Clinical trial NCT02651259
Conditions: Tuberculosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2017-03-13; Completion date: 2019-04-10
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the pharmacokinetics (PK), tolerability, and safety of once-weekly doses of rifapentine (RPT) and isoniazid (INH) in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women with latent tuberculosis (TB).

Detailed description:
TB is a major cause of illness and death in women of reproductive age. Pregnant and postpartum women with latent TB are at higher risk of developing active TB. This study evaluated the pharmacokinetics, tolerability, and safety of 12 once-weekly doses of RPT and INH in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women with latent TB.

This study enrolled HIV-1-infected and HIV-1-uninfected pregnant women with latent TB and their infants into two cohorts based on gestation. Cohort 1 participants were enrolled in their second trimester (greater than or equal to 14 to less than 28 weeks), and Cohort 2 participants were enrolled in their third trimester (greater than or equal to 28 to less than or equal to 34 weeks). All participants received 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits. Study researchers would perform an interim analysis to assess the PK of RPT during the study, and a dose adjustment could have been recommended based on this analysis.

Study visits occurred at days 0-3, once a week through week 11, and once a month until 24 weeks after delivery. Visits would include physical examinations, obstetrical exams, and blood collection. Infants were followed monthly until 24 weeks after birth.

Arms: arm 1: Participants received 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits. arm 2: Participants received 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits.
Interventions: intervention 1: Rifapentine (RPT) intervention 2: Isoniazid (INH) intervention 3: Pyridoxine (vitamin B6)
Intervention descriptions: intervention 1: 900 mg of RPT intervention 2: 900 mg of INH intervention 3: 25 mg to 100 mg of pyridoxine, based on the current local, national, or international dosing guidelines.

Protocol documents:
Prot_002.pdf: 
IMPAACT 2001 
 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of 
Once-Weekly Rifapentine and Isoniazid in HIV-1-infected and              
HIV-1-uninfected Pregnant and Postpartum Women with Latent 
Tuberculosis Infection  
 
 
A Study of the International Maternal Pediatric Adolescent 
AIDS Clinical Trials Network 
 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases 
Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
National Institute of Mental Health 
 
 
Pharmaceutical Support Provided by: 
Sanofi 
 
 
DAIDS ES #12026 
IND #XX,XXXX Held By DAIDS 
 
 
 
Protocol Chair: 
 
 
 
 
Jyoti Mathad, MD, MSc 
 
 
 
NIAID Medical Officer:  
 
 
 
Ellen Townley, MSN, FNP 
 
NICHD Medical Officer:   
 
 
Nahida Chakhtoura, MD, MsGH 
 
Clinical Trials Specialists:  
 
 
Charlotte Perlowski, MSPH 
 
 
 
 
 
 
 
Sarah Bradford, MPH 
 
 
 
Version 1.0 
10 November 2015 
 


IMPAACT 2001, Version 1.0 
Page 2 of 80 
10 November 2015 
IMPAACT 2001 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly 
Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and 
Postpartum Women with Latent Tuberculosis Infection 
 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................................................................................ 2 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 5 
PROTOCOL TEAM ROSTER .................................................................................................... 7 
SITE ROSTER ..........................................................................................................................11 
SCHEMA ..................................................................................................................................12 
1 
INTRODUCTION ...........................................................................................................15 
1.1 
Background ....................................................................................................................................... 15 
1.2 
Prior Research .................................................................................................................................. 16 
1.3 
Rationale ........................................................................................................................................... 19 
1.4 
Hypotheses ....................................................................................................................................... 20 
2 
OBJECTIVES ................................................................................................................20 
2.1 
Primary Objectives ............................................................................................................................ 20 
2.2 
Secondary Objectives ....................................................................................................................... 20 
2.3 
Exploratory Objectives ...................................................................................................................... 21 
3 
STUDY DESIGN ...........................................................................................................21 
3.1 
Identification of Study Design ............................................................................................................ 21 
3.2 
Summary of Major Outcomes ............................................................................................................ 21 
3.3 
Time to Complete Accrual ................................................................................................................. 21 
3.4 
Accrual into Cohorts .......................................................................................................................... 22 
3.5 
Expected Duration of Study Participation .......................................................................................... 22 
3.6 
Sites .................................................................................................................................................. 22 
4 
STUDY POPULATION ..................................................................................................23 
4.1 
Inclusion Criteria ............................................................................................................................... 23 
4.2 
Exclusion Criteria .............................................................................................................................. 24 
4.3 
Co-Enrollment Considerations .......................................................................................................... 25 
4.4 
Recruitment, Screening, and Enrollment Process ............................................................................. 25 
4.5 
Participant Retention ......................................................................................................................... 26 
5 
STUDY TREATMENT ...................................................................................................26 
5.1 
Regimens, Administration and Duration of Regimen ......................................................................... 27 
5.2 
Study Drug Formulation .................................................................................................................... 27 
5.3 
Product Supply/Acquisition, Distribution and Accountability .............................................................. 28 
5.4 
Study Drug Adherence Counseling ................................................................................................... 28 
5.5 
Prohibited and Precautionary Medications ........................................................................................ 28 
5.6 
Concomitant Medications .................................................................................................................. 28 
6 
STUDY VISITS AND PROCEDURES ...........................................................................29 
6.1 
Mother Screening Visit ...................................................................................................................... 29 
6.2 
Mother Entry/Intensive PK Visit ......................................................................................................... 30 
6.3 
Mother Weekly Visit (On Study Drug Regimen), Sparse PK Visit ..................................................... 31 


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6.4 
Mother Monthly Visits (Post-study drug regimen) and Study Exit Visit .............................................. 33 
6.5 
Infant/Newborn Visit .......................................................................................................................... 34 
6.6 
Infant Monthly Visits and Study Exit Visit .......................................................................................... 34 
6.7 
Clinical Evaluations and Procedures ................................................................................................. 35 
6.8 
Laboratory Evaluations and Procedures ........................................................................................... 36 
6.9 
Behavioral and Counseling Evaluations ............................................................................................ 37 
6.10 
Procedures for Premature Discontinuation of Study Drug Regimen/Study Participation .................. 37 
7 
SAFETY MONITORING, ASSESSMENT AND REPORTING .......................................37 
7.1 
Safety-Related Roles and Responsibilities ....................................................................................... 38 
7.2 
Safety-Related Recording on Case Report Forms ............................................................................ 38 
7.3 
Expedited Adverse Event (EAE) Reporting ....................................................................................... 39 
8 
PARTICIPANT MANAGEMENT – MOTHERS and infants ..........................................40 
8.1 
Management of Adverse Events ....................................................................................................... 40 
8.2 
Criteria for Premature Permanent Discontinuation of Study Drug ..................................................... 45 
8.3 
Criteria for Premature Discontinuation of Study Participation ........................................................... 45 
9 
STATISTICAL CONSIDERATIONS ..............................................................................46 
9.1 
General Design Issues ...................................................................................................................... 46 
9.2 
Outcome Measures ........................................................................................................................... 46 
9.3 
Stratification ...................................................................................................................................... 47 
9.4 
Accrual and Participant Number ........................................................................................................ 47 
9.5 
Sample Size Justification .................................................................................................................. 48 
9.6 
Study Monitoring: Statistical Aspects ................................................................................................ 49 
9.7 
Analysis ............................................................................................................................................. 50 
10 
CLINICAL PHARMACOLOGY PLAN ...........................................................................50 
10.1 
Pharmacology Overview and Objectives ........................................................................................... 50 
10.2 
Methods and Timing for PK Collections, Processing, Handling, and Storage ................................... 51 
10.3 
Interim Analysis and Dose Adjustment .............................................................................................. 51 
10.4 
Laboratory Performing the Assays .................................................................................................... 53 
10.5 
Primary and Secondary Data Analysis Plan ...................................................................................... 53 
10.6 
Anticipated Outcomes ....................................................................................................................... 54 
11 
DATA HANDLING AND RECORD KEEPING ...............................................................54 
11.1 
Data Management Responsibilities ................................................................................................... 54 
11.2 
Essential and Source Documents and Access to Source Data ......................................................... 54 
11.3 
Quality Control and Quality Assurance ............................................................................................. 55 
12 
CLINICAL SITE MONITORING .....................................................................................55 
13 
HUMAN SUBJECTS PROTECTIONS...........................................................................55 
13.1 
IRB/EC Review and Approval ........................................................................................................... 55 
13.2 
Vulnerable Participants ..................................................................................................................... 56 
13.3 
Informed Consent .............................................................................................................................. 56 
13.4 
Potential Benefits .............................................................................................................................. 57 
13.5 
Potential Risks .................................................................................................................................. 57 
13.6 
Potential Social Impacts .................................................................................................................... 58 
13.7 
Reimbursement/Compensation ......................................................................................................... 58 
13.8 
Privacy and Confidentiality ................................................................................................................ 58 


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13.9 
Communicable Disease Reporting .................................................................................................... 59 
13.10 Management of Incidental Findings .................................................................................................. 59 
13.11 Management of New Information Pertinent to Study Participation .................................................... 59 
13.12 Post-Study Access to Study Drug ..................................................................................................... 59 
14 
ADMINISTRATIVE PROCEDURES ..............................................................................59 
14.1 
Regulatory Oversight......................................................................................................................... 59 
14.2 
Protocol Registration ......................................................................................................................... 59 
14.3 
Study Implementation........................................................................................................................ 60 
14.4 
Protocol Deviation Reporting ............................................................................................................. 60 
14.5 
Critical Events Reporting ................................................................................................................... 60 
14.6 
ClinicalTrials.gov ............................................................................................................................... 61 
15 
PUBLICATIONS ...........................................................................................................61 
16 
REFERENCES ..............................................................................................................62 
APPENDICES...........................................................................................................................66 
Appendix I-A: 
Mother Schedule of Evaluations ...................................................................66 
Appendix I-B: 
Infant Schedule of Evaluations ......................................................................68 
Appendix II:          Modeling and Simulation Population Analysis Report – Rifapentine .............69 
Appendix III:         Sample Informed Consent Form ...................................................................72 
 
 
 


IMPAACT 2001, Version 1.0 
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IMPAACT 2001 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly 
Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and 
Postpartum Women with Latent Tuberculosis Infection 
 
ABBREVIATIONS AND ACRONYMS 
 
3HP 
 
Rifapentine (900mg) and isoniazid (900mg) weekly for 3 months 
3TC 
 
Lamivudine, Epivir 
9H 
 
INH 300mg daily for 9 months 
ACTG  
AIDS Clinical Trials Group 
AE 
 
Adverse Event  
AIDS  
Acquired Immunodeficiency Syndrome 
ALT 
 
Alanine Transaminase 
ART 
 
Antiretroviral Therapy 
ARV 
 
Antiretroviral 
AST 
 
Aspartate Aminotransferase 
AUC 
 
Area Under the Curve 
BSV 
 
Between subject variability 
cART  
Combination ART 
CBC 
 
Complete Blood Count   
CDC 
 
Centers for Disease Control and Prevention 
CFR 
 
Code of Federal Regulations 
CI 
 
Confidence interval 
CL/F 
 
Clearance 
CLIA  
Clinical Laboratory Improvement Amendments 
Cmax 
 
Peak Plasma Concentration 
CMC  
Clinical Management Committee 
Cmin 
 
Minimum Plasma Concentration 
CRF  
 
Case Report Form 
CRPMC 
Clinical Research Products Management Center 
CRS 
 
Clinical Research Site 
D4T 
 
Stavudine 
DAERS 
DAIDS Adverse Event Reporting System 
DAIDS  
Division of AIDS  
DAIDS PRO 
DAIDS Protocol Registration Office 
DDI 
 
Didanosine 
desRPT  
Desacetyl-rifapentine 
DMC  
Data Management Center 
DNA 
 
Deoxyribonucleic Acid 
DOT 
 
Directly Observed Therapy 
DSMB  
Data and Safety Monitoring Board 
EAE 
 
Expedited Adverse Event 
EC 
 
Ethics Committee 
EFV 
 
Efavirenz 
EIA 
 
Enzyme Immunoassay 
EQA 
 
External quality assurance 
FDA 
 
(US) Food and Drug Administration 
FSTRF  
Frontier Science and Technology Research Foundation 
GCLP  
Good Clinical Laboratory Practice 


IMPAACT 2001, Version 1.0 
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GCP 
 
Good Clinical Practices 
HAART 
Highly Active Antiretroviral Therapy  
HIV-1  
Human Immunodeficiency Virus Type 1 
IATA  
International Air Transport Association 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonisation 
IGRA  
Interferon Gamma Release Assay 
IMPAACT  
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IND 
 
Investigational New Drug 
INH 
 
Isoniazid 
INR 
 
International Normalized Ratio 
IRB  
 
Institutional Review Board 
IoR 
 
Investigator of Record  
LAR 
 
Legally Authorized Representative 
LC 
 
IMPAACT Laboratory Center 
LTBI  
Latent Tuberculosis Infection 
MDR TB 
Multi-drug resistant tuberculosis 
MOH  
Ministry of Health 
MOP 
 
Manual of Procedures 
MTB 
 
Mycobacterium tuberculosis 
MUAC  
Middle Upper Arm Circumference 
NIAID  
National Institute of Allergy and Infectious Diseases 
NICHD  
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
NIH 
 
National Institutes of Health 
NRTI  
Nucleoside Reverse Transcriptase Inhibitor 
NVP 
 
Nevirapine 
OHRP  
Office for Human Research Protections 
OCSO  
Office of Clinical Site Oversight 
PCR 
 
Polymerase Chain Reaction 
PEPFAR 
President’s Emergency Plan for AIDS Relief 
PI 
 
Protease Inhibitor 
PK 
 
Pharmacokinetics 
PT 
 
Prothrombin Time 
PTT 
 
Partial Thromboplastin Time 
RNA 
 
Ribonucleic Acid 
RPT 
 
Rifapentine 
RSE 
 
Relative standard error 
SAE 
 
Serious Adverse Event 
SDMC  
Statistical and Data Management Center 
SES 
 
Subject Enrollment System 
SoE 
 
Schedule of Evaluations 
SOP 
 
Standard Operating Procedure 
SSE 
 
Stochastic simulation-estimation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
 
Tuberculosis 
TBTC  
Tuberculosis Trials Consortium 
TST 
 
Tuberculin Skin Test 
ULN 
 
Upper Limit of Normal 
US 
 
United States of America 
WHO  
World Health Organization 
XDR 
 
Extensively drug-resistant tuberculosis 


IMPAACT 2001, Version 1.0 
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IMPAACT 2001 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly 
Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and 
Postpartum Women with Latent Tuberculosis Infection 
 
PROTOCOL TEAM ROSTER 
 
Protocol Chair 
Jyoti S. Mathad, MD, MSc 
Weill Cornell Medical College 
402 East 67th Street, 2nd floor 
New York, NY 10065 
Ph: (646) 962-8140 
Fax: (646) 962-0285 
Email: jsm9009@med.cornell.edu 
 
Protocol Vice Chairs 
Kelly Dooley, MD, PhD 
Johns Hopkins University School of Medicine 
600 N. Wolfe Street, Osler 527 
Baltimore, MD 21287 
Ph:  (410) 955-3100 
Fax:  (410) 614-9978 
Email:  kdooley1@jhmi.edu 
 
Sandesh Patil, M.B.B.S. D.G.O. 
Byramjee Jeejeebhoy Medical College CRS 
Jai Prakash Narayan Rd. 
Pune, Maharashtra 411001 
India 
Phone: 91-20-26052419 
Fax: 91-20-26125432 
Email: camsandesh@yahoo.co.in 
 
NIAID Medical Officer 
Ellen Townley, MSN, FNP 
Maternal Adolescent Pediatric Branch, 
HJF-DAIDS 
DAIDS/NIAID/NIH 
5601 Fishers Lane, Rm 8B37 
Rockville, MD 20892-9831 
Phone: (240) 292-4784 
Fax: (240) 627-3465 
Email: ellen.townley@nih.gov 
 
NICHD Medical Officer 
Nahida Chakhtoura, MD, MsGH 
Maternal & Pediatric Infectious Disease Branch 
Eunice Kennedy Shriver National Institute for 
Child Health and Human Development 
National Institutes of Health 
6100 Executive Boulevard, Rm. 4B11 
Bethesda, MD 20892-7510 
Phone: (301) 435-6872 
Fax: (301) 496-8678 
Email: nahida.chakhtoura@nih.gov 
 
Clinical Trials Specialists 
Sarah Bradford, MPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 
Phone: (919) 544-7040 x11685 
Email: sbradford@fhi360.org 
 
Charlotte Perlowski, MSPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 
Phone: (919) 544-7040 x11480 
Email: cperlowski@fhi360.org 
 
Protocol Statisticians 
Paula Britto, MS 
Statistical & Data Analysis Center 
Harvard School of Public Health 
Building 3-505C, Channing Laboratory 
677 Huntington Avenue 
Boston, MA 02115-5821 
Phone: (617) 432-2522 
Email: britto@sdac.harvard.edu 


IMPAACT 2001, Version 1.0 
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Vincent J. Carey, PhD 
Senior Statistician, Pediatric Division 
Statistical & Data Analysis Center 
Harvard School of Public Health 
Building 3-505C, Channing Laboratory 
677 Huntington Avenue 
Boston, MA 02115-5821 
Phone: (617) 525-2265 
Fax: (617) 731-1541 
Email: stvjc@channing.harvard.edu 
 
Protocol Data Managers 
Aaron Atlas, BS 
IMPAACT Data Manager 
Frontier Science & Technology Research 
Foundation, Inc. (FSTRF) 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7422 
Fax: (716) 834-8675 
Email: atlas@fstrf.org 
 
Stephanie Popson, PhD 
IMPAACT Data Manager 
FSTRF 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7356 
Fax: (716) 834-8675 
Email: popson@fstrf.org 
 
Protocol Pharmacist 
Oladapo Alli, PharmD 
HJF-Pharmacist/Contractor  
Pharmaceutical Affairs Branch 
Division of AIDS/OCSO/NIAID/NIH 
5601 Fishers Lane 
Room 9E16  MSC #9832 
Bethesda, MD 20892-9832 
Phone: (240) 627-3593 
Cell: (240) 743-6064 
Fax: (240) 627-3112 
Email: oladapo.alli@nih.gov 
 
Protocol Pharmacologists 
Rada Savic, PhD 
University of California San Francisco School of 
Pharmacy 
1550 4th Street, Bldg 19B 
San Francisco, CA 94158 
Phone: (415) 502- 0640 
Email: rada.savic@ucsf.edu 
 
Peter Smith, PhD 
Division of Pharmacology 
University of Cape Town 
K45 Old Main Building 
Groote Schuur Hospital, Observatory, 7925 
Cape Town, South Africa 
Phone: 27 21 406 6289 
Email: peter.smith@uct.ac.za  
 
Laboratory Center Specialists 
Carolyn Yanavich 
Children’s Hospital of Los Angeles 
4546 Sunset Blvd. 
Smith Research Tower, Room 902 
Los Angeles, CA 90027 
Phone: (443) 249-3851 
Fax: (323) 361-8599 
Email: cyanavich@impaactlabcenter.org 
 
Dale Dayton 
Children’s Hospital of Los Angeles 
4546 Sunset Blvd. 
Smith Research Tower 
Los Angeles, CA 90027 
Phone: 301-742-9077 
Email: ddayton@impaactlabcenter.org 
 
Laboratory Data Coordinators 
Sarah Strobino, BS 
FSTRF 
4033 Maple Road 
Amherst NY 14226 
Phone: (716) 834-0900 x7213 
Fax:  (716) 833-0655 
Email: strobino@fstrf.org 
 
Laboratory Technologist 
Vandana Kulkarni, MSc 
BJMC CTU 
BJ Medical College and Sassoon General 
Hospitals 
First Floor, Pathology Museum 
Jai Prakash Narayan Road 
Pune- 411001, India 
 
Phone: 91 20 26052419 
Fax: 91 20 26125432 
Email: vandana@jhumitpune.com  
 


IMPAACT 2001, Version 1.0 
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IMPAACT Community Advisory Board (ICAB) 
Representative 
Steven Mphonda 
UNC Project 
Kamuzu Central Hospital 
100 Mzimba Street 
Lilongwe, Malawi 
Phone: 265 999272759 
Email: smphonda@unclilongwe.org 
 
Community Program Associate 
Cheryl D. Cokley, BS 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 
Phone: (919) 544-7040 x11359 
Fax: (919) 544-0207 
Email: ccokley@fhi360.org 
 
Westat Project Manager 
Jennifer Bryant 
Westat, Inc. 
1441 W. Montgomery Ave. 
Rockville, MD 20850 
Phone: (301) 294-3949 
Fax: (301) 294-4494 
Email: jenniferbryant@westat.com 
 
Westat Clinical Research Associate 
Lolita Kelley 
Westat, Inc. 
1441 W. Montgomery Ave. 
Rockville, MD 20850 
Phone: (301) 610-8812 
Email: lolitakelley@westat.com 
 
Investigators 
Adrie Bekker, FCPaed (SA) 
Department of Neonatology 
Stellenbosch University of South Africa 
Tygerberg Hospital  
Francie van Zijl Drive, Tygerberg, 7505  
Phone: 27 21 938 9673  
Email: adrie@sun.ac.za 
 
Richard E. Chaisson, MD 
Center for AIDS Research and TB Research 
Johns Hopkins University School of Medicine  
1550 Orleans Street, Room 1M.08 
Baltimore, MD 21231 
Phone: (410) 955-1755 
Fax: (410) 955-0740 
Email: rchaiss@jhmi.edu 
 
Cathy Cluver, MBChB, FCOG, MMed 
Tygerberg Hospital, Stellenbosch University 
Parow, South Africa 
Phone: +27823210298  
Email: cathycluver@hotmail.com 
  
Amita Gupta, MD, MHS 
Center for Clinical Global Health Education 
Johns Hopkins School of Medicine & 
Bloomberg School of Public Health 
600 N. Wolfe Street, Phipps 540B 
Baltimore, MD 21287 
Phone: (410) 502-7696 
Fax: (443) 287-6440 
Email: agupta25@jhmi.edu 
 
Neil Martinson, MBBCH, DCH, MFGP, MPH 
Perinatal HIV Research Unit 
University of the Witwatersrand 
South Africa 
Phone: +27119899836 
Email: martinson@phru.co.za 
 


IMPAACT 2001, Version 1.0 
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Vidya Mave, MD, MPH 
Byramjee Jeejeebhoy Medical College Clinical 
Trials Unit 
1st Floor, BJ Medical College 
Jai Prakash Narayan Road 
Pune, Maharashtra 411001 
India 
Phone: 91-20-26052419 
Fax: 91-20-26125432 
Email: vidyamave@gmail.com 
 
Helen McIlleron MBChB, PhD 
Division of Clinical Pharmacology 
K45 Old Main Bldg 
Groote Schuur Hospital 
7925 Observatory, South Africa 
Phone: 27-21-4066292 
Fax: 27-21-4481989 
Email: helen.mcilleron@uct.ac.za 
 
Pharmaceutical Company Representative 
Marilyn Maroni, MD 
9, rue du Président ALLENDE - 
94256 GENTILLY Cedex - France 
Phone: +33 (0) 1 41 24 59 48  
Email: marilyn.maroni@sanofi.com 
 


IMPAACT 2001, Version 1.0 
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SITE ROSTER 
 
Site 5114, Bronx Lebanon Hospital Family 
Research Center 
Murli Purswani, MBChB, FAAP 
1685 Morris Ave., Suite 1G 
Bronx, New York 10457 
Phone: (718) 960-1010 x1018 
Email: mpurswan@bronxleb.org  
 
Site 5115, Siriraj Hospital Mahidol University 
Kulkanya Chokephaibulkit, MD 
Investigator of Record 
Pediatric Infectious Diseases Unit, Department 
of Pediatrics,  
Siriraj Hospital Mahidol University  
2 Prannok Road, Bangkoknoi,  
Bangkok, Thailand 10700 
Phone: +66 2 4195671 
Email: kulkanya.cho@mahidol.ac.th 
 
Site 5121, Kenya Medical Research Institute 
Walter Reed Project, Kericho 
Deborah C. Langat, MBChB 
Investigator of Record 
P.O. Box 1357-20200, Hospital Road 
Kericho, Kenya 
Phone: +254 52 20 20946 
Email: Deborah.langat@usamru-k.org 
 
Site 12001, University of North Carolina, 
Lilongwe Clinical Research Site 
Portia Kamthunzi, MD 
Private Bag 306 
100 Mzimba Rd. 
Lilongwe, Malawi 
Phone: +265 1755056 
Email: pkamthunzi@unclilongwe.org 
 
Site 30022, Les Centres GHESKIO 
Jean William Pape, MD 
33 Blvd. Harry Truman 
Port-Au-Prince, Haiti 
Phone: (509) 2940-1431 
Email: jwpape@gheskio.org  
 
Site 31890, Harare Family Care CRS 
Tsungai Chipato, MBChB, FRCOG              
Investigator of Record 
University of Zimbabwe College of Health 
Sciences 
Department of Obstetrics and Gynaecology 
P.O. Box A178, Avondale 
Mazowe Street 
Harare, Zimbabwe 00263 
Phone: 263-4-308848  
E-mail: tchipato@zol.co.zw 
 
Site 31790, Desmond Tutu TB Center 
Anneke Hesseling, MD, PhD 
Director, Paediatric Research 
Desmond Tutu TB Centre 
Department of Pediatrics and Child Health 
Stellenbosch, University South Africa 
Phone: +27 219389173 
Fax: +27 21 9389702 
Email: annekeh@sun.ac.za
 


IMPAACT 2001, Version 1.0 
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IMPAACT 2001 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly 
Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and 
Postpartum Women with Latent Tuberculosis Infection 
 
SCHEMA 
 
Purpose: 
To describe the pharmacokinetics, tolerability, and safety of 12 once-
weekly doses of rifapentine (RPT) and isoniazid (INH) in pregnant and 
postpartum women with latent tuberculosis (TB) and inform the practice 
on usage of this regimen in the second and third trimesters of pregnancy. 
 
Design: 
Prospective, open-label, multi-center study 
 
Study Population: 
HIV-1-infected and HIV-1-uninfected pregnant women with latent TB 
and their infants, enrolled in two cohorts based on gestation: 
• Cohort 1: Enrolled in second trimester (14 to <28 weeks) and on 
study drug for 12 weeks 
• Cohort 2: Enrolled in third trimester (28 to ≤34 weeks) and on study 
drug for 12 weeks 
 
Sample Size: 
Up to 82 pregnant women (and their infants) will be enrolled to yield a 
minimum of 25 evaluable women in each cohort. Within each cohort, 
enrollment of at least 10 evaluable HIV-1-infected women will be 
targeted. This sample size is selected to achieve a relative standard error 
(RSE) of five percent for estimation of clearance. 
 
Study Treatment: 
Twelve directly observed once-weekly doses of RPT (900mg) and INH 
(900mg) taken with pyridoxine (25 to 100mg). An interim analysis will 
be performed to assess the clearance of RPT compared to non-pregnant 
historical controls, and a dose adjustment may be recommended based on 
this analysis.   
 
Study Duration: 
Approximately 24 months total. Accrual is expected to require 
approximately 12 months, and each enrolled woman will be followed 
through pregnancy and 24 weeks postpartum. Infants will be followed 
for 24 weeks from birth. 
 
Primary Objectives 
 
• 
To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of RPT 
and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the second trimester 
and third trimester who are receiving once-weekly RPT (900mg or the new study dose, if a dose 
adjustment is indicated by the interim analysis) and once-weekly INH (900mg). 
 
• 
To estimate the incidence of serious adverse events (SAEs) related to RPT + INH dosed once weekly 
for 12 weeks in pregnant women. 
 
• 
To describe the infant safety outcomes among infants born to women receiving once-weekly RPT + 
INH. 
 
 


IMPAACT 2001, Version 1.0 
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Secondary Objectives 
 
• 
To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of RPT 
and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the postpartum 
period who are receiving once-weekly RPT (900mg or the new study dose, if a dose adjustment is 
indicated by the interim analysis) and once-weekly INH (900mg). 
 
• 
To assess the impact of covariates (gestational age, weight, age, HIV status) on primary PK 
parameters using population PK modeling. 
 
• 
To compare RPT and desRPT exposure pharmacokinetic parameters (AUC, Cmax, Cmin) for RPT in 
pregnant and postpartum women versus non-pregnant historical controls, using noncompartmental 
analyses. 
 
• 
To determine the RPT dose in pregnancy that achieves similar estimated exposure (AUC) of RPT as 
non-pregnant adults at standard doses. 
 
• 
To quantify RPT and desRPT concentrations at delivery among infants born to women receiving 
once-weekly RPT + INH. 
 
• 
To describe the tolerability of RPT + INH dosed once weekly for 12 weeks in pregnant and 
postpartum women. 
 
• 
To assess incidence of active TB in mother-infant pairs up to 24 weeks postpartum. 
 
• 
To explore the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of INH 
in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women (i.e., women who are and 
are not taking efavirenz (EFV)) who are receiving once-weekly RPT (900mg or the new study dose, if 
a dose adjustment is indicated by the interim analysis) and once-weekly INH (900mg). 
 
Exploratory Objectives 
 
• 
To quantify RPT and desRPT concentrations in breast milk of postpartum women receiving once-
weekly RPT + INH. 
 
 


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IMPAACT 2001 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly 
Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and 
Postpartum Women with Latent Tuberculosis Infection 
 
Figure 1: Study Visit Schedule - Mothers and Infants 
 
 
 


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IMPAACT 2001 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly 
Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and 
Postpartum Women with Latent Tuberculosis Infection 
1 
INTRODUCTION 
 
1.1 
Background  
 
An estimated two billion persons carry latent Mycobacterium tuberculosis (MTB). Treatment of latent 
tuberculosis infection (LTBI) is critical to global tuberculosis (TB) control and elimination (1, 2). 
Globally, the most commonly used current LTBI treatment regimen is six to nine months of INH (3, 4). 
Treatment completion rates of this regimen, however, are suboptimal, ranging from 5-64% in high-burden 
TB settings (5-7). Furthermore, potential concerns about the selection of drug resistance and drug 
toxicity, particularly hepatotoxicity, have hampered implementation of this regimen (8-10). 
 
Pregnant women: LTBI and its treatment 
Prevalence of latent LTBI in pregnant women is similar to that of the general population. Studies report a 
prevalence of 18%–34% among HIV-negative pregnant women in India and up to 49% in HIV-positive 
pregnant women in South Africa (8, 11). Pregnant women are at increased risk of progressing from latent 
LTBI to active tuberculosis (TB) because pregnancy suppresses the Th1 immune response (12-14).  
Symptoms of active TB may not be seen until after delivery, when Th1 suppression reverses and 
symptoms are exacerbated (13). A large study recently found that early postpartum women are twice as 
likely to develop TB as non-pregnant women, suggesting that biologic changes in pregnancy and 
postpartum influence TB epidemiology (15-19). 
 
The World Health Organization (WHO) currently recommends treating LTBI with daily INH for all HIV- 
infected pregnant women, but few programs have implemented this policy. Adherence and toxicity 
concerns remain the main barriers to treatment. Adherence rates for daily INH among postpartum 
Hispanic women in the US, for example, are as low as 6-21% (20). Pregnancy and infant outcomes of 
women taking INH for active TB treatment are comparable to normal pregnant women not receiving TB 
treatment, but toxicity concerns persist due to the suboptimal quality of existing studies (21). NIH-funded 
studies are under way to assess the optimal timing of initiation of INH for TB prophylaxis for HIV-1-
infected women (IMPAACT P1078), the pharmacology of first-line TB drugs for TB disease in HIV-1-
infected and HIV-1-uninfected pregnant and postpartum women (IMPAACT P1026s and R01HD06435), 
and pregnancy and treatment outcomes among pregnant women with tuberculosis and HIV 
(R01HD06435). 
 
The US Centers for Disease Control and Prevention (CDC) recommends the use of either nine months of 
daily INH monotherapy or a newer regimen of three months of weekly INH and RPT. The INH/RPT 
regimen is recommended in otherwise healthy patients over the age of 12 years who have LTBI. Though 
the CDC states that the regimen can be considered in other populations when it offers “practical 
advantages,” the regimen is not recommended in pregnant women, because the safety of the regimen in 
pregnancy is unknown. This study aims to address this gap in knowledge.  
 
Pharmacokinetics in pregnancy 
The physiologic changes associated with pregnancy can impact drug disposition significantly. 
Gastrointestinal motility, stomach pH, protein binding, hepatic metabolism, and renal blood flow are all 
altered by pregnancy and can affect drug absorption, distribution, metabolism, and clearance. Pregnant 
women experience increased gastrointestinal transit time, which can alter the extent of drug absorption. 
They also have decreased albumin, which can affect protein binding and drug distribution, as well as free 
drug concentrations. Moreover, progesterone increases CYP3A4 activity, while estrogen inhibits 
CYP1A2 and CYP2C19 (22, 23). The combination of these effects complicates dosing regimens for many 
medications. In HIV management, for example, the dose of lopinavir and darunavir need to be doubled 


IMPAACT 2001, Version 1.0 
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during pregnancy, but only during the third trimester (24). Clearly, given the complex physiologic 
changes that occur with pregnancy, a thorough understanding of the pharmacokinetics of new drugs or 
regimens in this population is needed before they can be administered safely and effectively to pregnant 
women. 
 
1.2 
Prior Research 
 
RPT and LTBI 
In the past four years, there have been three major studies published on the use of this regimen in different 
populations. These studies and their major findings are summarized here: 
 
• 
TB Trials Consortium (TBTC) Study 26: Recently, a large TBTC-sponsored open-label 
randomized non-inferiority trial comparing three months of directly observed once-weekly 
rifapentine (RPT) (900mg) plus INH (900mg) (3HP) versus nine months of self-administered 
daily INH (300mg) (9H) (TBTC Study 26) demonstrated that 3HP was as effective as (and 
potentially superior to) the standard 9H regimen and was associated with a higher completion rate 
(82% versus 69%) and less drug-related hepatotoxicity (0.4% versus 2.7%) (25). Women on 3HP 
were more likely to have drug-associated “possible hypersensitivity” reactions than men, but 
severe reactions were very rare, only occurring in 0.37% of all people taking RPT/INH (25).  
o In a substudy of TBTC Study 26, the 3HP regimen was also better tolerated in HIV-1-
infected participants compared to HIV-1-uninfected participants. Moreover, HIV-1-infected 
patients had experienced fewer adverse events with the 3HP than 9H (26, 27).  
 
• 
PREVENT TB Trial: This trial was conducted through TBTC and IMPAACT in children and 
adolescents from international sites and the US, to assess safety and efficacy of 3HP versus 9H 
regimen in this population. Treatment with 3HP resulted in higher adherence rates (88% in 3HP 
versus 81% in 9H). Importantly, neither arm exhibited any hepatotoxicity, Grade 4 adverse events 
or treatment-attributed deaths. None of the children in the 3HP arm developed active TB versus 3 
(0.74%) of the children in the 9H arm (28).  
 
Furthermore, there have been no reports of hemorrhage in studies of RPT for LTBI treatment. (A full 
summary of adverse events seen in trials using RPT/INH is shown in Table 1). In November 2014, the US 
FDA granted RPT a supplemental indication for LTBI treatment. 3HP is now being recommended by the 
CDC as an appropriate alternative for latent TB treatment in people ≥12 years old who are at high risk of 
developing active TB (e.g., recent exposure to known TB contact, conversion from negative to positive 
latent TB test, radiographic evidence of healed pulmonary TB, HIV-positive not on antiretrovirals) (29) . 
The CDC states that the regimen can be considered in other populations when it offers “practical 
advantages” but does not recommend its use in pregnant women because the safety of the regimen in 
unknown. IMPAACT 2001 aims to address this gap in knowledge. 
 
 
Table 1. Drug-related adverse events in trials of RPT/INH for LTBI treatment  
Adverse Event 
TBTC 26  
(HIV-negative) 
n=1861* 
TBTC 26 
 (HIV-positive) 
n= 207 
Martinson, et al 
Soweto study (HIV-
positive) n=328 
Hepatotoxicity 
11 (0.59%) 
3 (1.4%) 
5 (1.5%) 
Rash 
15(0.8%) 
1 (0.5%) 
0 (0%) 
Possible 
hypersensitivity 
85(4.6%) 
2 (1%) 
0 (0%) 
* confirmed HIV-uninfected  
 


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RPT pharmacokinetics in adults 
RPT is well absorbed and reaches a peak concentration in non-pregnant adults approximately five hours 
after ingestion. Bioavailability is improved when ingested with food, though lipid content does not appear 
to impact the magnitude of this effect (30).  In a substudy of TBTC 26, gender was not associated with 
variability in RPT PK parameters by population PK modeling (31). RPT’s half-life (t1/2) is five times 
longer than that of rifampin (11-18 hours versus 2-5 hours), resulting in measurable concentrations at and 
beyond 24 hours (32). Rifampin, a structurally similar rifamycin antibiotic, induces its own metabolism 
leading to reductions in half-life and AUC with repeat daily dosing. RPT also induces its own 
metabolism, but because of its longer half-life, accumulation occurs with multiple dosing (33, 34). RPT 
metabolism is not dependent on cytochrome P450. The effects of RPT on antiretrovirals’ concentrations 
is currently under investigation, but, in ACTG 5279, no clinically significant reductions in efavirenz 
(EFV) concentrations were seen among 30 patients receiving daily RPT 10 mg/kg and isoniazid together 
with EFV-based combination ART (35). Preliminary results from a Phase I trial sponsored by Sanofi also 
demonstrated that once-weekly RPT did not reduce EFV concentrations appreciably, so it is likely that 
these drugs can be used safely together (36, 37).  
 
EFV concentrations are marginally decreased among women in late pregnancy (38). However, few 
studies have evaluated this, and the numbers are small, largely because until recently, EFV was not used 
in pregnancy in many settings. EFV is now used without dose adjustment in pregnancy globally. There 
are no data about CYP2B6 activity among pregnant women taking EFV. Rifampin does not reduce EFV 
concentrations in pregnant women; in some women, INH increases EFV concentrations (depending on 
NAT2 genotype and CYP2B6 genotype). 
 
Further evaluations are being conducted to optimize RPT-containing regimens for LTBI and to extend the 
use of the 12-week RPT/INH regimen to all populations. A pharmacokinetic study was being conducted 
through TBTC (TBTC-S35) to determine the appropriate doses of RPT for young children (ages 0-2). Of 
note, dosing for children aged two years and older has been established and is in the product label (37). 
An actively enrolling ACTG clinical trial is assessing an ultra-short course of four weeks of daily INH 
(300mg) and RPT (450mg or 600mg, depending on weight) among non-pregnant HIV-1-infected persons 
greater than 13 years old (ACTG 5279). The PK and safety of these novel regimens have not been tested 
in pregnant women. 
 
Safety and tolerability of RPT in pregnancy and breastfeeding 
Like rifampin, which is routinely used for the treatment of active TB during pregnancy, RPT is a 
rifamycin derivative and was categorized as FDA Pregnancy Category C. This meant that animal studies 
showed adverse effects on the fetus, but, because there are no adequately controlled trials in humans, the 
use of the drug in pregnancy may be acceptable if the benefits are thought to outweigh the risks. RPT, like 
all rifamycins, may increase the risk of maternal hemorrhage and bleeding in the infant, although in an 
evaluation of six women on RPT during pregnancy, none had bleeding events (32). Fourteen patients with 
active tuberculosis that were treated with an anti-tuberculosis regimen that included rifapentine became 
pregnant during clinical studies. Six delivered normal infants; four had first trimester spontaneous 
abortions (of these, one patient abused ethanol and another patient was HIV-infected); one had an elective 
abortion; and outcome was unknown in three patients (37). None of these studies had pregnancy 
outcomes as a primary outcome, and the quality of reporting therefore varied by study. Moreover, the 
effect of rifapentine, specifically, could not be separated from the possible effect of the other TB drugs 
included in the active TB regimen. An ongoing study in South Africa examined safety events in pregnant 
women taking daily rifampin as part of an active TB regimen and found there were no associated bleeding 
events (39). 
 
In Study 26, 116 women became pregnant while on study (71 in 9H arm, 45 in 3HP arm). All women 
were taken off study drug at the time pregnancy was diagnosed. There were no drug-related bleeding 
events reported in TBTC 26. Occurrences of spontaneous abortions and live births were comparable 
between the two study arms as well as compared to the general population (see Table 2 below). No 
mortality (maternal or perinatal) or congenital anomalies were reported (40). Sixteen spontaneous 


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abortions occurred during the study, with major malformations either not detected or considered unknown 
in 15, and one fetus that screened positive for Down syndrome. A total of 12 elective abortions were 
reported during the study. Reasons for elective abortion were due to fetal diagnosis of Turner syndrome in 
one case and unknown reasons in 11 cases (37). 
 
Table 2: Pregnancy outcomes from TBTC - Study 26 versus general populationa 
 
No treatmentb 
(n=6,578,000) 
 
9 INH 
(n=71) 
3 RPT/INH 
(n=45c) 
Spontaneous abortion 
1.12 million 
(17%) 
9 
(13%) 
7 
(16%) 
Elective abortion 
1.21 million 
(18%) 
6 
(8.4%) 
6  
(13%) 
Live births 
4.25 million 
(65%) 
54 
(76%) 
31  
(69%) 
Postpartum hemorrhage d 
124,708 
(2.9%) 
0 
(0%) 
0 
(0%) 
a – 2 pregnancies with unknown outcomes occurred in each treatment group 
b – From Ventura, et al. – Pregnancy rates for 1900-2008 in the USA 
c – 1 patient had 2 pregnancies during the study (1 outcome spontaneous abortion and one live birth) 
d – From Callaghan, et al. – Trends in postpartum hemorrhage: United States 1994-2006, n=10,481,197 
 
Ventura S.J., Curtain S.C., Abma J.C. et al: National Vital Statistics Reports June 20, 2013. Volume 60 number 7. 
 
There are no data on RPT concentrations in breast milk, and it is unknown whether RPT is secreted in 
breast milk. The FDA label recommends discontinuation of the drug or nursing because of the lack of 
data. However, the CDC recommends that breastfeeding should not be discouraged in women taking this 
drug. For rifampicin, a related rifamycin antibiotic, breast milk concentrations are very low. Peak levels 
of 0.05% of those plasma levels are seen in breast milk with standard dosing for TB treatment (41, 42). 
The WHO also recommends that use of rifampicin is compatible with breastfeeding mothers (43). Of 
note, rifampicin given for TB treatment is given daily, whereas RPT in this study will be given once 
weekly. 
 
RPT, like other rifamycins, causes red-orange discoloration of body fluids. In trials where RPT was 
combined with INH and other antituberculosis drugs, rates of adverse reactions were similar between 
rifampin and RPT, with increased liver aminotransferase activity in about 5% of patients. No serious 
bleeding events were noted (32). In TBTC 26, 3HP was also well-tolerated among study participants 
compared to 9H. Clinical trials evaluating the efficacy of RPT as replacement for rifampin during the 
intensive phase of treatment for active TB in adults with and without HIV-1 infection have been 
completed or are in late stages of development; pregnant women, however, have been excluded from all 
of these trials (44, 45). 
 
Safety and tolerability of INH in pregnancy and breastfeeding: 
INH is used in pregnancy to treat active TB, where its benefit clearly exceeds the risk. It is an FDA 
Category C drug due to its limited data in pregnant women. INH crosses the placental barrier. It is not 
known to be associated with an increased rate of congenital abnormalities, and it is not considered to be 
teratogenic. INH is also reported to be safe and compatible with breastfeeding but does have potential for 
interference with nucleic acid metabolism, and hepatotoxicity has been documented in infants on 
treatment doses of INH (46-48). 
 
Safety and tolerability of vitamin B6 in pregnancy and breastfeeding: 
Pyridoxine (vitamin B6) is recommended with INH. In absence of INH, pyridoxine is safe to be used in 
pregnancy and postpartum at doses up to 100mg (49).  
 


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1.3 
Rationale 
 
Pregnancy is an important entry point for women to seek health care. Moreover, pregnant and postpartum 
women with LTBI are immunologically at higher risk of developing active TB. Maternal TB can lead to 
infant TB, which is even more difficult to diagnose, and is also associated with an increased risk of 
neonatal death, fetal distress, low birth weight, and prematurity (17, 43, 50-53). If a mother is co-infected 
with HIV and TB, she has double the risk of transmitting HIV to her infant (54). Children under five 
years of age have an eight times increased risk of death simply by living in the same home as a mother 
with active TB (55). Therefore, prevention of TB in pregnant women is an important priority for maternal 
and child health. Antenatal visits present an opportunity to screen women for both active and latent TB 
and to implement LTBI therapies to benefit the mother, her infant, and the household, especially in 
settings where HIV is highly prevalent. A three-month LTBI regimen during pregnancy would improve 
completion rates and allow close monitoring for drug toxicities compared to longer regimens. Once-
weekly RPT/INH offers the additional benefit of once-weekly dosing, which may improve adherence. In 
the mouse model, addition of INH to a three-month regimen of RPT improved activity against MTB 
compared to RPT alone (56). The three-month regimen of weekly RPT and INH (3HP) was also shown to 
be safe and efficacious in non-pregnant humans, including those with HIV who were on an EFV-based 
ART regimen (25, 26). However, trials with RPT have excluded pregnant and postpartum women, a 
group that has a higher risk of TB than the general population and for whom the disease has negative 
consequences for both maternal and infant health, particularly if the woman is HIV-1-infected (15, 17, 43, 
54, 57). The complex physiologic changes of pregnancy underscore the need for pharmacokinetic studies 
before newer regimens can be administered at the proper dose, safely and effectively to pregnant women. 
Furthermore, given the favorable safety profile, ease of use, potential advantages in cost and 
programmatic delivery, and opportunity for completing LTBI treatment during pregnancy, the three-
month combination Study 26 regimen has substantial potential benefits for this population.  
 
Rationale for study design 
IMPAACT 2001 will be the first detailed study of the newer, shorter, and more tolerable regimen of RPT 
and INH with a focus on the metabolic alterations associated with pregnancy. The dose selected is the 
standard of care for adults based on TBTC 26 (see Section 1.2) and what is known about the metabolism 
of rifapentine in other populations (see Appendix II). This dose is expected to be appropriate for pregnant 
women as well.  
 
The sampling strategy planned for IMPAACT 2001 is consistent with PK sampling in adults participating 
in TBTC trials of RPT, which will allow for comparison of the proposed IMPAACT 2001 study data with 
data from non-pregnant adults. Specifically, TBTC 26 used clearance as the main PK parameter, which 
will also be used as the primary PK parameter in IMPAACT 2001 for comparison with the non-pregnant 
historical controls (58). The sampling schedule is based on the expected PK profiles of RPT. The use of 
an intensive sampling strategy will support development of a model that estimates RPT PK well among 
pregnant women, including estimates for typical values and variability around absorption and elimination 
of the drug in this special population. The population PK modeling will be used to examine covariate 
effects (such as gestational age and weight) on PK parameters. With the sample size of 50 evaluable 
subjects, there will also be 90% power to detect one or more safety events for which the true rate of 
occurrence is 5 per 100 women or infants treated. The use of an interim analysis is a conservative 
approach, because there may be several different scenarios and variations in PK for RPT (e.g., changes in 
second trimester only, changes in third trimester only, similar changes in both trimesters, different 
changes in each trimester). With this approach, there will be power to detect all of them. To this end, a 
relatively large sample size is preferred to account for variability of the drug, itself, and possible 
physiologic differences between the second and third trimesters. Enrollment of half of each of the cohorts 
will provide sufficient power to detect a trimester-to-trimester effect. 
 
The key limitations of using historical controls include the possibilities that controls and treated 
individuals (a) represent incomparable populations, and/or (b) differ systematically on key factors that 
affect the relationship between treatment and endpoint, and/or (c) encounter important differences in 


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ancillary aspects of medical care as practices change over time. Because historical controls represent a 
source of information on level and variability of objectively measured endpoints, the limitations do not 
seem to indicate a serious risk of bias for this trial. Furthermore, there is a very good understanding of 
historic controls of measured endpoints that obviates repeating this again and an excellent understanding 
of RPT (see Appendix II). 
 
In summary, using these tools, this study will estimate the PK, safety and tolerability of rifapentine (RPT) 
and isoniazid (INH) dosed once weekly for 12 weeks in HIV-1-infected and high-risk HIV-1-uninfected 
pregnant women residing in moderate to high TB burden settings. The goal is to inform practice on 
appropriate use of this regimen in pregnant and postpartum women that achieves concentrations similar to 
non-pregnant adults, in whom efficacy has been established. The preliminary safety and tolerability of 
this regimen in this population will also be evaluated. It is anticipated that this study will generate useful 
PK data to help inform next steps for an amendment to this protocol or a separate future study. 
  
1.4 
Hypotheses 
 
Standard doses of once-weekly 900mg RPT and 900mg INH, when given to pregnant women in the 
second trimester, third trimester, and postpartum will have pharmacokinetic parameters within 25% of a 
well-established cohort of non-pregnant historical controls. At this dose, there will be no serious adverse 
events or safety concerns for pregnant women taking the regimen or their infants, respectively. 
 
2 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
2.1.1 To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of 
RPT and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the second 
trimester and third trimester who are receiving once-weekly RPT (900mg or the new study dose, if 
a dose adjustment is indicated by the interim analysis) and once-weekly INH (900mg). 
 
2.1.2 
To estimate the incidence of serious adverse events (SAEs) related to RPT + INH dosed once 
weekly for 12 weeks in pregnant women.  
 
2.1.3 
To describe the infant safety outcomes among infants born to women receiving once-weekly RPT 
+ INH. 
 
2.2 
Secondary Objectives 
 
2.2.1 
To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of 
RPT and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the 
postpartum period who are receiving once-weekly RPT (900mg or the new study dose, if a dose 
adjustment is indicated by the interim analysis) and once-weekly INH (900mg). 
 
2.2.2 
To assess the impact of covariates (gestational age, weight, age, HIV status) on primary PK 
parameters using population PK modeling.  
 
2.2.3 
To compare RPT and desRPT exposure pharmacokinetic parameters (AUC, Cmax, Cmin) for RPT 
in pregnant and postpartum women versus non-pregnant historical controls, using 
noncompartmental analyses. 
 
2.2.4 
To determine the RPT dose in pregnancy that achieves similar estimated exposure (AUC) of RPT 
as non-pregnant adults at standard doses. 
 


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2.2.5 
To quantify RPT and desRPT concentrations at delivery among infants born to women receiving 
once-weekly RPT + INH. 
 
2.2.6 
To describe the tolerability of RPT + INH dosed once weekly for 12 weeks in pregnant and 
postpartum women. 
 
2.2.7 
To assess incidence of active TB in mother-infant pairs up to 24 weeks postpartum. 
 
2.2.8 
To explore the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of 
INH in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women (i.e., women who 
are and are not taking efavirenz (EFV)) who are receiving once-weekly RPT (900mg or the new 
study dose, if a dose adjustment is indicated by the interim analysis) and once-weekly INH 
(900mg). 
 
2.3 
Exploratory Objectives 
 
2.3.1 
To quantify RPT and desRPT concentrations in breast milk of postpartum women receiving once-
weekly RPT + INH. 
 
3 
STUDY DESIGN 
 
3.1 
Identification of Study Design 
 
IMPAACT 2001 is an open-label, multi-center, intensive PK study to evaluate the pharmacokinetics, 
safety, and tolerability of RPT and INH dosed once weekly for 12 doses in HIV-1-infected and HIV-1-
uninfected pregnant women with latent TB infection at high risk for development of TB. Infants will also 
be enrolled, and breast milk samples from postpartum women who are still taking RPT/INH will be 
collected. 
 
Each enrolled woman will receive the study drug regimen and will be followed for 24 weeks postpartum, 
regardless of when she delivers. Therefore, it is expected that some women will continue the study drug 
regimen postpartum, while some women may have completed the study drug regimen prior to delivery. It 
is possible that a woman enrolled in Cohort 1 could continue the study drug regimen postpartum (e.g., if 
she delivers her infant pre-term). 
 
Two study cohorts are planned: 
Cohort 1: 
Pregnant women ≥14 weeks gestation through <28 weeks gestation (second trimester) 
Cohort 2: 
Pregnant women ≥28 weeks gestation through ≤34 weeks gestation (third trimester) 
 
An interim analysis to assess the PK of RPT will be conducted, and a dose adjustment may be indicated 
for each cohort (see Section 10). Dose adjustments indicated for Cohort 2 will be implemented for Cohort 
1 women as they enter their third trimester of pregnancy. See Section 3.4 for accrual into the cohorts, and 
Section 10.3 (Interim Analysis and Dose Adjustment) for further details regarding the interim analysis 
and dose adjustment.     
 
3.2 
Summary of Major Outcomes 
 
Outcomes are listed in Section 9.2. 
 
3.3 
Time to Complete Accrual 
 
Accrual is expected to be completed within 12 months from when the first woman is enrolled. 
 


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10 November 2015 
3.4 
Accrual into Cohorts 
 
Both cohorts will open to accrual at the same time.   
 
The interim analysis for Cohort 1 will occur either after the first 12 women are enrolled into Cohort 1 or 
after the first 12 women are enrolled into Cohort 2, whichever event occurs first. (If there are effects of 
pregnancy on drug disposition, those effects are likely to be most prominent late in pregnancy (i.e., in the 
third trimester)). Once PK samples for the 12th woman have been submitted, enrollment into Cohort 1 will 
be paused for three months or until results of the RPT exposure analysis are available, whichever event 
occurs first. 
 
The interim analysis for Cohort 2 will occur after the first 12 women are enrolled into Cohort 2. Once PK 
samples for the 12th woman have been submitted, enrollment into Cohort 2 will be paused for three 
months or until results of the RPT exposure analysis are available, whichever event occurs first. 
 
Following the interim analysis in each cohort, the appropriate accrual plan as outlined below will be 
conducted for the respective cohort: 
 
3.4.1 
If a dose adjustment is not indicated, women will continue to be enrolled at the original dose to 
complete the remaining accrual target of 25 evaluable women for that cohort. 
 
3.4.2 
If a dose adjustment to a higher dose is indicated, a target of 25 new evaluable women will be 
enrolled at the higher dose.  
 
3.4.3 
If a dose adjustment to a lower dose is indicated, subsequent newly-enrolled women will be given 
the lower dose. The accrual target in that cohort will remain at 25 evaluable women in total. That 
is, the 25 evaluable women will include some women who received the 900mg dose and some 
who received the lower dose. 
 
Women are considered evaluable if they meet any of the following criteria: 
• 
Contribute any data to the Intensive PK or Sparse PK sampling collections  
• 
Complete the study drug regimen (see Section 5.1.2 for adherence definition) 
 
Women who enroll into Cohort 1 will not contribute toward the Cohort 2 accrual target during their third 
trimester of pregnancy. See Section 10 (Clinical Pharmacology Plan) below for further details regarding 
interim analysis timing and dose adjustment determinations. 
 
Any pause in accrual to allow for an interim analysis and any changes in the dosing of the study drug 
regimen will be communicated by the IMPAACT 2001 Core Team to all participating sites. 
 
3.5 
Expected Duration of Study Participation 
 
After completing the study drug regimen, all women will be followed once monthly until 24 weeks 
postpartum to assess for the development of active TB disease. Infants will also be followed once 
monthly for the first 24 weeks of life.    
 
3.6 
Sites 
 
This study will be conducted at the IMPAACT sites listed in the Site Roster.   
 


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4 
STUDY POPULATION 
 
This study will be conducted among at least 50 evaluable pregnant women, and their infants, enrolled at 
study sites in Haiti, Kenya, Malawi, South Africa, Thailand, the United States, and Zimbabwe. Up to 82 
women will be enrolled across sites to yield a minimum of 25 evaluable women in each of two cohorts 
based on gestation. Women in Cohort 1 will be enrolled in the second trimester of pregnancy (14 to <28 
weeks); women in Cohort 2 will be enrolled in the third trimester of pregnancy (28 to ≤34 weeks). 
Within each cohort, enrollment of at least 10 evaluable HIV-1-infected women will be targeted.   
 
Women will be selected for the study according to the criteria in Sections 4.1 and 4.2 and the guidelines 
in Section 4.3. The study-specific approach to recruitment, screening, and enrollment is described in 
Section 4.4. Considerations related to participant retention are provided in Section 4.5. 
 
4.1 
Inclusion Criteria 
 
Women must meet all of the following criteria for inclusion in this study: 
 
4.1.1 
Age ≥ 18 years, or minimum age of consent according to locally applicable laws or regulations at 
screening, verified per site SOPs; and able and willing to provide written informed consent for 
study at screening 
 
4.1.2 
At screening, evidence by ultrasound of a viable singleton pregnancy with an estimated 
gestational age at enrollment of ≥ 14 weeks through ≤ 34 weeks as per screening ultrasound (see 
Section 6.7.3) 
 
4.1.3 
Has at least one of the following risk factors for TB: 
• 
Per participant report, household contact* with a known active pulmonary TB patient  
• 
Per medical records, confirmation of HIV-1 infection (see Section 4.1.5) with single positive 
TST or IGRA at any time in the past. If not available in medical record, perform at screening. 
 
*Note: A household contact is defined as a person who currently lives or lived in the same 
dwelling unit and shares or shared the same housekeeping arrangements and who reports 
exposure within the past two years to an adult index case with pulmonary TB.  
 
4.1.4 
Documentation of HIV-1 infection status, or confirmation of HIV-1 infection status (if unknown 
or undocumented) 
 
Confirmation of HIV-1 infection is defined as positive results from two samples (described 
below) collected at different time points. All samples tested must be whole blood, serum, or 
plasma. As this study is being conducted under an IND, all test methods should be FDA-
approved, if available. If FDA-approved methods are not available, test methods should be 
verified according to GCLP and approved by the IMPAACT Laboratory Center. 
 
If a participant has a negative result per medical history, or if her status is unknown, HIV-1-
uninfected status must be confirmed per Sample #1 requirements below within 14 days prior to 
enrollment. 
 
• 
Sample #1 may be tested by non-study public or PEPFAR programs. However, both the 
result and the assay date must be recorded in participant’s chart. Source documentation (e.g., 
participant’s medical record/chart, Ministry of Health (MOH) registers, laboratory results, 
etc.) must be available if requested. 
• 
Sample #1 may be tested using any of the following: 
o Two rapid antibody tests from different manufacturers or based on different principles 
and epitopes 


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o One enzyme immunoassay (EIA) OR Western Blot OR immunofluorescence OR 
chemiluminescence 
o One HIV DNA PCR 
o One quantitative HIV RNA PCR (above the limit of detection for evidence of infection) 
o One qualitative HIV RNA PCR 
o One HIV total nucleic acid test 
 
If Sample #1 is negative, the participant should be enrolled as HIV-1-uninfected with testing 
repeated as clinically indicated. If Sample #1 is positive, then collect and test Sample #2. 
 
• 
Sample #2 must be tested in a CAP/CLIA-approved laboratory (for US sites) or in a 
laboratory that operates according to GCLP guidelines and participates in appropriate 
external quality assurance program (for international sites). 
• 
Sample #2 may be tested using any of the following: 
o Rapid antibody test. If this option is used in combination with two rapid tests for Sample 
#1, at least one of the three rapid tests must be FDA-approved, and the third rapid test 
must be from a third manufacturer or based on a third principle or epitope. 
o One EIA OR Western Blot OR immunofluorescence OR chemiluminescence 
o One HIV DNA PCR 
o One quantitative HIV RNA PCR (above the limit of detection for evidence of infection) 
o One qualitative HIV RNA PCR 
o One HIV total nucleic acid test 
 
4.1.5 
If HIV-1-infected, documented current prescription of EFV + 2 NRTI regimen and reports taking 
regimen for at least two weeks prior to enrollment (regimens containing protease, integrase, or 
entry inhibitors are not permitted) 
 
4.1.6 
Documented laboratory values obtained within 30 days prior to enrollment: 
• 
Hemoglobin ≥ 7.5 g/dL 
• 
ALT < 3 times the upper limit of normal (ULN) 
• 
Total bilirubin < 2.5 times the ULN 
• 
Absolute neutrophil count (ANC) ≥ 750 cells/mm3 
• 
Platelet count > 100,000/mm3 
 
4.1.7 
Per participant report at screening, intent to remain in the current geographical area of residence 
for the duration of the study 
 
4.1.8 
Per participant report at screening, able to swallow whole tablets 
 
4.1.9 
Per participant report, intention to keep the pregnancy 
 
4.1.10 Per participant report, willingness to permit infant to participate in the study 
 
4.2 
Exclusion Criteria 
 
Women who meet any of the following criteria will be excluded from this study: 
 
4.2.1 
Evidence of confirmed or probable active TB disease per WHO symptom screen and 
confirmation by Gene Xpert, shielded chest x-ray, or sputum sample  
 
4.2.2 
Participant report of personal history of INH- or rifampin-resistant, multi-drug resistant (MDR), 
or extensively drug-resistant (XDR) TB 
 
4.2.3 
Participant report of personal history of active TB in the past 2 years 


IMPAACT 2001, Version 1.0 
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4.2.4 
Participant report of previous treatment for LTBI 
 
4.2.5 
Household contact (as defined above) with known active MDR or XDR TB disease 
 
4.2.6 
Known major fetal abnormality as detected on ultrasound 
 
4.2.7 
Known allergy/sensitivity or any hypersensitivity to components of study drugs or their 
formulation 
 
4.2.8 
Known history of liver cirrhosis at any time prior to study entry 
 
4.2.9 
Per participant report and/or medical records, evidence of acute clinical hepatitis, such as a 
combination of abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to 
entry 
 
4.2.10 Participant report and/or medical records of peripheral neuropathy Grade 2 or higher within 90 
days prior to entry 
 
4.2.11 Current use or history of 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 Participant report and/or clinical evidence of porphyria 
 
4.2.13 Any other condition that, in the opinion of the IoR/designee, would preclude informed consent, 
make study participation unsafe, complicate interpretation of study outcome data, or otherwise 
interfere with achieving the study objectives, including taking the study medication 
 
4.2.14 Planned or current participation in an interventional drug study  
 
4.2.15 Current use of any prohibited or precautionary medications (see Section 5.5), including 
didanosine (DDI) or stavudine (D4T) 
 
4.3 
Co-Enrollment Considerations 
 
Participants (i.e., women or infants) cannot be co-enrolled in an interventional drug study. Co-enrollment 
in other types of studies will be considered on a case-by-case basis. Sites will consult with the IMPAACT 
2001 Core Team, impaact.core2001@fstrf.org, and the other study team for co-enrollment considerations 
and questions. 
 
4.4 
Recruitment, Screening, and Enrollment Process 
 
Study visits and procedures are described in detail in Section 6. 
 
Recruitment: As part of participant outreach and recruitment strategies, study staff may pre-screen 
potential study participants at either on-site or off-site locations. It is anticipated that many women will be 
recruited from the antenatal clinic at the site. During these interactions, study staff may explain the study 
to potential participants and ascertain elements of presumptive eligibility (e.g., age, gestational age), to be 
confirmed at on-site screening visits. Process information (e.g., number of potential participants 
contacted, number presumptively eligible) may be recorded and stored at the study site in the absence of 
written informed consent, provided the information is collected in such a manner that it cannot be linked 
to potential participant identifiers. At each site, procedures and documentation will comply with local 
IRB/EC requirements. 
 


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Screening: Once referred, study staff will obtain written informed consent. Written informed consent for 
study participation must be obtained before any study-related procedures are performed. After informed 
consent is obtained from the woman, a study-specific screening number will be acquired for the mother-
infant pair through completion of the IMPAACT Screening Checklist. The checklist is part of the Subject 
Enrollment System (SES) located on the IMPAACT Data Management Center (DMC) website (at 
https://www.fstrf.org). Participant ID Numbers (PIDs) will be assigned at the site to both the woman and 
the infant. A PID is retrieved from the site’s PID list, which is generated at the DMC and sent to the sites. 
The screening visit procedures are found in Section 6.  
 
Enrollment: For mother-infant pairs who are found to be eligible for the study, enrollment will occur upon 
successful entry of required eligibility data into the SES (See Section 6.1). Successful entry into the SES 
will generate a study identification number (SID) for both the woman and the infant, as well as 
prescribing information for the study drug regimen. For pairs who are found ineligible or who do not 
enroll in the study for any reason, a Screening Failure Results case report form will be completed to 
record the screening outcome. The Entry Visit procedures are found in Section 6.   
 
The DMC will generate monthly screening and enrollment reports. Using these reports, the Protocol 
Team will monitor accrual closely, relative to the study-specific accrual plan that has been established in 
collaboration with the study sites. Based on this plan, accrual is projected to be completed within 12 
months. Each site must establish and implement SOPs to achieve the projected rates of enrollment 
specified in the accrual plan. Accrual will be assessed on team calls for each site, with an assessment of 
any issues surrounding enrollment. Should accrual rates fall below projections, the Protocol Team will 
work with study sites to take action as needed.   
 
4.5 
Participant Retention 
 
Once a woman enrolls in this study, the study site will make every effort to retain her and her infant for 
the protocol-specified duration of follow-up and thereby minimize potential biases associated with loss to 
follow-up. Each site must establish and implement SOPs that target retention rates that are sufficient to 
allow the primary study outcomes to be reliably estimated (a maximum 10% loss to follow-up is assumed 
in sample size calculations).   
 
The DMC will generate monthly reports of the number and percentage of participants completing follow-
up visits throughout the course of the study. Based on these reports, the Protocol Team will track 
retention closely and work with study sites as needed to take any required action to address below-target 
rates.  
 
5 
STUDY TREATMENT 
 
Study treatment for women consists of 12 once-weekly doses of RPT, INH, and pyridoxine (vitamin B6). 
All HIV-1-infected women are required to have been on efavirenz (EFV) + 2 NRTIs (not provided 
through the study) for at least two weeks prior to enrollment. 
 
Both RPT and INH will be provided through the study. 
 


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5.1 
Regimens, Administration and Duration of Regimen 
5.1.1 
Regimens and Administration  
The study drug regimen consists of 12 directly observed once-weekly doses of rifapentine (RPT) 900mg 
(six 150mg tablets), isoniazid (INH) 900mg (three 300mg tablets), and pyridoxine (vitamin B6) 25mg to 
100mg. HIV-1-infected and HIV-1-uninfected pregnant women with latent TB and their infants will be 
enrolled into two cohorts based upon gestation: 
 
Cohort 1: Pregnant women in the second trimester (≥14 to <28 weeks gestation). 
Cohort 2: Pregnant women in the third trimester ≥28 to ≤34 weeks gestation) and postpartum. 
 
Both cohorts will receive the study drug regimen weekly with food as described in the MOP. The study 
drug regimen dosing may be adjusted based on an interim analysis (see Section 10 (Clinical 
Pharmacology Plan)). Doses should be given 7 days part (± 2 days). Women will be provided a meal 
within 30 minutes prior to each dose. Following this meal, women will swallow whole RPT, whole INH, 
and whole or crushed pyridoxine tablets under direct observation of site staff (i.e., directly observed 
therapy, DOT).   
 
Women must receive the appropriate dose of pyridoxine 25mg to 100mg based on the current local, 
national, or international dosing guidelines. Pyridoxine can be taken as a whole tablet or crushed. 
5.1.2 
Duration and Adherence 
All enrolled women will receive 12 weekly directly observed doses of the study regimen and will be 
followed until 24 weeks postpartum. Infants will not directly receive the study drug regimen but will be 
followed on study for the first 24 weeks of life. 
 
Adequate adherence to the study drug regimen is defined as receipt of at least 90% of the prescribed 
doses. Women are to receive 12 weekly doses within a 16-week window (12 weeks consecutively is 
optimal). However, they will be considered to have completed the regimen if they receive at least 11 
doses (90%) during this 16-week study drug regimen window. Skipped doses should be taken late rather 
than missed. 
 
If a woman will not complete the therapy in the allotted 16 weeks (e.g., misses four doses in a row), there 
will be no limit to the number of times she can restart the study drug regimen. That is, if a woman 
chooses to stop participating or is lost to follow-up per Section 8.3 and then returns to the clinic while still 
within the gestational age requirements of the protocol, she will be allowed to restart the study drug 
regimen if she wishes. In this situation, the woman would be enrolled as a new participant into the 
appropriate cohort based on the gestational age at the time of restarting. The above definition must be met 
for the regimen to be considered complete.  
 
5.2 
Study Drug Formulation 
 
Rifapentine (RPT, Priftin®) will be supplied through the study as tablets for oral administration, each 
containing 150mg of rifapentine. Store at 25°C (77°F); excursions permitted from 15° – 30°C (59° – 
86°F). Protect from light and excessive heat and humidity. 
 
Isoniazid (INH) will be supplied through the study and must be stored in accordance with the 
manufacturer’s instructions.   
 
Pyridoxine (vitamin B6) will not be supplied through the study and must be stored in accordance with the 
manufacturer’s instructions. 


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5.3 
Product Supply/Acquisition, Distribution and Accountability  
5.3.1 
Study Product Supply/Acquisition/Distribution 
Rifapentine (RPT) will be supplied by Sanofi, and isoniazid (INH) will be supplied by Macleods 
Pharmaceuticals Limited. Both RPT and INH will be made available through the National Institute of 
Allergy and Infectious Diseases (NIAID) Clinical Research Products Management Center (CRPMC). The 
site pharmacist can obtain RPT and INH 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. 
ARVs are not provided by the study and are not considered part of the study drug regimen.   
 
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/Pages/Default.aspx 
5.3.2 
Study Product Accountability 
The site pharmacist is required to maintain complete records of all study products received from the 
NIAID CRPMC and subsequently dispensed. 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 
Study Drug Adherence Counseling 
 
Women will be counseled during the informed consent process at the Screening Visit on the study drug 
regimen and the importance of maintaining the study visits. All doses will be given under DOT. 
 
5.5 
Prohibited and Precautionary Medications  
 
Special attention should be paid to medications known to be metabolized by cytochrome P450 enzyme 
3A (CYP3A) because of potential drug interactions with rifapentine, which is an inducer of metabolizing 
enzymes. A list of prohibited and precautionary medications may be found on the IMPAACT 2001 
webpage on the IMPAACT website: http://impaactnetwork.org/.  
 
5.6 
Concomitant Medications  
 
All concomitant medications will be recorded on source documents. With the exception of vitamins, 
topical medications, alternative therapies, and vaccines, all concomitant medications (e.g., ARVs, 
contraceptives) will be recorded on CRFs. Whenever a concomitant medication or study agent is initiated 
or a dose changed, investigators must review the concomitant medication/study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from Division of AIDS, NIAID (DAIDS) 
to obtain the most current information on drug interactions, contraindications, and precautions. 


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While on the study drug regimen, currently only EFV-based and reverse transcriptase inhibitor (NRTI) 
based antiretroviral therapy (ART) regimens are permitted. Nevirapine (NVP), etravirine, rilpivirine, and 
other ART regimens (e.g., PI-based, entry inhibitors) are prohibited. Of note, infants born to mothers 
taking the study drug regimen can continue to receive NVP for prevention of perinatal transmission of 
HIV, as maternal rifapentine, like rifampin, is unlikely to affect levels of NVP in the infant (59).  
 
6 
STUDY VISITS AND PROCEDURES 
 
An overview of the study visit and evaluations schedule is provided in Appendix I; blood draw volumes 
for each visit are also detailed in Appendix I. Presented in this section is additional information on visit-
specific study procedures. Sections 6.7 and 6.8 below further describe Clinical Evaluations and 
Laboratory Evaluations, respectively. Section 10 further describes the PK specimen collection schedule.   
 
All visits and procedures must be performed at the clinical research site or associated facilities identified 
in each site’s approved Study Implementation Plan and must be documented in accordance with the 
NIAID Division of AIDS (DAIDS) policies for source documentation; refer to Section 11 for more 
information on documentation requirements and completion of CRFs. Refer to Section 7 for information 
on expedited adverse event (EAE) reporting, which may be required at any time during follow-up. As 
indicated in Appendix I, women will complete Screening and Entry Visits; infants will be enrolled in 
utero and will not complete Screening or Entry Visits after birth. Women will complete follow-up visits 
during pregnancy and postpartum; infants will complete follow-up visits postpartum.   
 
In addition to the protocol-specified procedures listed in this section, study staff may also complete other 
tasks consistent with site SOPs, including but not limited to collecting, reviewing, and updating 
demographic and locator information; reviewing elements of informed consent; scheduling visits; 
providing instructions for contacting study staff between visits; providing reminders for scheduled visits; 
and following up on missed visits. All such tasks should be documented consistent with site SOPs. Study 
staff should inform women of clinically meaningful physical exam findings and laboratory test results 
when available. 
 
6.1 
Mother Screening Visit 
 
The Screening Visit may take place up to two weeks prior to the Entry Visit. Multiple visits may be 
conducted within this timeframe to complete all required procedures, if necessary. Written informed 
consent will be obtained before any study-specific screening procedures are performed. For potential 
participants who do not meet the eligibility criteria, screening may be discontinued once ineligibility is 
determined. A Screening Failure Results CRF must be completed for any mother-infant pair who screen 
but do not enroll for any reason. Ineligible women may rescreen for study participation at a later time. 
 


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Mother Screening Visit Procedures (up to 2 weeks prior to enrollment) 
Administrative 
and Regulatory 
• Obtain written informed consent 
• Obtain screening number from SES 
• Assign PIDs to mother and infant 
• Assess eligibility 
Behavioral  
and Counseling 
• Provide HIV pre-/post-test counseling (if applicable) 
• Assess alcohol and drug use 
Clinical 
• Obtain medical and medications history 
• Perform complete physical examination  
• Perform obstetrical exam to assess fetal health  
• Assess TB symptoms, risk, and exposure  
• Gene Xpert, shielded chest x-ray, or sputum microscopy 
• Perform TST (if not available per medical record) 
Laboratory 
 
Collect blood for: 
• IGRA (if not available per medical record) 
• Complete blood count (CBC)  
• Liver Function Tests  
• HIV-1 test (confirmatory tests as needed)  
• Coagulation profile  
 
 
 
 
6.2 
Mother Entry/Intensive PK Visit 
 
The Entry Visit will be conducted over multiple days as a split visit. The administrative, regulatory, and 
clinical procedures should be conducted on the first day of the split visit; procedures that may provide 
information relevant to eligibility for the study (e.g., medical and medications history, physical 
examination, assessment of fetal movement and heart sounds) should be performed first, prior to final 
eligibility determination. In the event that a woman is found to be ineligible on the day of enrollment, 
enrollment should not occur. 
 
Additional requirements for sequencing of procedures at the Entry Visit are as follows: 
 
• 
Before enrollment: 
o Confirm final eligibility determination 
o Confirm the woman’s continued consent for study participation 
• 
After enrollment: 
o Prescribe study drug regimen 
o Provide meal 
o Perform first intensive PK blood draw 
o Administer study drug regimen (within 30 minutes after providing meal) 
o Complete remaining blood draws for intensive PK 
 
 


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*Perform prior to enrollment 
 
The Intensive PK sampling must be initiated on the same day (ideally in the morning) as the first dose of 
the study drug regimen, and conducted over the course of 72 hours according to the following time points: 
just prior to the first dose (t0), then 0.5h, 1h, 2h, 4h, 5h, 8h, 12h, 24h, 48h and 72h after the observed 
dose. Depending on site capacity, women may stay at the clinical research facility overnight after day 1 of 
the Entry Visit or return to the clinic at a designated time in the morning for administration of study drug 
and initiation of PK sampling. The same procedure can be followed for obtaining the PK samples at 48 
and 72 hours after dosing.  
 
Women will be asked to refrain from eating for two hours prior to each PK sampling dose of study drug, 
except for the meal provided by the site, which is to be eaten within 30 minutes before study drug 
administration. Women will be asked to refrain from further intake (except water) until three to four hours 
after the dose. The food type and quantity prior to each PK sampling dose will be recorded on CRFs.   
 
RPT PK testing will be performed on all Intensive PK samples, after which, the t0 and 2h (or 4h) samples 
will be stored for later INH PK testing (see LPC for further details). 
 
Women will be counseled about the signs and symptoms of active TB and asked to come to the clinic for 
an interim visit should any of the symptoms develop during the course of the study.    
 
6.3 
Mother Weekly Visit (On Study Drug Regimen), Sparse PK Visit  
 
Women will have weekly study visits while on the study drug regimen. Requirements for sequencing of 
procedures at the weekly visits are as follows: 
• 
Before administering study drug regimen: 
o Prescribe study drug regimen per site SOP 
o Provide meal 
 
Mother Entry/Intensive PK Visit Procedures (Day 0 and 72 hours following) 
Administrative and 
Regulatory 
• Review elements of informed consent and confirm woman’s 
continued consent for study participation* 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist data 
into SES to enroll the mother-infant pair, print and file a copy of 
the confirmation file 
• Provide meal within 30 minutes prior to administering study drug 
Behavioral  
and Counseling 
• Signs and symptoms of active TB Counseling 
Clinical 
• Assess TB symptoms, risk and exposure* 
• Update medical and medications history* 
• Perform targeted physical examination*  
• Provide available findings/test results 
• Record baseline AEs* 
• Assess fetal movement and heart sounds*  
Laboratory 
 
Collect blood for: 
• Intensive PK sample collection 
• CD4 count (HIV-1-infected only)  
• HBsAG, HBsAb, HCV Ab 
Study Product 
• Prescribe (according to local guidelines) study drug and 
administer RPT, INH, and pyridoxine under DOT 


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The PK sampling visits are ideally conducted in the morning. The Sparse PK sample collection will be 
conducted on the visit of the woman’s last dose of the study drug regimen over the course of 48 hours 
according to the following time points: 1h, 4h, 24h, and 48h after the observed dose. Women who are still 
taking study drug and breastfeeding postpartum will express breast milk, and plasma samples will also be 
drawn at the following time points: 
• 
First weekly visit after delivery, three hours after the study drug dose 
• 
Second weekly visit after delivery, six hours after the study drug dose 
• 
Last dose visit, 24 hours after the study drug dose (breast milk collection only) 
 
Women will be asked to refrain from eating for two hours prior to each PK sampling dose, except for the 
meal provided by the site, which is to be eaten within 30 minutes before study drug administration. 
Women will be asked to refrain from further intake (except water) until three to four hours after the dose. 
The food type and quantity prior to each PK sampling dose will be recorded on CRFs. 
 
RPT PK testing will be performed on all Sparse PK samples, after which, the 1h and 4h samples will be 
stored for later INH PK testing (see LPC for further details). 
 
 
Mother Weekly Visit Procedures (7 ± 2 days apart) 
Administrative 
and Regulatory 
• Provide meal within 30 minutes prior to administering study 
drug 
Behavioral  
and Counseling 
• Signs and symptoms of active TB Counseling 
• Assess infant feeding methods (postpartum only) 
Clinical 
• Perform targeted physical exam 
• Record/update medical and medications history 
• Record/update AEs 
• Provide available test results 
• Assess TB symptoms, risk and exposure 
• Assess fetal movement and heart sounds (until delivery) 
Laboratory 
 
Blood 
Collect blood for: 
• Sparse PK sample collection (during the visit of the last 
dose and 48 hours following) 
• Plasma sample collection (breast milk PK participants only, 
conducted first and second week postpartum) 
• Complete blood count (every four weeks) 
• Liver Function Test (every four weeks) 
• Coagulation profiles (at one visit at ≥34 weeks gestational 
age only) 
Breast milk  
Collect breast milk  for: 
• Breast milk PK sample collection (if eligible, conducted 
first and second week postpartum and on the visit of the last 
dose) 
Study Product 
• Prescribe (according to local guidelines) and administer 
RPT, INH, and pyridoxine under DOT 
 
 
 


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6.4 
Mother Monthly Visits (Post-study drug regimen) and Study Exit Visit 
 
The change from the weekly visit schedule (on study drug regimen) to the monthly visit schedule (post-
study drug regimen) is independent of the woman’s delivery date. It is possible that a woman enrolled in 
Cohort 1 could continue the study drug regimen postpartum (e.g., if she delivers her infant pre-term). 
Following the completed study drug regimen, all women will be followed once monthly (i.e., every four 
weeks counting from labor and delivery, ideally coinciding with infant monthly visits) until 24 weeks 
postpartum to assess for the development of active TB disease. At the final weekly visit, follow-up dates 
for the monthly visits will be provided to the woman. Contact information will also be obtained to 
improve retention if a visit is missed. A woman who does not present for a follow-up visit within two 
weeks of the scheduled visit will be considered as having missed that study visit.  
 
There is no required sequencing of procedures at these visits. 
 
The final study visit for women will occur 24 weeks postpartum and will ideally be scheduled to occur on 
the same day as the Infant Study Exit Visit. 
 
Mother Monthly Visit and Study Exit Visit Procedures ( ± 2 weeks) 
Administrative 
and Regulatory 
• None  
Behavioral  
and Counseling 
• Signs and symptoms of active TB Counseling 
• Assess infant feeding methods (postpartum only) 
Clinical 
• Complete physical exam 
• Record/update medical and medications history 
• Record/update AEs 
• Provide available test results 
• Assess TB symptoms, risk and exposure  
• Assess fetal movement and heart sounds (until delivery) 
Laboratory 
 
Collect blood for (no blood is collected at the Study Exit Visit): 
• Complete blood count 
• Liver Function Test 
• Coagulation profiles if clinically indicated (e.g., bleeding 
event) 
 
 
 


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6.5 
Infant/Newborn Visit 
 
The infant single PK sample collection will be conducted within three days of life, ideally in the morning. 
When a study participant is admitted for delivery, the research team should be notified (i.e., the medical 
records may indicate that the patient is enrolled in IMPAACT 2001, and the research staff’s contact 
information may be available). The participants may also be asked to contact the research staff once they 
are in labor. The infant single PK sample will only be collected if the mother’s most recent dose was 
taken within 72 hours of drawing the infant’s blood.  
 
At sites with capacity, cord blood PK sample collection will be offered to mothers to be conducted during 
labor and delivery. See Section 10 below for details and eligibility of the single PK sample and cord 
blood sample collections. Eligibility for single PK sampling must be confirmed prior to collection of this 
sample. 
 
Infant/Newborn Visit Procedures (within 3 days of life) 
Administrative 
and Regulatory 
• None 
Clinical 
• Assess eligibility for single PK sampling 
• Complete physical exam 
• Record medical and medications history 
• Record AEs 
• Provide available test results to mother 
Laboratory 
 
Collect blood for: 
• Single PK sample collection (if eligible) 
• Coagulation profile (if eligible) 
• Cord blood (optional if eligible, during mother’s delivery) 
 
 
6.6 
Infant Monthly Visits and Study Exit Visit 
 
Infants will be followed monthly for the first 24 weeks of life. Infants will be assessed at each visit for TB 
exposure and signs and symptoms suggestive of TB disease. The mother’s visits and the infant’s visits 
will ideally be scheduled to occur on the same day. 
 
There is no required sequencing of procedures at these visits. 
 
The final study visit for infants will occur at 24 weeks of life. 
 
Infant Monthly Visit and Study Exit Visit Procedures ( ± 2 weeks) 
Administrative 
and Regulatory 
• None 
Clinical 
• Limited physical exam 
• Record medical and medications history 
• Record/update AEs 
• Provide available test results to mother 
• Assess TB symptoms, risk and exposure  
Laboratory 
 
Collect blood for (no blood is collected at the Study Exit Visit): 
• Complete blood count (if clinically indicated)   
• Liver Function Test (if clinically indicated) 
• Coagulation profile (if clinically indicated)   
 
 
 


IMPAACT 2001, Version 1.0 
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6.7 
Clinical Evaluations and Procedures 
 
Additional clinical assessments may be performed at the discretion of the examining clinician in response 
to symptoms or illnesses present at the time of the exam. 
6.7.1 
Clinical assessment for development of TB disease 
TB symptoms, risk, and exposure will be assessed for each participant (i.e., women and infants) at each 
study visit. A pulmonary and lymph node exam will be conducted for participants with suspected TB 
disease. 
 
For women, the WHO TB symptom screen will be used. In addition, failure to have adequate weight gain 
in pregnancy will be recorded. 
 
For infants, TB will be assessed by known exposure or with the following symptoms: cough, respiratory 
distress, failure to gain weight, weight loss, or fever.  
 
See Section 8.1 for details regarding participant management of suspected and confirmed TB disease. The 
IoR/designee may conduct additional testing and confirmatory procedures per local standard of care for 
infants suspected of developing TB disease. Participants will remain on-study for follow-up visits. 
 
All participants (i.e., women and infants) confirmed with active TB disease will be referred to local 
standard of care for treatment.  Infants of mothers who develop active TB will also be referred for 
evaluation and initiation of TB preventive therapy as per local pediatric TB guidelines.   
6.7.2 
Physical Examination 
Maternal complete physical examination: 
For women, a complete physical exam will include the following: vital signs (temperature, pulse, blood 
pressure, and respiration), assessment of general appearance, cardiac exam, pulmonary exam, lymph node 
exam, and liver and spleen size per abdominal exam. Weight (so BMI and change in weight can be 
calculated) and mid-upper arm circumference (MUAC) will also be measured. Height will be assessed at 
the Entry Visit only. 
 
Maternal targeted physical examination: 
For women, a targeted physical exam during study follow-up will include vital signs (temperature, pulse, 
blood pressure, and respiration) and weight. Additional assessments should be driven by any previously 
identified or new signs or symptoms including diagnoses that the woman has experienced since the last 
visit. 
 
Infant complete physical examination: 
For infants, at the Newborn Visit, a complete physical exam will include the following: APGAR scores, 
birth weight and length, head circumference, gestational age, congenital abnormalities, demographics.  
 
Infant limited physical examination: 
For infants, at the monthly study visits, a limited physical exam will include the following: Weight 
(documented on a growth chart), length, head circumference, and vital signs (temperature, heart rate, and 
respirations). Additional assessments should be driven by any previously identified or new signs or 
symptoms including diagnoses that the infant has experienced since the last visit. 


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6.7.3 
Obstetrical Exam to Assess Fetal Health: Mothers 
At the Screening Visit, an obstetrical exam will be conducted to assess the following:  
• 
Gestational age, presence of severe fetal abnormalities, and presence of multiple births, by 
ultrasound 
• 
Fetal heart sounds confirmed on Doppler or fetal movements felt by mother  
 
The Entry Visit and follow-up visits will include the following assessments until the mother delivers: 
• 
  Fetal heart sounds confirmed on Doppler or fetal movements reported by mother 
 
6.8 
Laboratory Evaluations and Procedures 
 
Test results obtained from standard of care visits within 14 days of the participant’s monthly study visit 
will be used. Lab evaluations must be performed in DAIDS-approved laboratories that are participating in 
an external quality assurance (EQA) program.  
 
Note: NIH recommendations for maximum pediatric and adult blood draw volumes will be followed in 
this study. For women, the volume of blood drawn shall not exceed 10.5 mL/kg or 550 mL, whichever is 
smaller, over any eight week period. For infants, the volume of blood drawn at any study visit should not 
exceed 5 mL/kg in a single day and 9.5 mL/kg over any eight-week period. The priority order of sample 
collections will be as follows: samples needed for clinical safety assessments/AEs will be collected first 
(specific tests as determined by investigator), followed by samples needed for PK analysis. 
6.8.1 
Laboratory Evaluations 
Normal laboratory ranges will be the institutional values at the clinical research site. If a site does not 
have normal laboratory ranges, per an IMPAACT memorandum dated 11 December 2009, the site 
laboratory may adopt established ranges from another study or laboratory without verification. The 
medical director of the laboratory is responsible for the adoption of external unverified ranges, and s/he 
must provide reasonable evidence that the ranges are appropriate. Documentation of “reasonable 
evidence” may include the opinions of one or two local pediatricians, pathologists, or other 
knowledgeable laboratory personnel.   
 
For the maternal laboratory evaluations, the following will be recorded on the case report forms (CRFs): 
• 
Complete blood count will include white blood count, hemoglobin and platelets.   
• 
Liver function tests will include albumin, AST, ALT, and total bilirubin. 
• 
Coagulation profile will assess Prothrombin Time (PT) only.   
 
For women, blood will be collected at the Entry Visit for later testing of HBs AG, HBs Ab, HCV Ab, as 
determined by the Core Team.  
 
For the infant laboratory evaluations, the following will be recorded on the case report forms (CRFs): 
• 
A coagulation profile to assess PT will be collected at the Newborn Visit only if the mother is still 
on the study drug regimen. 
• 
Complete blood count will include white blood count, hemoglobin and platelets, if indicated 
based on symptoms.   
• 
Liver function tests will include albumin, AST, ALT, and total bilirubin, if indicated based on 
symptoms.   
6.8.2 
PK Specimen Collection 
Details regarding the Intensive, Sparse, and breast milk PK specimen collections (and the optional cord 
blood collection) for women, as well as the single PK specimen collection for infants are included in 
Section 10. 


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6.8.3 
Specimen Preparation, Testing, Storage, and Shipping 
The IMPAACT 2001 Laboratory Processing Chart (LPC) provides instructions regarding the collection, 
processing, and shipping of specimens for this study and is available on the IMPAACT website.   
6.8.4 
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.  
 
All infectious specimens will be sent using packaging that meets requirements specified by the 
International Air Transport Association Dangerous Goods Regulations for UN 3373, Biological 
Substance, Category B, and Packing Instruction 650. Refer to individual carrier guidelines (e.g., Federal 
Express or Airborne) as well as specific requirements of the host country for specific instructions required 
for ground transportation within that country. 
 
Infection control for active TB cases and good laboratory practices for TB isolation will be according to 
WHO guidance and best practices locally to minimize TB transmission. Please refer to instructions 
detailed in the International Air Transport Association (IATA) Dangerous Goods Regulations.  
 
6.9 
Behavioral and Counseling Evaluations 
 
Eligibility behavioral assessments conducted at the Screening Visit will assess a woman’s alcohol and 
drug use to determine whether related inclusion/exclusion criteria are met. 
 
Site staff will counsel enrolled women about the signs and symptoms of active TB at the enrollment visit 
and each study follow-up visit. Women will be asked to come to the clinic for an interim visit should any 
of the symptoms develop during the course of the study.   
 
HIV pre-/post-test counseling will be offered per local standard of care in the event that HIV testing must 
be performed by the site in order to confirm HIV status. Participants requiring HIV testing and counseling 
during study participation will be referred to local providers. 
 
6.10 Procedures for Premature Discontinuation of Study Drug Regimen/Study Participation 
 
Women who permanently discontinue the study drug regimen (i.e., RPT, INH, and pyridoxine) 
prematurely will remain on-study and follow the visit schedule until 24 weeks postpartum. Infants of 
mothers who permanently discontinue study drug regimen will also remain on study per the visit schedule 
until 24 weeks of life. 
 
Participants who must be withdrawn from study participation will be requested to complete their Study 
Exit Visit, if possible. 
 
7 
SAFETY MONITORING, ASSESSMENT AND REPORTING 
 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical research participant 
administered an investigational product and which does not necessarily have a causal relationship with the 
investigational product. As such, an AE can be an unfavorable or unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of an 


IMPAACT 2001, Version 1.0 
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investigational product, whether or not considered related to the product. This definition is applied at the 
time of enrollment (i.e., once a participant has successfully completed the SES). The term “investigational 
product” for this study refers to the study drug regimen.   
 
Women will be provided instructions for contacting the study site to report any untoward medical 
occurrences they or their infants enrolled in the study may experience. In cases of potentially life-
threatening events, participants will be instructed to seek immediate emergency care. Where feasible and 
medically appropriate, participants will be encouraged to seek evaluation at the hospital/clinic where a 
study clinician is based, and to request that the clinician be contacted upon their arrival.   
 
7.1 
Safety-Related Roles and Responsibilities 
 
Routine monitoring will be done by the IMPAACT 2001 Core Team which consists of the Protocol Chair, 
Vice Chairs, NIAID and NICHD Medical Officers, Protocol Statisticians, Protocol Data Manager, and the 
Clinical Trials Specialist (impaact.core2001@fstrf.org) or their designees. Site IoRs/designees are 
responsible for continuous close safety monitoring of all study participants, and for alerting the Core 
Team if unexpected concerns arise. The IMPAACT SDMC prepares routine safety monitoring and 
clinical data reports for review by the Core Team, which meets via conference call approximately twice 
per month or as needed throughout the period of study implementation to review safety data, discuss 
product use management, and address any potential safety concerns.  
  
An IMPAACT Study Monitoring Committee (SMC) will review the study regularly, at least twice 
annually, and on a more frequent or ad hoc basis for safety issues or any other concerns. Other study 
implementation issues, such as participant accrual, participant retention, and data quality, will also be 
monitored by the SMC. The protocol team may also request ad hoc SMC reviews if any potential safety 
concerns arise.  For example, if a potential concern is identified during a routine protocol team review of 
safety data, the team may request an ad hoc SMC review to further evaluate that potential concern. Based 
on any of its reviews, the SMC may recommend that the study proceed as currently designed, proceed 
with design modifications, or be discontinued. 
 
7.2 
Safety-Related Recording on Case Report Forms 
 
Study site staff will document in source documents all AEs reported by or observed in enrolled study 
participants regardless of severity and presumed relationship to study product.  
 
Pre-existing conditions and AEs identified in this study will be recorded on CRFs as abnormal laboratory 
test results, signs, symptoms, and diagnoses, as follows:  
 
Laboratory test results: The results of all protocol-specified screening, entry, and follow-up laboratory 
test results will be recorded on the relevant CRFs. In addition, throughout follow-up through the Study 
Exit Visit, Grade 2 or higher test results related to pregnancy complications, hepatotoxicity, hemorrhage, 
or peripheral neuropathy, all Grade 3 or higher test results, test results that result in discontinuation of 
study drug regimen, and test results that meet criteria for EAE reporting (included congenital anomalies) 
will be further evaluated, with additional data recorded on the relevant event evaluation CRF. 
 
Signs and symptoms: All signs and symptoms occurring from the Screening Visit through immediately 
prior to the first administration of study drug regimen will be recorded as pre-existing conditions on the 
relevant CRF. While maternal participants are receiving study drug, all signs and symptoms will be 
recorded on the relevant CRF. Thereafter, Grade 2 or higher signs and symptoms related to pregnancy 
complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, all Grade 3 or higher signs and 
symptoms, and signs and symptoms that meet EAE reporting criteria will be recorded on CRFs. In 
addition, throughout follow-up through the Study Exit Visit, Grade 3 or higher signs and symptoms, signs 
and symptoms that result in discontinuation of study drug regimen and signs and symptoms that meet 


IMPAACT 2001, Version 1.0 
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criteria for EAE reporting (included congenital anomalies) will be further evaluated, with additional data 
recorded on the relevant event evaluation CRF. 
 
Diagnoses: All diagnoses identified from the Screening Visit through immediately prior to the first 
administration of study drug regimen, except Grade 1 and Grade 2 diagnoses listed on the IMPAACT Do 
Not Record list (available at www.fstrf.org), will be recorded as pre-existing conditions on the relevant 
CRF. During follow-up through the Study Exit Visit, all diagnoses since the last study visit except Grade 
1 and Grade 2 diagnoses listed on the IMPAACT Do Not Record list will be recorded on the relevant 
CRF. In addition, throughout follow-up, Grade 2 or higher diagnoses related to pregnancy complications, 
hepatotoxicity, hemorrhage, or peripheral neuropathy, all Grade 3 or higher diagnoses, diagnoses that 
result in discontinuation of study drug regimen, and diagnoses that meet criteria for EAE reporting 
(including congenital anomalies) will be further evaluated, with additional data recorded on the relevant 
event evaluation CRF. All diagnoses recorded on CRFs should be recorded consistent with the 
specifications of the relevant diagnosis appendix (available at www.fstrf.org). 
 
With appropriate permission of the participant/mother, whenever possible, records from all non-study 
medical providers related to untoward medical occurrences will be obtained and required data elements 
will be recorded on study CRFs.   
 
7.3 
Expedited Adverse Event (EAE) Reporting 
7.3.1 
Adverse Event Reporting to DAIDS 
Requirements, definitions and methods for expedited reporting of adverse events (AEs) are outlined in 
Version 2.0 of the DAIDS EAE Manual, which is available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting system, must 
be used for expedited AE reporting to DAIDS. In the event of system outages or technical difficulties, 
expedited AEs may be submitted via the DAIDS EAE Form. For questions about DAERS, please contact 
DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site queries may also be sent from within the DAERS 
application itself. 
 
Where DAERS has not been implemented, sites will submit expedited AEs 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 expedited reporting, please contact DAIDS 
RSC (DAIDSRSCSafetyOffice@tech-res.com). 
7.3.2 
EAE Reporting Requirements for this Study 
• 
EAEs will be reported for women and infants enrolled in this study. 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used for 
this study. 
• 
The study agents for which expedited reporting is required are: rifapentine and isoniazid. Open-label 
pyridoxine (vitamin B6) and prenatal multivitamins are not to be considered for EAE reporting. 
7.3.3 
Grading Severity of Events 
Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric 
Adverse Events, Version 2.0 (dated November 2014 available on the RSC website (http://rsc.tech-
res.com/safetyandpharmacovigilance/), except for complications during pregnancy. Complications during 
pregnancy will be graded per the Complications of Pregnancy Section  of the Female Genital Grading 
Table for Use in Microbicide Studies (Version 1.0, dated November 2007) found on the DAIDS RSC 
website (http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx). 


IMPAACT 2001, Version 1.0 
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For any serious or expedited AEs (SAEs/EAEs) that are continuing at a participant’s study exit visit, the 
IoR/designee must establish a clinically appropriate follow-up plan for the AE, including referrals to local 
standard of care. The same approach must be taken for any AEs that are found to have increased in 
severity at the time of the study exit visit or continue requiring re-assessments beyond the study exit visit.     
 
Serious adverse events (SAEs) will be defined by the Manual for Expedited Reporting of Adverse Events 
to DAIDS (Version 2.0, January 2010), as AEs occurring at any dose that:  
• 
Results in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not result in death, be immediately life-threatening, or 
require hospitalization but may jeopardize the participant or require intervention to prevent one of 
the outcomes listed in the definition above   
7.3.4 
Expedited AE Reporting Period 
• 
The expedited AE reporting period for this study begins once the participant is enrolled and continues 
through and including the participant’s final study visit (Mother or Infant Study Exit). 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only suspected unexpected 
serious adverse reactions (SUSARs) as defined in Version 2.0 of the EAE Manual will be reported to 
DAIDS if the study staff become aware of the events on a passive basis (from publicly available 
information). 
 
8 
PARTICIPANT MANAGEMENT – MOTHERS AND INFANTS 
 
Guidelines for clinical management and temporary hold/permanent discontinuation of the study drug 
regimen are outlined in this section. In general, the IoR/designee has the discretion to hold study drug 
regimen temporarily at any time if s/he feels that continued use would be harmful to the woman or 
interfere with treatment deemed clinically necessary, and s/he should notify the Core Team in such cases. 
Unless otherwise specified below, the IoR/designee should immediately consult the Core Team for further 
guidance on resuming study drug regimen, continuing the hold temporarily, or progressing to permanent 
discontinuation of study drug regimen. The IoR/designee will document all temporary study drug regimen 
holds and permanent discontinuations on applicable CRFs. When indicated, sites should notify the Core 
Team within 48 hours. Unless otherwise specified, study drug regimen refers to RPT, INH, and 
pyridoxine. 
 
8.1 
Management of Adverse Events 
 
Management of adverse events will be according to the best clinical practice and the judgment of the site 
investigator. Enrolled infants of women participating in IMPAACT 2001 are not actively provided with 
the study drug regimen but may be exposed in utero or through breastfeeding. Infant management is the 
responsibility of the clinical care provider at the site. AEs involving these infants should be reported 
according to requirements in Section 7 as well as to the local Institutional Review Board/Ethics 
Committee according to prevailing local law and Good Clinical Practices. All protocol-specific reportable 
events and SAEs will be recorded on CRFs as per Section 7.2. Unless otherwise specified, participants 
will remain on-study for the duration of the scheduled follow-up visits. 
 


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All adverse events identified in infants in this study will be source documented consistent with the 
policies and procedures referenced in Section 11. Among other details, source documentation will include 
the severity of each event (graded as described in Section 7.3.3) and its relationship to study product, 
assessed by the site clinician according to the following categories and definitions: 
 
• 
Definitely Related: The adverse event and administration of the medication are related in time, 
and a direct association can be demonstrated. 
• 
Probably Related: The adverse event and administration of the medication are reasonably related 
in time, and the adverse event is more likely explained by the medication than other causes. 
• 
Possibly Related: The adverse event and administration of the medication are reasonably related 
in time, and the adverse event can be explained equally well by causes other than the medication. 
• 
Probably Not Related: A potential relationship between the medication and the adverse event 
could exist (i.e., the possibility cannot be excluded), but the adverse event is most likely 
explained by causes other than the medication. 
• 
Not Related: The adverse event is clearly explained by another cause not related to the 
medication. 
 
Note: The above classification applies for AE documentation (source documentation and CRF 
completion) and management but does not apply for expedited adverse event (EAE) reporting. EAEs will 
be reported, per the DAIDS EAE Manual, as related or not related. Please see Section 7.3 for more 
information on EAE reporting. 
8.1.1 
Suspected TB Disease 
• 
Hold study drug regimen (i.e., RPT, INH, and pyridoxine) for suspected TB disease 
• 
Perform confirmatory test (specific test as determined by site IoR/designee) 
• 
If active TB disease is confirmed, permanently discontinue study drug regimen and notify the Core 
Team. Women and infants diagnosed with active TB during the study will be referred to local care for 
active TB management and treatment, where (if available) they will have a sputum sample (or other 
appropriate sample if extrapulmonary TB) sent for drug susceptibility testing (DST) to ensure 
susceptibility to first-line regimens. . 
• 
If active TB disease is not confirmed and the IoR/designee suspects active TB based on clinical 
judgment, the IoR/designee may choose to permanently discontinue study drug regimen, refer 
participant to local care for TB management, and notify the Core Team.  
• 
If active TB disease is not confirmed, the IoR/designee may resume the woman on the study drug 
regimen. 
8.1.2 
Rifamycin hypersensitivity syndrome (RHS) 
For women who develop signs or symptoms suggestive of RHS (e.g., fever, myalgia, rash, hypotension, 
clinical hepatitis): 
• 
Hold study drug regimen 
• 
Assess the women for RHS (see note below for definition) through clinical evaluation and laboratory 
testing, including comprehensive metabolic panel, CBC with manual differential, and other tests that, 
at the discretion of the site IoR/designee, are necessary to exclude likely alternative diagnoses (e.g., 
should symptoms suggest influenza, a nasopharyngeal aspirate for viral testing could be sent).  
• 
If > Grade 2 AE or toxicity meets the case definition for RHS, permanently discontinue the study 
drug regimen and notify the Core Team. 
 
In the event of treatment discontinuation, participants will remain on-study and continue to be 
followed through 24 weeks postpartum.  
 


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Note: RHS is defined as follows:  
• 
Hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, or 
neutropenia that occurred in relation to study drug regimen; or  
• 
More than four of the following that occurred in relation to study drug (one of which must be 
assessed as having been > Grade 2): weakness, fatigue, muscle pain, nausea, vomiting, headache, 
fever, aches, sweats, dizziness, shortness of breath, flushing, rash, itching, syncope, cough, 
palpitations, chills, or eosinophilia. 
• 
A complete listing of RHS symptoms reported by the woman should be recorded on the appropriate 
CRFs.  
8.1.3 
Gastrointestinal 
For Grade 2 AE with symptoms not present at the previous visit, or for nausea/vomiting and/or diarrhea ≥ 
Grade 3:  
• 
Hold study drug regimen until the symptoms have resolved. Antiemetic and antidiarrheal medication 
may be used at the site investigator's discretion 
 
For nausea and vomiting occurring as a result of hepatitis (determined as unrelated to study drug 
regimen), hold study drug regimen until the symptoms return to baseline levels. 
8.1.4 
Cutaneous 
For Grade 2 or 3 rash, or showing a significant increase over baseline, hold study drug regimen. When the 
AE resolves or returns to baseline, resume study drug regimen. 
 
For Grade 4 cutaneous or Grade 4 mucocutaneous rash, hold study drug regimen. Study drug regimen 
may be interrupted and resumed at the discretion of the site investigator. If Grade 4 returns and is 
determined to be related, permanently discontinue study drug regimen.   
8.1.5 
Drug-Associated Fever 
If ≥ Grade 3, hold the study drug regimen. When the temperature returns to normal, resume the study 
drug regimen. If symptoms recur, permanently discontinue and notify Core Team.   
8.1.6 
Peripheral Neuropathy 
Peripheral neuropathy associated with INH is usually avoided by the concurrent administration of vitamin 
B6, and is expected to be rare given the once-weekly dosing and duration of the study drug regimen (12 
weeks). In this study, all women will take vitamin B6 as part of the complete study drug regimen. If 
peripheral neuropathy develops, every effort should be made to determine the etiology (i.e., to uncover 
other potential contributing factors such as alcohol use or concomitant drugs with this side effect). 
Women with Grade 1 peripheral neuropathy may be entered into the study, but should be monitored 
carefully for any progression of peripheral neuropathy. 
 
Grade 1 or 2: 
Continue the study drug regimen and assess the woman for progression of peripheral neuropathy.  
 
Grade 3 or 4: 
• 
Hold study drug regimen and assess weekly until toxicity resolves to Grade ≤2; then study drug 
regimen may be reintroduced at the site investigator's discretion.  
• 
If peripheral neuropathy does not resolve to Grade ≤2, then the study drug regimen can be 
discontinued or reintroduced at the site investigator's discretion. 
 


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8.1.7 
Asymptomatic Elevations in AST/ALT 
Every effort should be made to determine the etiology (i.e., whether the elevated AST/ALT is due to 
RPT/INH toxicity, alcohol, or other factors) in instances of suspected hepatotoxicity.  Reintroduction of 
potential hepatotoxic non-study concomitant medications is at the discretion of the site investigator and 
the study participant. If a participant becomes symptomatic, follow guidance for symptomatic hepatitis. 
 
Grade 1: 
• 
Continue study drug regimen. 
• 
Repeat test as soon as possible and within seven days. 
• 
If repeat assessment is Grade ≤ 1, continue study drug regimen. 
 
Grade 2: 
• 
Continue study drug regimen. 
• 
Repeat test as soon as possible and within seven days. 
- 
Assess for alcohol use, non-study medication-related drug toxicity, lactic acidosis syndrome, pre-
eclampsia, fatty liver of pregnancy, and viral hepatitis as the cause of the AST/ALT elevation. If 
the AST/ALT elevation is considered most likely to be due to concomitant illness or medication, 
standard management, including discontinuation of the likely causative agent, should be 
undertaken 
• 
If repeat assessment is Grade ≤ 2, continue study drug regimen. 
 
Grade 3: 
• 
Continue study drug regimen. 
• 
Repeat test within three working days. 
- 
Assess for alcohol use, non-study medication-related drug toxicity, lactic acidosis syndrome, pre-
eclampsia, fatty liver of pregnancy, and viral hepatitis as the cause of the AST/ALT elevation.  
• 
If repeat assessment is Grade ≤ 2, manage as per Grade 2. 
• 
If repeat assessment is Grade 3 and is attributed to concomitant illness or medication (not related to 
study drug), study drug regimen may be continued at the discretion of the site investigator, and the 
Core Team notified. Treat the underlying illness or remove the likely causative agent.  
• 
If the repeat assessment is Grade 3 and is assessed as related, hold study drug regimen.  
- 
Repeat testing weekly, and once the toxicity grade is Grade ≤ 2, resume study drug regimen and 
notify the Core Team. 
• 
When study drug regimen is resumed following a hold for Grade 3 AST/ALT, repeat testing should 
be performed one week after resumption. If the result of this testing is Grade 3 or 4, consult the Core 
Team.  
 
Grade 4: 
• 
Hold study drug regimen. 
• 
Repeat test within three working days, in addition to total bilirubin and INR if available at the site.  
- 
Assess for alcohol use, non-study medication-related drug toxicity, lactic acidosis syndrome, pre-
eclampsia, fatty liver of pregnancy, and viral hepatitis as the cause of the AST/ALT elevation.  
• 
If repeat assessment is Grade < 4, manage per the grade of the repeat assessment. 
• 
If repeat assessment is Grade 4, continue to hold study drug regimen.   
- 
Repeat ALT/AST testing weekly, and consult the Core Team on study drug regimen and 
frequency of repeat assessments.   
- 
Once the repeat testing results in Grade ≤ 1, resume study drug regimen. 
• 
When study drug regimen is resumed following a hold for Grade 4 AST/ALT, repeat testing should 
be performed one week after resumption. If the result of this testing is Grade 3 or 4, consult the Core 
Team.  
 


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8.1.8 
Hepatotoxicity (Symptomatic Hepatitis) 
Signs and symptoms of hepatitis include but are not limited to fatigue, malaise, anorexia, nausea, acholic 
stools, bilirubinuria, jaundice, liver tenderness, and/or hepatomegaly (icteric sclera in isolation without 
systemic complaints would not be considered symptomatic). 
• 
Hold study drug regimen. 
• 
Immediately perform AST and ALT tests, in addition to total bilirubin and INR if available at the site; 
stored assays for hepatitis B/C should be processed. Follow general management guidelines based on 
the highest grade sign or symptom. 
• 
Consult the Core Team on study drug regimen and frequency of repeat assessments (in general, at 
least weekly re-assessment is recommended). 
8.1.9 
HIV-1 Infection 
Participants (i.e., women or infants) who become infected with HIV during the course of the study will be 
referred to local care for treatment. HIV-1-infected women who are changed from an EFV + 2 NRTI 
regimen by their HIV treatment provider and are prescribed a triple or quadruple NRTI regimen can 
continue to take study drugs as planned. 
• 
Continue on study drug regimen, as long as they are not initiated on contraindicated medications (e.g., 
protease inhibitors).  
• 
If not taking an EFV-based regimen, permanently discontinue the study drug regimen. Such women 
and their infants will remain on-study for follow-up visits to complete follow-up through 24 weeks 
postpartum. Infant feeding, prevention and treatment of HIV and other co-morbidities will also be 
according to local standard of care.   
8.1.10 Postpartum Hemorrhage 
There are multiple causes of postpartum hemorrhage. Rifampin, another rifamycin product, may increase 
the risk for maternal postpartum hemorrhage and bleeding in the exposed neonate. This has not been 
reported in mothers on rifapentine or rifampin-containing active TB regimens. As a precautionary 
measure, mothers will have their prothrombin time (PT) monitored at baseline, in late third trimester, and 
as clinically indicated during monthly follow-up. Infants will be monitored for PT at birth and as 
clinically indicated during monthly follow-up. If there is an increase in PT with associated prolonged 
bleeding in the mother or infant, treatment with vitamin K may be indicted as per local standard of care. 
For maternal postpartum hemorrhage or bleeding in infants: 
 
Grade 1 or 2: 
• 
Continue study drug regimen. 
• 
Follow local standard of care and monitor PT.  
 
Grade 3 or 4: 
• 
Hold study drug. 
• 
Assess for signs and symptoms of active bleeding and other pregnancy-related etiologies. 
• 
If no signs of active bleeding or other etiologies of elevated PT are found, administer vitamin K per 
local standard of care and repeat PT within three working days. 
• 
If repeat PT is ≤ Grade 2, resume study drug regimen. Continue to monitor PT until it normalizes 
(i.e., returns to Grade 1 or lower). 
• 
If repeat PT is ≥ Grade 3, permanently discontinue study drug regimen. Continue to monitor PT until 
it normalizes (i.e., returns to Grade 1 or lower). 
• 
If signs of active bleeding are found, permanently discontinue study drug regimen. Administer 
vitamin K per local standard of care. Continue to monitor bleeding and repeat PT until it is resolved 
to Grade 1 or lower. 
 


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Note: Postpartum hemorrhage is defined as blood loss greater than 500 mL in vaginal delivery and 1,000 
mL in caesarean section within 24 hours of birth, at the discretion of the site investigator.  
8.1.11 Pregnancy 
For women who become pregnant again (during study follow-up) while still on the study drug regimen, 
permanently discontinue study drug regimen and refer to local standard of care. They will remain on-
study and complete the study procedures and evaluations per the schedule, with follow-up through 24 
weeks postpartum from the initial pregnancy. For women who are HIV-1-infected, the new pregnancy 
will be reported on the ARV Pregnancy Registry (http://www.apregistry.com/). At the end of this new 
pregnancy, site staff will contact the woman so the pregnancy outcome can be recorded on a CRF. 
8.1.12 General Management of Adverse Events (Not Otherwise Specified) - Mothers 
Grades 1 and 2:   
A woman who develops a Grade 1 or 2 AE (regardless of relatedness to study drug regimen) may 
continue the study drug regimen at the discretion of the site investigator.  
 
Grades 3 and 4:   
Study drug regimen should be temporarily held until the AE returns to baseline (enrollment visit levels) if 
baseline was > Grade 2, until < Grade 2, or within normal limits if baseline was ≤ Grade 2. If the Grade 3 
or 4 AE does not resolve within four weeks, then the study drug regimen may be permanently 
discontinued and the Core Team notified.   
 
8.2 
Criteria for Premature Permanent Discontinuation of Study Drug  
 
In the event of treatment discontinuation, women and their infants will remain on-study but off study 
treatment to complete follow up for 24 weeks postpartum. 
• 
Participant has been confirmed as having developed active pulmonary or extrapulmonary TB, per 
Gene Xpert, shielded chest x-ray, or AFB sputum smear microscopy, or other available TB 
diagnostics 
• 
Drug toxicity requires permanent study drug discontinuation as defined in Section 8.1 above 
• 
Repeat pregnancy during study follow-up 
• 
For HIV-1-infected women, not taking an EFV-based HIV regimen 
• 
If the woman chooses to discontinue the study drug regimen, the Core Team should be notified within 
48 hours. The site should complete the evaluations specified in Section 6.10 within seven days after 
stopping the study drug regimen.  
 
8.3 
Criteria for Premature Discontinuation of Study Participation 
 
A participant must be withdrawn from study participation if: 
 
• 
The participant withdraws consent and/or does not wish to continue in the study.  
• 
The site investigator determines further participation would be detrimental to the participant’s health 
or well-being. 
• 
The participant fails to comply with study requirements, so as to cause harm to self or seriously 
interfere with the validity of the study results. 
• 
The study is cancelled at the discretion of IMPAACT, the Food and Drug Administration (FDA), 
NIAID, the Office for Human Research Protections (OHRP), the local and/or national IRB or EC, or 
a country-specific governmental agency. 
 
Note: Lost to follow-up is defined as a participant having missed four or more consecutive study visits 
without contact with study staff. 
 


IMPAACT 2001, Version 1.0 
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See Section 6.10 for procedures to be conducted in the event of premature discontinuation of study 
participation. 
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
This study is a Phase I/II, open-label, multi-center, intensive PK study to evaluate the pharmacokinetics, 
safety, and tolerability of RPT and INH dosed once weekly for 12 doses in HIV-1-infected and HIV-1-
uninfected pregnant women with latent TB infection at high risk for development of TB. Infants will also 
be enrolled, and breast milk samples from postpartum women who are still taking RPT/INH will be 
collected. 
 
Two study cohorts are planned: 
Cohort 1: 
Pregnant women ≥14 weeks gestation through <28 weeks gestation (second trimester) 
Cohort 2: 
Pregnant women ≥28 weeks gestation through ≤34 weeks gestation (third trimester) 
 
An interim analysis to assess the PK of RPT will be conducted, and a dose adjustment may be indicated 
for each cohort. Dose adjustments indicated for Cohort 2 will be implemented for Cohort 1 women as 
they enter their third trimester of pregnancy. See Section 3.4 for accrual into the cohorts, and Section 10 
(Clinical Pharmacology Plan) for further details regarding the interim analysis and dose adjustment.  
 
In this section, only analyses related to Objectives 2.1.2, 2.1.3, 2.2.4, 2.2.6, and 2.2.7 are described. All 
other analyses are described in Section 10, as they are pharmacology objectives. 
  
Primary analyses in this study estimate pharmacokinetic parameters cross-sectionally and longitudinally. 
The fundamental concern is to assess maintenance of drug levels between second and third trimesters of 
pregnancy, along with assessment of postpartum drug levels in women and infants. Dose-exposure 
relationships will be modeled, concentrations in infant blood samples and breast milk will be quantified, 
and safety-related event rates will be estimated. 
 
9.2 
Outcome Measures 
 
The primary outcome measures for pregnant women during the second trimester, third trimester, and 
postpartum period who are receiving a dose of RPT 900mg once weekly together with once-weekly INH 
(900mg) are detailed below. All outcome measures will be collected and recorded on the CRFs according 
to standard IMPAACT procedures and transmitted to the Data Management Center for inclusion in 
standard database tables. Standard quality assurance procedures will be followed throughout the data 
lifetime.   
9.2.1 
Primary Outcome Measures 
9.2.1.1 Estimates of CL/F, absorption, and volume of distribution of RPT and its desacetyl-
rifapentine metabolite (desRPT). 
9.2.1.2 Safety (maternal) 
o Incidence of related serious adverse events (SAEs) in pregnant and postpartum 
women taking once-weekly RPT + INH 
o Grade 2 adverse events (AEs) judged to be related to study drug regimen 
o All Grade 3 and 4 AEs 
o All serious AEs 
o All AEs leading to permanent discontinuation of study drug regimen (i.e., RPT, INH, 
and pyridoxine) 


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9.2.1.3 Safety (infant) 
Incidence of related serious adverse events (AEs) in infants born to women taking once-
weekly RPT + INH. 
9.2.2 
Secondary Outcome Measures 
9.2.2.1 Vd, CL/F, Ka for pregnant women in their second or third trimester. 
9.2.2.2 RPT and desRPT concentrations in infants born to women receiving once-weekly RPT + 
INH. 
9.2.2.3 Tolerability 
o Permanent discontinuation of study drug regimen (i.e., RPT, INH, and pyridoxine) 
o  All AEs leading to permanent discontinuation of study drug regimen (i.e., RPT, 
INH, and pyridoxine) 
9.2.2.4 RPT and des-RPT concentrations in breast milk of postpartum women receiving once-
weekly RPT + INH. 
9.2.2.5 Incidence of active TB in mother-infant pairs up to 24 weeks postpartum. 
9.2.2.6 Estimates of CL/F, absorption, and volume of distribution of INH. 
 
 
9.3 
Stratification 
 
Pregnant women will be stratified by gestational age. Cohort 1 includes pregnant women ≥14 weeks 
gestation through <28 weeks gestation, and Cohort 2 includes pregnant women ≥28 weeks gestation 
through ≤34 weeks gestation. The eligibility determinations will guarantee enrollment of at least 10 HIV-
1-infected women in each cohort, and the algorithm will endeavor to balance sites with respect to number 
of HIV-1-infected women per site. 
 
9.4 
Accrual and Participant Number 
 
Up to 82 pregnant women will be accrued to yield 50 evaluable women (a minimum of 25 evaluable 
women in each cohort) and their infants. A target of at least 10 evaluable HIV-1-infected pregnant women 
will be enrolled in each cohort. 
 
Women are considered evaluable if they meet any of the following criteria: 
• 
Contribute any data to the Intensive PK or Sparse PK sampling collections 
• 
Complete the study drug regimen (see Section 5.1.2 for adherence definition) 
 


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9.5 
Sample Size Justification 
9.5.1 
Precision of RPT Clearance Estimation 
The stochastic simulation-estimation (SSE) methodology for clinical trial simulation and re-estimation 
was employed to evaluate sample sizes required to evaluate key pharmacokinetic parameters with 
precision adequate for decision making on use of RPT + INH in pregnancy (60). This methodology 
simulates the data from a planned trial with proposed design (number of samples, patients), followed by 
the estimation of the parameters under the true and alternative model. This is repeated at least 1,000 
times, and parameter estimates, relative standard error (RSE), and between subject variability (BSV) 
estimates are assessed. Table 3 below shows that the RSE of the estimated contrast between median 
clearance in second trimester and median clearance in third trimester (CL_3rd, column 3) reaches a 
desirable level of 18% for a total evaluable sample size of 50 women. Precision of estimation of other 
parameters (CL, V, ka) and BSV are seen to be very good for this sample size, and the estimation of 
between-participant variation achieves reasonable precision at N=50 as well. In general, RSE of 5% for a 
pharmacokinetic parameter (e.g. CL, V, ka), 10% for impact of covariate (e.g., impact of pregnancy on 
CL), and 20% for BSV is considered satisfactory. This is based on literature reviews where RSE 
associated with these parameters are often higher than proposed values here. 
 
Table 3: Evaluation of sample sizes and power 
Number of 
participants 
RSE 
(CL) (%) 
RSE, CL_3rd 
(%) 
RSE (V) 
(%) 
RSE (ka) 
(%) 
RSE  
(BSV-CL) 
(%) 
RSE 
(BSV-V) 
(%) 
Power (%) 
10 
9 
39 
9 
12 
36 
41 
82.2 
15 
8 
33 
8 
10 
33 
35 
91 
20 
7 
27 
7 
9 
29 
32 
94.6 
30 
6 
23 
6 
7 
25 
27 
98.2 
40 
5 
20 
5 
6 
22 
24 
99.5 
50 
5 
18 
4 
6 
20 
22 
99.9 
60 
4 
17 
4 
5 
18 
19 
100 
70 
4 
14 
4 
5 
17 
18 
100 
 
The power for an interim analysis sample of size 12 has been computed in comparison to a fixed 
historical value via a likelihood ratio test at the 0.01 level. Using the stochastic simulation and estimation 
methodology (60) and employing all available historical data, for Type I error rate of 1%, the power to 
detect an average 25% departure from mean historical value of CL with 12 individuals is 96%.  
9.5.2 
Precision of Estimation of Adverse Events Incidence 
With a sample size of 50 evaluable subjects, there is 90% power to detect one or more safety events for 
which the true rate of occurrence is 5 per 100 women or infants treated (see Table 4). The sample size of 
25 per cohort is sufficient to rule out only very extreme safety incidence rates. For example, if zero safety 
events are noted for a cohort of size 25, the upper bound of a 95% confidence interval for the event rate is 
approximately 15%. If two events are observed for such a cohort, the upper bound is in the vicinity of 
30%. Such statistics are, at best, marginally useful for decision making about the risk-benefit ratio for use 
of this regimen in pregnancy but should nevertheless contribute information on the tolerability and safety 
of the treatment. All women receiving any dose of study drug will be included in the safety analysis.  
 


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9.6 
Study Monitoring: Statistical Aspects 
 
Table 4: Power assessment for safety of protocol treatments 
Cell entries are minimum sample size required to detect one or more safety events at the given rates 
 
Safety Event Rates 
Power 
0.05 
0.1 
0.15 
0.8 
33 
17 
11 
0.9 
47 
24 
16 
Cell entries are minimum sample size required to detect two or more safety events at the given rates 
 
Safety Event Rates 
Power 
0.05 
0.1 
0.15 
0.8 
60 
30 
20 
0.9 
78 
39 
26 
 
 
Sections 4.4 and 4.5 detail monitoring activities at the DMC concerning recruitment, enrollment, and 
retention. Section 7 describes procedures for safety monitoring, assessment, and reporting.  
 
A monitoring plan will be developed for this study to ensure that the data collected are clean, complete, 
and of high quality and to make the team aware of the study’s progress in an ongoing manner. Monthly 
conference calls will be held by the study team to assess study progress, and follow-up statistics will be 
reported to the team by the DMC on a monthly basis. Rate of enrollment will be closely monitored, with 
input provided from team members and participating sites on methods to speed enrollment if needed.  
9.6.1 
Study Monitoring Committee 
The study will be monitored intensely by the protocol team, which will review safety and 
pharmacokinetic data approximately monthly. In addition, the study will be monitored by an SMC 
according to standard IMPAACT procedures. The committee will meet via conference call to review 
relevant data as described below and in Section 7.1 to ensure participant safety. The SMC could meet at 
least once annually and more frequently if indicated by the protocol team or the study sponsor. 
9.6.2 
Study Safety Monitoring 
Since Phase I studies are not routinely reviewed by a Data and Safety Monitoring Board (DSMB), it is the 
responsibility of the Protocol Team to interpret safety data and make decisions regarding AEs that are 
needed to protect participants from undue risk. Per Section 7.1, the Core Team will review routine safety 
monitoring and clinical data reports. In addition, the Study Monitoring Committee described above is 
appointed to provide impartial reviews in situations where participant safety is in question.  
 
The safety and tolerability of the study agent will be monitored by means of adverse events reports and 
toxicity reports presenting laboratory and clinical events. The data required for the toxicity reports must 
be entered into the database within 48 hours of the time at which the results of the laboratory tests or 
clinical examinations become available.  
 
Reports compiled by the DMC will be reviewed and discussed by the Protocol Team on conference calls 
held approximately monthly. The attribution of relationship of ≥ Grade 3 AEs to RPT/INH will be 
determined by the protocol team, and any discrepancies of assessments between site investigators and the 
protocol team will be reconciled during the conference calls. For safety monitoring, a drug-related AE is 
an AE that is judged to be definitely, probably, or possibly related to study drug (RPT/INH).  
 


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Data on accrual, pharmacokinetics and toxicity will be reviewed by the study’s Study Monitoring 
Committee:  
1) When the consensus among the site investigator, the protocol team and the DAIDS medical officers 
regarding to relationship of AEs to the study drug cannot be established  
2) When there is any specific safety concern.  
 
Adverse events will be monitored from screening onward throughout the follow-up period. If any Grade 4 
AEs that are possibly, probably, or definitely related to the study regimen or deaths occur, or if the 
protocol team identifies any potentially treatment-related toxicities that could compromise participant 
safety, the study may be paused, and the Study Monitoring Committee will review all relevant data and 
will determine whether, and under what conditions, the study will be allowed to proceed. 
 
9.7 
Analysis 
9.7.1 
Pharmacokinetic Outcomes 
Analysis for objectives 2.1.1, 2.2.1, 2.2.2, 2.2.3, 2.2.4, 2.2.5, 2.2.8, and 2.3.1 is fully described in Section 
10 below.  
9.7.2 
Safety Outcomes 
The primary safety analysis will include all women who have been exposed to RPT/INH at any dose in 
the study. Women whose doses have been adjusted for inadequate PK will be included in the primary 
safety analysis. Women who have been removed from treatment due to toxicities while on the optimal 
dose will be included and treated as safety failures in the primary safety analysis. Additional analyses will 
look at the combined data from women whose doses failed and those who have been treated solely at the 
optimal doses determined for their cohorts. Each woman’s safety data will be summarized as: the worst 
grade of adverse event experienced during study treatment and the worst grade of adverse event judged to 
be at least possibly related to study treatment during this time period.  
 
Frequency distributions of these safety outcomes will be presented in the aggregate and broken down by 
cohort. Listings of all ≥ Grade 3 or ICH defined serious events will be provided,  
The proportions of participants experiencing ≥ Grade 3 or ICH defined serious adverse events will be 
presented in aggregate and broken down by cohort, with these proportions bounded by exact 95% 
confidence intervals. Similar analyses will present the proportions of participants exhibiting ≥ Grade 3 or 
ICH defined serious events which have been judged to be at least possibly related to study medication, 
again bounded by exact 95% confidence intervals. 
 
For objectives 2.1.2, 2.1.3, and 2.2.6, Poisson regression will be used to estimate the incidence of serious 
adverse events related to treatment, adjusting for important cofactors. Analyses of tolerability and safety 
for infants will employ standard descriptive techniques; events of intolerability or compromise to infant 
safety are expected to be rare. 
 
10 CLINICAL PHARMACOLOGY PLAN 
 
10.1 Pharmacology Overview and Objectives  
 
The goal of this study is to assess the pharmacokinetics of RPT, des-RPT, and INH in pregnant women. 
Population pharmacokinetics will be estimated based on the sample, and exposure parameters will also be 
compared between the pregnant cohort and non-pregnant historical controls (58). Finally, this study will 
determine how stage of pregnancy impacts the pharmacokinetics of RPT and des-RPT and dosing.  
 


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The design and analysis plans for objectives 2.1.1, 2.2.1, 2.2.2, 2.2.3, 2.2.4, 2.2.5, 2.2.8, and 2.3.1 are 
described in this section. 
 
10.2 Methods and Timing for PK Collections, Processing, Handling, and Storage 
10.2.1 Intensive and Sparse PK collections: Mother 
Both the Intensive and Sparse PK sampling are ideally conducted in the morning. The Intensive PK 
sampling must be initiated on the same day as the first dose of the study drug regimen per Section 6.2. As 
mentioned in Section 6.2 above, the Entry Visit may be conducted as a split visit. The Sparse PK 
sampling will be completed after the final study drug dose per Section 6.3. Depending on site capacity, 
women may stay at the clinical research site or affiliated health care facility the evening prior to and after 
the PK sampling dose in order for an early morning PK sampling to be initiated. Further operational 
details on these visits are found in Sections 6.2 and 6.3. 
10.2.2 Breast Milk PK Collection: Mothers 
Postpartum women who are breastfeeding while still on the study drug regimen will be eligible for the 
breast milk PK sample collection. Breast milk will be expressed by the woman, and a plasma sample 
collection will also be drawn per Section 6.3. 
10.2.3 Cord Blood PK Collection:  Mothers 
At sites with capacity, women will be offered an option of also having a cord blood sample taken. Women 
must have received a study drug regimen dose within 72 hours prior to delivery to be eligible for the cord 
blood sample collection.  
10.2.4 Single PK collection: Infant 
For infants meeting PK sampling eligibility criteria described below, a single PK sample will be obtained 
within the first three days of life. Ideally, the single PK sample for the infants will be obtained prior to the 
mother being discharged from the hospital.   
 
Infants must meet all of the criteria below to be eligible for the Infant PK Sample Collection: 
• 
Infant birth weight > 1000 grams 
• 
Infant NOT receiving disallowed medications described in Section 5.5 
• 
Infant does not have any severe congenital malformation or other medical condition not 
compatible with life or that would interfere with study participation or interpretation, as judged 
by the site investigator   
• 
The mother’s most recent dose was taken within 72 hours of drawing the infant’s blood 
10.2.5 Processing, Handling, and Storage of PK Specimens 
Detailed blood processing, handling, and storage procedures can be found in the IMPAACT 2001 
Laboratory Processing Chart (LPC) and study-specific MOP. 
 
10.3 Interim Analysis and Dose Adjustment 
 
An interim analysis will be conducted for each cohort to determine whether a dose adjustment is indicated 
by comparing the median parameter estimates of clearance (CL/F) of RPT in the participants to those of 
non-pregnant historical controls.   
 


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For each cohort, the dose of RPT will be judged acceptable if: 
 
• 
Median exposure following this dose is not altered > 25% compared to the exposures from non-
pregnant historical controls 
 
These guidelines will be reviewed by the Core Team and the SMC during an interim analysis (further 
described below and in Section 3.4). If these guidelines are not met, the Core Team will carefully assess 
whether a dose adjustment is needed (see Section 10.3.2). 
 
Accrual into each cohort (including pausing for interim analysis) will proceed as described in Section 3.4. 
Follow-up of already-enrolled women will continue as planned during a pause for interim analysis. Any 
pause in accrual to allow for an interim analysis and any changes in the dosing of the study drug regimen 
will be communicated by the IMPAACT 2001 Core Team to all participating sites. 
 
If there is an effect of pregnancy on drug disposition, those effects are likely to be most prominent late in 
pregnancy (i.e., in the third trimester). Therefore, a dose adjustment indicated for Cohort 2 will be 
implemented for Cohort 1 women as they enter their third trimester of pregnancy.   
 
Based on the robust data on RPT PK in other populations including non-pregnant women, the current 
proposed design with intensive PK sampling provided during the second trimester (Cohort 1, visit 1) and 
third trimester (Cohort 2, visit 1) in this study will be sufficient to accurately estimate any required dose 
change that would be needed to achieve PK parameters similar to non-pregnant controls. To date, a dose 
change has not been indicated for RPT in any of the adult populations studied, including those who are 
HIV-1-infected. A similar approach was used to recommend dose change in children and adolescents, 
which was graded by developmental stage and weight (see Appendix II).  
10.3.1 Timing of Interim Analysis 
The timing of the interim analysis may differ between the two cohorts: 
 
• 
The interim analysis will be conducted for Cohort 1 when the first 12 women of Cohort 1 have 
completed the Intensive PK sampling or after the first 12 women have enrolled into Cohort 2, 
whichever event occurs first. (If there are effects of pregnancy on drug disposition, those effects 
are likely to be most prominent late in pregnancy (i.e., in the third trimester)). 
 
• 
The interim analysis for Cohort 2 will be conducted when 12 women have enrolled into Cohort 2 
and completed the Intensive PK sampling. 
10.3.2 Starting Dose and Dose Adjustment 
Prior to the interim analysis, all women will be started at a 900mg rifapentine dose (see Section 1.3 for 
rationale for study design). If a dose adjustment is indicated by the interim analysis, all women enrolled 
thereafter will be started at the adjusted dose. 
 
Based on the data reviewed during the interim analysis, if the median parameter estimates of CL/F differ 
more than 25% compared to CL/F in non-pregnant historical controls (2.07 L/h for 60.0 kg female if 
fasting and 1.47 L/h if tablet taken with any food), a dose adjustment will be discussed. There will be no 
intra-person dose adjustments done based on an individual’s PK data during the course of the study. 
 
• 
Clearance within 25% of clearance in non-pregnant controls: If the median clearance is similar to 
that of non-pregnant controls, then the remaining accrual target will be enrolled for a total of 25 
evaluable women on the 900mg dosing in the respective cohort.  
 


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• 
Clearance decreased by >25% of clearance in non-pregnant controls: If the PK analysis suggests 
that a dose decrease is required, then the remaining accrual target in the respective cohort will be 
enrolled at the lower dose. The dose will be decreased to deliver the appropriate target AUC 
(defined as dose over clearance) in increments of available tablet size (e.g., 150mg): % change in 
CL/F corresponds to the % change in required dose (e.g., if CL/F is decreased 30%, that will 
require dose decrease of 30% (approximately 300mg) leading to a new dose of 600mg). Women 
enrolled into Cohort 1 after the interim analysis for Cohort 2 is completed will transition to the 
lower dose in their third trimester.  
 
• 
Clearance increased by >25% of clearance in non-pregnant controls: If the PK analysis suggests 
that a dose increase is required, 25 evaluable women will be newly enrolled into the respective 
cohort at the higher dose, because safety will need to be adequately assessed at the higher dose. 
The dose will be increased to deliver the appropriate target AUC (defined as dose over clearance) 
in increments of available tablet size (e.g., 150mg): % change in CL/F corresponds to the % 
change in required dose (e.g., if CL/F is increased 30%, that will require dose increase of 30% 
(approximately 300mg) leading to a new dose of 1200mg). Women enrolled into Cohort 1 after 
the interim analysis for Cohort 2 is completed will transition to the higher dose in their third 
trimester. 
 
10.4 Laboratory Performing the Assays 
 
Plasma RPT and desRPT concentrations will be determined by a validated procedure performed 
according to written standard operating procedures. The intraday accuracy and intraday precision will be 
obtained with quality control samples, which will be analyzed concurrently with each set of volunteer 
samples. Quality control procedures will be in place to ensure stability of sample materials. 
 
10.5 Primary and Secondary Data Analysis Plan 
 
Primary:  
Pharmacokinetic data (concentration-time data) and safety data of rifapentine and 
desacetyl-rifapentine in pregnant women; safety outcomes in infants 
 
Secondary:  
Pharmacokinetic data of rifapentine and desacetyl-rifapentine in postpartum women and 
infants; pharmacokinetic data of isoniazid in pregnant and postpartum women 
 
Population-based estimates of RPT CL/F, absorption, and volume of distribution will be derived for 
pregnant women in second and third trimesters of pregnancy and in the postpartum period. Study data 
will provide a mix of longitudinal and cross-sectional observations, which will be combined using 
standard algorithms in wide use in pharmacology research. The pharmacokinetics of the desacetyl-
rifapentine (des-RPT) metabolite of RPT and INH will be estimated based on the sample in like fashion. 
Rates of adverse events and other safety-related parameters will be computed and reported for study 
monitoring and regulatory use. Secondary objectives are: characterization of PK data of RPT and des-
RPT in the postpartum period, description of adverse and safety outcomes in pregnant women, 
assessment of impact of covariates on primary PK parameters, comparison of RPT and des-RPT 
exposures between study participants and non-pregnant historical controls, estimation of effective RPT 
dose for pregnant women, estimation of RPT concentrations in newborns, description of pregnancy and 
infant safety outcomes, description of RPT + INH tolerability in pregnancy, and characterization of PK 
data of INH in pregnant and postpartum women. 
 


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The primary tool for estimation of parameters of interest is the single compartment model for RPT 
absorption and disposition kinetics: 
 
𝒅𝑨(𝟏)
𝒅𝒕
= −𝒌𝒂× 𝑨(𝟏); Absorption compartment 
𝒅𝑨(𝟐)
𝒅𝒕
= 𝒌𝒂× 𝑨(𝟏) −
𝑪𝑳
𝑽× 𝑨(𝟐); Central Plasma compartment 
The parameters CL and V will be elaborated upon to incorporate allometric scaling and effects of 
gestational age. 
 
10.6 Anticipated Outcomes 
 
The anticipated outcomes of the pharmacology evaluations are: 
• 
Estimates of all PK parameters including CL (in relationship to the pregnancy stage), volume of 
distribution, model-based Cmax and exposure (AUC) as well as estimates between participant 
variability associated with all these parameters.  
• 
Absorption rate constant (ka) of RPT. 
• 
Incidence of adverse safety events in pregnant women and their infants. 
 
11 DATA HANDLING AND RECORD KEEPING 
 
11.1 Data Management Responsibilities 
 
As described in Section 4.4, data on screening and enrollment in this study will be collected using the 
DMC SES.   
 
Study sites must maintain adequate and accurate research records containing all information pertinent to 
the study for all screened and enrolled participants, including CRFs and supporting source data. In 
maintaining these records, sites must comply with the standards of source documentation specified in the 
DAIDS policy on Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical 
Trials (available on the web site referenced in Section 11.2). 
 
CRFs are completed by site staff and, following quality control and quality assurance reviews, are keyed 
using a remote data entry system designated by the DMC and transferred electronically to the DMC. 
Selected laboratory data are transferred electronically to the DMC through the LDMS. At the DMC, 
computerized checks are applied to the transferred data and, when required, data queries are issued for 
resolution by site staff. All data must be transferred to the DMC within timeframes specified in the forms 
instructions; queries must also be resolved in a timely manner.  
 
Further information on the study CRFs and IMPAACT data management procedures, including a Forms 
Manual: Policies and Procedures for Forms Completion for DAIDS-Sponsored Clinical Trials, a 
comprehensive Computing Manual, and a User Manual for the SES, is available on the DMC portal at 
www.fstrf.org.   
 
11.2 Essential and Source Documents and Access to Source Data 
All DAIDS policies referenced in this section are available at: 
http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Pages/ClinicalSite.aspx 
 
Study sites must comply with the DAIDS policies on Requirements for Essential Documents at Clinical 
Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials and Requirements for 
Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials. In its policy on Requirements 
for Manual of Operational Procedures, DAIDS requires sites to establish SOPs for maintaining essential 


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and source documents in compliance with these policies. Site SOPs should be updated and/or 
supplemented as needed to describe roles, responsibilities, and procedures for this study, and site SOPs 
should be followed throughout the study.  
Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must be 
stored in a manner that ensures privacy, confidentiality, security, and accessibility during the conduct of 
the study and after the study is completed. Records must be retained for a minimum of three years after 
the completion of the study. Per 21 CFR 312.62, records must be maintained for two years after the date a 
marketing application is approved for one or more of the study drugs for the indication for which it is 
evaluated in this study; or, if no application is filed, or if the application is not approved for this 
indication, records must be retained two years after the study is discontinued and the FDA is notified.  
All study records must be accessible for inspection, monitoring, and/or auditing during and after the 
conduct of the study by authorized representatives of the study sponsors and their contracted monitors, the 
companies that provide the study products, IMPAACT, site IRBs/ECs, site IBCs, the FDA, OHRP, and 
other applicable regulatory entities. Participants’ study information will not be released without their (or, 
if applicable, other authorized guardian’s) written permission, except as necessary for the aforementioned 
inspection, monitoring, and/or auditing. Records must be kept on site throughout the period of study 
implementation; thereafter, instructions for off-site storage may be provided by NIAID or NICHD.  No 
study records may be removed to an off-site location or destroyed prior to receiving approval from NIAID 
or NICHD.  
11.3 Quality Control and Quality Assurance 
 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the DAIDS policy on 
Requirements for Clinical Quality Management Plans, which is available at: 
 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/qmppolicy.pdf 
 
12 CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities and 
review participant study records including consent forms, CRFs, medical records, laboratory records, and 
pharmacy records to ensure protection of study participants, compliance with the IRB/EC approved 
protocol, and accuracy and completeness of records. The monitors also will review essential document 
files to ensure compliance with all applicable regulatory requirements. Site investigators will make study 
facilities and documents available for inspection by the monitors.   
 
13 HUMAN SUBJECTS PROTECTIONS 
 
13.1 IRB/EC Review and Approval  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this protocol and 
site-specific ICFs in accordance with 45 CFR 46 and 21 CFR 56; subsequent to initial review and 
approval, IRBs/ECs must review the study at least annually. Site investigators must also promptly report 
to the IRB/EC any changes in the study and any unanticipated problems involving risks to participants or 
others.  
 


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All IRB/EC policies and procedures must be followed, and complete documentation of all correspondence 
to and from the IRBs/ECs must be maintained in site essential document files. Sites must submit 
documentation of both initial review and approval and continuing review to the DAIDS Protocol 
Registration Office (PRO) in accordance with the DAIDS Protocol Registration Manual (see also Section 
14.2). 
 
13.2 Vulnerable Participants 
 
The NIH is mandated by law to ensure that pregnant women and children be included in clinical research 
when appropriate (61, 62). This study responds to that mandate and will provide clinical research data to 
inform TB treatment guidelines for pregnant women. Nonetheless, the pregnant women, fetuses, and 
children who take part in this study are considered vulnerable participants per the US Code of Federal 
Regulations, and site IRBs/ECs must consider the potential risks and benefits to maternal, fetal, and infant 
participants as described in 45 CFR 46 Subpart B (for pregnant women, fetuses, and neonates) and 45 
CFR 46 Subpart D (for children).   
 
With respect to 45 CFR 46 Subpart B, the specifications of 45 CFR 46.204 (d) are considered to apply; 
therefore, women will be asked to provide written informed consent for their own and their children’s 
study participation.   
 
With respect to 45 CFR 46 Subpart D, IRBs/ECs must determine the level of risk to children in the 
categories specified in 45 CFR 46.404-407. Documentation of this determination is required to complete 
the DAIDS protocol registration process described in Section 14.2, and the risk category assigned by the 
IRB/EC further determines the parental informed consent requirements for the study at each site.  Per 45 
CFR 46.408 (b), the IRB/EC may find that the consent of one parent is sufficient for research to be 
conducted under 46.404 or 46.405. If the IRB/EC finds that the research is covered by 46.406 or 46.407, 
both parents must give their consent, unless one parent is deceased, unknown, incompetent, or not 
reasonably available or when only one parent has legal responsibility for the care and custody of the child 
(as determined locally). IRBs/ECs must document their risk determination, and study sites should adapt 
the signature pages of their site-specific ICFs as needed to accommodate the parental consent 
requirements associated with the IRB/EC determination.   
 
Study sites must comply with the requirements of the DAIDS policy on Enrolling Children (including 
Adolescents) in Clinical Research, which is available at: 
www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/ClinicalSite.aspx.  
 
13.3 Informed Consent 
 
Written informed consent for study participation will be obtained before any study-specific procedures 
are performed. It is generally expected that women will provide informed consent for their own and their 
children’s participation in this study. However, parental consenting requirements at each site will depend 
on the IRB/EC risk determination described in Section 13.2, and all IRB/EC requirements will be 
followed. Refer to Section 4.4 and the study-specific MOP for further information on informed consent 
procedures for this study. 
 
Should the consenting mother of an enrolled infant die or no longer be available for any reason, no further 
study-specific visits or procedures may be performed with her infant until informed consent for continued 
study participation is obtained from a locally authorized guardian. In accordance with the DAIDS policy 
on Enrolling Children (including Adolescents) in Clinical Research (available at the website referenced in 
Section 13.2), all study sites must establish and maintain written procedures describing the standards that 
will be followed to identify who may serve as guardian for an enrolled infant, reflective of applicable 
IRB/EC guidance for conduct of human subjects research within the context of available local law, 
regulation, or government policy. 
 


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13.4 Potential Benefits 
 
There is a prospect of direct benefit to the participants, both mother and infant. Taking anti-TB medicine, 
as well as vitamin B6, may provide a benefit to the mother and her infant. Furthermore, early detection of 
TB may be a benefit and would help prevent transmission of TB to the infant. Maternal TB is also 
associated with an increased risk of neonatal death, fetal distress, low birth weight, prematurity, and 
increased risk of perinatal transmission of HIV. Therefore, participation in this trial may provide a direct 
benefit to the infant as well by reducing these risks. Participants will receive clinical evaluations, 
laboratory testing, and TB signs and symptoms counseling. For other medical conditions identified as part 
of the study screening and/or follow-up procedures, participants will be referred to other sources of care 
available in their community. Some participants may have the opportunity to access expedient treatment 
and decreased morbidity due to early diagnosis and treatment of abnormalities identified during tests, 
examinations and referrals.  
 
Participants in this study may experience no direct benefit. Participants and others may benefit in the 
future from information learned from this study. Specifically, information learned in this study may lead 
to the development of treatment guidelines tailored for pregnant women with latent TB infection. 
Participants also may appreciate the opportunity to contribute to the field of TB research. 
 
13.5 Potential Risks  
 
The potential risks of this study are those associated with having blood drawn, treatment failure, 
resistance to TB medications, suboptimal dosing for latent TB, possible reactions to the RPT + INH 
investigational product and breach of confidentiality. 
 
Drawing blood may cause transient discomfort and fainting. Fainting is typically transient and managed 
by having the participant lie down. Bruising at the blood draw site may occur, but can be prevented or 
lessened by applying pressure to the draw site for several minutes. There is a slight risk of infection 
associated with drawing blood. 
 
A chest x-ray may be indicated to confirm active TB disease. The radiographic exposure required is 
minimal and is far below the maximum allowed, even for pregnant women. Therefore, this procedure is 
associated with minimal risk. 
 
The following side effects have been associated with the use of RPT:  
 
• 
Rash  
• 
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: 
o Unexplained loss of appetite 
o Pale-colored stools 
o Yellowing of the eyes or skin 
o Pain in the upper abdomen 
o Dark urine 
o Loss of appetite 
o Low blood counts (for example, for the blood cells that help your body fight infection) 
o Dizziness  
o Hypertension  
o Headache 
o Low blood sugar 
o Upset stomach or vomiting 


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o Decreased effectiveness of hormonal contraceptives and other medications. Tell your 
doctor about all medications that you are taking. 
 
Women taking rifapentine may have a serious allergic reaction called Rifamycin Hypersensitivity 
Syndrome (RHS) that can be dangerous if not caught right away. Women will be told to report to the 
study clinic as soon as possible for an evaluation if they report any of the symptoms (defined in Section 
8). 
 
When administered during the last few weeks of pregnancy, rifampin, another rifamycin product, has 
been shown (in rare cases) to increase the risk of maternal postpartum hemorrhage and bleeding in the 
exposed neonate (see Section 8.1.10). 
 
13.6 Potential Social Impacts 
 
Participation in clinical research includes the risk of loss of confidentiality. Although study sites make 
every effort to protect participant privacy and confidentiality, it is possible that participants' involvement 
in the study could become known to others, and that social harms may result (e.g., because participants 
could become known as having LTBI). For example, participants could be treated unfairly or 
discriminated against or could have problems being accepted by their families and/or communities.  
 
13.7 Reimbursement/Compensation 
 
Pending IRB/EC approval, women will be reimbursed for costs associated with completing study visits 
(e.g., transport costs).  Reimbursement amounts will be specified in site-specific ICFs or other materials if 
applicable per IRC/EC policies and procedures.  
  
13.8 Privacy and Confidentiality 
 
All study procedures will be conducted in private, and every effort will be made to protect participant 
privacy and confidentiality to the extent possible. Each study site will implement confidentiality 
protections that reflect the local study implementation plan and seek the input of study staff and 
community representatives to identify potential confidentiality issues and strategies to address them. In 
addition to local considerations, the protections described below will be implemented at all sites. 
 
All study-related information will be stored securely. All participant information will be stored in locked 
areas with access limited to study staff. All laboratory specimens, study data collection, and 
administrative forms will be identified by coded number only to maintain participant confidentiality. All 
records that contain names or other personal identifiers, such as locator forms and informed consent 
forms, will be stored separately from study records identified by code number. All local databases will be 
secured with password protected access systems. Forms, lists, logbooks, appointment books, and any 
other listings that link participants’ ID numbers to identifying information will be stored in a separate, 
locked file in an area with limited access. After receiving appropriate approval, all study documents/data 
will be properly disposed of, including the proper destruction and/or deletion of paper files, electronic 
study data, and electronic documents. If used, audio files will be transcribed and destroyed as soon as 
transcription and analyses are completed.  
 
Study sites are encouraged but not required by DAIDS policies to store study records that bear participant 
names or other personal identifiers separately from records identified by PID. All local databases must be 
secured with password protected access systems. Lists, logbooks, appointment books, and any other 
documents that link PID numbers to personal identifying information should be stored in a separate, 
locked location in an area with limited access.   
 


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13.9 Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases including HIV-1 
identified among study participants to health authorities. Participants (or other authorized guardians if 
applicable) will be made aware of reporting requirements during the informed consent process. 
 
13.10 Management of Incidental Findings 
 
Site clinicians will inform participants (or other authorized guardians if applicable) of clinically 
meaningful physical exam findings and laboratory test results, including results of HIV tests. Participants 
will not receive PK test results. When applicable, site clinicians will provide referrals to non-study 
sources of medical care for further evaluation and/or treatment of these findings.  
 
13.11 Management of New Information Pertinent to Study Participation 
 
Participants (or other authorized guardians if applicable) will be provided any new information learned 
over the course of the study that may affect their willingness to participate and/or remain in the study or 
their willingness to allow their children to participate and/or remain in the study.   
 
13.12 Post-Study Access to Study Drug 
 
Participants will complete the study drug regimen prior to exiting the study. Therefore, post-study access 
to study drug is not applicable. 
 
14 ADMINISTRATIVE PROCEDURES 
 
14.1 Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), Eunice 
Kennedy Shriver National Institute of Child Health and Development (NICHD), and National Institute of 
Mental Health (NIMH), which are part of the United States National Institutes of Health (NIH). The study 
drug rifapentine (RPT) is provided by Sanofi; however, this organization is not involved in sponsorship or 
regulatory oversight of this study.   
 
The Division of AIDS (DAIDS) within the NIAID is responsible for regulatory oversight of this study 
and holds the Investigational New Drug (IND) application under which the study will be conducted. 
DAIDS will distribute safety-related information pertaining to the study products prior to and during the 
conduct of the study in accordance with its sponsor obligations. 
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be conducted.  
Each institute contracts with independent clinical site monitors who will perform monitoring visits as 
described in Section 12. As part of these visits, monitors will inspect study-related documentation to 
ensure compliance with all applicable US and local regulatory requirements. 
 
14.2 Protocol Registration 
 
Prior to implementation of this protocol and prior to any subsequent full version amendments, each site 
must have the protocol and the protocol informed consent form approved, as appropriate, by their local 
IRB/EC and any other applicable regulatory entity (RE). Upon receiving final approval, sites will submit 
all required protocol registration documents to the DAIDS Protocol Registration Office (DAIDS PRO) at 
the Regulatory Support Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received. 
 


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Site-specific 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.  
 
For any future protocol amendments, upon receiving final IRB/EC and any other applicable regulatory 
entity approvals, sites should implement the amendment immediately.  Sites are required to submit an 
amendment registration packet to the DAIDS PRO at the RSC. Site-specific ICFs will not be reviewed 
and approved by the DAIDS PRO, and sites will receive an Amendment Registration Notification from 
the DAIDS PRO that indicates successful completion of the amendment protocol registration process. A 
copy of the final amendment Registration Notification issued by the DAIDS PRO 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, 
which is available on the RSC website: http://rsc.tech-res.com/protocolregistration/. 
 
14.3 Study Implementation 
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US and local regulations. Study implementation will also be guided by the 
study-specific MOP, LPC, and other study implementation materials, which will be available on the 
IMPAACT web site: www.impaactnetwork.org. 
Study implementation at each site will also be guided site SOPs. The DAIDS policy on Requirements for 
Manual of Operational specifies the minimum set of SOPs that must be established at sites conducting 
DAIDS-funded and/or -sponsored clinical trials (available on the website referenced in Section 11.2). 
These SOPs should be updated and/or supplemented as needed to describe roles, responsibilities, and 
procedures for this study. 
 
14.4 Protocol Deviation Reporting 
 
Per the policy for Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical 
Trials (available at the website referenced in Section 11.2), all protocol deviations must be documented in 
participant research records. Reasons for the deviations and corrective and preventive actions taken in 
response to the deviations should also be documented.  
 
Deviations should be reported to site IRBs/ECs and other applicable review bodies in accordance with the 
policies and procedures of these review bodies. Serious deviations that are associated with increased risk 
to one or more study participants and/or significant impacts on the integrity of study data must also be 
reported within IMPAACT, following procedures specified in the IMPAACT Manual of Procedures. 
 
14.5 Critical Events Reporting 
 
Per the DAIDS policy on Identification and Classification of Critical Events, a critical event is defined as 
an unanticipated study-related incident that is likely to cause harm or increase the risk of harm to 
participants or others or has a significant adverse impact on study outcomes or integrity. All such events 
must be reported following procedures specified in the DAIDS Critical Events Manual, which is available 
at: 
http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Pages/Safety.aspx    
 


IMPAACT 2001, Version 1.0 
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14.6 ClinicalTrials.gov 
 
This protocol is not subject to the Food and Drug Administration Amendments Act of 2007 (FDAAA); 
however, it will be registered in https://clinicaltrials.gov/ to meet International Committee of Medical 
Journal Editors (ICMJE) requirements.  
15 PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT policies, 
which are available in the IMPAACT Manual of Procedures. 
 
 


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44. 
Dorman SE, Savic RM, Goldberg S, Stout JE, Schluger N, Muzanyi G, et al. Daily rifapentine for 
 
treatment of pulmonary tuberculosis: a randomized, dose-ranging trial. American journal of 
 
respiratory and critical care medicine. 2014(ja). 
45. 
Dorman SE, Golderg S, Stout JE, Muzanyi G, Johnson JL, Weiner M, et al. Substitution of 
 
Rifapentine for Rifampin During Intensive Phase Treatment of Pulmonary Tuberculosis: Study 
 
29 of the Tuberculosis Trials Consortium. J Infect Dis. 2012;206(7):1030-40. 
46. 
O'Brien RJ, Long MW, Cross FS, Lyle MA, Snider DE, Jr. Hepatotoxicity from isoniazid and 
 
rifampin among children treated for tuberculosis. Pediatrics. 1983;72(4):491-9. 
47. 
Snider DE, Jr., Caras GJ. Isoniazid-associated hepatitis deaths: a review of available information. 
 
AmRevRespirDis. 1992;145(2 Pt 1):494-7. 
48. 
Singh N, Golani A, Patel Z, Maitra A. Transfer of isoniazid from circulation to breast milk in 
 
lactating women on chronic therapy for tuberculosis. BrJ ClinPharmacol. 2008;65(3):418-22. 
49. 
Thaver D, Saeed MA, Bhutta ZA. Pyridoxine (vitamin B6) supplementation in pregnancy. 
 
CochraneDatabaseSystRev. 2006(2):CD000179. 
50. 
Cantwell MF, Shehab ZM, Costello AM, Sands L, Green WF, Ewing EP, Jr., et al. Brief report: 
 
congenital tuberculosis. NEnglJ Med. 1994;330(15):1051-4. 
51. 
Jana N, Vasishta K, Jindal S, Khunnu B, Ghosh K. Perinatal outcome in pregnancies complicated 
 
by pulmonary tuberculosis. International Journal of Gynecology & Obstetrics.  
 
1994;44(2):119-24. 
52. 
Jana N, Vasishta K, Saha SC, Ghosh K. Obstetrical outcomes among women with 
 
extrapulmonary tuberculosis. New England journal of medicine. 1999;341(9):645-9. 
53. 
Lin HC, Lin HC, Chen SF. Increased risk of low birthweight and small for gestational age infants 
 
among women with tuberculosis. BJOG : an international journal of obstetrics and gynaecology. 
 
2010;117(5):585-90. 
54. 
Gupta A, Bhosale R, Kinikar A, Gupte N, Bharadwaj R, Kagal A, et al. Maternal tuberculosis: a 
 
risk factor for mother-to-child transmission of human immunodeficiency virus. The Journal of 
 
infectious diseases. 2011;203(3):358-63. 
55. 
Gomes VF, Andersen A, Wejse C, Oliveira I, Vieira FJ, Joaquim LC, et al. Impact of tuberculosis 
 
exposure at home on mortality in children under 5 years of age in Guinea-Bissau. Thorax. 
 
2011;66(2):163-7. 
56. 
Chapuis L, Ji B, Truffot-Pernot C, O'Brien RJ, Raviglione MC, Grosset JH. Preventive therapy of 
 
tuberculosis with rifapentine in immunocompetent and nude mice. American journal of 
 
respiratory and critical care medicine. 1994;150(5):1355-62. 
57. 
Deluca A, Chaisson RE, Martinson NA. Intensified case finding for tuberculosis in prevention of 
 
mother-to-child transmission programs: a simple and potentially vital addition for maternal and 
 
child health. JAcquirImmuneDeficSyndr. 2009;50(2):196-9. 
58. 
Weiner M, Savic RM, Mac Kenzie WR, Wing D, Peloquin CA, Engle M, et al. Rifapentine 
 
pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and 
 
isoniazid for latent tuberculosis infection. Journal of the Pediatric Infectious Diseases Society. 
 
2014:pit077. 


IMPAACT 2001, Version 1.0 
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10 November 2015 
59. 
McIlleron H, Martinson N, Paolo D, Mashabela F, Hunt J, Shembe S, et al. Effects of maternal 
 
tuberculosis (TB) treatment on nevirapine (NVP) concentrations among neonates receiving NVP 
 
for prevention of mother to child transmission of HIV: the TSHEPISO study team.  7th IAS 
 
Conference on HIV Pathogenesis, Treatment and Prevention; 30 June - 3 July; Kuala Lumpur, 
 
Malaysia. 2013. 
60. 
Keizer RJ, Karlsson MO, Hooker A. Modeling and Simulation Workbench for NONMEM: 
 
Tutorial on Pirana, PsN, and Xpose. CPT: pharmacometrics & systems pharmacology. 
 
2013;2:e50. 
61. 
National Institutes of Health. Guidelines for the Inclusion of Women and Minorities as Subjects 
 
in Clinical Research.  Federal Register. 1994 March 18. 
62. 
National Institutes of Health. NIH Policy and Guidelines on the Inclusion of Children as 
 
Participants in Research Involving Human Subjects. NIH Guide. . 1998 March 6.  
63. 
Marshall JD, Abdel-Rahman S, Johnson K, Kauffman RE, Kearns GL. Rifapentine 
 
pharmacokinetics in adolescents. The Pediatric infectious disease journal. 1999;18(10):882-8. 
64. 
Blake MJ, Abdel-Rahman SM, Jacobs RF, Lowery NK, Sterling TR, Kearns GL. 
 
Pharmacokinetics of rifapentine in children. The Pediatric infectious disease journal. 
 
2006;25(5):405-9. 
65. 
Schechter M, Zajdenverg R, Falco G, Barnes GL, Faulhaber JC, Coberly JS, et al. Weekly 
 
rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. 
 
Am J Respir Crit Care Med. 2006;173(8):922-6. 
66. 
Weiner M, Bock N, Peloquin CA, Burman WJ, Khan A, Vernon A, et al. Pharmacokinetics of 
 
rifapentine at 600, 900, and 1,200 mg during once-weekly tuberculosis therapy. Am J Respir Crit 
 
Care Med. 2004;169(11):1191-7. 
67. 
Peloquin CA, Durbin D, Childs J, Sterling TR, Weiner M. Stability of antituberculosis drugs 
 
mixed in food. Clinical infectious diseases : an official publication of the Infectious Diseases 
 
Society of America. 2007;45(4):521. 
 


IMPAACT 2001, Version 1.0 
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10 November 2015 
 
APPENDICES 
 
Appendix I-A: Mother Schedule of Evaluations 
 
 
SCR 
(up to 2 weeks 
prior to entry) 
Entry/Intensive PK 
Sampling 
(Days 0-3) 
Weekly 
(7 ± 2 days apart)  
(weeks 1-12) 
Monthly (Every 4 
weeks ±2 weeks) 
(until 24 weeks after 
delivery) 
Study Exit/ 
Early 
Discontinuation 
Administrative and Regulatory 
Obtain written informed consent 
X 
 
 
 
 
Assign participant identification numbers (PIDs) to 
mother and infant 
X 
 
 
 
 
Obtain screening number from SES 
X 
 
 
 
 
Complete eligibility checklist and enter into SES 
 
X 
 
 
 
Assign separate study identification numbers to 
mother and infant 
 
X 
 
 
 
Assess eligibility 
X 
X 
 
 
 
Provide meal prior to administering study drug 
 
X 
X 
 
 
Behavioral and Counseling 
Provide HIV pre-/post-test counseling if applicable 
X 
 
 
 
 
Assess alcohol and drug use 
X 
 
 
 
 
Signs and symptoms of active TB Counseling 
 
X 
X 
X 
X 
Assess infant feeding methods (postpartum only) 
 
 
X 
X 
 
Clinical 
Obtain/update medical and medications history 
X 
X 
X 
X 
X 
Perform physical examination 
X 
X 
X 
X 
X 
Perform obstetrical exam/assess fetal movement and 
heart sounds (until delivery) 
X 
X 
X 
X 
 
Perform ultrasound 
X 
 
 
 
 
Provide available findings/test results 
 
X 
X 
X 
X 
Assess TB symptoms, risk, and exposure  
X 
X 
X 
X 
X 
Gene Xpert, shielded chest x-ray, or sputum 
microscopy 
X 
 
 
 
 
Record/update AEs 
 
X 
X 
X 
X 
TST (if not available per medical record) 
X 
 
 
 
 
Study Product 
Prescribe and administer DOT of study drug regimen 
 
X 
X 
 
 
 
 


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Laboratory 
IGRA (3mL) (if not available per medical record) 
3mL 
 
 
 
 
Complete blood count (CBC) 
3mL 
 
3mL (every 4 weeks) 
3mL 
 
Liver Function tests 
3mL 
 
3mL (every 4 weeks) 
3mL 
 
HIV-1 test (confirmatory tests as needed) 
6mL 
 
 
 
 
CD4 count (HIV-1-infected only) 
 
3mL 
 
 
 
Coagulation profile 
5mL 
 
5mL (at one visit at 
≥34 weeks gestational 
age only) 
5mL (if clinically 
indicated) 
 
HBsAG, HBsAb, HCV Ab 
 
6mL 
 
 
 
Intensive PK sample collection 
 
22mL 
 
 
 
Sparse PK sample collection 
 
 
8mL (last dose) 
 
 
Plasma sample collection (breast milk PK eligible 
only) 
 
 
24mL (first and 
second week 
postpartum) 
 
 
Breast milk PK sample collection (if eligible) 
 
 
X (first and second 
week postpartum and 
last dose) 
 
 
TOTAL BLOOD 
17-20mL 
28-31mL 
11-43mL 
6-11mL 
 
 
 
 


IMPAACT 2001, Version 1.0 
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Appendix I-B: Infant Schedule of Evaluations 
 
 
Newborn Visit 
(within 3 days of life) 
Monthly (Every 4 weeks ± 2 weeks) 
(until 24 weeks after delivery) 
Study Exit/Early 
Discontinuation 
Clinical 
Assess eligibility for single PK sampling 
X 
 
 
Physical exam 
X 
X 
X 
Record/update medical and medications history 
X 
X 
X 
Record/update AEs 
X 
X 
X 
Provide available test results to mother 
X 
X 
X 
Assess TB symptoms, risk and exposure 
 
X 
X 
Laboratory 
Single PK sample collection (if eligible) 
2mL 
 
 
Coagulation profile (if eligible) 
2mL 
2 mL (if clinically indicated) 
 
Complete blood count (if clinically indicated) 
 
1mL 
 
Liver Function Test (if clinically indicated) 
 
2mL 
 
Cord blood (optional if eligible, during mother’s delivery) 
X 
 
 
TOTAL BLOOD 
2-4mL 
1-5mL 
 


IMPAACT 2001, Version 1.0 
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10 November 2015 
 
Appendix II: Modeling and Simulation Population Analysis Report – Rifapentine 
 
This population pharmacokinetic (PK) analysis estimates the pharmacokinetics of rifapentine (RPT) and 
its main metabolite 25-desacetyl-rifapentine (25-des-RPT) based on the combined dataset from 4 clinical 
studies in children, healthy adolescents and adult patients with active or latent tuberculosis infection 
(LTBI) where rifapentine was administered either as a single dose or weekly: two Phase I clinical studies 
(children, adolescents) (63, 64), one Phase I/II clinical study (TBTC Study 25) (65) and one Phase III 
clinical study (TBTC Study 26) (25). 
 
The population PK analysis comprised a total of 1634 rifapentine and 25-desacetyl-rifapentine serum 
concentrations from 227 children, adolescents and patients with active or latent tuberculosis who received 
a range of 300-1200 mg oral doses of rifapentine as a single agent (children, adolescents), or in 
combination with isoniazid (INH) in TBTC Study 25 and TBTC Study 26. Serum concentration data of 
RPT and 25-des-RPT were modeled simultaneously using a population analysis approach to estimate RPT 
and 25-des-RPT population PK parameters (mean and inter-patient variability) as well as the relationship 
between PK parameters and covariates.  
 
The structural model that best described the pharmacokinetics of rifapentine was a 1-compartment model 
with a transit compartment chain for description of the absorption delay. All clearance and volume of 
distribution parameters were allometrically scaled using standard exponents (e.g. 0.75 for clearance and 1 
for volume). The following typical population estimates (%RSE) of rifapentine pharmacokinetics were 
obtained: oral clearance (CL/F) for 70kg patient 2.32 L/h (11 %); central volume of distribution (Vc/F) 
for 70 kg patient 51.7 L (10 %); absorption rate constant (ka) 1.69 (34) h-1, mean transit time (MTT) 0.62 
h (27) and number of transit compartments (n) 1.8 (76). The inter-patient variability was 40% (13 %) for 
CL/F, 47% (15 %) for V/F and 90% (47 %) for MTT. 
 
The structural model that best described the pharmacokinetics of 25-des-RPT was a 1-compartment 
model. The typical population estimates (%RSE) of 25-des-RPT apparent clearance (CLm/Fm) and 
apparent volume (Vm/Fm) for 70kg patient were 2.05 L/h (10 %) and 21.9 L (7 %), respectively. The 
inter-patient variability was 64% (18 %) for CLm/Fm.  
 
Apparent clearance per kilogram body weight was significantly higher in children than adults. This 
relation was described by a maturation function, where clearance for the youngest child (age, 2 y) was 
0.052 L/h/kg, decreasing to the fully matured value of 0.026 L/h/kg by older age (half-life, 1.5 y (38% 
RSE), resulting with fully matured value by approximately age 10). Relative bioavailability of rifapentine 
in fasting condition for higher doses, 900 mg and 1200mg compared to the lowest available dose in adults 
(600 mg) was found to be 0.96 (19% RSE) and 0.76 (16% RSE) respectively. Food increased relative 
bioavailability by 40% (8% RSE). Children who received crushed tablets had 26% (36% RSE) decreased 
relative bioavailability. There was no autoinduction with once-weekly dosing. Gender and race have also 
been investigated, and were not associated with rifapentine pharmacokinetics. 
 
SUMMARY OF STUDY FEATURES 
This population PK analysis evaluated data obtained from 4 clinical studies of rifapentine (TBTC Study 
25, TBTC Study 26, children and adolescent study) (25, 63-65). A summary of the studies is provided in 
Table 1. PK profiles from a total of 227 subjects were used in this analysis. 
 


IMPAACT 2001, Version 1.0 
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Table 1. Summary of Studies Included in the Population PK Analysis 
Study 
Phase 
na 
Population 
Treatment 
DrugX Dose 
TBTC 25 
I/II 
35 
Adult Patients 
with TB 
RPT+INH 
600mg, 
900mg, 
1200mg 
weekly 
TBTC 26 
III 
157 
Children and 
Adults with 
LTBI 
RPT + INH 
300- 900mg 
weekly 
 
children 
I 
23 
Children w/o 
TB 
RPT 
150mg, 300mg 
single dose 
adolescent 
I 
12 
Healthy 
Adolescents 
RPT 
450mg, 600mg 
single dose 
 
a Number of subjects receiving RPT included in the population PK analysis  
 
TBTC Study 25 
TBTC Study 25 was a prospective, double-blind, randomized Phase II trial to evaluate the 
tolerability of once-weekly, continuation phase, directly observed therapy with rifapentine at three doses 
(600, 900, and 1,200 mg) and of isoniazid in 150 HIV-seronegative patients with drug susceptible 
tuberculosis. The pharmacokinetic substudy included 35 adult patients with tuberculosis (continuation 
phase therapy) who received commercial formulation of rifapentine (600, 900, or 1200 mg once weekly), 
usually without food. Pharmacokinetic data were collected after ≥ 3 weeks of once-weekly treatment. 
Plasma samples for rifapentine and metabolite concentrations were collected (11 samples: baseline, 2, 4, 
6, 8, 10, 12, 18, 24, 48, and 72 h after the dose) (65, 66). 
 
TBTC Study 26 (PREVENT-TB Study) 
TBTC Study 26 was a Phase 3, randomized treatment trial of 8,053 patients with LTBI, comparing a 12-
dose, once-weekly rifapentine and isoniazid regimen (3HP) to nine months of daily isoniazid (25). 161 
patients were recruited into PK substudy from the Phase 3, PREVENT TB trial, of whom 157 had 
evaluable PK samples (80 children and 77 adults). Risk groups in the treatment trial were recent close 
contacts of pulmonary tuberculosis cases, HIV-infected persons, those with a recent tuberculin skin test 
conversion, or those with fibrotic or fibronodular abnormalities consistent with old, healed tuberculosis 
on chest radiograph. All patients had evidence of latent tuberculosis infection (e.g. positive tuberculin 
skin test) and no evidence of active tuberculosis. Children enrolled in this substudy were age 2 to 11 years 
and all children and adults in the PK substudy were treated with 3HP. Rifapentine was administered as 
150 mg tablets. Rifapentine doses in children ranged from 300 to 900 mg based on weight and dosage 
(Table 2) and the rifapentine dose in adults was 900 mg (all patients weighed more than 45 kg). Children 
who could not swallow tablets were administered a suspension of crushed rifapentine and isoniazid tablets 
in either a soft food or liquid. Other foods consumed within two hours of drug administration were 
documented. For children, the once-weekly dosage of isoniazid was 25 mg/kg, (900 mg maximum), and 
adults were administered isoniazid 15 mg/kg (900 mg maximum) (25). 
 
Table 2. Rifapentine dosing algorithm used for children in the PREVENT-TB study 
Weight (kg) 
Rifapentine 
dose (mg) 
Rifapentine 
dosage (mg/kg) 
 
Number of 
children in 
each group 
Age of study 
patients (mean 
+SD in years) 
10-14 
300 
21-30 
34 
2.6 ± 0.8 
>14-25 
450 
18-32 
40 
4.5 ± 1.6 
>25-32 
600 
19-24 
7 
7.4 ± 2.2 
>32-50 
750 
15-23 
16 
9.7 ± 2.4 
>50 
900 
<18 
3 
10.0 ± 1.0 
 


IMPAACT 2001, Version 1.0 
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After at least three once-weekly doses of rifapentine and isoniazid, a single plasma sample collected 24-
hours after administration of study drugs (C24) was used in the sampling protocol. A 2 mL venous blood 
sample for PK analysis was obtained 23 to 25 hours after drug administration and was processed 
according to standard procedures (67). Plasma concentrations of rifapentine and 25-des-RPT were 
determined using a validated high-pressure liquid chromatography assay (66). 
 
Children study 
The pharmacokinetic study in children included 23 children (age, 2 to 12 y) without tuberculosis. The 
children received rifapentine tablets (150 or 300 mg) without food. If a child had difficulty swallowing 
tablets, the tablets were crushed before administration (that was the case in 9 out of 23 children). Plasma 
samples for rifapentine and metabolite concentrations were collected (11 samples: before the dose and 
0.5, 1, 2, 3, 4, 6, 10, 12, 24, and 32 h after the dose) (64). 
 
Adolescent study 
The pharmacokinetic study in adolescents included 12 healthy subjects (age, 12 to 15 y) who received 
rifapentine (1 dose; 450 mg for adolescents weighing < 45kg or 600 mg for adolescents weighing >45 kg) 
without food. Plasma samples for rifapentine and metabolite concentrations were collected (11 samples: 
before the dose and 2, 3, 4, 5, 6, 8, 12, 24, 48, and 72 h after the dose) (63). 
 
 


IMPAACT 2001, Version 1.0 
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Appendix III: Sample Informed Consent Form 
 
IMPAACT 2001 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly Rifapentine and 
Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and Postpartum Women with Latent 
Tuberculosis Infection 
 
VERSION 1.0, DATED 10 NOVEMBER 2015 
 
INTRODUCTION 
You are being asked to take part in this research study with your baby because you are pregnant and may 
be at risk for developing tuberculosis (TB). This study is sponsored by the National Institutes of Health 
(NIH) in the United States. The person in charge of this study at this site is: [insert name of Investigator 
of Record]. Before you decide if you want to take part in this study with your baby, we want you to know 
about the study. 
 
This is a consent form. It provides you with 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 form. You will be given a copy to keep. 
 
WHY IS THIS STUDY BEING DONE? 
Tuberculosis (TB) is a major cause of illness and death in women of reproductive age. In countries where 
TB is common, up to half of all women are infected with TB.  
 
There are two types of TB that you should know about. When exposed to TB, there are two types of TB 
that may occur. In one type, people may become sick with symptoms such as cough and fever. These 
people are also contagious, meaning they can pass TB to other people. This type of TB is known as active 
TB disease. In the other type, people do not become sick or contagious, but they still have TB in an 
inactive form. This inactive form is known as latent TB.  
 
If latent TB is not treated, it can become active TB, and this often happens for women around the time of 
pregnancy. There are medicines that help prevent latent TB from becoming active TB. These medicines 
are widely used by people who are not pregnant. The purpose of this study is to test the use of these 
medicines during pregnancy and soon after delivery. The study will look at the safety of the medicines for 
pregnant women and their unborn babies. It will also look at how the medicines are taken up in the bodies 
of pregnant women and their babies. The tests that are done to look at how the medicines are taken up in 
the body are called “pharmacokinetic” or “PK” tests. 
 
The medicines tested in this study are rifapentine (RPT), isoniazid (INH), and pyridoxine (vitamin B6). If 
you are taking antiretroviral medicines for HIV (ARVs), you will continue to receive these the way you 
usually do, but they will not be provided through the study. RPT and INH help prevent latent TB from 
becoming active TB. Vitamin B6 is being given to help prevent numbness and tingling that may be caused 
by INH. The medicines will be taken in the study clinic once per week for 12 weeks. Women with latent 
TB are asked to take part in the study while they are pregnant and for six months after delivery, with their 
babies. The purpose of the study is to find out how the medicines are processed and tolerated in pregnant 
women and to test their safety for pregnant women and their babies. 
 
WHAT DO MY BABY AND I HAVE TO DO AS PART OF THIS STUDY? 
Screening 
After having learned about this study, if you decide that you would like to take part, you will first have 
some screening tests to see if you are eligible. These tests will be done on the same day, after you have 
read and signed this form. [Sites: add local information regarding how long the Screening Visit will take]. 
 


IMPAACT 2001, Version 1.0 
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The screening tests will include: 
• 
Medical history: You will be asked questions about your health, your pregnancy, medications you are 
taking now and have taken in the past, and contacts with other people who have had TB. You will be 
asked about your drug and alcohol use.   
• 
Physical exam: You will have an examination that includes measuring your height and weight. A 
machine will be used to listen to your baby’s heartbeat, determine how long you have been pregnant, 
and check for any abnormalities.  
• 
TB test: You may have a skin or blood test for TB, if you have not had one done recently. If a skin 
test is done, you will have a small injection under your skin that study staff will check in two to three 
days for evidence of exposure to TB. If a blood test is done, about 3 mL (about ½ teaspoon) will be 
drawn from a vein for the test. If you have symptoms of TB, you may also have other TB tests, 
including a Gene Xpert test, chest x-ray, or test of your sputum.  
• 
Blood tests: You will have about 17-20 mL (about 3-4 teaspoons) of blood taken from a vein for: 
o HIV tests. These tests may be needed depending on the types of tests you had in the past and 
whether the results are available in medical records. [Sites: add local information regarding HIV 
pre-/post-test counseling.] 
o Routine safety tests. These tests check on your overall health, your liver, your blood cells, and 
how your blood clots.   
 
You will be asked to return to the clinic within two weeks to receive your screening test results and find 
out if you are eligible for the study. If the test shows that you have active TB or other abnormalities, you 
will not be eligible for the study. However, the study staff will refer you to other sources of care and 
treatment that you may need.  
If you do not join the study: 
If you are not eligible for the study, or do not take part for any reason, we will still use the information 
from your screening tests. For example, your information may help us learn more about the reasons why 
people do not join the study.  
 
If you join the study:  
You will have an Entry Visit within two weeks after screening. You will then have study visits while you 
are pregnant and for six months after delivery of your baby. Depending on when you join the study and 
when your baby is born, you may have 18-24 study visits. The Entry Visit will require 3 days of your 
time. The next 12 visits will be weekly visits; that is, you will come to the clinic once a week for 12 
weeks in a row. The last weekly visit will require 2 days of your time. After that, the visits will be 
monthly. More information about each of the visits and visits for your baby is given below.  
 
At the Entry Visit you will: 
• 
Answer questions about your health and medicines 
• 
Have a physical exam, including assessments of your baby’s health 
• 
Have counseling for signs and symptoms of active TB 
• 
Be given a meal and the first dose of study medicines  
• 
Have blood collected for the first pharmacokinetic (PK) visit (see below) 
• 
Have about 6-9mL (about 1-2 teaspoons) of blood collected for future testing for hepatitis (if you 
become sick later) and CD4 cell count (if you are HIV-infected). CD4 cells fight HIV and other 
infections. 
 
First PK Visit 
There are two PK visits for women in this study, on the day of the first dose of study medicines and on 
the day of the last dose of study medicines.  
 
The first PK visit will begin the morning you take the first dose of the study medicines. If the study clinic 
is able, you may be allowed to stay at the clinic the night before and during your first PK visit. You will 


IMPAACT 2001, Version 1.0 
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10 November 2015 
be asked not to eat or drink (except water) for two hours before and four hours after taking the study 
medicines, other than the meal given to you at the clinic. You will stay at the clinic for 12 hours after you 
take the study medicines. Then you will need to return to the clinic 24, 48, and 72 hours after you took the 
medicines. Samples of your blood will be collected at 11 times during this period, for a total of 22 mL 
(about 5 teaspoons) over three days. [Sites: add local information explaining if there will be a new needle 
stick for each blood draw or if a line/port will be established.] These samples will be used to test the 
amount of RPT in your blood, and some of the samples will be stored to test the amount of INH in your 
blood at a later time.   
 
At weekly visits while taking study medicines, you will: 
• 
Answer questions about your health and medicines 
• 
Have a physical exam, including assessment of your baby’s health 
• 
Have counseling for signs and symptoms of active TB 
• 
Be given a meal and weekly doses of study medicines provided by the clinic staff 
• 
Have blood collected every four weeks for tests that check on your overall health, your liver, your 
blood cells (11mL or a little more than 2 teaspoons).   
• 
Have blood collected once during your 12 weekly visits to test how your blood clots (5 mL or 1 
teaspoon) 
• 
Have breast milk and additional blood (24mL or about 5 teaspoons) collected at the first two 
visits after delivery if you are still receiving study medicines at these visits. You will also have 
breast milk collected 24 hours after you receive the last dose of study medicines. These samples 
will be used to test the amount of study medicines in the blood and breast milk at these time 
points. 
 
Second PK Visit 
The second PK visit will begin the morning you take your last dose of the study medicine. If the study 
clinic is able, you may be allowed to stay at the clinic the night before and during your second PK visit. 
You will be asked not to eat or drink (except water) for two hours before and four hours after taking the 
study medicines, other than the meal given to you at the clinic. You will stay at the clinic for four hours 
after you take the study medicines. Then you will need to return to the clinic 24 and 48 hours after you 
took the medicines. Samples of your blood will be collected at four times during this period, for a total of 
8 mL (about 2 teaspoons) over two days. [Sites: add local information explaining if there will be a new 
needle stick for each blood draw or if a line/port will be established.] These samples will be used to test 
the amount of RPT in your blood, and some of the samples will be stored to test the amount of INH in 
your blood at a later time.   
 
At monthly visits (every four weeks) after you have finished taking study medicines, you will: 
• 
Answer questions about your health and medicines 
• 
Have a physical exam, including assessments of your baby’s health (while you are pregnant) 
• 
Have counseling for signs and symptoms of active TB 
• 
Have blood collected for tests that check on your overall health, your liver, your blood cells, and 
how your blood clots (6-11mL or 1-2 teaspoons) except at the last visit, when no more tests will 
be done. 
 
The procedures listed above will also be done, if possible, if you end study participation early. 
 
Study visits for your baby: 
• 
Once your baby is born, a PK visit will be done within the first three days of life. You may be 
asked to contact the research staff once you are in labor. Two mL (about ½ teaspoon) of blood 
will be collected to test the amount of RPT in the baby’s blood. This visit will only be done if you 
received study medicines within 3 days before you delivered. Two mL (about ½ teaspoon) of 
blood may also be collected from your baby to test for clotting. 


IMPAACT 2001, Version 1.0 
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10 November 2015 
• 
If the study clinic is able, and you are still taking the study drug when you deliver, blood may be 
taken from the umbilical cord to test for the amount of RPT and INH. 
• 
Your baby will then have monthly visits (with you) for six months. At these visits, you will be 
asked questions about your baby’s health and medicines. The baby will have a physical exam. 
Blood (about 1-3 mL, or less than 1 teaspoon) may be collected to test the baby’s overall health, 
liver, and blood cells. 
 
The procedures listed above will also be done, if possible, if your baby ends study participation early. 
OTHER INFORMATION 
You will receive results from blood tests done on study visits at the next study visit following your blood 
draw or within two weeks. All blood samples for the first and second PK tests, and the blood samples 
from your baby’s single PK test, will be shipped to a laboratory in South Africa where the tests will be 
performed. You or the site doctor will not be told the results of the PK tests, because the tests are for 
investigation only and will be done after the study is completed. 
Any leftover blood samples after testing is completed for this study will be destroyed. 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
At least 50 and up to 82 pregnant women and their babies will take part in this study.  
HOW LONG WILL I/MY BABY BE IN THIS STUDY? 
You will be in this study from the time that you enter the study until 24 weeks after you have your baby. 
Depending on when you enroll, this could be for about six months or up to about one year. 
Your baby will be in this study for about six months.  
WHY WOULD I OR MY BABY BE TAKEN OFF THIS STUDY EARLY? 
The study doctor may need to take you or your baby off the study early without your permission if: 
• 
Staying in the study would be harmful to your/your baby’s health or well-being. 
• 
The study is cancelled by the National Institutes of Health (NIH), U.S. Food and Drug Administration 
(FDA), IMPAACT, Sanofi, Office for Human Research Protections (OHRP), the site’s Institutional 
Review Board (IRB) or Ethics Committee (EC), or other country-specific governmental agencies as 
part of their duties to ensure that research participants are protected. An IRB or EC is a committee 
that watches over the safety and rights of research participants. 
• 
You are/your baby is not able to attend the study visits as required by the study. 
The study doctor may also need to take you off the study medicines early without your permission if: 
• 
You are diagnosed with active TB. 
• 
Continuing the study medicines may be harmful to you/your baby. 
• 
You/your baby need(s) a treatment that you/your baby may not take while on the study medicines. 
• 
You are not able to take the study medication as required by the study. 
• 
You become pregnant again. 
 


IMPAACT 2001, Version 1.0 
Page 76 of 80 
10 November 2015 
If you become pregnant again during the study, the site staff will contact you at the end of your pregnancy 
to record information about the outcome of your pregnancy. If you become pregnant again and you are 
HIV-1-infected, your new pregnancy will be reported to the ARV Pregnancy Registry. If you are taken 
off the study medicines, you and your baby will still stay in the study and have all of the visits described 
in this form. 
WHAT IF I DEVELOP ACTIVE TB? 
If you develop active TB, you will stop taking the study medicines and be referred to local sources of TB 
care and treatment.  
It is possible that taking the study medicines while you have active TB could cause resistance. When 
resistance occurs, a medicine no longer works against TB, and different medicines may need to be taken. 
This is why you will stop taking study medicines if you develop active TB – to avoid resistance. 
Tests for TB are done as part of your or your baby’s clinical care, and no additional research tests, except 
for blood draws, are done only for the purpose of this study. These tests will only be done if the site 
investigator thinks the tests will help you and your baby. The site investigator will discuss any risks that 
may occur, at the time the tests are needed and the appropriate plan of care, depending on the results.  
WHAT ARE THE RISKS OF THE STUDY? 
Taking part in this study may involve some risks and discomfort. These include risks of blood draws, 
risks of study medicine and risks to your/your baby’s privacy. 
Risks of Blood Draws: 
Drawing blood can cause pain, bruising or bleeding at the place where the needle goes into the skin. 
There is also a small risk of swelling or infection of the vein. These risks are greater for babies than for 
adults. In rare cases lightheadedness or fainting can occur. 
Risks of Study Medicines: 
There have not been many studies of the medicines used in this study in pregnant women. Studies of the 
study medicines in animals have shown some negative effects, but the benefits of the medicines for 
pregnant women are thought to be greater than the risks. These medicines 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 
medicines. These lists include the more serious or common side effects with a known or possible 
relationship. If you have questions concerning additional study drug side effects please ask the medical 
staff at your site. 
 
There are no known side effects associated with the study dose of vitamin B6. 
 
Both RPT and INH can cause damage to the liver, which may be seen in abnormal liver test results and 
other symptoms such as rash, changes in the color of urine, pale-colored stools, yellowing of the eyes or 
skin, pain in the upper abdomen, loss of appetite, upset stomach or vomiting, and low blood counts. RPT 
and INH may also cause diarrhea (loose or watery stools), including bloody diarrhea, which may be 
serious. These side effects may be worsened during pregnancy and when taking antiretroviral medicines 
for HIV (ARVs). These side effects can also be worsened when taking alcohol. The study staff will give 
you information and counseling about the risks of alcohol during pregnancy and while in this study. 
 


IMPAACT 2001, Version 1.0 
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10 November 2015 
Risk of TB Resistance:  
 
If you are diagnosed with active TB while on the study medicines, there is a risk that you may have 
developed resistance to these medicines. If you develop active TB, you will be treated with other 
medicines for TB. 
 
Risk of a Receiving Too Low a Dose of TB Medicine: 
 
There is a risk that the dose of study medicines you receive for your latent TB may be too low. The 
dosing we are using has been used in many other clinical trials. The best dose during pregnancy is not 
known. 
Rifapentine (RPT, Priftin®) 
 
Other side effects of RPT may include: reddish coloring of urine, sweat, sputum, saliva, tears, and breast 
milk (contact lenses and dentures may be permanently stained); dizziness; hypertension; headache; low 
blood sugar; decreased effectiveness of hormonal contraceptives and other medications (tell your doctor 
about all medications that you are taking). In general, these side effects are temporary.   
People taking RPT or drugs like it may have a serious allergic reaction called Rifamycin Hypersensitivity 
Syndrome (RHS). If you have any of the following reactions while taking RPT, call the study doctor right 
away:  rash; fever; yellow eyes or skin or dark urine; achiness, general or extreme tiredness; dizziness or 
confusion; or easy bruising or bleeding. If you develop signs or symptoms of RHS, you will come to (or 
stay in) the clinic to be evaluated and have tests for this condition. 
When given during the last few weeks of pregnancy, a drug similar to RPT may (in rare cases) increase 
the risk of bleeding in the mother and the baby. If you or your baby have increased bleeding, you will 
come to (or stay in) the clinic to be evaluated and treated for this condition. 
Isoniazid (INH) 
Other side effects of INH may include: changes in vision; clumsiness or unsteadiness; memory loss; 
confusion; trouble sleeping; changes in behavior or mood; seizures; high blood sugar; joint pain; weight 
loss, fever; tingling and numbness in the hands and feet which is the most common side effect; weakness 
and fatigue. In general, these side effects are temporary.   
 
Other risks 
There may be other risks to taking part in this study that are not known at this time. It is possible that 
others may learn of your participation in this study, and because of this, may treat you unfairly or 
discriminate against you. For your and your baby’s safety, you must tell the study staff about all 
medications you/your baby are taking before starting the study and also before starting any new 
medications while on study, including medicines bought from the store or pharmacy and herbal or natural 
remedies. In addition, you must tell the study staff before you or your baby enrolls in any other clinical 
trials while on this study. 
 
Breastfeeding 
If you are breastfeeding your baby, he or she may get some of study medicines that you are taking from 
the breast milk. It is unknown whether the anti-TB medication may cause harm to your baby. Information 
learned from this study may show how safe the medication is for pregnant women and their babies.  
 


IMPAACT 2001, Version 1.0 
Page 78 of 80 
10 November 2015 
WHAT ABOUT CONFIDENTIALITY? 
Efforts will be made to keep personal information about you and your baby confidential. Your and your 
baby’s personal information may be disclosed if required by law. Any publication of this study will not 
use your/your baby’s name or identify you/your baby personally. 
The outreach workers may contact you so we need to know the best way to reach you (such as home visit 
or phone call). Your records and those of your baby may be reviewed by the IMPAACT, the U.S. Food 
and Drug Administration (FDA), [insert name of site] Institutional Review Board (IRB) or Ethics 
Committee (EC), National Institutes of Health (NIH), Office for Human Research Protections (OHRP), 
study staff, study monitors, host country regulatory authorities, and drug companies supporting this study 
or their designees. 
[U.S. sites only should include the following: In addition to the efforts of the study staff to help keep your 
personal information private, we have obtained a Certificate of Confidentiality from the US Federal 
Government. This certificate protects study staff from being forced to tell people who are not connected 
with this study, such as the court system, about your participation or information you give for study 
purposes. However, if the study staff learns of possible child abuse and/or neglect or a risk of harm to you 
or others, they will be required to tell the proper authorities. This certificate does not prevent you from 
releasing information about yourself and your participation in the study.] 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
If you and your baby take part in this study, there may be a direct benefit to you and your baby, but no 
guarantee can be made. Taking anti-TB medicines such as INH and RFP may be of benefit to you and 
your baby. Taking vitamin B6 may be of benefit to you and your baby. Having TB detected early may be 
of benefit to you and your baby.   
It is also possible that there may be no direct benefit to you or your baby from taking part in this study. 
Information learned from this study may reduce women’s risk of getting active TB after having a baby, 
and it may help others who have TB or others who do not have TB but live with someone who does. 
WHAT OTHER CHOICES DO MY BABY AND I HAVE BESIDES THIS STUDY? 
Instead of being in this study you have the choice of not being in the study. [Sites: Please fill in 
information about available alternatives at the site].   
Please talk to your doctor about these and other choices available to you. Your doctor will explain the 
risks and benefits of these choices. 
WHAT ARE THE COSTS TO ME? 
There is no cost to you or your baby for the study visits, examinations, or blood tests. 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/your baby is taking part in a research 
study.  [Sites: Modify or delete language regarding insurance as appropriate for your site.] 
WILL I RECEIVE ANY PAYMENT? 
You may receive reimbursement for some expenses for this study (for example, for transportation or 
meals). [Sites: This statement can be modified or deleted as needed for your site.] 
 


IMPAACT 2001, Version 1.0 
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10 November 2015 
WHAT HAPPENS IF I AM/MY BABY IS INJURED? 
 
If you are and/or your baby is injured as a result of being in this study, the study doctor will give or will 
refer you and/or your baby for immediate medical treatment. The cost for this treatment may be charged 
to you or your insurance company. There is no program for compensation either through this institution or 
the National Institutes of Health (NIH). You will not be giving up any of your legal rights by signing this 
consent form. 
[Sites: modify or delete language regarding insurance as appropriate for your site and insert appropriate 
language for local costs]. 
WHAT ARE MY/MY BABY’S RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary. You may choose not to participate or to allow your 
baby to participate in this study or take yourself/your baby out of this study at any time. You/your baby 
will be treated the same no matter what you decide. Your decision will not have any impact on your/your 
baby’s participation in other studies conducted by NIH and will not result in any penalty or loss of 
benefits to which you/your baby is otherwise entitled. 
We will tell you about new information from this or other studies that may affect your/your baby’s health, 
welfare, or willingness to stay in this study. If you want to be informed about the results of this study, 
please let the study staff know. 
[Sites: include local information about how participants can find out about study results if applicable]. 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
[Site name of the investigator or other study staff] 
• 
[telephone number of above ] 
 
For questions about your/your baby’s rights as a research participant, contact: 
• 
[Name or title of person on the Institutional Review Board (IRB) or other organization appropriate 
for the site] 
• 
[telephone number of above] 
 
 


IMPAACT 2001, Version 1.0 
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10 November 2015 
SIGNATURE PAGE   
 
If you have read this consent form (or had it explained to you), all your questions have been answered, 
and you agree for yourself and your baby to take part in this study, please sign or make your mark below. 
 
 
 
____________________________ 
_________________________________________ 
Maternal Participant’s Name (print) 
Maternal Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 
 
 

SAP_000.pdf: 
IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
1 
 
 IMPAACT 2001  
Final Statistical Analysis Plan  
Version 2.0 
 
 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of 
Once-Weekly Rifapentine and Isoniazid in HIV-1-infected and HIV-1-
uninfected Pregnant and Postpartum Women with Latent 
Tuberculosis Infection 
Protocol Version 1.0 
ClinicalTrials.gov Identifier: NCT02651259 
 
June 26, 2019 
This is IMPAACT 2005 SAP Version 2.0 with names of authors redacted 
SDAC/Harvard T. H. Chan School of Public Health 
 
 
 


IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
2 
 
Table of Contents 
1 
INTRODUCTION .................................................................................................................................... 3 
1.1 
Purpose ........................................................................................................................................ 3 
1.1 
Key SAP Updates ........................................................................................................................ 3 
2 
PROTOCOL OVERVIEW ....................................................................................................................... 4 
2.1 
Study design ................................................................................................................................ 4 
2.2 
Sample size .................................................................................................................................. 4 
2.3 
Study regimen .............................................................................................................................. 4 
2.4 
Study duration ............................................................................................................................. 5 
2.5 
Study objectives .......................................................................................................................... 5 
2.6 
Protocol History ........................................................................................................................... 6 
2.7 
Monitoring .................................................................................................................................... 6 
2.8 
Study Monitoring Committee (SMC) reviews............................................................................ 7 
3 
SELECTED OUTCOME MEASURES.................................................................................................... 7 
3.1 
Primary Outcome Measures ....................................................................................................... 8 
3.2 
Secondary outcome measures include: ................................................................................... 8 
4 
STATISTICAL METHODS ..................................................................................................................... 8 
4.1 
General statistical considerations ............................................................................................. 8 
4.2 
Analysis Approaches .................................................................................................................. 9 
5 
REPORT COMPONENTS .................................................................................................................. 109 
 
 
 


IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
3 
 
 
 
1 
Introduction 
1.1 
Purpose 
This Final Statistical Analysis Plan (or Primary SAP) describes the primary and secondary outcomes 
measures of IMPAACT 2001 that will be included in the primary manuscript, which address the primary 
and secondary objectives of the study.  The Primary SAP outlines the general statistical approaches that 
will be used in the analysis.  It has been developed to facilitate discussion of the statistical analysis 
components among the study team, and to provide agreement between the study team and statisticians 
regarding the statistical analyses to be performed and presented in the primary statistical analysis report.  
It also describes the results for the primary and secondary outcome measures that will be posted on 
ClinicalTrials.gov.  Detailed outlines of tables, figures, and coding descriptions that will be included in the 
Primary Statistical Analysis Report are included in the Analysis Implementation Plan (AIP).  Data for the 
Final Statistical Analysis Report will be downloaded once all participants are off study and all queries 
have been resolved, and the database frozen for analysis.   
This Final SAP is limited to analyses that will be conducted by the Statistical Data Analysis Center 
(SDAC) protocol statisticians; hence it will only address primary objectives (2) and (3), and 
secondary objectives (6) and (7), which are listed in Section 2.5 of this document. The Final 
Statistical Analysis Report will be based on this Final SAP. The analyses for the PK objectives (primary 
objective (1) and secondary objectives (1), (2), (3), (4), (5), and (8) which are listed in section 2.5 of this 
document) will be performed by the protocol pharmacologists and the results will be reported in a 
separate PK analysis report,  
The Final Statistical Analysis Report will be used for submission of results to ClinicalTrials.gov. Results 
for primary outcomes are required to be submitted within one year of the primary completion date (PCD), 
which is the date the last participant is examined for the purposes of data collection for the primary 
outcome measure.  For this study, the PCD is based on when the last participant was off study. 
1.1 
Key SAP Updates  
Version 
Changes Made 
Rationale 
Effective Date 
1.0 
Original Version 
 
20 October 2017 
2.0 
Modified as per SOP 
requirements 
To align with 
CLIN.10070 Version 5.0. 
25 June 2019 
 
 
 
 
 
 
 
  


IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
4 
 
.   
2 
Protocol Overview 
2.1 
Study design 
IMPAACT 2001 is a Phase I/II,  open-label, multi-center, intensive pharmacokinetic (PK) study to evaluate 
the pharmacokinetics, safety, and tolerability of rifapentine (RPT) and isoniazid (INH) dosed once weekly 
for 12 doses  in HIV-1-infected and HIV-1-uninfected pregnant women with latent TB infection at high risk 
for development of TB. Infants were also enrolled, and breast milk samples from postpartum women who 
were still taking RPT/INH were collected. 
Each enrolled woman received the study drug regimen and were followed until 24 weeks postpartum, 
regardless of when she delivered. Therefore, it is expected that some women were to continue the study 
drug regimen postpartum, while some women may have completed the study drug regimen prior to 
delivery. It is possible that a woman enrolled in Cohort 1 could continue the study drug regimen 
postpartum (e.g., if she delivers her infant pre-term). 
Two study cohorts are planned: 
Cohort 1: Pregnant women ≥14 weeks gestation through <28 weeks gestation (second trimester) 
Cohort 2: Pregnant women ≥28 weeks gestation through ≤34 weeks gestation (third trimester) 
An interim analysis to assess the PK of RPT was to be conducted, and a dose adjustment may be 
indicated for each cohort (see protocol Section 10). Dose adjustments indicated for Cohort 2 would be 
implemented for Cohort 1 women as they enter their third trimester of pregnancy. See Section 3.4 for 
accrual into the cohorts, and Section 10.3 (Interim Analysis and Dose Adjustment) for further details 
regarding the interim analysis and dose adjustment. 
2.2 
Sample size  
Up to 82 pregnant women (and their infants) were to be enrolled to yield a minimum of 25 evaluable 
women in each cohort. Within each cohort, enrollment of at least 10 evaluable HIV-1-infected women 
were to be targeted. This sample size is selected to achieve a relative standard error (RSE) of five 
percent for estimation of clearance. 
2.3 
Study regimen 
Twelve directly observed once-weekly doses of RPT (900mg) and INH (900mg) taken with pyridoxine (25 
to 100mg). An interim analysis was to be performed to assess the clearance of RPT compared to non-
pregnant historical controls, and a dose adjustment may be recommended based on this analysis.  


IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
5 
 
2.4 
Study duration 
Approximately 24 months total. Accrual was expected to require approximately 12 months, and each 
enrolled woman would be followed through pregnancy and 24 weeks postpartum. Infants were to be 
followed for 24 weeks from birth. 
2.5 
Study objectives 
Primary Objectives 
1. To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of 
RPT and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the 
second trimester and third trimester who are receiving once-weekly RPT (900mg or the new 
study dose, if a dose adjustment is indicated by the interim analysis) and once-weekly INH 
(900mg). 
2. To estimate the incidence of serious adverse events (SAEs) related to RPT + INH dosed once 
weekly for 12 weeks in pregnant women. 
3. To describe the infant safety outcomes among infants born to women receiving once-weekly RPT 
+ INH. 
Secondary Objectives  
1. To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of 
RPT and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the 
postpartum period who are receiving once-weekly RPT (900mg or the new study dose, if a dose 
adjustment is indicated by the interim analysis) and once-weekly INH (900mg). 
2. To assess the impact of covariates (gestational age, weight, age, HIV status) on primary PK 
parameters using population PK modeling. 
3. To compare RPT and desRPT exposure pharmacokinetic parameters (AUC, Cmax, Cmin) for RPT 
in pregnant and postpartum women versus non-pregnant historical controls, using 
noncompartmental analyses. 
4. To determine the RPT dose in pregnancy that achieves similar estimated exposure (AUC) of RPT 
as non-pregnant adults at standard doses. 
5.  To quantify RPT and desRPT concentrations at delivery among infants born to women receiving 
once-weekly RPT + INH. 
6. To describe the tolerability of RPT + INH dosed once weekly for 12 weeks in pregnant and 
postpartum women. 
7.  To assess incidence of active TB in mother-infant pairs up to 24 weeks postpartum. 


IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
6 
 
8.  To explore the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of 
INH in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women (i.e., women who 
are and are not taking efavirenz (EFV)) who are receiving once-weekly RPT (900mg or the new 
study dose, if a dose adjustment is indicated by the interim analysis) and once-weekly INH 
(900mg). 
Exploratory Objectives  
1. To quantify RPT and desRPT concentrations in breast milk of postpartum women receiving once-
weekly RPT + INH. 
   
2.6 
Protocol History 
Protocol Version 1.0 was finalized in November 10, 2015.   Letter of Amendment (LoA) #1 was issued on 
January 22, 2016, and was to incorporate clarifications to 1) the number of maternal weekly visits and 2) 
initiation of the maternal intensive pharmacokinetic (PK) on the day of enrollment.  LoA #2 was issued on 
October 18, 2016 and incorporated modifications to the inclusion criteria, toxicity management, case 
report form requirements, reporting requirements for expedited adverse events (EAEs), and the sample 
ICF to provide additional safety guidance and participant management regarding hepatotoxicities. Other 
corrections and updates were made to the inclusion criterion 4.1.3, procedures for premature 
discontinuation of the study drug regimen, and the schedule of evaluations. The first two LOAs required 
IRC approval at the sites before site activation to enroll.  LoA #3 was issued on May 7, 2018 and the key 
changes was to clarify 1) study drug management for general grade 3 and 4 adverse events (AEs) for 
consistency with baseline values permitted at entry, 2) clarify PK and tolerability outcomes measures and 
3) as per ICH and DAIDS requirements it is mandatory that all DAIDS-sponsored and/or supported trials 
include language that informs participants that other US, local, and international regulatory entities may 
also review study records.  There were three Clarification Memos also issued on 8 April, 2016, 1 June 
2016 and 8 February 2017 to clarify details in the protocol. 
 
2.7 
Monitoring 
It is the responsibility of the protocol team to interpret safety data and make decisions regarding adverse 
events that are needed to protect participants from undue risk. The safety and tolerability of the study 
agent was to be monitored by means of adverse event and toxicity reports summarizing laboratory and 
clinical events. The data required for the toxicity reports must be entered into the database within 48 
hours of when the results of the laboratory tests or clinical examinations become available. Reports 
compiled by the DMC were to be reviewed and discussed by the team on conference calls held at least 
monthly. The attribution of relationship of ≥ Grade 2 AEs to RPT/INH were to be determined by the 
protocol team, and any discrepancies of assessments between site investigators and the IMPAACT 2001 


IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
7 
 
protocol team would be reconciled during the conference calls. For safety monitoring, a drug-related AE is 
an AE that is judged to be definitely, probably, or possibly related to study drug (RPT/INH). Data on 
participant accrual, pharmacokinetics, and toxicity would be reviewed. 
2.8 
Study Monitoring Committee (SMC) reviews 
The study was monitored by an SMC according to standard IMPAACT procedures.  The committee was 
to meet via conference call to review relevant data as described below and in Section 7.1 of the protocol 
to ensure participant safety. The SMC could meet at least once annually and more frequently if indicated 
by the SMC, the protocol team or the study sponsor. The study was to be reviewed for the quality of study 
conduct and participant safety, including [but not limited to]:  
 
Study progress and safety 
 
Participant accrual 
 
Retention (study/participant summary report) 
 
Data specimen and completeness 
 
Pharmacokinetics (as available given the general batching strategy) 
The protocol team could also request ad hoc SMC reviews if any potential safety concerns arise. For 
example, if a potential concern was identified during a routine protocol team review of safety data, the 
team could request an ad hoc SMC review to further evaluate that potential concern. Based on any of its 
reviews, the SMC could recommend that the study proceed as currently designed, proceed with design 
modifications, or be discontinued. 
Data on accrual, pharmacokinetics (when made available by the protocol pharmacologist) and toxicity 
were to be reviewed by the study’s SMC: 
1) When the consensus among the site investigator, the protocol team and the DAIDS medical officers 
regarding to relationship of AEs to the study drug cannot be established. 
2) When there is any specific safety concern. 
Adverse events were to be monitored from screening onward throughout the follow-up period. If any 
Grade 4 AEs that were possibly, probably, or definitely related to the study regimen or deaths occur, or if 
the protocol team identifies any potentially treatment-related toxicities that could compromise participant 
safety, the study could be paused, and the SMC was to review all relevant data and would determine 
whether, and under what conditions, the study would be allowed to proceed. 
3 
Selected Outcome Measures 
The primary outcome measures for pregnant women during the second trimester, third trimester, and 
postpartum period who were receiving a dose of RPT 900mg once weekly together with once-weekly INH 
(900mg) are detailed below.  


IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
8 
 
3.1 
Primary Outcome Measures  
 
Estimates of CL/F, absorption, and volume of distribution of RPT and its desacetyl-rifapentine 
metabolite (desRPT) during the second trimester and third trimester among pregnant women 
receiving study drug.  
 
Safety (maternal) 
o 
Incidence of related serious adverse events (SAEs) in pregnant and postpartum women 
taking once-weekly RPT + INH (during treatment period) 
o 
Grade 2 or higher adverse events (AEs) judged to be related to study drug regimen up to 
week 24 pospartum 
o 
All Grade 3 or 4 AEs up to week 24 postpartum 
o 
All serious AEs up to week 24 postpartum 
o 
All AEs leading to permanent discontinuation of study drug regimen (i.e., RPT, INH, and 
pyridoxine)  
 
Safety (infant) 
Incidence of related serious adverse events (AEs) in infants born to women taking once-weekly 
RPT + INH. 
3.2 
Secondary outcome measures include: 
 
Vd, CL/F, Ka of RPT and desRPT, AUC, Cmax, and Cmon for pregnant women in their second or 
third trimester 
 
RPT and desRPT concentrations in infants born to women receiving once-weekly RPT + INH. 
 
Tolerability 
o 
Permanent discontinuation of study drug regimen due to intolerance (i.e., RPT, INH, and 
pyridoxine) 
 
RPT and des-RPT concentrations in breast milk of postpartum women receiving once-weekly 
RPT + INH.  
 
Incidence of active TB in mother-infant pairs up to 24 weeks postpartum.  
 
Estimates of CL/F, absorption, and volume of distribution of INH in pregnant and postpartum 
women taking the study drug.   
4 
Statistical methods 
4.1 
General statistical considerations 
 
a. 
This is not a randomized study. Tables and figures in the primary report will be presented by  
cohort. 
b. 
The primary analyses in this study are: (i) to estimate PK parameters cross-sectionally and 
longitudinally, and (ii) to describe safety outcomes of the women and their infants during the course of the 
study.   The fundamental concern is to assess maintenance of drug levels between second and third 
trimesters of pregnancy along with assessment of postpartum drug levels in women and infants.  


IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
9 
 
c. 
This is a Phase I/II single arm study and not subject to NIH requirements of primary analyses of 
treatment comparisons.   
 
4.2 
 
Analysis Approaches 
The primary maternal safety analysis will include all women who have been exposed to RPT/INH at any 
dose in the study. Women whose doses have been adjusted for inadequate PK will be included in the 
primary safety analysis. Women who have discontinued treatment due to toxicities will be included and 
treated as safety failures in the primary safety analysis.  Each woman’s safety data will be summarized 
as: the worst grade of adverse event experienced during study treatment and the worst grade of adverse 
event judged to be at least possibly related to study treatment during this time period. 
Frequency distributions of these safety outcomes will be presented in the aggregate and broken down by 
cohort.  Listing of all ≥ Grade 3 or ICH defined serious events will be provided.  The proportions of 
participants experiencing ≥ Grade 3 or ICH defined serious events will be presented in aggregate and 
broken down by cohort, with these proportions bounded by exact 95% confidence intervals.  Similar 
analyses will present the proportions of participants exhibiting ≥ Grade 3 or ICH defined serious events 
which have been judged (based on team attribution) to be at least possibly related to study medication, 
again bounded by exact 95% confidence intervals. 
The primary infant safety analysis will include all infants whose mothers were included in the primary 
safety analysis (that is, all women who have been exposed to RPT/INH at any dose in the study).  Infants 
were followed for 24 weeks post-delivery.  The analysis of tolerability outcome will also include all women 
in the primary maternal analysis.  Analysis of TB incidence will include all mother-infant pairs, except 
women who were determined to have TB at study entry.  Analyses of infant serious adverse events 
judged to be related to study treatment, tolerability and incident TB will follow the analyses described 
above for the primary maternal safety outcomes. 
For primary objective 2, Poisson regression will be used to estimate the incidence of serious adverse 
events, related to treatment, adjusting for important cofactors if data allows and for primary objective 3 
(analyses of safety for infants), and secondary objectives 6 (analyses of tolerability) and 7 (analyses of 
incidence of active TB) will employ standard descriptive techniques. 
NOTE: All objectives/outcome measures related to PK parameters will be 
conducted by the protocol pharmacologist 
 
 


IMPAACT 2001 FINAL STATISTICAL ANALYSIS PLAN 
 
10 
 
5 Report Components 
Detailed descriptions of the content of each of the following sections are given in the AIP.   
1. Enrollment 
2. Eligibility Violations 
3. Protocol Deviations 
4. Baseline Characteristics 
5. Study Status 
6. Safety 
7. TB assessment 
8. Tolerability 
 

SAP_001.pdf: 
P2001 PHARMACOKINETIC ANALYSIS PLAN 
Prepared by Priya Jayachandran, PharmD, MSE 
Last revised on March 31, 2020 
1
IMPAACT 2001  
Final Pharmacokinetic Statistical Analysis Plan  
 
 
A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly 
Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and 
Postpartum Women with Latent Tuberculosis Infection 
Protocol Version 1.0 
 
ClinicalTrials.gov Identifier: NCT02651259 
 


P2001 PHARMACOKINETIC ANALYSIS PLAN 
Prepared by Priya Jayachandran, PharmD, MSE 
Last revised on March 31, 2020 
2
OBJECTIVES  
Primary 
Pharmacokinetic (PK, concentration-time) data and safety data of rifapentine (RPT) and desacetyl-
rifapentine (des-RPT, metabolite) in pregnant women 
 
Secondary 
PK data of RPT and des-RPT in postpartum women and infants; PK data of isoniazid (INH) in pregnant 
and postpartum women 
 
DATA 
Dataset checking 
Source datasets provided to UCSF will be checked by IMPAACT against the original database. Datasets 
may need to be subsequently manipulated during the PK analysis. Each time manipulations are performed 
the new dataset will be checked against the original dataset. The following checks will be performed: 
 Comparison of number of subjects in the new dataset to those expected to be retained from the initial 
dataset 
 Number of observations per subject in the new dataset to those expected to be retained from the initial 
dataset 
 Check of dosing history (PK sampling times relative to dosing, missing dosing or sampling times). 
 
Any discrepancies/errors found in the dataset will be corrected and documented. 
 
Exclusion of data points 
All evaluable data will be used for analysis. All data exclusions will be documented. 
 
Identification of outliers 
Individual data points that are clearly aberrant and/or with residuals (weighted, conditional weighted, 
and/or individual weighted) greater than 6 will be considered for omission. An assessment of their impact 
on the analysis will be documented. 
 
Handling of missing data 
The population median value at each time point may be used for missing data from a continuous variable 
(e.g. age, weight, and serum creatinine level) for a particular subject. If any value is missing at baseline, 
screening values may be used for imputation, if available. 
 
METHODOLOGY 
 
RPT and des-RPT 
Adults  
Approach 
Population-based estimates of PK parameters for RPT (CL/F, absorption, volume of distribution) and des-
RPT (CLmetabolite/F) will be derived for  
(1) pregnant women in the second and third trimesters of pregnancy and  
(2) women after delivery (postpartum).  
 
Secondary PK parameters for RPT and des-RPT (area under the curve (AUC), maximum concentration 
(Cmax), and minimum concentration (Cmin )) will be derived from the model for pregnant women in the 
second and third trimesters of pregnancy. 


P2001 PHARMACOKINETIC ANALYSIS PLAN 
Prepared by Priya Jayachandran, PharmD, MSE 
Last revised on March 31, 2020 
3
 
The study data, which provide a mix of longitudinal and cross-sectional observations, will be combined 
and modeled using nonlinear mixed effects approaches that are widely used in pharmacology research. 
Nonlinear mixed effects modeling will be performed using NONMEM v7.4. Dataset manipulation and 
data visualization will be performed using R v3.5.1 and Microsoft Office Excel. Perl-speaks-NONMEM 
(PsN) v4.8.1 and Xpose4 v4.6.1 will be used for model evaluation. 
 
Exploratory data analysis 
Prior to beginning modeling analyses, the following exploratory data analyses will be performed: 
 Scatterplots of dependent variable (DV) versus time, stratified by treatment outcome, cohort, or 
disease status 
 Summary statistics including the number of patients, samples, samples per patient, and number of 
patients with samples at each visit. 
 
Structural model development 
The absorption and disposition kinetics of RPT and des-PRT will be described by a one compartment 
model with first-order (linear) elimination and first-order oral absorption. More complex models with 
respect to absorption (e.g. transit compartments), distribution, and elimination will be explored if 
necessary. 
 
Goodness-of-fit diagnostic plots will be used to assess the structural model: 
 Observations versus population and individual predictions 
 Population, individual, and conditional weighted residuals versus time 
 
Stochastic model development  
Exponential error models will be used to characterize the between-subject-variability of the model 
parameters. A diagonal sigma-structure will be used, and off-diagonal elements may be included. 
 
For continuous data, additive, proportional, and combined (additive and proportional) error models will 
be used to characterize the residual variability.  
 
The appropriateness of the random error models will be assessed using diagnostic plots: 
 Observations versus population and individual predictions 
 Population, individual, and conditional weighted residuals versus time 
 Observations versus time with population and individual fits 
 Histogram of ETA estimates 
 
Model evaluation 
Visual predictive checks will be used to evaluate how well the model describes the data. 
 
Infants  
Approach 
Summary statistics will be compiled for plasma and cord blood RPT and des-RPT concentrations in infants 
collected within 72 hours following birth. 
 
Dataset manipulation and data visualization will be performed using R v3.5.1 and Microsoft Office Excel. 
 
Summary statistics 


P2001 PHARMACOKINETIC ANALYSIS PLAN 
Prepared by Priya Jayachandran, PharmD, MSE 
Last revised on March 31, 2020 
4
Cord blood and plasma concentration data for RPT and des-RPT will be summarized by 
 Count 
 Minimum concentration and maximum concentration 
 Mean and median 
 First quantile and third quantile. 
 
INH 
Adults: Approach 
Population-based estimates of PK parameters for INH (CL/F, absorption, volume of distribution) will be 
derived for all pregnant women irrespective of pregnancy trimester or pre-/post-partum status. 
 
The study data, which provide a mix of longitudinal and cross-sectional observations, will be combined 
and modeled using nonlinear mixed effects approaches that are widely used in pharmacology research. 
Nonlinear mixed effects modeling will be performed using NONMEM v7.4. Dataset manipulation and 
data visualization will be performed using R v3.5.1 and Microsoft Office Excel. Perl-speaks-NONMEM 
(PsN) v4.8.1 and Xpose4 v4.6.1 will be used for model evaluation. 
 
Exploratory data analysis 
Prior to beginning modeling analyses, the following exploratory data analyses will be performed: 
 Scatterplots of dependent variable (DV) versus time, stratified by treatment outcome, cohort, or 
disease status 
 Summary statistics including the number of patients, samples, samples per patient, and number of 
patients with samples at each visit. 
 
Structural model development 
The absorption and disposition kinetics of INH will be described by a one compartment model with first-
order (linear) elimination and first-order oral absorption. More complex models with respect to absorption, 
distribution, and elimination (e.g. mixture models) will be evaluated if necessary. 
 
Goodness-of-fit diagnostic plots will be used to assess the structural model: 
 Observations versus population and individual predictions 
 Population, individual, and conditional weighted residuals versus time 
 
Stochastic model development  
Exponential error models will be used to characterize the between-subject-variability of the model 
parameters. A diagonal sigma-structure will be used, and off-diagonal elements may be included. 
 
For continuous data, additive, proportional, and combined (additive and proportional) error models will 
be used to characterize the residual variability.  
 
The appropriateness of the random error models will be assessed using diagnostic plots: 
 Observations versus population and individual predictions 
 Population, individual, and conditional weighted residuals versus time 
 Observations versus time with population and individual fits 
 Histogram of ETA estimates 
 
Model evaluation 
Visual predictive checks will be used to evaluate how well the model describes the data.