6) is clinically significant in individuals taking RPT, INH, and EFV is 
unknown and requires investigation in HIV-infected persons.  
 
Currently, there are no published data on the effects of RPT when administered 
with EFV in HIV-infected persons. Additionally, there are no data on plasma 
concentrations of EFV when given with RPT and INH. The possible interaction 
between INH and EFV in a select genotypic group of individuals may decrease or 
even cancel out the interaction between EFV and RPT caused by the enzyme 
inducing properties of RPT. 
 
2.2 
Rationale 
 
Successful population-level treatment of LTBI has been hindered by several factors: (1) 
poor adherence to long courses of therapy; (2) the administrative burden of directly 
observed therapy (DOT); (3) toxicities related to INH; and (4) concerns related to the 
inability to effectively rule out subclinical TB and the attendant risk of drug resistance in 
the setting of possible INH monotherapy. In resource-limited settings with high TB 
prevalence, uptake of IPT remains dismally low as well, especially among HIV-infected 
patients. Estimates from the WHO indicate that in 2009, among HIV-infected persons 
screened and found not to have active TB, fewer than 1% were started on IPT [1]. 
Although longer durations of IPT may be more effective than conventional 6-12 month 
courses, similar considerations are likely to continue to impede implementation of IPT. 
New regimens that shorten treatment duration will improve adherence and, if more 
effective regimens are employed, will substantially reduce the burden on public health 
clinics associated with providing and monitoring prolonged DOT, and reduce the risk for 
the development and transmission of active TB in the most vulnerable settings. 
 
While it is clear that adherence is better with shorter regimens, and that safety and 
efficacy in TB prevention is comparable to those measured in comparator arms with INH 
administered for 6-12 months, uptake of either INH or short-course RIF-containing 
regimens has been minimal in the very settings in which treatment for LTBI is most 
needed. Whether even shorter course LTBI treatment will be more acceptable and cost-
effective in public health settings and sufficiently so to trigger broad uptake remains to 
be established. As well, the safety and efficacy of and adherence to a 1-month daily 
RPT/INH regimen have yet to be evaluated. We propose a randomized, controlled trial to 
compare the safety, tolerability, efficacy, and adherence of short-course, daily RPT/INH 
with the standard regimen for LTBI, 9 months of INH, in patients at high risk of 
developing active TB. As detailed in the package insert, RPT is an inducer of CYP450 
enzymes [Priftin package insert 2009]. Concomitant use of RPT with other drugs 


 
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metabolized by these enzymes, such as PIs and NNRTI, may cause a significant 
decrease in plasma concentrations and loss of therapeutic effect of the PI or NNRTI. For 
this reason, patients requiring PI-based therapy during the first month of the trial will be 
excluded, and PK analyses of NNRTI levels will be performed as part of the study for 
those persons on a NNRTI regimen. In summary, development of a potent, ultra-short, 
effective treatment for LTBI could dramatically reduce the global incidence of active TB.  
 
Cost-Effectiveness Analysis 
The uptake of any new therapy is highly dependent on several factors, of which cost is 
one of the most significant. New therapies (especially those containing new drugs) are 
frequently significantly more expensive than standard regimens. Therefore, in programs 
with fixed and limited resources, these new regimens must be expected to provide either 
significant improvements in efficacy or long-term savings when compared to the current 
standard of care. Cost-effectiveness analysis performed in conjunction with a clinical trial 
can assist with this latter comparison and is most effective when performed in 
conjunction with the clinical trial [57]. 
 
We plan to examine the cost-effectiveness of RPT/INH compared with both 9 months of 
INH and other regimens. We would expect that the shorter regimen would lead to more 
patients completing a course of therapy, which should result in fewer cases of active TB 
over time. Also, because the costs of the RPT/INH regimen in most areas with high TB 
incidence are largely unknown, we can use modeling to determine price thresholds 
above which RPT/INH will no longer be cost-effective; these thresholds can be used by 
public health officials in setting local policy. Furthermore, while study participants will all 
be HIV-positive, any new regimen proven to be effective in this population will likely be 
used in other populations as well. Because most of these populations will have 
significantly lower baseline risk of TB activation than the study population, the benefits of 
a shorter-course regimen may not be as marked. Therefore, we will seek out cost-
effectiveness thresholds for cost, efficacy, and underlying risk. 
 
By performing this analysis in conjunction with the clinical trial, we will be able to collect 
detailed treatment data that can be used to estimate costs in a wide variety of settings. 
More importantly, if the study regimen proves effective, we will be able to provide 
guidance to public health officials as soon as study results become available. 
 
Rationale for Choice of RPT 
The rifamycins are the chief sterilizing drugs in the modern short-course regimen for 
treatment of active TB. Compared to RIF, RPT is more potent against MTB in vitro (MIC, 
0.06 vs. 0.25 mg/L) [58] and provides greater drug exposures at a given mg/kg dose in 
mice and in humans, owing largely to its longer serum half-life (see below). In murine 
models of both active and latent TB infection, the increased rifamycin exposure obtained 
with substitution of RPT for RIF results in greater sterilizing activity and significant 
shortening of the duration of treatment needed to prevent relapse [36, 25, 26]. For 
example, in a murine model of active TB, substitution of RPT 10 mg/kg in place of RIF 
10 mg/kg administered in combination with INH/PZA 5 days/week shortens the time 
needed to prevent relapse from 6 months to 3 months or less in all mice [24, 25]. In a 
murine model of latent TB infection, which provided the pre-clinical evidence base for 
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HIV-infected persons [17, 19, 27], RPT 10 mg/kg and the combination of RPT/INH 
administered 5 days/week were significantly more effective in reducing the rate of active 
TB than the same dose of RIF alone or RIF/INH [26]. In this experiment, all mice 
receiving RPT alone were rendered culture negative after 6 weeks, and 40%, 7%, and 
0% of mice, respectively, developed culture-positive TB infection in the 3 months after 
completing treatment for 4, 6, or 8 weeks. RPT/INH rendered 4 of 5 mice culture 
negative after 4 weeks, and 86%, 14%, and 0% of mice, respectively, developed culture-
positive TB infection in the 3 months after completing treatment for 4, 6, or 8 weeks. 
Among mice treated with RIF/INH, 100% and 47% of mice, respectively, developed 
culture-positive TB infection in the 3 months after completing treatment for 4 or 8 weeks 
(the efficacy of 6 weeks of RIF/INH was not assessed), consistent with the 3-month 
treatment duration recommended when RIF/INH is used for LTBI in humans [59]. RIF 
alone was less effective than RIF/INH. These results suggest that a regimen containing 
RPT at 10 mg/kg/day may treat LTBI in 2 months or less. Daily RPT/INH for 6-8 weeks 
(42-56 doses) would not offer cost-benefit advantage when compared to the upcoming 
3-month once-weekly administration (12 doses) evaluated in TBTC Study 26. Data 
generated in the murine model at 4 weeks indicated that sterilization had occurred in a 
proportion of infected mice, suggesting that a 4-week regimen of daily RPT/INH could be 
sufficient to prevent development of active TB in patients. In a second experiment in the 
same model, one month of RPT/INH (5/7) resulted in relapse rates similar to 4 months of 
RIF (5/7), 3 months of RIF/INH (5/7), and 3 months of RPT/INH (1/7).These unpublished 
data showing comparable outcomes with three efficacious LTBI regimens provide further 
support for a 1-month treatment duration of RPT/INH treatment [E. Nuermberger, 
unpublished data]. 
 
The safety and tolerability of daily RPT has been evaluated in a phase I PK study in 
healthy volunteers [29]. Twenty-three healthy males were randomized to receive two of 
the following treatments in a 2-period, 4-treatment, incomplete block, cross-over design: 
single once-daily oral RPT at 150 mg, 300 mg, or 600 mg on study days 1 and 4 through 
10, or single oral RPT 600 mg doses given every 3 days for 4 doses. All regimens 
reached steady state RPT concentrations and RPT was well tolerated in all four 
treatment periods. Urine discoloration was the most common AE, and occurred in all 
study participants. Other treatment-related AEs were upset stomach (n=4), 
lightheadedness (n=3), dry mouth (n=2), diarrhea (n=2), flatulence (n=1), and headache 
(n=1). No abnormalities of liver chemistries were reported.   
 
TBTC Study 29, Evaluation of a Rifapentine-Containing Regimen for Intensive Phase 
Treatment of Pulmonary Tuberculosis, is a phase II trial comparing daily RPT (5 days 
per week) at 10 mg/kg to standard dose RIF in patients with newly diagnosed, smear-
positive pulmonary TB. All patients also receive standard INH, PZA, and EMB. The 
primary endpoint is sputum culture conversion after 8 weeks. As of August 16, 2010, the 
study had recruited 465 patients and undergone six Data and Safety Monitoring Board 
(DSMB) reviews since enrollment began. No serious and unanticipated toxicities had 
been reported as of that date. 
 
The safety and tolerability of RPT used daily has also been evaluated by the 
manufacturer in clinical phase II studies in AIDS patients with bacteremia caused by 
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Multicenter Dose Escalation Study to Evaluate Tolerance, Safety, and Activity of 
Rifapentine Alone and in Combination Therapy in AIDS Patients with MAC Bacteremia 
(Hoechst Marion Roussel protocol number 000473PR0005). 
The primary objective of this phase II, open-label, multicenter, dose-escalation study 
was to determine the tolerance and safety of escalating RPT doses alone and in 
combination therapy for disseminated MAC bacteremic patients with AIDS. This study 
started in 1995 and ended in 1996. Patients were treated with RPT monotherapy for 14 
days and then randomized to combination therapy with clarithromycin or combination 
therapy with clarithromycin/EMB. The combination therapy phase lasted 28 days. RPT 
was dosed once daily. Thirty patients were enrolled in the study; 8 received RPT 450 
mg/day, and 22 received RPT 300 mg/day. All patients experienced one or more 
nonserious AEs; the high incidence was “indicative of the poor health status of this 
patient population”. Seventeen (56.7%) patients had one or more treatment-related AEs 
(AEs defined by the investigator as “definitely”, “probably”, or “possibly” related to study 
medication). Among these 17 patients, 6 (20% of total) had a hematologic AE (2 patients 
with anemia, 3 with neutropenia, and 1 with hemoglobin/hematocrit disease), 6 patients 
had a hepatic/biliary AE (5 with bilirubinemia, 1 with cholestatic hepatitis), 4 patients 
(13% of total) had a body-as-a-whole AE (3 with abdominal pain and 1 with ascites), and 
3 (10% of total) had a gastrointestinal AE (2 with nausea and 1 with vomiting). There 
were 13 serious AEs (SAEs), 7 of which were death, and 6 of which were nonfatal. None 
of the deaths were judged to be related to study medication. Among the 6 nonfatal 
SAEs, 1 was judged not related to study medication, 1 was judged unlikely to be related 
to study medication (blindness in a patient known to have cytomegalovirus [CMV] 
retinitis); 2 were judged possibly related to study medication (depression and suicide 
attempt in 1 patient, and hepatic failure in 1 patient receiving 450 mg/day), and 2 were 
judged probably related to study medication (neutropenia in 1 patient receiving 300 
mg/day, and dysarthria/confusion and AIDS in 1 patient). The rate of patient 
discontinuation due to treatment-related AEs was higher among patients receiving 450 
mg/day (4 patients among 8 who received this dose) than among patients receiving 300 
mg/day (5 patients among 22 who received this dose). However, among the 4 patients 
receiving 450 mg/day who discontinued, in only 1 patient was the AE attributed to study 
medication, and this AE was listed as “dysarthria/confusion/AIDS”.    
 
Tolerance, Safety, and Activity of Rifapentine Alone and in Combination Therapy in 
AIDS Patients with Mycobacterium avium complex (MAC) Bacteremia (Hoechst Marion 
Roussel protocol number 000473PR0018). 
The primary objective of this phase II, open-label, multicenter trial was to determine the 
tolerability of RPT alone and in combination therapy in disseminated MAC bacteremic 
patients with AIDS. This study started in 1995 and ended in 1997; enrollment was closed 
in 1997 because of the marked decrease in the incidence of disseminated MAC infection 
following the widespread availability of potent combination ART. Twenty-one patients 
were enrolled in this study. Four patients were enrolled to RPT monotherapy (3 received 
300 mg/day and 1 received 450 mg/day); 3 patients completed 21 days of monotherapy 
and went on to complete 42 days of RPT-containing combination therapy. Seventeen 
patients were enrolled to RPT combination therapy only (11 received RPT 300 mg/day 
and 6 received RPT 450 mg/day); 13 completed 42 days of combination therapy. Twenty 
of 21 patients had ≥ 1 AE. As in the prior study, this was felt to be “indicative of the poor 
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related nonserious AE.  Among these, 5 patients (23.8% of total patients) had a 
gastrointestinal AE, and 3 (14.3%) had a dermatologic AE. There were 17 SAEs (10 
patients). Included among these SAEs were 3 deaths, none of which was judged by the 
investigator to be related to study drugs. There were 14 nonfatal SAEs, none of which 
was judged by the investigator to be related to study drugs. There were 4 permanent 
discontinuations due to AEs (3 deaths, plus 1 additional discontinuation due to an AE not 
related to study drugs), and 1 temporary discontinuation (due to rash; study drugs were 
stopped, and then reintroduced without return of the rash). Study conclusions were that 
AEs were overwhelmingly symptoms associated with AIDS and few were attributable to 
study drugs, and that RPT was well-tolerated at either dose level given as monotherapy 
or as combination therapy.  
 
An Open-Label, Multicenter Extended Treatment Phase Study with Rifapentine in AIDS 
Patients Who Have Completed Protocol 000473PR0018 (Hoechst Marion Roussel 
protocol number 000473PR0019). 
The primary objective of this study was to provide RPT for extended treatment to 
patients who, in the opinion of the investigator, responded to treatment during the 
preceding RPT protocol (000473PR0018). Eight patients were enrolled in this extended 
use study, and the duration of treatment for a given patient was based on individual 
response. Seven patients received RPT 300 mg/day, and one patient received RPT 450 
mg/day. Median number of weeks of RPT use in this study was 18 (range 4 to 52 weeks, 
mean 24.5 weeks). Four nonserious AEs were judged to be related (possibly, probably, 
or definitely) to study drugs: one patient each with dry mouth, conjunctival erythema, 
burning eyes, and erythematous ear canal. There were 14 SAEs including 3 deaths; 
none of the 14 SAEs was judged to be related to study drugs. Study conclusions were 
that AEs were overwhelmingly symptoms associated with AIDS and that RPT was well 
tolerated.  
 
Importantly, individuals in the above studies had advanced AIDS complicated by 
disseminated MAC, each of which is associated with substantial morbidity and mortality. 
For example, Chaisson et al. reported in 1992 that the median duration of survival after 
disseminated MAC diagnosis in AIDS patients was 221 days, and that the probability of 
1-year survival from the time of disseminated MAC diagnosis was 0.29 (95% CI 0.24-
0.34) [60]. More recently, Benson et al. reported results of an ACTG study of three 
contemporary, clarithromycin-based regimens for treatment of disseminated MAC in 
AIDS patients [61]. Among the treatment groups, 8-25% died during the first 4 months of 
the study, and 28-50% died during the 48-week study period. Furthermore, 9-14% of 
patients stopped therapy due to protocol-defined toxicity, 9-25% had Grade 3 or higher 
anemia, and 6-14% had Grade 3 or higher hepatitis.   
 
Impact of New PK Data on A5279 
Previous research using intermittent doses of RPT had shown that P450 
cytochrome induction was approximately 75-80% the magnitude of that caused by 
RIF. On this basis, Version 1.0 of the A5279 protocol originally excluded patients 
taking PI-containing ART regimens, but allowed enrollment of patients taking EFV- 
or NVP-containing regimens, and planned to include the first 90 of each group in a 
PK substudy of the interaction of RPT on trough concentrations of these agents. 
Recent data from TBTC Study 29B [62] reveal that daily dosing of RPT results in 


 
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greater induction of cytochromes than with RIF. The protocol pharmacologist and 
leadership team, as well as independent pharmacologists, reviewed the new data 
and concluded that while it is reasonable and safe to continue plans to enroll 
patients taking EFV, it would be most prudent to hold off on enrollment of patients 
taking NVP until more data were available. EFV is metabolized largely by CYP2B6 
and to a lesser extent by CYP3A4, the isoenzyme induced by RPT. NVP, however, 
is largely metabolized by CYP3A4.  
 
The protocol team accelerated the collection and analysis of PK data from the EFV 
substudy of A5279 to determine the potential effect that RPT might have on NVP 
PK. These PK analyses showed that concomitant dosing of EFV and RPT results 
in adequate drug exposure. Thus, patients taking NVP will be enrolled and similar 
PK analyses will be conducted. 
 
RPT in Children 
This study proposes to evaluate a shortened course of daily RPT and INH in adults and 
adolescents of age 13 and older. Data evaluating use of RPT in children are limited. 
However, PK data in children aged 2-12 years are available [63]. In this study, 24 were 
enrolled in a two-dose level, multicenter, PK study of orally administered RPT tablets. 
Single-dose PK data for children weighing 10-30 kg who received 150 mg RPT and 
children weighing 30-60 kg who received 300 mg RPT resulted in doses of 5-15 mg/kg, 
which approximates the labeled adult dose of RPT 600 mg. Overall, the mean peak RPT 
level was 7.26 +/- 2.64 mcg/mL; 6.87 +/- 2.82 mcg/mL among children who received 150 
mg and 7.63 +/- 2.52 among children who received 300 mg (p=0.50). The mean time to 
peak level was 3.2 +/- 1.2 hours, and the t ½ was 20.5 +/- 18.0 hours. When stratified 
according to children who received 5-8.5 mg/kg vs. 8.6-11 mg/kg, there was no 
difference in peak concentration (7.36 vs. 7.19 mcg/mL; p=0.89), t ½ (18.9 vs. 21.8 
hours; p=0.71), or AUC (117.8 vs. 119.0). There was no clear relationship between RPT 
dose and exposure, due primarily to a large degree of inter-individual variability. PK 
evaluation conducted in healthy patients 12-15 years old revealed PK parameters similar 
to those observed in healthy adults [Priftin package insert 2009; 64]. In this latter study, 
12 adolescents with a mean age of 13.3 years were administered RPT 450 mg if <45kg, 
or 600 mg if ≥45 kg. The average weight of participants was 54.8 ± 10.4 kg. The RPT 
Cmax and AUC0- ∞ were 9.66 to 18.63 µg/mL and 397 ± 148 µg.h/L, respectively. 
Additional data will be available from TBTC Study 26, which is enrolling children and 
adolescents 2-18 years old.  
 
Sample Storage 
The protocol team feels it is important to store specimens on this study for future 
secondary work and New Work Concept Sheets (NWCS) in this population. However, 
the team also recognizes that storage of 5 years or more of longitudinal samples on 
3000 participants, most of whom will not have TB on study, is not warranted nor cost-
effective. The study will store plasma, serum, and peripheral blood mononuclear cells 
(PBMC) at entry and every 48 weeks on the first 30 participants enrolled by each site in 
a country with a high TB burden and on the first 50 participants enrolled by all U.S. sites 
combined. Samples will also be stored at TB diagnosis in any participant who develops 
active TB. This strategy will result in storage of longitudinal samples on a maximum of 
about 650 participants. Not all sites will enter 30 participants, and 40-50 of those with 


 
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longitudinal samples stored will be TB cases. Thus, this plan will store longitudinal 
samples on about 500 participants (controls) who never develop TB on study and about 
40-50 participants (cases) who do develop TB. This will also provide one-time storage at 
the diagnosis of TB on about 200 other participants (cases) who do develop TB on 
study. This provides about a 2:1 ratio of controls to TB cases which will allow matching 
and subgroup analyses, as well as high power to detect differences if all participants are 
used. This also provides longitudinal storage on a reasonable number of eventual TB 
cases for intensive analyses. We envision the ACTG reserving the latter for targeted 
high-profile work and encouraging proposers to do pilot and developmental work on the 
larger group of TB cases with one-time storage.   
 
 
3.0 
STUDY DESIGN 
 
This study is a multicenter, randomized, open-label, phase III clinical trial of an 
experimental TB treatment regimen (Arm A) of RPT/INH daily for 4 weeks compared to a 
standard TB treatment regimen (Arm B) of INH daily for 36 weeks in HIV-infected 
participants who do not have evidence of active TB. Randomization will be 1:1. 
Participants will be stratified based on (1) the most recent CD4+ cell count obtained 
within 180 days prior to entry (<100, 100-250, and >250 cells/mm3) and (2) ART use 
at entry (Yes/No). Each participant will be followed for 3 years (156 weeks) after the last 
participant is enrolled. 
 
Weeks 
Arm A (Experimental) 
Arm B (Standard) 
1 – 4 
RPT weight-based dosing*/ 
INH 300 mg daily 
INH 300 mg daily 
5 – 36 
No treatment 
INH 300 mg daily 
37-close to follow-up 
No treatment 
No treatment 
*For weight 30 to <35 kg: RPT 300 mg once daily 
*For weight 35 to <45 kg: RPT 450 mg once daily 
  
*For weight >45 kg: RPT 600 mg once daily 
*Average RPT dosage of ~10 mg/kg/administration 
 
Participants must receive pyridoxine (vitamin B6) 25 or 50 mg with each dose of INH. 
Sites will be expected to provide participants with the vitamin B6 necessary for the study. 
 
Under Version 1.0, EFV concentrations were evaluated early in the first 90 
participants in Arm A who were receiving EFV at entry and who met other criteria 
in Section 10.0. EFV PK data were evaluated on an on-going basis, as described in 
Section 10.3, to determine whether standard EFV dosing results in adequate PK 
drug exposure in the presence of RPT treatment. The A5279 team determined that 
concomitant dosing of EFV and RPT results in adequate drug exposure; thus, the 
study was opened to participants receiving NVP. NVP concentrations will be 
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meet other criteria in Section 10.0.  
 
At the implementation of Version 2.0: 
 
1. EFV concentrations and pharmacogenetics will be evaluated in an additional 
30 participants from Arm A. These 30 participants will undergo PK sampling at 
weeks 0, 2, 4, and 16.  
 
2. EFV concentrations and pharmacogenetics will be evaluated in the first 90 
participants in Arm B who are receiving EFV at entry and who meet other 
criteria in Section 10.0. PK sampling will be performed at weeks 0, 2, and 4.  
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral load. Two or more HIV-1 RNA viral loads of >1,000 copies/mL are 
also acceptable as documentation of HIV infection. 
 
NOTE: The term ‘licensed’ refers to a FDA-approved kit which is required for all 
IND studies, or for sites located in countries other than the US, a kit that has 
been certified or licensed by an oversight body within that country and validated 
internally. Non-U.S. sites are encouraged to use FDA-approved methods for IND 
studies.  
 
WHO and CDC guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. A reactive 
initial rapid test should be confirmed by either another type of rapid assay or an 
E/CIA that is based on a different antigen preparation and/or different test 
principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 
RNA viral load. 
 
4.1.2 TST reactivity ≥5 mm, or a positive interferon gamma release assay (IGRA) at 
any time prior to study entry, OR living in a high TB burden area 
 
NOTE A: In general, high TB burden areas are defined as areas with an 
estimated or reported TB prevalence of 60/100,000, according to the WHO or 
national or local health authorities. (Please refer to the A5279 protocol-
specific web page [PSWP] for the WHO link to TB prevalence information 
by country. The protocol core team [actg.corea5279@fstrf.org] should be 
consulted if a site has data to suggest that the local TB burden differs 
significantly from the WHO country estimates and, therefore, should be 
considered in the application of this inclusion criterion.)   


 
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NOTE B: At entry, all participants must have a TST performed unless one 
has been performed within 60 days prior to entry, regardless of whether 
they live in a high TB burden area. 
 
4.1.3 Laboratory values obtained within 30 days prior to entry  
 
• 
Absolute neutrophil count (ANC) >750 cells/mm3 
• 
Hemoglobin ≥7.4 g/dL 
• 
Platelet count ≥50,000/mm3 
• 
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase 
[SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic 
transaminase [SGPT]) ≤3 X upper limit of normal (ULN) 
• 
Total bilirubin ≤2.5 X ULN 
 
4.1.4 Chest radiograph or chest computed tomography (CT) scan without 
evidence of active tuberculosis, unless one has been performed within 30 
days prior to entry. 
 
4.1.5 Female participants of reproductive potential must have a negative serum or 
urine pregnancy test performed within 7 days prior to study entry. 
 
NOTE: Female participants of reproductive potential are defined as women who 
have reached menarche or who have not been post-menopausal for at least 24 
consecutive months (i.e., who have had menses within the preceding 24 months) 
or have not undergone surgical sterilization (e.g., hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation). 
 
4.1.6 All participants must agree not to participate in a conception process (e.g., active 
attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization) 
while receiving RPT and for 6 weeks after stopping this drug. 
 
4.1.7 Female participants who are participating in sexual activity that could lead to 
pregnancy must agree to use one reliable non-hormonal form of contraceptive 
(i.e., condoms, IUD, diaphragm with spermicide, or cervical cap with 
spermicide) while receiving RPT and for 6 weeks after stopping this drug.   
 
NOTE: Female participants who are not of reproductive potential, as defined 
above, or whose male partner(s) have undergone successful vasectomy with 
documented azoospermia or have documented azoospermia for any other 
reason, are eligible without requiring the use of contraceptives. Participant-
reported history is acceptable documentation of menopause, hysterectomy, or 
bilateral oophorectomy or bilateral tubal ligation. 
 
4.1.8 Men and women age ≥13 years 
 
4.1.9 Weight ≥30 kg 
 


 
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4.1.10 Ability and willingness of participant or legal guardian to provide informed 
consent 
 
4.2 
Exclusion Criteria 
 
4.2.1 Treatment for active or latent TB (pulmonary or extrapulmonary) within 2 years 
prior to study entry or, at screening, presence of any confirmed or probable TB 
based on criteria listed in the current ACTG Diagnosis Appendix  
 
4.2.2 History of multi-drug resistant (MDR) or extensively-drug resistant (XDR) TB at 
any time prior to study entry 
 
4.2.3 Known exposure to MDR or XDR TB (e.g., household member of a person with 
MDR or XDR TB) at any time prior to study entry 
 
4.2.4 Treatment for >14 consecutive days with a rifamycin or >30 consecutive days 
with INH at any time during the 2 years prior to enrollment. 
 
4.2.5 For participants taking ART at study entry, only approved NRTIs with EFV or 
NVP for at least 4 weeks are permitted. Any other regimens at entry are 
exclusionary. A list of approved antiretroviral drugs is located on the A5279 
PSWP. Participants on NVP must be dosed at 200 mg twice daily (BID).   
 
NOTE A: NVP trough levels will be evaluated in the first 90 participants in 
Arm A who are receiving NVP at entry and who meet other criteria in 
Section 10.0, after which enrolment for participants on NVP may be 
temporarily halted. NVP PK data will be evaluated to determine whether 
standard NVP dosing results in adequate PK drug exposure in the 
presence of RPT treatment. If the A5279 team determines that concomitant 
dosing of NVP and RPT results in adequate drug exposure, the study may 
continue enrollment of participants receiving NVP.   
 
NOTE B: Participants randomized to Arm A may initiate any ART regimen 
after completing four weeks of RPT/INH. Participants randomized to Arm B 
may initiate any ART regimen after study entry. 
 
4.2.6 History of liver cirrhosis at any time prior to study entry 
 
4.2.7 Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or 
light stools within 90 days prior to entry 
 
4.2.8 Diagnosis of porphyria at any time prior to study entry 
 
4.2.9 Peripheral neuropathy ≥Grade 2 according to the December 2004 (Clarification, 
August 2009) Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to 
study entry  
 


 
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4.2.10 Known allergy/sensitivity or any hypersensitivity to components of study drugs or 
their formulation 
 
4.2.11 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements 
 
4.2.12 Serious illness requiring systemic treatment and/or hospitalization within 30 days 
prior to entry 
 
4.2.13 Breastfeeding 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (PRO) at the Regulatory Support Center 
(RSC). The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all of the required documents have been received. Protocol activation 
is also required before each non-U.S. site can enroll participants into the study, 
and may be required before each U.S. site can enroll any participants. 
 
Site-specific informed consent forms (ICFs) will be reviewed and approved by the 
DAIDS PRO and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICFs 
WILL NOT be reviewed and approved by the DAIDS PRO and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the parent or 
legal guardian if the participant is younger than 18 years of age or under 
guardianship) will be asked to read and sign the approved protocol consent form.  


 
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For participants from whom a signed informed consent has been obtained, an 
ACTG Screening Checklist must be entered through the Data Management 
Center (DMC) Participant Enrollment System.  
 
For candidates from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the protocol, an ACTG Screening 
Failure Results form must be completed and keyed into the database.  
 
4.3.2 Randomization 
 
Participants who meet eligibility criteria for A5279 will be randomized to A5279 
according to standard ACTG DMC procedures.  
 
4.4 
Coenrollment Guidelines 
 
Sites are encouraged to coenroll participants in A5128 or A5243. Coenrollment in 
A5128, “Plan for Obtaining Informed Consent to Use Stored Human Biological Materials 
(HBM) for Currently Unspecified Analyses,” or A5243, “Plan for Obtaining Human 
Biological Samples at Non-U.S. Clinical Research Sites for Currently Unspecified 
Genetic Analyses,” does not require permission from the A5279 protocol chairs. For 
specific questions and approval for coenrollment in other studies, sites must contact the 
protocol chairs via e-mail as described in the Study Management section. 
 
 
5.0 
STUDY TREATMENT 
 
Study treatment for Arm A participants is RPT plus INH for 4 weeks, followed by no 
treatment through week 36. Study treatment for Arm B participants is INH for a total of 
36 weeks. All participants will be followed for 3 years (156 weeks) after enrollment of the 
last participant. 
 
The study-provided products are rifapentine (RPT) and isoniazid (INH). 
 


 
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5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens and Duration 
 
At entry, participants will be randomized (1:1) to one of the following two arms: 
Weeks 
Arm A (Experimental) 
Arm B (Standard) 
1 – 4 
Rifapentine (RPT, Priftin®),  
based on weight at entry 
For weight 30 to <35 kg: 300 mg once daily* 
For weight 35 to <45 kg: 450 mg once daily* 
 For weight >45 kg: 600 mg once daily* 
PLUS 
Isoniazid (INH) 300 mg once daily 
Isoniazid (INH) 
300mg once daily 
 
5 – 36 
No treatment 
Isoniazid (INH) 
300mg once daily 
* Average dosage of ~10 mg/kg/administration 
 
All participants must receive pyridoxine (vitamin B6) 25 or 50 mg with each dose 
of INH based on the current local, national, or international dosing guidelines. 
Sites will be expected to provide participants with the vitamin B6 necessary for 
the study. 
 
ART will not be provided by this study. Study clinicians, in conjunction with 
participants, should determine the optimal ART regimen for each participant, if 
indicated. However, for participants taking ART who are randomized to Arm A, 
only approved NRTIs with EFV or NVP are permitted for the first 4 weeks of 
study treatment with RPT; a list of approved antiretroviral drugs is located 
on the A5279 PSWP. If a participant must switch to an ART regimen that 
includes an antiretroviral drug that is not on the approved list while on 
RPT/INH, then RPT/INH must be discontinued; this participant will be followed off 
treatment, on study. 
 
At the entry visit, the site pharmacist will dispense enough study products to last 
until the next study visit. Participants must return any remaining study product 
after the completion of randomized therapy. Participants in Arm A will have 8 
weeks from enrollment to complete 4 weeks of treatment, and those in Arm B will 
have 54 weeks to complete 36 weeks of treatment. 
 
5.1.2 Administration 
 
RPT 300 mg: will be administered as two 150 mg tablets orally once daily with 
INH and is to be taken with food. 
 
RPT 450 mg: will be administered as three 150 mg tablets orally once daily with 
INH and is to be taken with food. 
 
RPT 600mg: will be administered as four 150 mg tablets orally once daily with 


 
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INH and is to be taken with food.  
 
INH 300 mg: will be administered as one 300 mg tablet or three 100 mg tablets 
orally once daily*. 
 
*NOTE: For Arm A participants, when INH is administered with RPT, both 
products will be taken together with food. For Arm B participants, when INH is 
administered alone (i.e., without RPT), INH may be taken with or without food.  
 
Pyridoxine (vitamin B6) 25 mg: will be administered as one 25 mg tablet orally 
once daily with INH. 
 
Pyridoxine (vitamin B6) 50 mg: will be administered as two 25 mg tablets or one 
50 mg tablet orally once daily with INH.  
 
5.2 
Study Product Formulation and Preparation 
 
Rifapentine will be supplied as tablets for oral administration, each containing 150 mg of 
rifapentine. Store at 25°C (77°F); excursions permitted from 15° – 30°C (59° – 86°F).  
Protect from excessive heat and humidity. 
 
Isoniazid provided through the study will be supplied as tablets for oral administration, 
each containing 300 mg of isoniazid. Store below 30°C (86°F). 
   
Isoniazid 100 mg or 300 mg tablets locally procured by the site and approved for 
use in A5279 by the protocol team must be stored in accordance with the 
manufacturer’s instructions. INH locally procured by the site must be the same 
strength and formulation for the duration of the study. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Rifapentine (RPT, Prifitin®) will be supplied by sanofi-aventis. Isoniazid (INH) will 
be supplied through the study with support from sanofi-aventis. Rifapentine 
(RPT, Prifitin®) and isoniazid (INH) will be available through the National Institute 
of Allergy and Infectious Diseases (NIAID) Clinical Research Products 
Management Center (CRPMC); however, if INH is not available through the 
CRPMC, sites may obtain a supply of INH locally to be subsequently 
dispensed to the participant. The A5279 Site Implementation Plan (SIP) 
located on the A5279 PSWP must be completed by each site for protocol 
team notification and authorization of locally sourced INH.  
 


 
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Any study product not provided by the study must comply with the NIAID 
(DAIDS) policy that outlines the process for authorizing the use of study 
products not marketed in the US in NIAID (DAIDS)-supported and/or 
sponsored clinical trials. This policy is available on the NIAID (DAIDS) 
website at: 
http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/D
ocuments/NonFDAapprovedProducts.pdf 
 
If sites have received registration approval for A5279 Version 1.0 LOA #4 or 
Version 2.0, sites may order INH from the CRPMC and should begin to use 
that drug in lieu of any INH obtained locally (as previously outlined in 
A5279 Version 1.0, LOA #2). Sites may not order INH obtained from 
Macleods via the CRPMC until they have received registration approval for 
A5279 Version 1.0, LOA #4 or Version 2.0. Additionally, for sites switching 
from locally obtained INH to INH from the CRPMC, sites should document 
and notify the A5279 core team (actg.corea5279@fstrf.org) with the date 
that INH from Macleods Pharmaceuticals Limited is implemented at the 
site.  
 
The site pharmacist can obtain the study products for this protocol by following 
the instructions in the manual Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks in the section Study Product Management 
Responsibilities.  
 
Pyridoxine (vitamin B6) will not be supplied through the study and must be 
obtained locally by the site.   
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC or other sources and subsequently 
dispensed. At US CRSs, all unused study products must be returned to the 
NIAID CRPMC (or as otherwise directed by the sponsor) after the study is 
completed or terminated. The site pharmacists at non-US CRSs must follow the 
instructions provided in the manual Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks in the section Study Product Management 
Responsibilities for the destruction of unused study-provided products. 
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medications’ and study agents' most recent 
package inserts, Investigator’s Brochures, or updated information from DAIDS to obtain 
the most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Pharmacology drug table located 
at: https://member.actgnetwork.org/cms/dl/12692. 
 


 
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5.4.1 Required Medications 
 
While on INH, pyridoxine (vitamin B6) 25 or 50 mg once daily 
 
5.4.2 Prohibited Medications 
 
The A5279 prohibited medications are listed on the A5279 PSWP. 
 
5.4.3 Precautionary Medications 
 
The A5279 precautionary medications are listed on the A5279 PSWP. 
To avoid adverse drug interactions, package inserts of anti-TB agents, 
antiretroviral agents, and other concomitant medications should be referenced 
whenever a concomitant medication is initiated or dose changed, to avoid drug 
interaction AEs. 
 
5.5 
Adherence Assessment  
 
Pill counts and self-report adherence interviews for both arms will be used to assess 
adherence during the treatment phase of each arm. Participants will also be asked to 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events 
Evaluation 
Screening 
Entry 
Treatment Phase  
Post-
Treatment 
Phase (every 
12 weeks, 
starting at 
week 48)  
Diagnosis 
of TB 
Premature Study 
Discontinuation 
Arm A: 
RPT/INH  
(weeks 2, 4, 8, 
12,16, 20, 24, 
36) 
Arm B:  
INH-only  
(weeks 2, 4, 8, 
12, 16, 20, 24, 
36) 
Documentation of HIV 
X 
 
 
 
 
 
 
Medical History/Medication 
History 
X 
 
 
 
 
 
 
Clinical Assessment1 (including 
TB assessment, adverse events, 
concomitant medications) 
X 
X 
X 
X 
X 
X 
X 
Chest Radiograph or Chest CT 
X2 
 
If indicated 
If indicated 
If indicated 
If indicated 
 
TST or IGRA 
X3 
TST 
only4 
 
 
 
 
 
Hematology 
X 
X 
Week 4 and 
if indicated 
Week 4 and 
if indicated 
If indicated 
If indicated 
X 
Liver Function Tests 
X 
X 
Week 4 and 
if indicated  
Week 4 and 
if indicated 
If indicated 
If indicated 
X 
Chemistry 
X 
X 
Week 4 and 
if indicated  
Week 4 and 
if indicated 
If indicated 
If indicated 
X 
Pregnancy Testing 
X 
 
If indicated 
If indicated 
 
 
 
 
1 A complete physical exam is required at entry; at post-entry visits, a targeted physical exam is required. 
2 Chest radiograph or chest CT is required unless one has been performed within 30 days prior to entry. 
3 For participants not living in a high TB burden area, if prior positive TST/IGRA results are not available. 
4 TST is required unless one has been performed within 60 days prior to entry for all participants, regardless of whether they live in a high TB burden 
area. An IGRA cannot be substituted at entry. 
 


 
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6.1 
Schedule of Events (Cont'd) 
 
Evaluation 
Screening 
Entry 
Treatment Phase  
Post-
Treatment 
Phase (every 
12 weeks, 
starting at 
week 48)  
Diagnosis 
of TB 
Premature Study 
Discontinuation 
Arm A: 
RPT/INH  
(weeks 2, 4, 8, 
12,16, 20, 24, 
36) 
Arm B:  
INH-only  
(weeks 2, 4, 8, 
12, 16, 20, 24, 
36) 
CD4+ 
X5 
X 
 
 
Every 48 
weeks 
 
 
Plasma HIV-1 RNA for 
Participants on ART 
 
X 
 
 
 
 
 
Sputum Acid Fast Bacilli Smear 
and/or Xpert plus Sputum 
Culture 
If indicated 
 
If indicated 
If indicated 
If indicated 
X 
 
Pill Count 
 
 
Weeks 2 
and 4 only 
X 
 
 
 
Adherence Interview 
 
 
Weeks 2 
and 4 only 
X 
 
 
 
Stored Plasma/PBMC/Serum6 
 
X 
 
 
Every 48 
weeks  
X 
 
PK Samples7, 8 
 
X 
Weeks 2 
and 4; plus 
week 16 for 
subset10  
Weeks 2 
and 4 
 
 
 
Pharmacogenetic Sample7, 9 
 
X 
 
 
 
 
 
 
5 A screening CD4+ cell count will only be collected if not done within 180 days prior to study entry. 
6 These samples will be collected on a subset of participants; see section 6.3.13.  
7 Only for participants who meet criteria in section 10.0. See section 10.0 for PK sampling directions. 
8 A subset of the participants in the PK study will have a week 16 sample collected; see section 6.3.14.    
9 If not collected at entry, this sample may be collected at week 2 or 4. 
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6.1 
Schedule of Events (Cont'd) 
 
Evaluation 
Screening 
Entry 
Treatment Phase  
Post-
Treatment 
Phase (every 
12 weeks, 
starting at 
week 48)  
Diagnosis 
of TB 
Premature Study 
Discontinuation 
Arm A: 
RPT/INH  
(weeks 2, 4, 8, 
12,16, 20, 24, 
36) 
Arm B:  
INH-only  
(weeks 2, 4, 8, 
12, 16, 20, 24, 
36) 
Stored Plasma for Virology7 
 
 
Week 8  
only 
 
 
 
 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant’s starting study 
medications. Screening evaluations to determine eligibility must be completed 
within 30 days prior to study entry unless otherwise specified.  
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a screening log and entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
On-study evaluations will occur after randomization. Entry evaluations must 
occur at least 24 hours after screening evaluations unless otherwise specified 
and be completed before initiating randomized treatment. Participants must begin 
treatment within 72 hours after randomization. 
 
6.2.3 Post-Entry Evaluations 
 
On-Treatment Evaluations  
The window for the week 2 and week 4 study visits is +/- 7 days. The window for 
all other study visits during the treatment phase is +/- 14 days. 
 
Post-Treatment Evaluations  
During the follow-up phase, the window for study visits is +/- 14 days. 
 
Diagnosis of TB 
This visit should occur at the time of or as soon as possible after the diagnosis of 
TB, preferably within 4 weeks.  
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment 
All case report forms (CRFs) must be completed and keyed for the period up to 
and including week 0 (entry). 
 
Premature Treatment Discontinuation Evaluations  
Participants who prematurely discontinue study treatment will continue to be 
followed on study, off study treatment for the remainder of the study follow-up, 
according to the schedule of events. 
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue the study will have evaluations 
performed as indicated in the schedule of events. 
 


 
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6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
Web site for information about what must be included in the source document:  
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourced
ocappndx.pdf. 
 
All protocol-required evaluations are to be recorded on the CRF and keyed into the 
database unless otherwise specified. This includes events that meet the International 
Conference on Harmonisation (ICH) definitions for a SAE: 
 
• 
Results in death 
• 
Life threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Congenital anomaly/birth defect 
• 
Other important medical event (may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the events listed above.)   
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 1.0, December 2004 (Clarification, August 2009), which can be 
found on the DAIDS RSC Web site: http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
6.3.1 Documentation of HIV-1 
 
Please refer to section 4.1.1 regarding assay requirements for HIV-1 
documentation. HIV-1 documentation is not recorded on the CRF. 
 
6.3.2 Medical History 
 
The medical history must include all prior TB, AIDS-defining events, and liver 
disease. In addition, it must include all diagnoses identified by the ACTG criteria 
for clinical events and other diagnoses within 30 days prior to study entry. For 
current criteria, refer to the appendix identified in the study CRF. Allergies to any 
medications and their formulations must be documented.  
 
6.3.3 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. A complete HIV and active or latent TB treatment 
history must be present, with start and stop dates of any antiretroviral or TB 
medication (estimated if the exact dates cannot be obtained), immune-based 
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6.3.4 Clinical Assessments 
 
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. 
The complete physical exam will also include signs and symptoms, diagnoses, 
vital signs (temperature, pulse, respiration rate, and blood pressure), height, and 
weight. 
 
TB Assessment   
To exclude active TB at study entry or to diagnose active TB on study, 
assessment of signs and symptoms should include at least the following: 
• 
Any cough, fever, night sweats and/or involuntary weight loss 
• 
Lymphadenopathy and/or abnormalities on lung examination 
 
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 
At entry, signs and symptoms of all grades that occurred 30 days before entry 
must be recorded; post-entry, only signs and symptoms Grade ≥3 must be 
recorded. Record all signs and symptoms that led to a change in treatment, 
regardless of grade. 
 
Diagnoses 
Record all diagnoses identified by the ACTG criteria for clinical events and other 
diseases.  
 
Concomitant Medications 
All new concomitant medications, including all antiretroviral medications, taken 
since the last report and current concomitant medications modified since the last 
report should be recorded.  
 
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. 
 
6.3.5 Chest Radiograph or Chest CT 
 
At screening, or within 30 days prior to study entry, and whenever active TB is 
suspected, a chest radiograph or chest CT should be performed. 
 


 
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6.3.6 TST or IGRA  
 
For those participants who are not living in a high TB burden area, a TST or a 
licensed IGRA assay will be performed at screening if prior positive test results 
are not already available. High TB burden areas are defined as areas with all 
cases of TB prevalence ≥60/100,000 of the country’s population, according to the 
WHO (http://apps.who.int/globalatlas/predefinedreports/tb/index.asp). 
 
All participants require a TST performed within 60 days prior to study entry 
or on the day of entry. If a TST was done at screening within 60 days of 
study entry, a repeat TST is not needed. If TB exposure was documented 
through an IGRA, or a TST that was performed more than 60 days prior to 
study entry, or by living in a high burden country, a TST must be performed 
within 60 days prior to study entry or at entry. Participants must return 
within 7 days to have the results read. 
 
6.3.7 Laboratory Evaluations 
 
At screening and entry, all protocol-required laboratory values must be recorded. 
For post-entry assessments, record all Grade ≥3 protocol-required laboratory 
values. All laboratory toxicities that led to a change in treatment, regardless of 
grade, must be recorded.  
 
Hematology 
Hemoglobin, hematocrit, red blood cells, white blood cell count, ANC, and 
platelets.  
 
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 has signs of jaundice.  
 
Blood Chemistries 
Sodium, potassium, chloride, bicarbonate, creatinine, and albumin.  
 
Pregnancy Test 
For women with reproductive potential: Serum or urine β-HCG (urine test must 
have a sensitivity of 15-25 mIU/mL). 
 
6.3.8 Immunologic Studies 
 
CD4+ 
CD4+ cell counts (both absolute and percentage counts) will be performed 
throughout the study at the same DAIDS-approved laboratory, if possible.   
A screening CD4+ cell count will only be collected if not done within 180 
days prior to study entry. A DAIDS-approved laboratory is not required for 


 
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the screening CD4+ count. 
 
Because of the diurnal variation in CD4+ counts, determinations for individual 
participants should be obtained consistently in either the morning or the 
afternoon throughout the study, if possible. 
 
NOTE: If the flow lab is using dual platform technology to obtain the results, each 
time a measurement is obtained, the local lab must perform a white blood cell 
count and differential from a sample collected at the same time. 
 
6.3.9 Virologic Studies 
 
Plasma HIV-1 RNA for Participants on ART 
Quantitations must be performed at a DAIDS-approved laboratory in real time 
using a licensed assay. 
 
6.3.10 Sputum Acid Fast Bacilli Smear and/or Xpert plus Sputum Culture 
 
Whenever active TB is suspected, sputum AFB smear and/or Xpert plus sputum 
culture should be performed; additional tests may be performed. Positive 
cultures should undergo speciation, and drug susceptibility testing if positive for 
MTB. A regional or central reference laboratory may be used. 
 
6.3.11 Pill Count 
 
Pill counts for INH and RPT study treatment should be performed during the 
treatment phase as indicated in the schedule of events.  
 
6.3.12 Adherence Interview 
 
Self-report interviews on adherence to INH and RPT study treatment should be 
performed during the treatment phase as indicated in the schedule of events.  
 
6.3.13 Stored Plasma/PBMC/Serum 
 
Prior to June 1, 2014, the first 30 participants enrolled at each non-US site 
and the first 50 participants enrolled in the US were assigned to have 
plasma and serum stored at entry and every 48 weeks. Samples from these 
participants will continue to be collected for the duration of the study. In 
addition, at sites with the capability, viable PBMCs are being stored for future 
testing at all time points specified above for participants assigned to have 
PBMC stored.  
 
Participants enrolled after May 31, 2014 will not be assigned to have 
plasma, serum, or PBMC samples collected at entry and every 48 weeks.   
 
At the time of or as soon as possible after diagnosis (see section 6.2.3 of 
the protocol), all participants diagnosed with active TB, regardless of 


 
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enrollment date, will have plasma, serum, and PBMCs collected (where 
possible) for future testing. Participants already selected for 
plasma/PBMC/serum storage will continue to have samples taken every 48 
weeks as previously scheduled. Otherwise, no additional 
plasma/PBMC/serum storage samples will be collected.  
 
Sites will follow storage, testing, and shipping instructions provided on the A5279 
PSWP. 
 
6.3.14 PK Samples 
 
Under Version 1.0, samples were collected from the first 90 participants in Arm 
A who were taking EFV at entry and meet other criteria in Section 10.0.  
 
Samples will be collected from the first 90 participants in Arm A who are taking 
NVP and meet other criteria in Section 10.0. 
 
Once Version 2.0 of this study is implemented: 
 
1. EFV concentrations will be evaluated in an additional 30 participants 
from Arm A. These 30 individuals will serve as controls for the EFV 
analysis. A PK sample will be collected in these 30 individuals at weeks 
0, 2 and 4 similar to the other EFV PK analysis; however, an additional 
week 16 sample will be collected as an “EFV only” sample. The week 16 
sample will allow for a washout period after completion of RPT and INH. 
 
2. Samples will also be collected in the first 90 participants in Arm B 
enrolled into Version 2.0 who are taking EFV at entry and meet other 
criteria in Section 10.0. 
 
6.3.15 Pharmacogenetic Sample 
 
This sample will be collected from those participants in Arm A and Arm B who 
are taking part in the PK study. This will include those individuals in Arm A 
who are serving as controls for EFV PK, and have consented to the collection 
of this sample. It should be collected at entry; however, if it is not collected at 
entry, it may be collected at week 2 or 4. 
 
6.3.16 Stored Plasma for Virology 
 
For those participating in the PK portion of the study, plasma will be collected at 
week 8 and stored for HIV virology. 
 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
This study will use the DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, 


 
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August 2009), which can be found on the DAIDS RSC Web site: http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
7.1 
Toxicity  
 
If study drugs are held for toxicity, participants in Arm A will have 8 weeks from 
enrollment to complete 4 weeks of treatment, and those in Arm B will have 54 weeks to 
complete 36 weeks of treatment.  
 
Grades 1 and 2: Participants may continue INH and RPT, at the discretion of the site 
investigator with careful follow-up.  
 
Grades 3 and 4: Study drugs should be held until return to baseline (entry visit levels) if 
baseline was >Grade 2, or until ≤Grade 2 or within normal limits if baseline was ≤Grade 
2. Study drugs may be permanently discontinued at the discretion of site investigator. 
Gastrointestinal 
For nausea/vomiting and/or diarrhea ≥Grade 3 or Grade 2 toxicity if symptoms were not 
present at the previous visit, all study drugs should be held until the symptoms have 
resolved. Reintroduce study drugs with caution. 
 
Antiemetic and antidiarrheal medication may be used at the site investigator's discretion. 
 
If nausea and vomiting occur as a result of hepatitis that is not due to study drugs, every 
effort should be made to reintroduce the study drugs after the symptoms subside to 
baseline levels. 
 
Cutaneous 
If Grade 2 or 3 or showing a significant increase over baseline, all study drugs should be 
held until the toxicity resolves. Study drugs should be reintroduced with caution. Grade 4 
cutaneous or Grade 4 mucocutaneous rash is a major toxicity, and all study drugs 
should be interrupted pending resolution of the toxicity. Study drugs may be permanently 
discontinued if believed to be the cause of toxicity. Study drugs may also be interrupted 
and reintroduced at the discretion of the site investigator. 
 
Drug-Associated Fever 
If ≥Grade 3, all study drugs should be held until the temperature returns to normal. Study 
drugs should be reintroduced with caution. Recurrence of symptoms on reintroduction 
will result in permanent discontinuation of the responsible agent. No alteration of dose 
will occur. 
 
Elevated Liver-Associated Enzymes  
If AST (SGOT), ALT (SGPT), or total bilirubin increase two grades over baseline (if 
baseline is <Grade 2) to maximum of Grade 3, study drugs should be held until the 
levels return to baseline or Grade 2. Reintroduce the study drug(s) with caution. 
 
If baseline was Grade 2 and liver-associated enzyme(s) increase to Grade 3, no action 
is required. 
 


 
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Grade 4 is a major toxicity, and study drugs will be interrupted pending resolution of the 
toxicity. Permanent discontinuation of study drugs is at the site investigator’s discretion. 
 
Peripheral Neuropathy 
Peripheral neuropathy associated with INH is usually avoided by the concurrent 
administration of vitamin B6. In this study, all participants will take vitamin B6 
concomitantly with INH. If peripheral neuropathy develops, every effort should be made 
to determine the etiology (i.e., whether the neuropathy is due to INH toxicity, alcohol, or 
other factors). Participants with peripheral neuropathy <Grade 2 may be entered into the 
study, but should be monitored carefully for any progression of peripheral neuropathy. 
 
For Grade 1 or 2, continue the study drugs and follow the participant more frequently for 
progression of peripheral neuropathy. Consider increase in vitamin B6 dose. For Grade 3  
or 4, discontinue INH until toxicity resolves to Grade <2; then INH may be reintroduced 
at the site investigator's discretion. If peripheral neuropathy does not resolve despite 
discontinuation of INH, the INH may be reintroduced at the site investigator's discretion. 
 
7.2 
Pregnancy 
 
Pregnant women will discontinue RPT and be treated according to in-country standard of 
care. They will be encouraged to continue on study and complete the evaluations per the 
schedule of events. At the end of the pregnancy, the outcome and AEs for the 
participant and the infant will be recorded on an outcome CRF. 
 
Disclosure of pregnancy to parents of participants who are minors will be handled 
according to in-country standard of care. 
 
Pregnancies that occur on study in female participants receiving ART should be reported 
by the CRS to The Antiretroviral Pregnancy Registry. More information is available at 
www.apregistry.com. For U.S. sites: Phone: 800-258-4263; Fax: 800-800-1052. For non-
U.S. sites: Phone: 910-679-1598; Fax: 44 1628-789-666 or 910-246-0637 
 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Permanent Treatment Discontinuation 
• 
Drug-related toxicity (see section 7.1) 
• 
Requirement for prohibited medications (see section 5.4) 
• 
Pregnancy or breastfeeding while receiving RPT 
• 
Reaching a defined clinical endpoint 
• 
Completion of treatment phase as defined by the protocol 
• 
Request by participant to terminate treatment 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity section of the protocol 
 
8.2 
Premature Study Discontinuation 
• 
3 or more consecutive missed study visits 
• 
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• 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant 
• 
Participant judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results 
• 
At the discretion of the ACTG, NIAID, IRB or EC, US FDA, Office for Human 
Research Protections (OHRP), investigator, pharmaceutical supporter, or other 
government agencies as part of their duties to ensure that research participants are 
protected.  
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
This is an open-label, randomized, phase III study to evaluate whether a short-course, 4-
week RPT/INH regimen is non-inferior to a standard 9-month daily INH regimen (9-INH) 
for the prevention of active TB in HIV-infected participants. We intend to recruit 3000 
participants. Each participant will be followed until 3 years after entry of the last 
participant. We anticipate accrual to occur at the rate of approximately 100-120 
participants per month, once a substantial number of sites that intend to participate have 
initiated accrual.  
 
9.2 
Endpoints 
 
9.2.1 Primary Endpoint: time from randomization to first diagnosis of active TB 
 
9.2.2 Secondary Endpoints 
 
9.2.2.1 Safety and tolerability:  
9.2.2.1.1 Safety endpoints: 
a) Occurrence of one or more SAEs vs. no SAEs 
b) Highest reported grade of each new Grade 3 or 4 
laboratory value or sign or symptom that is at least one 
grade increase from baseline for targeted events [i.e., 
nausea and vomiting, cutaneous, drug-associated fever, 
elevated AST (SGOT), ALT, (SGPT), or bilirubin, and 
peripheral neuropathy] 
9.2.2.1.2 Tolerability: 
Ordered categorical variable indicating most stringent level 
of study drug management due to toxicity that was required 
over the treatment period: 
1. Premature permanent treatment discontinuation 
2. Treatment hold for more than 7 consecutive days 
3. None of the above 
 
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9.2.2.3 Time from randomization to death due to a non-TB event 
 
9.2.2.4 EFV plasma concentrations at weeks 0, 2 and 4 in the first 90 
participants randomized to Arm A who enter the study taking EFV and 
who meet dose timing criteria; and, under Version 2.0, at weeks 0, 2, 
4, and 16 in the first 30 participants randomized to Arm A who 
enter the study taking EFV and who meet dose timing criteria. 
 
9.2.2.5 NVP plasma concentrations at weeks 0, 2 and 4 in the first 90 
participants randomized to Arm A who enter the study taking NVP and 
who meet dose timing criteria. 
 
9.2.2.6 Under Version 2.0, EFV plasma concentrations at weeks 0, 2, and 4 
in the first 90 participants randomized to Arm B who enter the 
study taking EFV and who meet dose timing criteria. 
 
9.2.3 Additional secondary endpoints for supportive/exploratory analyses that will be 
defined in more detail in separate analysis plans: 
 
9.2.3.1 Adherence to TB treatment: self-reported number of pills missed since 
last visit and pill count while on study drug 
 
9.2.3.2 Antibiotic resistance pattern of MTB isolates in participants who develop 
active TB 
 
9.2.3.3 HIV-1 RNA changes from baseline to week 8 in the first 90 participants 
entering the study taking EFV and who meet PK analysis dose timing 
criteria and in the first 90 participants entering the study taking NVP and 
who meet PK analysis dose timing criteria (may be evaluated only in a 
subset, e.g., those with very low EFV or NVP levels) 
 
9.2.3.4 Polymorphisms in host genes involved in metabolism or transport of EFV, 
NVP, and RPT including: CYP2B6, CYP3A4/5, SLCO1B1, CYP2A6, 
UGT2B7, PXR (pregnane X receptor), CAR (constitutive androstane 
receptor), and HFN4A (hepatocyte nuclear factor).   
 
9.2.3.5 Cost-effectiveness measures 
 
9.3 
Randomization and Stratification 
 
Participants will be randomized in a 1:1 ratio to the two arms using permuted blocks. 
Randomization will be stratified by: CD4+ cell count <100, 100-250, and >250 cells/mL; 
ART, receiving ART at entry versus not.   
 
9.4 
Sample Size and Accrual 
 
In a recently-completed phase III clinical trial comparing 6 months of daily INH (6-INH) to 
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(including death ascribed to TB) was 1.77/100 PY both in the 6-INH arm (N=328) and in 
the study as a whole (N=1150) with no attenuation over time [65]. This study excluded 
participants with an indication for ART and whose CD4+ cell counts were relatively high. 
A5279 will enroll participants with any CD4+ cell counts; thus, the team anticipates a 
higher rate of active TB. In addition, a survey of ACTG studies conducted at non-U.S. 
sites found that approximately 15% of deaths occurring at non-U.S. sites had an 
unknown cause (including causes such as “HIV disease” or “natural causes” as 
unknown). This is fewer deaths with unknown COD than in the TB study referenced 
above [personal communication]. Both because we anticipate entering participants with 
lower CD4+ cell counts and because we anticipate identification of nearly all TB-related 
deaths, we expect the rate of active TB (including death ascribed to TB) will be at least 
2.00/100 PY, and possibly higher. We will use a noninferiority design to test the 
hypothesis that the ultra-short-course RPT/INH regimen has efficacy that is no worse 
than the 9-INH control arm (standard of care [SOC]) within an accepted tolerance to 
define noninferiority. We will perform the study with a one-sided 0.025 significance level 
(i.e., 2-sided 0.05-level) and will target 90% power to confirm noninferiority if it is, in fact, 
true. Follow-up will continue to 3 years beyond entry of the last participant. Participants 
lost to follow-up and those who die from causes unrelated to TB will be censored. 
Participants with an unknown COD will be considered to be TB endpoints. Non-TB 
mortality (including unknown COD) is expected to be lower than the rate of active TB, 
and the number of deaths with unknown COD should be minimal: nonetheless, 
sensitivity analyses described below will be conducted.  
 
The following table provides total sample sizes needed to confirm the noninferiority of 
short-course RPT/INH for TB incidence rates of 2.00 and 2.25/100 PY on the SOC arm 
and a range of tolerance expressed as TB incidence rate per 100 PY of observation. The 
9-INH arm is the SOC. To provide concrete numbers for comparison and to put the 
tolerance regions in scale, the table provides the 3- and 5-year percentages of active TB 
for the control (9-INH) arm and for a range of noninferiority tolerance rates of TB per 100 
PY. We anticipate accrual will be 2 years, but could be 1.5 to 2.5 years from the time 
when substantial sites have joined the study.   
 
 
Rate/ 
100PY 
Active TB 
Percent 
Total accrual given accrual duration and 
target baseline TB rates/100PY 
 
 
3yr % 
5yr % 
1.5yr acc 
2.0yr acc 
2.5yr acc 
 
 
 
 
2.00 
2.25 
2.00 
2.25 
2.00 
2.25 
SOC arm 
2.00 
5.9% 
9.6% 
 
 
 
 
 
 
 
2.25 
6.6% 
10.8% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tolerance 
3.00 
8.7% 
14.1% 
3723 6587 3410 
6224 3335 
5945 
 
3.25 
9.4% 
15.2% 
2596 4025 2452 
3804 2326 
3608 
 
3.5 
10.1% 
16.3% 
1950 2782 1842 
2628 1747 
2494 
 
3.75 
10.8% 
17.4% 
1544 2449 1459 
1968 1383 
1867 
 
This has been adjusted for 10% total loss to follow-up (LFU) and non-TB death by 3 
years which has been modeled as an exponential competing risk, and for interim 
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Given substantial issues of adherence, which can lead to drug resistance, failure to 
complete the full 9 months of INH, and cost in use of 9-INH in clinical practice, the team 
feels an incidence rate of 3.25/100 PY as the tolerance boundary for evaluation of short-
course RPT/INH would be acceptable. This leads to a sample size of around 2452 
participants. The team proposes to accrue 3000 participants to allow essential 
subgroups, such as the CD4+ cell count and ART strata, to be evaluated with some 
degree of certainty. Should a stratum break 60:40, with 3000 participants, there is 80% 
power (2-sided alpha=0.05) to test non-inferiority within the larger stratum with the same 
3.25/100 PY tolerance. With the larger sample size, the confidence bounds on the 
difference in the TB incidence rate between the arms in the full study will be narrower 
than required to rule out the tolerance of TB incidence of 3.25/100 PY. Thus, should the 
true difference be much smaller, this can be detected to inform the field.  
 
When setting the tolerance region for a study such as this, an important consideration is 
whether the tolerance region is therapeutic. Section 2.1 contains a table of studies 
reporting placebo arm TB incidence rates in studies in HIV-infected individuals. A5279 
requires PPD or IGRA positivity or residence in an area with a high TB burden. This 
table presents the 3- and 5-year percentages of active TB for a range of incidence rates 
for active placebo in participants who were PPD+ or who were PPD+/- in a country with 
a high TB burden.   
 
 
Rate/ 
100PY 
Active TB 
Percent 
 
 
3yr % 
5yr % 
 
 
 
 
Placebo  
  5.00 
14.3% 
22.6% 
  8.00 
22.1% 
34.1% 
10.00 
27.1% 
41.0% 
 
The targeted tolerance region for this study demonstrates a considerable reduction in 
active TB compared to the reported rates with placebo. It should also be remembered 
that the tolerance region represents the limits of a 95% CI; that is, if noninferiority is 
confirmed, the actual observed rate in the short-course regimen will be substantially less 
than the tolerance boundary.   
 
9.5 
Monitoring 
 
This study will be reviewed at least annually by the NIAID African DSMB. For all reviews, 
the DSMB will be provided detailed information on safety (including mortality and 
regimen tolerability) and administrative aspects (screening failures, accrual, compliance 
with visits, specimen collection, and participant retention).   
 
We anticipate the first efficacy analysis will be performed at approximately the second 
annual review. Should accrual initiate rapidly, the review may be accelerated to ensure 
the DSMB has considered early information on the rates of active TB before accrual 
closes. Especially early in the study, an important function of the DSMB will be to 
consider the consistency of the magnitude of event rates with the design assumptions. 
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A Peto use function will be employed for formal between-arm comparisons.   
  
The primary focus of this study is relatively long-term outcomes. The team urges caution 
in considering early stopping or release of information on this study, especially if interim 
results are based on short follow-up. The team suggests that the following guidance be 
considered in deliberations: 
 
• 
If there is early evidence of the noninferiority of short-course RPT/INH, the team 
intends that the study continue to full accrual and follow-up to confirm that long-term 
results are consistent with early evidence, and to evaluate the possible superiority of 
short-course RPT/INH.  
• 
If the 99.9% CI at early interim analysis excludes an IRD of 0.00/100PY in favor of 
the RPT arm (i.e., early evidence of the superiority of RPT), the team intends that the 
study continue to full accrual and follow-up to confirm that long-term results are 
consistent with early evidence.  
• 
If the 99.9% CI at early interim analysis excludes an IRD of 0.00/100PY in favor of 
the 9-INH arm, the team intends that the study continue with close monitoring. 
• 
If the 99.9% CI at interim analysis excludes an IRD of 1.25/100PY suggesting the 
RPT arm is significantly worse than the allowed tolerance boundary, the team 
intends that consideration be given to stopping the study. 
 
Reports on safety will be provided to the DAIDS Clinical Representative every 6 months. 
In addition, periodic reports of data pooled over arm will be provided to the team that 
detail accrual, participant status, and the delinquency of forms and specimens. The 
study co-chairs will receive pooled safety information periodically. The form and 
schedule of these will be detailed in the Monitoring Plan to be developed by SDAC, the 
DMC, and the team. Some secondary objectives will not be evaluated until the end of 
the study either because they are based on subgroups that will be identified 
retrospectively or because they are not related to safety or the primary outcomes, but 
study monitoring will include assessment of the availability of data needed for identified 
analyses (eg, isolates from prophylaxis failures). 
 
The team will conduct monitoring for EFV and NVP PK as described in Section 10.0. 
 
9.6 
Analyses 
 
Primary 
The primary objective will be evaluated by calculating a CI around the difference 
between the observed TB incidence rates with the confidence level adjusted for 
stratification and interim monitoring. Data from prior studies are consistent with a 
constant TB rate, but this will be confirmed in these data. If this assumption does not 
hold, other methods will be employed (e.g., piece-wise models) to confirm whether non-
inferiority holds or not over the time frame of the study. As noted above, deaths 
attributed to TB will be considered to be endpoints. Deaths attributed to causes other 
than TB will be censored. Deaths from unknown causes are expected to be minimal. For 
the primary analysis, deaths from unknown causes will be coded as TB events. 
Sensitivity analyses will include censoring all deaths from unknown causes, including all 
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deaths from unknown causes to be due to TB or non-TB causes based on predictors of 
COD in deaths with known COD. 
 
This is functionally a strategy study, comparing 9 months of treatment to an ultra-short-
course. While strict intention-to-treat (ITT) analyses are preferred in classical superiority 
studies, they can bias noninferiority studies to erroneously confirm noninferiority if non-
compliant participants in both arms dilute the treatment difference. However, in this 
study, clinical practice in long-term INH prophylaxis suffers from noncompliance both in 
terms of adherence and also drop-off. A 9-INH arm that includes participants with non-
adherence and courses that are shorter than 9 months is the true comparator arm. Thus, 
for this noninferiority study, the ITT analysis will be primary. An ‘as treated’ analysis 
confined to those with pre-specified adherence levels and/or full course treatment (we 
anticipate poorer adherence in the 9-INH arm) will be performed for exploratory 
purposes. 
 
We will also perform multi-covariate analyses of predictors of active TB.  As required by 
NIH, interactions of gender and race/ethnicity with treatment will be formally tested and 
presented. As noted above, we will evaluate the noninferiority of short-course RPT/INH 
within the CD4+ cell count and ART strata as differences could be important to inform 
the field. There will be no adjustment to the alpha level for multiple comparisons, and 
results will be presented cautiously.   
 
Secondary 
Safety analyses will consider the rates and nature of SAEs and of Grades 3 and 4 
events, treatment modifications including temporary holds, and treatment 
discontinuations. These will be analyzed as dichotomous measures (percent of 
participants who meet a given event criterion), failure time measures (eg, time to first 
treatment modification; time to first safety event), and counts (eg, number of combined 
SAE + Grades 3 and 4 events per person). 
 
Overall mortality and non-TB mortality, including all deaths as events and possibly 
censoring traumatic death, will be evaluated with log rank tests stratified by CD4+ count 
and ART use. If there are sufficient deaths, proportional hazards modeling will be 
performed to evaluate risk factors. 
 
Adherence will be evaluated with the results of self-report interviews and pill counts. 
Associations of adherence and outcome will be explored using pre-defined levels of 
adherence. We will also explore whether there are adherence differences between the 
arms during the first month when both arms receive active intervention.   
 
The rate and pattern of antibiotic resistance among participants who are diagnosed with 
active TB will be described. Should active TB rates be around 2.00/100 PY in each arm, 
there will be about 8% TB overall on the study or 240 cases which will provide some 
opportunity to compare the rates of resistance, patterns of antibiotics to which the MTB 
organisms are resistant, and time trends in resistance.  
 
An exploratory analysis among participants in the PK study (see Section 10.0) will 
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control) and safety with both the directly observed concentrations of EFV and NVP and 
also the trough antiretroviral levels and select PK parameters (eg, AUC) derived from the 
Bayesian modeling. The EFV and NVP parameters will be evaluated both as continuous 
measures and also dichotomized at 1 mg/L (EFV) and 3 mg/L (NVP), levels that define 
acceptance in Section 10.0. 
 
9.7 
Cost-Effectiveness Analysis 
 
A previously described model of LTBI treatment will be used to estimate the costs and 
cost-effectiveness of RPT/INH as compared with other treatment strategies and no 
treatment [66]. Efficacy, adherence, and toxicity data for RPT/INH will be obtained from 
the trial, with other parameters taken from the available literature. The underlying 
probability of activation will be varied using a risk multiplier to simulate various high-risk 
populations not included in the study (HIV-negative contacts, diabetes mellitus, end-
stage renal disease, etc.). 
In the best-case scenario, costs for treatment of LTBI and active TB will be based on 
current U.S. practice. Because the costs of treating LTBI and active TB in most high-
incidence areas are largely unknown, we will make certain assumptions and then 
perform a sensitivity analysis over a wide range of estimates. 
 
Costs and cost-effectiveness (measured in cost per quality-adjusted life-years) will be 
calculated for all regimens. Analysis will focus on determining thresholds for cost, 
efficacy, and adherence parameters above (or below) which the optimal strategy 
changes. Calculations will be repeated for other simulated high-risk populations to inform 
public health policy on the appropriate use of the new regimen in various TB control 
programs. 
 
 
10.0 
PHARMACOLOGY PLAN 
 
10.1 
Pharmacology Objectives 
 
10.1.1 Primary: To investigate the effects of concomitant RPT/INH administration on 
EFV or NVP PK and assess these concentrations relative to baseline values and 
historical controls with and without RIF, and accepted minimal effective EFV and 
NVP concentrations.  
 
For this study, the historical control for EFV PK data will be from the 
pharmacology substudy conducted as part of A5095. This study population 
consisted of HIV-infected persons who were treatment-naïve with plasma HIV 
RNA levels >400 copies/mL and not receiving concomitant agents that interact 
with EFV. The first choice for historical control data for NVP, like EFV, will be 
from ACTG studies. One published population PK study of NVP is from ACTG 
241, a study in HIV-infected persons who also received ZDV and ddI [67].   
 
10.1.2 Secondary: To investigate the PK of RPT.   
 


 
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10.1.3 Secondary: To investigate relationships among genetic characteristics of drug 
metabolizing enzymes and drug transporters and the PK characteristics of EFV, 
NVP, and RPT.   
 
10.1.4 Determine the PK characteristics of EFV and its 7-OH-EFV and 8-OH-EFV 
metabolites when given in combination with RPT+INH (Arm A) and when 
given with INH alone (Arm B). 
 
10.1.5 Compare EFV PK data obtained from combination therapy with RPT+INH 
and INH alone with a control group consisting of a set of plasma samples 
with participants receiving ART containing EFV but not RPT or INH, which 
will be collected from individuals in Arm A that have completed RPT/INH 
therapy and have allowed for a washout period.  
 
10.2 
Pharmacology Study Design 
 
The pharmacologic evaluations are designed to provide information on whether RPT, 
because of its CYP3A-inducing properties, decreases the concentrations of the NNRTIs, 
EFV and NVP, which are both substrates for CYP3A. The hierarchy for rifamycin 
enzyme-inducing potency is: RIF > RPT > rifabutin (RFB). RIF reaches maximal enzyme 
induction at a dose of 600 mg once daily. RPT enzyme induction exhibits dose 
dependency. At a RPT dose of 600 mg once daily, the enzyme induction appears close 
to that of RIF at 600 mg once daily; lower RPT doses of 300 mg once daily or 600 mg 
every 3 days produce less enzyme induction than RPT at 600 mg once daily and RIF at 
600 mg once daily [30]. There is considerable information on the PK of EFV and NVP 
when given with RIF; there are no data available on the effect of RPT on the PK of EFV 
and NVP. The pharmacologic evaluations for A5279 are designed to provide data on the 
effects of RPT on the PK of EFV and NVP.   
  
The effect of RPT on the PK of EFV was evaluated before participants on NVP 
were allowed to enroll into this study. The A5279 team reviewed the EFV PK data 
on an on-going basis, as described in section 10.3. Since these data showed 
adequate EFV exposure in the presence of RPT treatment, the study is open to 
participants on NVP, and NVP PK will be evaluated in the first 90 participants in 
Arm A taking NVP at entry. NVP PK will be evaluated in a similar manner as the 
EFV PK analysis was conducted. 
 
Data are accumulating to suggest that INH affects EFV clearance primarily 
through the CYP2A6 pathway. The effect of RPT on EFV clearance is expected to 
occur through induction of the CYP2B6 pathway. Each of these two pathways 
leads primarily to different metabolites of EFV. The 8-hydroxy-efavirenz metabolite 
is the primary metabolite formed via the CYP2B6 pathway, while the 7-hydroxy-
efavirenz metabolite is the primary metabolite formed via the CYP2A6 pathway. 
Therefore, quantitation of these metabolites of EFV will allow investigation of the 
separate effects of RPT and INH on EFV metabolism.   
 
At the implementation of Version 2.0: 
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A. These 30 participants will serve as controls for the EFV analysis. A PK 
sample will be collected in these 30 individuals at weeks 0, 2, and 4 similar to 
 the other EFV PK analysis; however, an additional week 16 sample will be 
collected as an “EFV only” sample. The week 16 sample will allow for a 
washout period after completion of RPT and INH. 
 
2. Additional pharmacologic assessments will be made in Arm B (INH only) to 
investigate the effect of INH on EFV metabolism.  Arm B participants receive 9 
months of daily INH therapy. Pharmacologic evaluations, similar to those 
performed in the first 90 participants in Arm A, will be made in the first 90 
subjects in Arm B who are taking EFV at entry at the time of implementation of 
protocol Version 2.0. These PK assessments will take place at weeks 0, 2, and 
4, as they are in Arm A. EFV and its major metabolites, 7-OH-EFV and 8-OH-
EFV will be quantified in human plasma. Concentrations of EFV and its 
metabolites will also be determined from the samples already collected from 
first 90 participants in Arm A. The addition of these assessments from Arm B 
patients will allow the team to better understand what role each of the anti-
tuberculosis drugs, INH and RPT, individually have on EFV metabolism. At 
present, there are no such data available.  
 
A sparse sampling approach will be used in A5279. The rationale for this approach is 
based on the following considerations. First, data exist on the PK of EFV and NVP in 
HIV-infected participants with and without concomitant RIF administration [67; 68, 69, 
70]; unpublished data from ACTG studies A5095/A5097s and A5221]. Second, RPT at a 
dose of 600 mg/day is not expected to produce enzyme induction any greater than that 
of RIF 600 mg/day [29]. Therefore, third, if RPT indeed reduces EFV and NVP 
concentrations, this reduction should not be greater than that observed with RIF. These 
considerations allow a sparse sampling approach (versus an intensive dose-interval PK 
study) to investigate whether EFV and NVP concentrations in the presence of RPT are 
more comparable to historical controls who are receiving RIF, or to historical controls 
who are not receiving RIF. 
 
Exposure-response relationships between EFV and NVP concentrations and virologic 
failure have been demonstrated. For example, Cohen recently reported that in an 
evaluation of 142 HIV-infected persons, EFV concentrations <1 mg/L were strongly 
associated with an increased risk for virologic failure (odds ratio 12.5, 95% CI, 2.7-57.3) 
[69]. The collective data for EFV indicate an increased risk of virologic failure if trough 
(or mid-interval) concentrations are less than 1 mg/L. EFV PK data from A5097 indicate 
that 21% of participants receiving the standard dose of EFV had trough concentrations 
less than 1 mg/L. These data provide a basis to select for this study that the proportion 
of participants who have trough concentrations less than 1 mg/L when EFV is combined 
with RPT is not greater than 20%. Several investigations have found relationships 
between low NVP trough concentrations and an increased risk of virologic failure. de 
Vries-Sluijs reported a 5-fold increased risk of virologic failure in participants who had 
NVP trough concentrations less than 3 mg/L. A NVP trough of less than 3 mg/L is the 
present consensus threshold for an increased risk of virologic failure [71]. In adults 
receiving the usual NVP dose of 200 mg twice daily, the proportion of participants who 
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These data form a basis, like that for EFV, that proportion of participants with trough 
NVP concentrations less than 3 mg/L is not greater than 20%.   
 
Differences among patients in their PK characteristics of EFV, NVP, and RPT are known 
to arise as a result of differences in genes that encode for drug-metabolizing enzymes 
and drug transporters. Because PK variability has been associated with differences in 
drug response, understanding whether the differences in concentrations has a genetic 
basis in how the drug is metabolized, or a nongenetic basis (e.g., patient medication 
adherence) is important to understand the treatment outcomes of A5279. Participants 
will be asked to provide informed consent to study polymorphisms in host genes 
involved in metabolism or transport of EFV, NVP and RPT. Consent for genetic testing is 
optional, and a participant may refuse genetic sampling and still participate in the study. 
The genes of interest for A5279 are: CYP2B6, CYP3A4/5, SLCO1B1, CYP2A6, 
UGT2B7, PXR (pregnane X receptor), CAR (constitutive androstane receptor), and 
HFN4A (hepatocyte nuclear factor).   
 
1. EFV Sample Size: 90 participants receiving EFV and RPT/INH (Arm A) sampled at 
weeks 0, 2, and 4. 
 
Version 2.0 will also include the following EFV evaluations:  
 
a. 30 additional participants receiving EFV from Arm A sampled at weeks 0, 2, 
4, and 16, to serve as controls 
b.  90 participants receiving EFV and INH (Arm B) sampled at weeks 0, 2, and 4. 
 
2. NVP Sample Size: 90 participants receiving NVP and RPT/INH (Arm A) sampled at 
weeks 0, 2, and 4. 
 
3. EFV Sampling Strategy 
The sampling strategy for EFV assumes that EFV doses will be taken in the evening.  
Blood samples for quantitation of EFV will be obtained at three study visits: entry 
(prior to the start of RPT and INH, Arm A) and the weeks 2 and 4 study visits. The 
control participants from Arm A (n=30), who will be enrolled with Version 2.0, 
will have an additional PK sample obtained at week 16, in addition to weeks 0,2 
and 4. One blood sample will be obtained at each visit. With the dose taken the night 
before, this sample should be approximately 12 hours post dose, but should not be 
drawn any sooner than 10 hours after the previous evening’s dose or any later than 
24 hours after the dose. 
 
If the study participant is taking EFV in the morning, the participant should change to 
evening dosing for the PK studies. After completion of the week 4 PK study, the 
participant may then change back to morning dosing, with the exception of 
controls who should wait until after the week 16 sample has been drawn to 
change their dosing time. The following schedule may be used for the conversion 
from morning to evening dosing. 
 
Entry Day -4 
Four days prior to the entry (week 0) PK visit, the morning 
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Entry Day -3 
Three days prior to the entry visit and the pre-RPT PK sample, 
a morning dose should be taken as usual.  Additionally on this 
day, a bedtime dose should be taken; this dose will be taken 
approximately 12 hours after the morning dose. 
Entry Day -2 
NO morning dose should be taken. A bedtime dose of EFV 
should be taken. 
Entry Day -1 
A bedtime dose should be taken. 
 
 
Entry/PK Study 
Day 0 
Blood samples for the PK study will be taken as described 
above. A bedtime dose of EFV should be administered. The 
bedtime dosing schedule for EFV should be maintained 
through the week 4 PK sample, or week 16 for the controls.   
+1 day after week 
4 (or 16 in a 
subset) PK 
A morning dose of EFV should be taken; this dose will be 
approximately 12 hours after the evening dose given on Study 
Day 0. NO bedtime dose should be taken. 
+2 day after week 
4 (or 16 in a 
subset) PK 
The participant’s usual dosing schedule for EFV should be 
resumed. 
 
4. NVP Sampling Strategy 
The sampling strategy for NVP assumes twice daily administration with one dose in 
the morning and one dose in the evening. Blood samples for quantitation of NVP will 
be obtained at three study visits: entry (prior to the start of RPT and INH, Arm A) and 
the weeks 2 and 4 study visits. One blood sample will be obtained at each visit. This 
sample should be obtained before the morning dose of NVP is administered, and 
thus should be approximately 12 hours after the prior evening’s dose. This sample 
should not be taken any earlier than 10 hours or later than 14 hours after the prior 
dose.   
 
5. Medication Adherence 
In all cases, the times and dates of all doses of RPT and either EFV or NVP taken in 
the previous 3 days must be recorded on the CRF. Samples should not be collected 
from participants who have missed any doses of RPT and EFV, or NVP within 3 days 
prior to the study visit.  
 
6. EFV, 7-OH-EFV, 8-OH-EFV, and NVP Quantitation 
EFV, 7-OH-EFV, 8-OH-EFV, and NVP concentrations will be determined in a Clinical 
Laboratory Improvement Amendments (CLIA)-certified laboratory. The goal is for 
EFV and NVP concentration information from the entry and weeks 2 and 4 (and 16 
in a subset) samples to be available for evaluation by the A5279 team during the 
course of the study. 
 
7. RPT PK 
At the time that a blood sample is obtained for EFV or NVP at the weeks 2 and 4 
visits, an additional blood sample will be obtained for RPT. RPT has an approximate 
15-hour half-life which allows sampling at the same time that samples are collected 
for EFV or NVP. 
 


 
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8. Pharmacogenetics. 
An optional blood sample for genetic testing of variations in drug metabolizing 
enzymes and drug transporters for EFV, NVP, and RPT will be collected at the entry 
visit (prior to the start of RPT and INH) from participants who are also having an 
entry sample obtained for measurement of either EFV or NVP. If this sample is not 
collected at entry, it may be collected at week 2 or 4.  
 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
1. The EFV PK data will be judged acceptable if we have evidence that >80% of 
participants have EFV concentrations ≥1 mg/L. 
 
2. The NVP PK data will be judged acceptable if we have evidence that >80% of 
participants have NVP concentrations ≥3 mg/L.   
 
Any participant who has a baseline (pre-RPT) sample or a week 2 or 4 sample in 
which the concentration for the relevant ARV is below the limit of quantitation will be 
deemed to be non-adherent, and the PK data will not be evaluable. The observed 
concentrations of EFV and NVP and the times post dose that these concentrations were 
obtained will be summarized. In addition, because exact trough levels (pre-dose 
concentrations) are not required to be obtained, the PK characteristics of EFV and NVP 
may be estimated for each individual participant and trough concentrations estimated 
using these EFV and NVP PK parameters. Parameter estimation will be accomplished 
using Bayesian estimation methods implemented in ADAPT II (Biomedical Simulations 
Resource at the University of Southern California, Los Angeles, CA). This approach 
utilizes maximum a posterior Bayesian estimation (MAP) to estimate individual PK 
parameters utilizing prior information for the population mean and variances of the PK 
characteristics of EFV. Prior PK data for EFV indicate that its PK characteristics are 
sufficiently well described with a 1-compartment structural model. A proportional 
variance model will be used to describe the output error associated with the 
concentration-time data (variance model). Each observation will be inversely weighted 
by the model-based estimated variance (of the corresponding predicted value), 
assuming the variance is proportional to the predicted value and coefficient of variation 
of 10% for the assay. The primary estimated PK parameters will include the volume of 
the distribution (V), and elimination rate constant (ke). Apparent oral clearance (CL/F), 
elimination half-life (T1/2), and AUC will be calculated from these parameters using 
standard equations.  
 
The team wishes to detect any issues that might exist with EFV or NVP 
concentrations very early in accrual of participants receiving these ARVs. The 
team will assess the proportion of participants who have acceptable (as defined above) 
EFV and NVP concentrations up to four times during the study for EFV and NVP 
separately. The first phase of the evaluation will be conducted in the first 31 
evaluable participants who are distributed across key geographic regions, 18 
years or older, and receiving an ARV. The second phase assessment will be made 
when trough levels are available for a total of approximately 90 evaluable participants at 
weeks 2 and 4. Samples in the first phase (first 31 evaluable participants who are 
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evaluation and decision making in this early phase. Should early accrual of 
participants receiving EFV or NVP be so rapid that a substantial number of the 90 
would be entered before the first 31 who are 18 years or older can be evaluated, 
accrual of participants receiving that ARV may be suspended pending results of 
the first phase assessment. Accrual of participants receiving that ARV would be 
resumed if the results in the first phase were acceptable. 
 
The first phase assessment will be conducted in 2 or 3 stages depending on the 
rate of accrual of evaluable participants. Accrual for the PK evaluation may pause 
within the first phase for evaluation of data, such as adherence or the metabolizer 
and transporter genes noted above, should early results be of concern. Assuming 
the first phase is conducted in three stages, the first evaluation for each agent will 
be made when weeks 2 and 4 trough levels are available for 9 evaluable 
participants; if ≤4 of the 9 have acceptable ARV levels at both weeks 2 and 4, the 
team would consider this to be of concern. The second evaluation will be made 
when weeks 2 and 4 trough levels are available for 21 evaluable participants; if 
≤12 of the 21 have acceptable ARV levels at both weeks 2 and 4, the team would 
consider this to be of concern. The third evaluation will be made when weeks 2 
and 4 trough levels are available for 31 evaluable participants; if ≤20 of the 31 
have acceptable ARV levels at both weeks 2 and 4, the team would consider this 
to be of concern. This rule was developed to have a high likelihood (95% or 
higher) of continuing to accrue participants if the true underlying rate of having 
acceptable ARV concentrations is greater than 80% and meets both Optimum and 
Min/Max criteria [72; conducted with PASS 2011]. Should accrual of participants 
receiving an ARV be so rapid that the first phase evaluation with 21 participants 
would be uninformative, it will not be performed and the first and third evaluation 
rules will apply: ie, the team would be concerned if ≤4/9 or ≤20/31 participants 
have acceptable ARV levels.   
 
The following table provides overall probabilities that ARV levels will be found 
acceptable in the first phase assessment for a range of values for the true 
underlying proportion who fail to have acceptable ARV levels at weeks 2 and 4. 
These probabilities are provided for the 3-stage and 2-stage options in the first 31 
evaluable participants. 
 
Underlying rate 
Failing criteria 
Prob finding 
Acceptable  
3-stage 
Prob finding 
Acceptable 
2-stage 
0.20 
0.951 
0.954 
0.40 
0.225 
0.221 
0.45 
0.096 
0.098 
0.50 
0.033 
0.033 
0.60 
0.001 
0.002 
 
That is, if the true probability of failing to meet the ARV level is 20% (so greater 
than 80% having acceptable drug levels), there is greater than 95% likelihood of 
finding the drug levels at weeks 2 and 4 to be acceptable. If, however, the true 
probability of failing to meet the ARV level criterion is 45% (so showing evidence 


 
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that the true rate achieving acceptable levels might be only 55%), there is less 
than a 10% chance of erroneously concluding the drug levels at weeks 2 and 4 to 
be acceptable in the first 31 evaluable participants. This design has very low 
likelihood of failing to detect very high probabilities of low drug concentrations, 
and we will be conducting a second phase assessment in 90 participants that will 
have a high likelihood of detecting true smaller proportions with unacceptable 
drug levels. As noted above, PK samples in the first 31 participants will be 
assayed rapidly; should the pharmacologists note early issues before an 
assessment stage is accrued (e.g., if it becomes clear before 9 participants have 
data that only 4 or fewer evaluable participants will have acceptable drug levels), 
the A5279 core team will be notified. Of note, the 3- and 2-stage designs have very 
similar probabilities of finding various proportions acceptable; however, the 3-
stage design provides an earlier time point to detect unacceptable levels should 
the accrual rate be modest.   
 
The second phase assessment will include all 90 participants with detectable ARV 
levels at baseline and weeks 2 and 4, and will also consider all participants with a 
detectable level at baseline. The primary evaluation will consist of constructing a 
lower 95% confidence interval (CI) on the proportion of participants who have 
acceptable drug levels at both weeks 2 and 4. The CI in all 90 will not be adjusted 
for the first phase assessment as the first phase is conducted only in those 18 
years of age or older. If the first 31 were a true subset of all 90, adjustment for the 
multi-phase (with 2 or 3 stages in the first phase) would ‘shift’ the lower 95% CI on 
the observed success rate upward in a more favorable direction. Thus, not making 
an adjustment in all 90 is conservative. We will confirm this by constructing an 
adjusted CI for the proportion who have acceptable drug levels in all participants 
18 years or older among the 90 in the primary analysis.  
 
The team may also apply a bioequivalence approach for an evaluation of the baseline 
(pre-RPT) and the weeks 2 and 4 samples. This approach will evaluate whether the 90% 
CIs of the ratios of plus RPT trough concentrations of EFV and NVP relative to the 
baseline (or no RPT) troughs are contained within a specified no effect boundary. The 
usual FDA no effect range is 0.80 to 1.25. However, where exposure-response data 
exist, these data may be used to establish the no effect boundary. The threshold troughs 
for EFV and NVP, which have clinical support, could be used as these no-effect 
boundaries. If the 90% CI for exposure ratios falls entirely within the equivalence range 
we could conclude that a clinically significant effect of RPT on EFV and NVP is not 
found. 
 
Prior to the implementation of Version 2.0 of the protocol, the A5279 team 
reviewed the EFV PK data, as described in section 10.3. Since these data showed 
adequate EFV exposure in the presence of RPT treatment, the study was opened 
to participants on NVP, and NVP PK will be evaluated in the first 90 participants in 
Arm A taking NVP at entry. NVP PK will be evaluated in a similar manner as the 
EFV PK analysis was conducted. 
 
Relationships between concentrations of EFV, its 7 and 8 hydroxy metabolites, 
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EFV is predominantly formed via the CYP2A6 pathway whereas the 8-hydroxy 
metabolite is formed via the CYP2B6 pathway. Metabolite profiles will yield insight 
into which pathway is the dominant metabolizing pathway in genetic subsets of 
individuals taking EFV and INH ± RPT. Additionally, analyzing metabolite profiles 
will separate the interactions of INH and RPT with EFV. Geometric mean ratios 
(GMR) will be developed for estimated clearance values for the populations in 
each study arm. The GMR of EFV clearance from the control group of participants 
on EFV (no RPT or INH) to the clearance of those participants on Arm B (INH) of 
the study will give the field important insight into what effect INH has on EFV 
clearance.  CYP2A6 status will be defined as a covariate for this analysis. 
Secondly, a GMR for control (EFV only) to Arm A (RPT+INH) participants’ 
clearance will be developed.  From this data, we will be able to test whether the 
induction effects of RPT on CYP2B6 are negated by INH inhibition of CYP2A6, and 
what the overall effect on EFV metabolism is, again using participants’ genotypes 
as covariates for the analysis. The control EFV participants will be established 
from a set of participants in Arm A on EFV containing regimens. These 
participants will serve as the EFV only controls and will have a PK sample drawn 
at weeks 0, 2, 4, and additionally week 16.  
 
Pharmacodynamic (PD) Modeling   
For this analysis, the PK characteristics of EFV and NVP will be evaluated using 
NONMEM version V (GloboMax, Hanover, MD), which uses mixed effects (random and 
fixed) regression to estimate population means and variances of PK parameters and to 
identify patient characteristics (covariates) that may influence these parameters. Base 
models will be developed using first-order conditional estimation with interaction (FOCE-
I). A stepwise procedure will be used to determine whether a 1- or 2-compartment model 
best fits the plasma data under the principle of parsimony. An exponential error 
distribution will be assumed for the description of both interpatient and intrapatient 
(residual) PK parameter variability. Residual error will be modeled as an additive plus 
proportional error model. If necessary, poorly identified structural parameters, such as 
the absorption rate constant, may be fixed to usual adult values. Covariates including 
sex, age, weight, race, and genetic characteristics of drug metabolizing enzymes and 
transporters will be investigated. The influence of each covariate on the PK 
characteristics of EFV and NVP will be tested sequentially. At the end of the analysis, all 
covariates that show an influence on the parameters will be evaluated again by 
comparison of the full model (with all factors included) with a model from which each of 
the factors is deleted sequentially. NONMEM uses extended least squares to calculate 
the objective function and the difference in the value of the objective function between 
models is approximately chi squared distributed. A difference in objective function of 
greater than 6.6 is considered significant (6.6 corresponds to a chi square for p=0.01 
with 1 degree of freedom) when one parameter is added or the covariate (e.g., body 
weight, HIV-1 RNA) is replaced. This is analogous to the commonly used F test to select 
among regression models. The outcome of this analysis is to identify the model that best 
describes the plasma PK of EFV and NVP, and to investigate whether any patient 
characteristics influence the PK of these antiretroviral agents. Following finding the 
model that best describes the plasma PK characteristics of EFV and NVP, we will next 
develop a linked PK and PD model to investigate relationships among the PK 
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of safety and tolerance such as liver function tests. These PD models may be in the form 
of a linear or a sigmoid Emax relationship where, for example, lower EFV concentrations 
are related to detectable levels of HIV-1 RNA in plasma.   
 
RPT PK  
The observed concentrations of RPT and the times post dose that these concentrations 
were obtained will be summarized. The concentration data will be evaluated for evidence 
of adherence to RPT. Additionally, a population PK analysis using an approach as 
described above for EFV and NVP may be performed. Finally, RPT concentration 
information may be used in the evaluation of the primary (efficacy) and secondary 
(safety, adherence, and resistance) endpoints of the A5279 study.   
 
10.4 
Anticipated Outcomes 
 
At present, there are no data on the PK of EFV or NVP when combined with RPT. These 
PK evaluations will provide information on EFV and NVP concentrations when given 
concomitantly with RPT and whether the proportion of participants who have EFV or 
NVP concentrations less than the accepted minimum values is higher than observed in 
participants taking EFV and NVP without inducers of drug metabolism. Information will 
be obtained as to whether host genetic differences contribute to differences among 
participants in EFV, NVP, and RPT concentrations. The pharmacologic data from A5279 
should provide guidance as to whether a significant drug-drug interaction exists that 
would warrant further evaluation, or in the absence of such a signal, information for 
clinicians that EFV and NVP may be combined with RPT.   
 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
CRFs will be provided for each participant. Participants must not be identified by name 
on any CRFs. Participants will be identified by the patient identification number (PID) 
and study identification number (SID) provided by the ACTG DMC upon randomization. 
 
11.2 
Role of Data Management 
 
11.2.1 Instructions concerning the recording of study data on CRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
11.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 


 
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11.3 
Clinical Site Monitoring and Record Availability 
 
11.3.1 Site monitors under contract to the NIAID will visit participating CRSs to review 
the individual participant records, including consent forms, CRFs, supporting 
data, laboratory specimen records, and medical records (physicians’ progress 
notes, nurses’ notes, individuals’ hospital charts), to ensure protection of study 
participants, compliance with the protocol, and accuracy and completeness of 
records. The monitors also will inspect sites’ regulatory files to ensure that 
regulatory requirements are being followed and sites’ pharmacies to review 
product storage and management. 
 
11.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily available 
for inspection by the local IRB or EC, the site monitors, the US FDA, the NIAID, 
the OHRP, and the pharmaceutical supporter or designee, or other government 
agencies for confirmation of the study data. 
 
11.4 
Expedited Adverse Event (EAE) Reporting  
 
11.4.1 AE Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC 
website at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
The DAIDS Adverse Events Reporting System (DAERS), an internet-based 
reporting system must be used for EAE reporting to DAIDS. In the event of 
system outages or technical difficulties, EAEs may be submitted via the DAIDS  
EAE Form. For questions about DAERS, please contact DAIDS-ES at DAIDS-
ESSupport@niaid.nih.gov. Site queries may also be sent from within the DAERS 
application itself. 
 
Sites where DAERS has not been implemented will submit EAEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: http://rsc.tech-
res.com/safetyandpharmacovigilance/. For questions about EAE reporting, 
please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2 Reporting Requirements for this Study 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study from the time of enrollment until 8 weeks after 
the participant permanently discontinues all study agents. After this time, the 
SUSAR Reporting Category will be used. 
 
The study agents for which expedited reporting are required are rifapentine and 
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11.4.3 Grading Severity of Events 
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification dated 
August 2009) must be used and is available on the DAIDS RSC Web site at: 
http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
11.4.4 EAE Reporting Period 
 
The EAE reporting period for this study is the entire study duration for an 
individual participant (from study enrollment until study completion or 
discontinuation of the participant from study participation for any reason). 
 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected unexpected serious adverse reactions (SUSARs) as defined in 
Version 2.0 of the EAE Manual will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (e.g., from publicly available 
information). 
 
 
12.0 
HUMAN PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB or EC responsible for oversight 
of the study. A signed consent form will be obtained from the participant (or parent or 
legal guardian for those below the legal age of consent). The consent form will describe 
the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy of the consent form will be given to the participant, parent, or legal 
guardian, and this fact will be documented in the participant’s record. 
 
12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by ACTG, IRB or EC, NIAID, US FDA, 
OHRP, the pharmaceutical supporter or designee, or other government agencies.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, NIAID, IRB or EC, US FDA, 
OHRP, the pharmaceutical supporter, or other government agencies as part of their 
duties to ensure that research participants are protected.  
 
 


 
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13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the 
pharmaceutical supporter prior to submission.  
 
 
14.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. All dangerous goods materials, including diagnostic 
specimens and infectious substances, must be transported using packaging mandated 
by CFR 42 Part 72.  
 
Please refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  


 
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15.0 
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repeated administration of rifapentine and its lack of effect on steady-state rifapentine 
pharmacokinetics: part I. Int J Tuberc Lung Dis 1999;3:426-36. 
30. Dooley K, Flexner C, Hackman J, et al. Repeated administration of high-dose 
intermittent rifapentine reduces rifapentine and moxifloxacin plasma concentrations. 
AAC 2008;52(11):4037-42. 
31. Zvada SP, Van Der Walt J-S, Smith PJ, et al. Effect of four different meals types on the 
population pharmacokinetics of single dose rifapentine in healthy volunteers. AAC 
2010;58(8):3390-4. 
32. Prasad B, Bhutani H, Singh S. Study of the interaction between rifapentine and isoniazid 
under acid conditions. Pharmaceut  Biomed Anal 2006;41:1438-41. 


 
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33. Weiner M, Prihoda TJ, Peloquin C, et al. Effects of tuberculosis, race, and human gene 
SLCO1BI polymorphisms on rifampin concentrations. Antimicrob Agents Chemother 
2010;54(10):4192-200. 
34. Keung A, Eller MG, McKenzie KA, et al. Single and multiple dose pharmacokinetics of 
rifapentine in man: part II. Int J Tuberc Lung Dis 1999;3:437-44. 
35. Kenny MT, Strates B. Metabolism and pharmacokinetics of the antibiotic rifampin. Drug 
Metab Rev 1981;12:159-218. 
36. Rosenthal IM, Williams K, Tyagi S, et al. Potent twice-weekly rifapentine-containing 
regimens in murine tuberculosis. Am J Respir Crit Care Med 2006;174:94-101. 
37. Peloquin CA, Jaresko GS, Yong CL, et al. Population pharmacokinetic modeling of 
isoniazid, rifampin, and pyrazinamide. Antimicrob Agents Chemother 1997;41:2670-79. 
38. Almeida D, Nuermberger E, Tasneen R, et al. Paradoxical effect of isoniazid on the 
activity of rifampin-pyrazinamide combination in a mouse model of tuberculosis. 
Antimicrob Agents Chemother 2009;53:4178-84.  
39. Dooley KE, Flexner C, Andrade AS. Drug interactions involving combination 
antiretroviral therapy and other anti-infective agents: Repercussions for resource-
limited countries. J Infect Dis 2008;198(7):948-61. 
40. Lopez-Cortes LF, Ruiz-Valderas R, Viciana P, et al. Pharmacokinetic interactions 
between efavirenz and rifampicin in HIV-infected patients with tuberculosis. Clin 
Pharmacokinet. 2002;41(9):681-90. 
41. Manosuthi W, Chumpathat N, Chaovavanich A, Sungkanuparph S. Safety and 
tolerability of nevirapine-based antiretroviral therapy in HIV-infected patients 
receiving fluconazole for cryptococcal prophylaxis: A retrospective cohort study. 
BMC Infect Dis. 2005;5:67. 
42. Manosuthi W, Sungkanuparph S, Thakkinstian A, et al. Efavirenz levels and 24-
week efficacy in HIV-infected patients with tuberculosis receiving highly active 
antiretroviral therapy and rifampicin. AIDS. 2005;19(14):1481-86.  
43. Pedral-Sampaio DB, Alves CR, Netto EM, Brites C, Oliveira AS, Badaro R. Efficacy 
and safety of efavirenz in HIV patients on rifampin for tuberculosis. Braz J Infect 
Dis. 2004;8(3):211-6. 
44. Friedland G, Khoo S, Jack C, Lalloo U. Administration of efavirenz (600 mg/day) 
with rifampicin results in highly variable levels but excellent clinical outcomes in 
patients treated for tuberculosis and HIV. J Antimicrob Chemother. 
2006;58(6):1299-1302. 
45.  Friedland G, Jack C, Khoo S, Lalloo U, Naidoo V. Efavirenz levels and clinical 
outcomes in patients with TB and HIV treated concomitantly with ART and 
rifampin-containing TB regimen, abstract 891. 12th Conference on Retroviruses 
and Opportunistic Infections (CROI), Boston, MA. 2007. 
46. Patel A, Patel K, Patel J, Shah N, Patel B, Rani S. Safety and antiretroviral 
effectiveness of concomitant use of rifampicin and efavirenz for antiretroviral-
naive patients in india who are coinfected with tuberculosis and HIV-1. JAIDS 
2004;37(1):1166-9. 


 
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47. Autar RS, Wit FW, Sankote J, et al. Nevirapine plasma concentrations and 
concomitant use of rifampin in patients coinfected with HIV-1 and tuberculosis. 
Antivir Ther. 2005;10(8):937-43. 
48. Ramachandran G, Hemanthkumar AK, Rajasekaran S, et al. Increasing nevirapine 
dose can overcome reduced bioavailability due to rifampicin coadministration. J 
Acquir Immune Defic Syndr. 2006;42(1):36-41. 
49. Boulle A, Van Cutsem G, Cohen K, et al. Outcomes of nevirapine- and efavirenz-
based antiretroviral therapy when coadministered with rifampicin-based 
antitubercular therapy. JAMA. 2008;300(5):530-9. 
50. Avihingsanon A, Manosuthi W, Kantipong P, et al. Pharmacokinetics and 48-week 
efficacy of nevirapine: 400mg versus 600 mg per day in HIV-tuberculosis 
coinfection receiving rifampicin. Antivi Ther. 2008; 13 (4): 529-36. 
51. Swaminathan S, Padmapriyadarsini C, Venkatesan P, et al. Efficacy and safety of 
once-daily nevirapine- or efavirenz-based antiretroviral therapy in HIV-associated 
tuberculosis: a randomized clinical trial. Clin Infect Dis. 2011 Oct;53(7):716-24. 
52. Dooley K, Bliven-Sizemore EE, Weiner M, et al. Safety and pharmacokinetics of 
escalating daily doses of rifapentine, an anti-tuberculosis drug, in healthy 
volunteers. Clin Pharmacol Therapeu. 2012; 91: 881-88. 
53. Self TH, Chrisman CR, Baciewicz AM, Bronze MS. Isoniazid drug and food 
interactions. Am J Med Sci. 1999;317(5):304.  
54. Wen X, Wang JS, Neuvonen PJ, Backman JT. Isoniazid is a mechanism-based 
inhibitor of cytochrome P 450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver 
microsomes. Eur J Clin Pharmacol. 2002;57(11):799-804.  
55. Bertrand J, Verstuyft C, Chou M et al. Dependence of efavirenz- and rifampicin-
isoniazid-based antituberculosis treatment drug-drug interaction on CYP2B6 and 
NAT2 genetic polymorphisms: ANRS 12154 Study in Cambodia. J Infect Dis. 2014 
Feb 1;209(3):399-408. 
56. Luetkemeyer A, Rosenkranz SL, Lu D, et al.  Relationship between weight, 
efavirenz exposure and virologic suppression in HIV-infected patients on rifampin-
based tuberculosis treatment in the AIDS Clinical Trials Group A5221 STRIDE 
study.  Clin Infect Dis 2013;57:586-93 
57. Hlatky MA, Owens DK, Sanders GD. Cost-effectiveness as an outcome in randomized 
clinical trials. Clin Trials 2006;3(6):543-51. 
58. Heifets LB, Lindholm-Levy PJ, Flory MA. Bactericidal activity in vitro of various 
rifamycins against Mycobacterium avium and Mycobacterium tuberculosis. Am Rev 
Respir Dis 1990;141:626-30. 
59. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and 
management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 
1998;53:536-48. 
60. Chaisson RE, Moore RD, Richman DD, et al. Incidence and natural history of 
Mycobacterium avium-complex infections in patients with advanced human 
immunodeficiency virus disease treated with zidovudine. Am Rev Respir Dis 
1992;146(2):285-9. 


 
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61. Benson CA, Williams PL, Currier JS, et al. A prospective, randomized trial examining the 
efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for 
the treatment of disseminated Mycobacterium avium complex disease in persons with 
acquired immunodeficiency syndrome. Clin Infect Dis 2003;37(9):1234-43.  
62. Dooley K et al. CYP3A Induction by rifampin and rifapentine: which drug and dose 
does it best? 4th International Workshop on Clinical Pharmacology of TB Drugs, 
Chicago, IL, September 2011. 
63. Blake MJ, Abdel-Rahman SM, Jacobs RF, et al. Pharmacokinetics of rifapentine in 
children. Pediatr Infect Dis J 2006: 25(5):405-9. 
64. Marshall J, Abdel-Rahman S, Johnson K, et al. Rifapentine pharmacokinetics in 
adolescents. Ped Infect Dis J 1999;18(10):882-8. 
65. Martinson N, Barnes G, Msandiwa R, et al. Novel regimens for treating latent TB in HIV-
infected adults in South Africa: a randomized clinical trial. In: Program and Abstracts of 
the 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, 
February 2009; Abstr. 36bLB. 
66. Holland DP, Sanders GD, Hamilton CD, et al. Costs and cost-effectiveness of four 
treatment regimens for latent tuberculosis infection. Am J Respir Crit Care Med 
2009;179(11):1055-60. 
67. Zhou XJ, Sheiner LB, D'Aquila RT, et al. Population pharmacokinetics of nevirapine, 
zidovudine, and didanosine in human immunodeficiency virus-infected patients. 
Antimicrob Agents Chemother 1999;43(1):121-8. 
68. Ribera E, Pou L, Lopez RM, et al. Pharmacokinetic interaction between nevirapine and 
rifampicin in HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr 
2001;28(5):450-3. 
69. Cohen K, Grant A, Dandara C, et al. Effect of rifampicin-based antitubercular therapy 
and the cytochrome P450 2B6 516G>T polymorphism on efavirenz concentration in 
adults in South Africa. Antivir Ther 2009;14:687-95. 
70. Elsherbiny D, Cohen K, Jansson B, et al. Population pharmacokinetics of nevirapine in 
combination with rifampicin-based short-course chemotherapy in HIV- and tuberculosis-
infected South African patients. Eur J Clin Pharmacol 2009;65(1):71-80. 
71. de Vries-Sluijs TE, Dieleman JP, Arts D, et al. Low nevirapine plasma concentrations 
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2003;42:599-605. 
72. Chen TT. Optimal three-stage designs for phase II cancer clinical trials. StatMed 
1997; 16:2701-11 
 


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APPENDIX I 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
SAMPLE INFORMED CONSENT 
 
For protocol: 
 
A5279: Phase III Clinical Trial of Ultra-Short-Course Rifapentine/Isoniazid for the Prevention of 
Active Tuberculosis in HIV-Infected Individuals with Latent Tuberculosis Infection, FINAL 
Version 2.0, dated 08/28/14 
 
SHORT TITLE FOR THE STUDY: Short-course RPT/INH for latent TB in HIV-infected 
individuals 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with HIV (the 
virus that causes AIDS) and either have tested positive for the bacteria that causes tuberculosis 
(TB) or live in an area where TB infection occurs frequently. This study is sponsored by the 
National Institutes of Health (NIH). The doctor in charge of this study at this site is: (insert name 
of Principal Investigator). Before you decide if you want to be a part of this study, we want you 
to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
Some people are infected with the bacteria that cause TB, but their immune systems (the 
system in a person’s body that helps fight infections) prevent the bacteria from multiplying and 
they do not have any symptoms from the infection; these people are said to have latent TB 
infection. Latent TB can develop into active disease and cause sickness, especially in people 
with weakened immune systems, such as those with HIV.  
 
The standard way to keep latent TB from becoming active is treatment with 6 to 9 months of 
daily isoniazid, an anti-TB drug. ACTG researchers are interested in seeing if shorter treatments 
work just as well as this standard treatment. This study will compare the standard treatment with 
a much shorter treatment (4 weeks) of the anti-TB drugs rifapentine and isoniazid, to find if this 
shorter treatment is as good. The study will also compare the safety and tolerability of the two 
treatments. Both rifapentine and isoniazid are approved by the United States (US) Food and 
Drug Administration (FDA). 
 
 


 
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WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to join this study, you will need to be seen in the clinic about 10 times in the first 9 
months and then about every 3 months for as long as you are on the study, which may be 3 to 5 
years or longer. The evaluations required at most visits will take about 1 hour to complete, 
although you may need to be at the clinic longer than this. The schedule of visits and study 
procedures are explained in Appendix I-A. 
 
If you do not join the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of this screening visit, some demographic (for 
example, age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory 
information is being collected from you so that ACTG researchers may help determine whether 
there are patterns or common reasons why people do not join a study. 
 
If you enter the study 
At the study entry visit, you will be assigned to one of these two treatment groups: 
 
 
 
 
 
 
 
 
 
 
Because your assignment is random, like the flip of a coin, you will have an equal chance of 
being in either group. You will not be able to choose your group, but you and the study doctor, 
as well as the study staff, will know which group you are in.  
 
If you are in Group A, you will take rifapentine and isoniazid for 4 weeks. Depending on your 
weight, you will take 2, 3, or 4 tablets of rifapentine and one tablet of isoniazid with food once a 
day. Rifapentine and isoniazid will be provided to you.  
 
If you are in Group B, you will take isoniazid for 9 months. You will take one tablet of isoniazid 
with or without food once a day. Isoniazid will be provided to you. 
 
Regardless of which group you are in, you must also take vitamin B6 once a day while taking 
isoniazid, to help prevent possible side effects of isoniazid. Vitamin B6 will be provided to you. 
 
While you are in the study, you will be asked to tell the study doctor if you have signs that you 
might have active TB. If you have symptoms such as cough, fever, night sweats, or weight loss, 
you should contact the study doctor right away.   
 
Group A: 
Rifapentine plus Isoniazid 
for 4 weeks 
Group B: 
Isoniazid for 9 months 
Study Entry 


 
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Other 
If you are one of the first 90 people enrolled in Group A who is taking efavirenz, or one of the 
first 90 people enrolled in Group A who is taking nevirapine, an additional blood sample will be 
collected from you at entry and again at weeks 2 and 4. This blood will be tested for levels of 
rifapentine and either efavirenz or nevirapine. In addition, at week 8, you will have some blood 
collected and stored for future testing to look at your HIV viral load (a test that shows how much 
HIV is in your blood) and the levels of study drugs in your body. 
 
Once Version 2.0 of this study is started: 
 
1. If you are one of the first 90 people enrolled into Version 2.0 in Group B who is taking 
efavirenz, additional blood samples will be collected from you at entry and again at 
weeks 2 and 4. This blood will be tested for levels of efavirenz and its metabolites. 
 
2. If you are one of the 30 efavirenz control participants in Group A, blood samples will 
be collected at entry and again at weeks 0, 2, 4, and 16. This blood will be tested for 
concentrations of efavirenz and its major metabolites. At week 8, you will have some 
blood collected and stored for future testing to look at your HIV viral load and the 
levels of study drugs in your body.   
 
If you are part of this group of people who will have levels of rifapentine and either efavirenz or 
nevirapine tested, you will be asked to have another blood sample collected and stored for 
genetic testing, to see if differences in certain genes may affect the levels of some anti-HIV and 
study drugs in the blood. The facilities where this blood will be stored for genetic testing will not 
have information that identifies you. Since this genetic testing is optional, please indicate below 
if you agree to have this blood collected. If you do not agree, then this sample will not be 
collected. If you agree now and later change your mind, your sample will not be used for genetic 
testing. No matter what you decide, it will not affect your participation in the A5279 study. 
 
________ YES, I agree to have blood collected and stored for this genetic testing.  
 
________ NO, I do not agree. Do not collect this extra blood sample from me. 
 
If you agree, some of your blood that is left over after all required study testing is done may be 
stored (with usual protections of your identity) and used for future ACTG-approved research that 
is separate from this study. Genetic testing will not be done on these blood samples. Samples 
collected from you will be stored in the US.  These samples may be stored for an indefinite 
period of time. Results of testing performed on these samples will not be given to you. You may 
withdraw your consent for research on stored specimens at any time and the specimens will be 
discarded. No matter what you decide, it will not affect your participation in the study. 
 
________ YES, I agree to have my leftover blood stored.  
 
________ NO, I do not agree. 
 


 
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HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 3000 people will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
This study will last for about 3 years after the last participant is enrolled. You will be in this study 
between 3 and 5 years, or maybe even longer, depending on the how long it takes the study to 
fill up and when you join.   
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
• 
The study is stopped or cancelled. 
• 
A Data Safety Monitoring Board (DSMB) recommends that the study be stopped early. (A 
DSMB is an outside group of experts who monitor the study.) 
• 
You are not able to attend the study visits as required by the study. 
 
The study doctor may also need to take you off the study drugs without your permission if: 
 
• 
continuing the study drugs may be harmful to you 
• 
you need a treatment that you may not take while taking the study drugs 
• 
you become pregnant or begin breastfeeding and are taking rifapentine  
 
If you must stop taking the study drugs before the study is over, the study doctor may ask you to 
continue to be part of the study and return for study visits and procedures. 
 
If you must permanently stop taking study-provided rifapentine and/or isoniazid before your 
study participation is over, the study staff will discuss other options that may be of benefit to 
you. 
 
After you have completed your study treatment period, the study will not be able to continue to 
provide you with rifapentine and/or isoniazid. If continuing to take these or similar drugs would 
be of benefit to you, the study staff will discuss how you may be able to obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects, please ask the medical staff at your 
site. 


 
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Risks of Antibacterials 
Some medications used to treat TB are antibacterials that may be associated with diarrhea, 
including bloody diarrhea, which may be severe. 
 
Isoniazid (INH) 
The following side effects have been associated with the use of isoniazid: 
 
Serious and sometimes life threatening liver damage may develop even after many months of 
treatment. Older age, already having some liver disease, drinking alcohol regularly and using 
injection drugs are all associated with an increased risk of developing liver damage. Woman, 
particularly black and Hispanic woman, or if they are pregnant or recently gave birth to a baby, 
may also be at increased risk of life threatening liver damage. If you develop any of the following 
symptoms, you should call your doctor right away: 
• 
unexplained loss of appetite 
• 
nausea and or vomiting 
• 
pale colored stools 
• 
yellowing of the eyes or skin 
• 
pain in the upper abdomen 
• 
dark urine 
 
Additional side effects may include: 
• 
tingling and numbness in the hands and feet 
• 
memory loss, confusion, trouble sleeping, changes in behavior or mood 
• 
unsteadiness or dizziness 
• 
seizures 
• 
low blood counts 
• 
rash and itching 
• 
high blood sugar 
• 
joint pain 
• 
reduced vitamin B6 levels (a vitamin that helps with many functions in your body) 
 
Rifapentine (RPT, Priftin) 
The following side effects have been associated with the use of rifapentine:  
 
• 
reddish coloring of urine, sweat, sputum, saliva, tears, and breast milk. Contact lenses 
and dentures may be permanently stained.  
• 
liver damage that may include abnormal liver function tests. If you develop any of the 
following symptoms of liver damage, you should call your doctor right away: 
• 
unexplained loss of appetite 
• 
nausea and/or vomiting 
• 
pale-colored stools 
• 
yellowing of the eyes or skin 
• 
pain in the upper abdomen 
• 
dark urine 
• 
loss of appetite 


 
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Page 6 of 12 
 
 
• 
low blood counts 
• 
low blood sugar 
• 
upset stomach or vomiting 
• 
decreased effectiveness of hormonal contraceptives and other medications, including 
some anti-HIV medications. Tell your doctor about all medications that you are taking. 
 
Non-Study Medications 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. In addition, you must tell the study doctor or nurse before 
enrolling in any other clinical trials while on this study. 
 
Risks of Drawing Blood 
Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the 
body, lightheadedness, and in rare cases, fainting or infection. 
 
Risks of TB Skin Test 
In rare cases, a TB skin test can cause severe redness and swelling of the arm in people who 
had a positive TB skin test in the past. There have even been a few cases where this reaction 
was seen in people who had not had this test before.  
 
Risks of Chest X-ray 
The amount of high-energy radiation used in a chest x-ray is relatively small and does not pose 
any significant risk to you. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV or TB 
status secret from people close to you. This may lead to unwelcome discussions about or 
reactions to your HIV or TB status. Please talk with the study staff if you have any concerns in 
this regard. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
Rifapentine may be unsafe for unborn babies. If you are having sex that could lead to 
pregnancy, you must agree not to become pregnant while you are taking rifapentine and for 6 
weeks after stopping this drug. You must use one of the following barrier methods of birth 
control that you discuss with the study staff: 
 
• 
male or female condoms  
• 
diaphragm or cervical cap with a cream or gel that kills sperm 
• 
intrauterine device (IUD) 
 


 
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A barrier method of birth control is required because rifapentine can prevent birth control pills 
and other hormonal birth control methods from working. 
 
[Insert language describing how your site will handle pregnancies in minors.]  
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made. For example, the TB treatment you receive could help prevent you from developing TB. It 
is also possible that you may receive no benefit from being in this study. Information learned 
from this study may help others who have HIV and risk the possibility of having TB. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
• 
treatment with prescription drugs available to you 
• 
treatment with experimental drugs, if you qualify  
• 
no treatment 
 
Please talk to your doctor about these and other choices available to you. Your doctor or the 
study doctor will explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For US Sites: We will do everything we can to protect your privacy. In addition to the efforts of 
the study staff to help keep your personal information private, we have gotten a Certificate of 
Confidentiality from the U.S. Federal Government. This certificate means that researchers 
cannot be forced to tell people who are not connected with this study, such as the court system, 
about your participation. Also, any publication of this study will not use your name or identify you 
personally.  
 
People who may review your records include the ACTG, Office of Human Research Protections 
(OHRP), FDA, (insert name of site) Institutional Review Board (IRB) or Ethics Committee (EC), 
NIH, study staff, study monitors, the drug company supporting this study, and its designees. 
Having a Certificate of Confidentiality does not prevent you from releasing information about 
yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
OR 
 


 
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Page 8 of 12 
 
 
For Non-US Sites: Efforts will be made to keep your personal information confidential. We 
cannot guarantee absolute confidentiality. Your personal information may be disclosed if 
required by law. Any publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the ACTG, OHRP, FDA, (insert name of site) IRB or EC, NIH, 
national regulatory/health agencies, study staff, study monitors, and the drug company 
supporting this study, and its designees. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required 
by U.S. law. This Website will not include information that can identify you. At most, the 
Website will include a summary of the results. You can search this Website at any time.  
WHAT ARE THE COSTS TO ME? 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study.   
WHAT HAPPENS IF I AM INJURED? 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the NIH. You will not be 
giving up any of your legal rights by signing this consent form. 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not affect medical care you receive at this site. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about this study or a research-related injury, contact: 
 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
• 
name or title of person on the IRB, EC, or other organization appropriate for the site 
• 
telephone number of above 


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


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APPENDIX I-A:  A5279 STUDY VISITS 
 
The study staff can answer any questions you have about individual study visits, how long they 
will last, or about the tests that will occur. The table below can be used as a quick reference for 
you, along with the explanations that follow. 
 
I.  
Study Schedule 
Evaluation 
or 
Procedure 
Screening1 
Entry2 
Visits in 
First 9 
Months3 
Follow-
up 
Visits4 
Diagnosis 
of TB5 
Early 
Discontinuation6 
Consent & 
contact 
information 
collected 
√ 
 
 
 
 
 
HIV 
confirmed 
√ 
 
 
 
 
 
TB test 
√ 
√ 
 
 
 
 
Chest x-ray 
√ 
 
If needed 
 
 
Physical 
exam 
√ 
√ 
√ 
 
√ 
Blood 
collected 
√ 
√ 
√ 
√ 
√ 
Pregnancy 
test 
√ 
 
If needed 
 
 
 
Sputum 
collected 
If needed 
 
If needed 
√ 
 
Pill count 
 
 
√ 
 
 
 
Adherence 
questions 
 
 
√ 
 
 
 
 
1Screening Visit: After you have read and signed the consent form, you will have several tests 
done to make sure that you meet the requirements for joining the study.  
 
2Entry Visit: If you are able to join the study, you will come to the clinic to enter the study and 
receive your treatment assignment. At this visit, you will find out if you receive rifapentine plus 
isoniazid for 4 weeks or isoniazid for 9 months.  
 
3Visits in First 9 Months: You will return to the clinic at weeks 2, 4, 8, 12, 16, 20, 24, and 36 after 
the entry visit. 
 
4Follow-up Visits: After the first 9 months, you will have visits every 12 weeks for the rest of the 
time you are on the study, which may be 3 to 5 years or longer. 
 
5Diagnosis of TB: If you develop TB, you will come to the clinic for an extra visit.  
 
6Early Discontinuation: If you stop the study early, you will be asked to come in for a final visit. 


 
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APPENDIX I-A (Cont'd) 
Page 11 of 12 
 
 
II. 
Explanation of Evaluations  
 
Below are descriptions of the evaluations. You will be told the results of all tests performed with 
the exception of those tests to look at the levels of study drugs in your body and those 
performed on blood stored for future virology and pharmacology tests and for future ACTG-
approved testing. 
 
Consent and contact information collected  
After you read the consent and have had a chance to ask questions about the study, you will 
sign the consent form if you want to continue and join the study. You will also be asked how to 
be contacted in case you miss a visit or there are problems with your tests, and whether you 
give the study team permission to contact you. 
 
HIV infection confirmed  
If there is no record available, another HIV test will be done. If an HIV test has to be done, you 
may have to sign a separate consent form before this is done. You will be told the results of the 
HIV test as soon as it is available.   
 
TB test 
If you do not live in an area where TB occurs often, at screening, you may be asked to have a 
test to see if you have latent TB, unless you have results from a previous test for latent TB. For 
this test, you will either have a small amount of blood drawn (about 5 mL or 1 teaspoon) or an 
injection into the skin on the underside of your lower arm (called a tuberculin skin test or TST). 
When you enter the study, you will be required to have a TST if you have not had one in the 
past 60 days, regardless of whether you live in an area where TB occurs often. 
 
Chest x-ray  
You will have a chest x-ray during screening. If your doctor thinks that you may have active TB 
at any time during the study, you will have another chest x-ray. 
 
Physical examination 
You will have a physical exam and will be asked questions about your health and about any 
medicines you have taken or are taking now. 
 
Blood collected  
Between 5 and 60 mL (1 teaspoon to 4 tablespoons) of blood may be collected at any one visit. 
 
Blood will be collected from you for various tests during the study. These include: routine blood 
tests for safety, HIV viral load, CD4+ count (a test that shows how many infection-fighting cells 
you have in your blood), liver function tests, and possibly a TB test.  
 
At entry and again at 2, 4, and possibly 16 weeks after entry, you may have some blood 
collected for tests to look at the levels of some anti-HIV and study drugs in your body. If you 
agree, at entry, you may also have some blood collected for genetic testing, to see if differences 
in specific genes may affect the levels of some anti-HIV and study drugs in the blood. Collection 
of blood for this genetic testing is optional. 
 
At week 8, you may also have some blood collected and stored for future testing to look at your 
HIV viral load and the levels of study drugs in your body. The study staff will tell you if you will 
have blood drawn for this testing.  


 
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At entry and every 48 weeks for the duration of the study, if you agree, some of the blood that is 
collected will be stored for future ACTG-approved testing. The study staff will tell you if you will 
have blood drawn for this future testing. 
 
Pregnancy test  
If you are a woman who is able to become pregnant, you will be asked to give a small urine or 
blood sample (about 5 mL or 1 teaspoon) for a pregnancy test at screening and anytime during 
the first 9 months of the study, if you think you might be pregnant.  
 
Sputum collected  
If your doctor or the study doctor thinks that you may have active TB at any time during the 
study, you will be asked to provide a sputum sample that will be used to confirm whether you 
have TB. To provide this sample, you will be asked to cough deeply and then spit into a cup. If 
you need help to cough deeply, the clinic staff may ask you to briefly breathe a mist of saltwater 
through a tube or a mask. 
 
Pill count 
While you are taking study drug, you will be asked to bring in your study drug at each visit so 
that the study staff may count the number of pills. 
 
Adherence questions 
At the visits that occur while you are taking study drugs, you will be asked questions about how 
well you remember to take the study drugs. When you are taking rifapentine, you will also be 
asked about taking this drug with food. 
 

SAP_000.pdf: 
 
Statistical Analysis Plan 
A5279 
Phase III Clinical Trial of Ultra-short-Course Rifapentine/Isoniazid for 
the Prevention of Active Tuberculosis in HIV-Infected Individuals with 
Latent Tuberculosis Infection 
ClinicalTrials.Gov Identifier: NCT01404312 
V4.0 December 12, 2017 
 
 
This is A5279 SAP Version 4.0 with names of authors, names of publication writing team members and 
analysis timeline redacted.


A5279 Statistical Analysis Plan V4.0 
                                                                                          
 
 
2 
TABLE OF CONTENTS 
INTRODUCTION .......................................................................................................................... 3 
1.1 Purpose of the Statistical Analysis Plan (SAP) 
3 
1.2 Summary of Major Changes from V 3.0 
3 
2 
STUDY OVERVIEW (PROTOCOL VERSION 1.0; 2.0 CHANGES IN BOLD) ....................... 3 
2.1 Primary Objectives 
4 
2.2 Secondary Objectives 
4 
3 
OUTCOME MEASURES ........................................................................................................ 4 
3.1 Primary Outcome 
4 
3.2 Secondary Outcomes 
4 
4 
STATISTICAL METHODS ...................................................................................................... 5 
4.1 Primary Objective 
5 
4.2 Secondary Objectives 
7 


A5279 Statistical Analysis Plan V4.0 
                                                                                          
 
 
3 
Introduction 
1.1 
Purpose of the Statistical Analysis Plan (SAP) 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcome 
measures of ACTG A5279 that will be included in the primary manuscript addressing the major 
primary and secondary objectives of the study, as well as the primary and secondary outcome 
measures for which results will be posted on ClinicalTrials.gov. The Primary SAP also outlines 
the general statistical approaches that will be used in the analysis of the study. It has been 
developed to facilitate discussion of the statistical analysis components amongst the study 
team; and to provide agreement between the study team and statisticians regarding the 
statistical analyses to be performed and presented in the primary statistical analysis report. 
This SAP is modified from version 3.0 to comply with version 4.0 of the SDAC’s updated SAP 
SOP (effective 11/1/2017). This document provides a general overview of analysis plans for 
primary and secondary outcome measures of A5279; a separate Analysis Implementation Plan 
(AIP) provides more specific coding details of the analysis (e.g. additional table/figure 
specifications, data sources, validation requirements). 
1.2 
Summary of Major Changes from V 3.0 
 
Exploratory objectives and outcome measures were removed. 
 
Removed DSMB report specifications. 
 
Added per-protocol assessment of primary outcome measure. 
 
Sensitivity analyses added to treat deaths differently than the primary analysis 
specifications. 
 
2 Study Overview (Protocol Version 1.0; 2.0 changes in bold)  
This study is a multicenter, randomized, open-label, phase III clinical trial comparing a 4-week 
rifapentine (RPT)/isoniazid (INH) regimen to a standard 9-month daily INH regimen for the 
prevention of tuberculosis (TB) in HIV-infected participants. The primary objective will be 
efficacy of TB prevention. The study will also assess safety and tolerability of the regimens, 
adherence to the treatments, and patterns of antibiotic resistance among Mycobacterium 
tuberculosis (MTB) isolates in participants who fail on these prophylactic regimens. 
The study population is HIV-1 infected men and women ≥13 years old and ≥ 30 kg without 
evidence of active TB who: 1) Have tuberculin skin test (TST) reactivity ≥ 5 mm or a positive 
interferon gamma release assay (IGRA), OR 2) Live in high burden areas, defined as areas with 
an estimated or reported TB prevalence ≥ 60 cases/100,000 population/year. If a participant is 
taking antiretroviral therapy (ART) at study entry, only approved nucleoside reverse 
transcriptase inhibitors (NRTIs) with EFV or NVP for at least 4 weeks are permitted. 
Participants will be stratified based on (1) CD4+ cell count at entry and (2) ART use at entry, 


A5279 Statistical Analysis Plan V4.0 
                                                                                          
 
 
4 
and randomized within strata in a 1:1 ratio to receive either: 
 
ARM A: 4-week daily regimen of weight-based RPT and INH, plus vitamin B6, or 
 
ARM B: 9-month (36-week) daily INH regimen, plus vitamin B6  
Each participant will be followed for 3 years (156 weeks) after the last participant is enrolled. 
The primary hypothesis is that ultra-short course (4-week) rifapentine (RPT)/isoniazid (INH) is 
not inferior to a standard 9-month (36-week) daily INH regimen for the prevention of tuberculosis 
(TB) in HIV-infected patients. 
This Primary SAP addresses the following primary and secondary objectives listed in the study 
protocol. Other study objectives in the protocol will be addressed in subsequent analysis plans. 
2.1 
Primary Objectives  
To compare the efficacy of a 4-week daily regimen of weight-based RPT/INH to a standard 9-
month (36 week) daily INH regimen for TB prevention in HIV-infected individuals 
2.2 
Secondary Objectives 
 To compare safety and tolerability of the regimens 
 To compare overall and non-TB mortality rates among participants receiving the two 
regimens  
3 Outcome Measures 
3.1 
Primary Outcome 
The primary study outcome measure is the time to active TB, death due to TB, or death from 
unknown cause.  
Active TB is defined as Confirmed or Probable Pulmonary TB or Extra-pulmonary TB as defined 
by ACTG criteria for clinical and other events (Appendix 100) and judged to be such by at least 
one of two independent reviewers who are clinicians with expert knowledge in the diagnosis of 
TB, are not part of the study team, and are not involved in patient management of participants in 
the study. The reviewers are blinded to the participant ID, site, treatment arm, and treatment 
status.  Deaths attributed to active TB confirmed by independent review will be considered to be 
a TB endpoint.  For primary analyses, deaths with an unknown cause of death (COD) judged to 
be such by independent review will also be coded as TB outcomes as described in the protocol.   
3.2 
Secondary Outcomes 
 Occurrence of one or more Serious Adverse Events (SAE) vs no SAE. 
 
 Highest reported grade of each grade 3 or 4 laboratory value or sign/symptom that is 
at least one grade increase from baseline for the following targeted events: nausea 


A5279 Statistical Analysis Plan V4.0 
                                                                                          
 
 
5 
and vomiting; cutaneous, drug-associated fever; elevated AST (SGOT), ALT 
(SGPT), or bilirubin; peripheral neuropathy. 
 
 Tolerability: Ordered categorical variable indicating most stringent level of study drug 
management due to toxicity that was required over the treatment period. 
1) Premature permanent treatment discontinuation 
2) Treatment hold for more than 7 consecutive days 
3) None of the above 
 
 Time from randomization to death from any cause. 
 
 Time from randomization to death due to a non-TB event. 
 
 EFV plasma concentrations at weeks 0, 2, and 4 for the first 90 eligible participants 
who are randomized to arm A under protocol version 1.0, and in the first 30 eligible 
participants randomized to arm A under protocol version 2.0. 
 Under protocol version 2.0, EFV plasma concentrations at week 16 in the first 30 
eligible participants who are randomized to arm A. 
 Under protocol version 2.0, EFV plasma concentrations at weeks 0, 2, and 4 in the 
first 90 eligible participants randomized to arm B. 
 
 NVP plasma concentrations at weeks 0, 2 and 4 in the first 90 eligible participants 
randomized to arm A 
o Note: Due to shipping problems from one site, the full results for this outcome 
measure may not be available within one year of the primary completion date. 
4 Statistical Methods 
4.1 
Primary Objective 
 
For each participant, the time to TB is defined as the time from randomization to the first 
diagnosis of active TB at any level of certainty, or time from randomization to death if there was 
no prior active TB diagnosis and the death is to be included as an endpoint.  The diagnosis date 
of ‘confirmed TB’ will be the date the specimen was collected that was positive for 
Mycobacterium tuberculosis. The diagnosis date of ‘probable TB’ is that listed on the CRF by 
the site.   
For the primary analysis of the time to TB, participants’ time at risk will be censored at the last 
visit with a TB assessment prior to loss to follow-up, including events unrelated to treatment or 
outcome such as incarceration, moving, and site closure; at death where the Cause of Death is 


A5279 Statistical Analysis Plan V4.0 
                                                                                          
 
 
6 
known to be not related to TB; or at the last visit with a TB assessment prior to close of follow-
up otherwise. 
This will be a modified intent-to-treat (mITT) analysis, with all eligible participants that initiated 
treatment analyzed according to randomized study arm.  The reason for the exclusion of those 
that did not initiate treatment is that some left the study immediately, some were followed on 
study per the SOE, and some remained on study with little or no follow-up until declared lost 
follow-up.   
The primary objective will be evaluated by calculating a confidence interval (CI) around the 
difference between the observed TB incidence rates in the RPT and INH arms, with the 
confidence level adjusted for interim monitoring. For DSMB analyses specified by the group 
sequential design (see the Study Monitoring Plan and protocol) and the final analysis, the IRD 
between treatment arms will be presented as a stratified Mantel-Haenszel estimate with the 
confidence interval (CI) computed using the method of Greenland and Robins (Biometrics 
1985;41:55-68) that adjusts the variance estimate for rare events.  The CI will be appropriately 
adjusted for sequential monitoring with a Haybittle-Peto use function boundary (alpha-value) at 
both interim and final analyses, where interim analyses will use a 99.9% CI and the final will use 
a (95.0 + 0.1*k)% CI where k is the number of DSMB meetings that review formal interim 
analyses of the IRD. There was 1 interim analysis, conducted for the 2016 DSMB, so the final 
analysis will use a 95.1% CI. This is slightly more conservative than the Haybittle-Peto bound, 
but used to ensure no inflation of the type I error. SAS PROC STDRATE will be employed. 
Randomization was stratified by: (1) the most recent CD4+ cell count obtained within 180 days 
prior to entry (<100, 100-250, and >250 cells/mm3) and (2) ART use at entry (Yes/No).  
However, slightly less than 2.5% had screening CD4 <100; to avoid over-stratification, the lower 
two categories of screening CD4 counts will be combined for stratified analyses. Non-inferiority 
of ultra-short-course RPT/INH regimen will be demonstrated if the upper bound of the 
confidence interval for the IRD is less than 1.25/100PY.    
Data from prior studies are consistent with a constant TB rate over time, but this will be 
confirmed in these data. If this assumption does not hold, a piecewise constant hazards model 
will be used to estimate the incidence rate difference. The intervals over which hazards are 
constant will be chosen upon visually inspecting plots of the empirical hazard functions. As 
noted above, deaths attributed to TB will be considered to be TB endpoints. Deaths attributed to 
known causes other than TB will be censored. Deaths from unknown causes are expected to be 
minimal. For the primary analysis, deaths from unknown causes will be coded as TB events.  
Sensitivity analyses   
1) A per-protocol analysis that will exclude any participants who had permanently 
prematurely discontinued treatment 
2) Including all non-traumatic deaths as a primary outcome event  
3) Censoring all deaths from unknown causes  
4) Competing risk analysis that treats deaths from unknown cause as a competing risk 


A5279 Statistical Analysis Plan V4.0 
                                                                                          
 
 
7 
5) Competing risk analysis that treats all deaths not due to TB or of unknown cause as a 
competing risk 
6) Competing risk analysis that treats all deaths as a competing risk  
For competing risk analyses above, hazard ratios and 95% CI will be presented for the 
treatment effect. 
As required by NIH, interactions of sex and race/ethnicity with treatment will be formally tested 
and presented. This will be done by treating sex and race/ethnicity, and the combination of the 
two, as stratification factors and presenting the incidence rate difference estimates and 95% CIs 
within each level of the strata. As noted above, we will also evaluate the non-inferiority of short-
course RPT/INH within the CD4+ cell count and ART strata as differences could be important to 
inform the field. There will be no adjustment to the alpha level for multiple comparisons, and 
results will be presented cautiously.   
 
4.2 
Secondary Objectives 
The safety population will be the same as the primary efficacy population.  
 Proportion of participants with one or more SAEs will be compared between arms 
using Fisher’s exact test. 
 
 Proportion of participants with a targeted event (described in section 3.2) of grade 3 
or 4 and one grade increase from baseline will be compared between arms using 
Fisher’s exact test. Rates of targeted events of grade 3 or 4 and one grade increase 
from baseline will be compared between arms using a Poisson regression model. If 
overdispersion is present, a negative binomial or quasi-Poisson model will be used 
instead. 
 Tolerability will be compared between arms using a proportional odds model, with 
the ordered categories as described in section 3.2. If the proportional odds 
assumption appears to be violated, a baseline category logit model will be used 
instead. 
 Time from randomization to death from any cause will be compared between arms 
using a log-rank test. 
 
 Time from randomization to death due to TB or unknown cause will be compared 
between arms using the Fine-Gray model for competing risks, with death not due to 
TB treated as a competing risk. 
 
 Time from randomization to death due to a non-TB event of known cause will be 
compared between arms using the Fine-Gray model for competing risks, with death 
due to TB or unknown cause treated as a competing risk. 


A5279 Statistical Analysis Plan V4.0 
                                                                                          
 
 
8 
 EFV plasma concentrations will be summarized in arm A and arm B at weeks 0, 2, 
and 4, and in arm A at week 16 
 NVP plasma concentrations will be summarized in arm A at weeks 0, 2, and 4