Clinical trial NCT01494038
Conditions: HIV Infections Tuberculosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2014-08-19; Completion date: 2017-09-06
Enrollment: 956 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Tuberculosis (TB) is a leading cause of death among HIV-infected persons in low-income settings and can be a serious complication for HIV-infected pregnant women and their infants. Isoniazid (INH) preventive therapy (IPT) is effective in preventing TB infection in HIV-infected adults, but the safety of IPT in pregnant women is unknown. This study evaluated the safety of IPT among HIV-infected pregnant women.

Detailed description:
TB disease is the most common HIV-related opportunistic infection and is a leading cause of death among HIV-infected persons in low-income settings. When TB occurs during or soon after pregnancy, it can cause complications for the mother as well as infant TB or death. Infant TB is very difficult to diagnose, and up to half of infant TB cases are caused by maternal TB. It has been shown that treatment for active TB is safe and effective during pregnancy and that IPT is safe and effective in preventing TB infection in HIV-infected adults. However, the safety of IPT in HIV-infected pregnant women is not known, especially in regard to its combination with highly active retroviral therapy (HAART). This study evaluated the safety of immediate (antepartum, or before delivery) versus deferred (postpartum, or after delivery) IPT among HIV-infected pregnant women in high TB incidence settings.

HIV-infected pregnant women were randomly assigned (1:1) to one of two arms: Arm A (immediate/antepartum INH) and Arm B (deferred/postpartum INH group). Women in both arms received oral prenatal multivitamins and pyridoxine (vitamin B6) once daily from study entry through Week 40 postpartum.

Study visits for women occurred at screening, entry, every 4 weeks until labor and delivery, at labor and delivery, and every 4 weeks after delivery until 48 weeks postpartum. Visits consisted of giving a medical history and undergoing a physical exam and blood collection; all visits through the delivery visit also included an obstetrical exam. Presence of HIV infection was documented at screening and a tuberculin skin test (TST) was administered at the delivery visit and at the Week 44 postpartum visit. Study visits for infants occurred at birth and at several time points through Week 48. These visits included a medical history, physical exam, and blood collection. Intensive pharmacokinetic (PK) samples, that is, samples taken at many different time points within a 24-hour test period, were collected from a small subset of women, one test period at antepartum and one at postpartum. Sparse PK samples, that is, samples taken at fewer time points within the test period, were collected on all women, once each at antepartum and postpartum.

Arms: arm 1: Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum. arm 2: Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum.
Interventions: intervention 1: Isoniazid (INH) intervention 2: Placebo for isoniazid (INH)
Intervention descriptions: intervention 1: 300-mg tablet once daily by mouth, either from entry through Week 28 antepartum (Arm A) or from Week 12 postpartum through Week 40 postpartum (Arm B) intervention 2: Placebo tablet once daily by mouth, either from Week 28 visit through Week 40 postpartum (Arm A) or from entry until Week 12 postpartum visit (Arm B)

Protocol documents:
Prot_001.pdf: 
IMPAACT P1078 
 
A PHASE IV RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL TO 
EVALUATE THE SAFETY OF IMMEDIATE (ANTEPARTUM-INITIATED) VERSUS 
DEFERRED (POSTPARTUM-INITIATED) ISONIAZID PREVENTIVE THERAPY 
AMONG HIV-INFECTED WOMEN IN HIGH TB INCIDENCE SETTINGS 
 
“TB APPRISE” Stands for TB Ante vs. Postpartum Prevention with INH in HIV 
Seropositive mothers and their Exposed infants 
 
A Multicenter International Trial of the 
International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) 
 
Sponsored by: 
The National Institute of Allergy and Infectious Diseases (NIAID); 
The Eunice Kennedy Shriver  
National Institute of Child Health and Human Development (NICHD); 
Scientific Collaboration with the Tuberculosis Trials Consortium (TBTC)  
of the Centers for Disease Control and Prevention 
 
DAIDS ES # 10732 
IND # 113,835 
 
 
The IMPAACT Tuberculosis 
Scientific Committee Chair:  
Anneke Hesseling, MBChB, MSc, PhD 
 
Protocol Chair: 
Amita Gupta, MD, MHS 
 
Protocol Vice Chairs: 
Adriana Weinberg, MD 
 
Timothy Sterling, MD  
 
Gerhard Theron, MD 
 
 
NIAID Medical Officers:  
Patrick Jean-Philippe, MD 
 
NICHD Medical Officer: 
Nahida Chakhtoura, MD, MsGH  
 
Clinical Trials Specialist: 
Katie McCarthy, MPH 
 
Sarah Bradford, MPH 
 
 
Final Version 2.0 
28 October 2015 


IMPAACT P1078 – Version 2.0 
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IMPAACT P1078 SITE REQUIREMENTS 
 
An approved Site Implementation Plan (SIP) is required, for sites to be eligible to enroll.  Please 
see Section 4.5 for additional information.  P1078 protocol documents are available to download 
from the study webpage on the IMPAACT website: www.impaactnetwork.org.  For the 
pharmacokinetic subset (see Section 9.0) planned in P1078, certain laboratory capabilities and 
training will also be required.  
 
 


IMPAACT P1078 PROTOCOL TEAM ROSTER 
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28 October 2015 
Protocol Chair 
Amita Gupta, MD, MHS 
Johns Hopkins University  
Phipps Building 540B 
600 North Wolfe Street  
Baltimore, MD 21287 
Phone: (410) 502-7696 
Fax: (443) 287-6440 
Email: agupta25@jhmi.edu 
 
Protocol Vice Chair/Immunologist 
Adriana Weinberg, MD 
University of Colorado Denver 
12700 East 19th Avenue  
Mail stop 8604, Room 11126  
Aurora, CO  80045 
Phone: (303) 724-4480 
Fax: (303) 724-4485 
Email: adriana.weinberg@ucdenver.edu  
 
Protocol Vice Chairs 
Timothy Sterling, MD 
TB Trials Consortium (TBTC)  
Vanderbilt University 
A2209 Medical Center North 
1161 21st Avenue South 
Nashville, TN 37232 
Phone: (615) 322-2035 
Fax: (615) 343-6160 
Email: timothy.sterling@vanderbilt.edu 
 
Gerhard Theron, MD 
Stellenbosch University 
Department of Obstetrics and Gynaecology 
Faculty of Health Sciences 
Francie van Zyl Drive 
Parow Valley  
Cape Town  
7505 South Africa 
Phone: 27-21-9389209 
Fax: 27-21-9322455 
Email: gbth@sun.ac.za 
NIAID Medical Officer 
Patrick Jean-Philippe, MD 
Maternal Adolescent Pediatric Research 
Branch, DAIDS/NIAID/NIH 
5601 Fishers Lane, Room 8B49, MSC 9831 
Rockville, MD 20852-9831 
Phone: (240) 292-4790 
Fax: (240) 627-3465   
Email: jeanphilippep@niaid.nih.gov 
 
NICHD Medical Officer 
Nahida Chakhtoura, MD, MsGH 
Maternal and 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, USA 
Phone: (301) 435-6872 
Fax: (301) 496-8678 
Email: nahida.chakhtoura@nih.gov  
 
Clinical Trials Specialists 
Katie McCarthy, MPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701, USA 
Phone: (919) 544-7040 x11439 
Email: kmccarthy@fhi360.org 
 
Sarah Bradford, MPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701, USA 
Phone: (919) 544-7040 x11685 
Email: sbradford@fhi360.org 
 


IMPAACT P1078 PROTOCOL TEAM ROSTER 
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Protocol Statisticians 
Grace Montepiedra, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health   
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: (617) 432-1141 
Fax: (617) 432-3163 
Email: gmontepie@sdac.harvard.edu 
 
Lisa Aaron, MS 
Harvard School of Public Health 
Statistical and Data Analysis Center 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: (617) 432-7845 
FAX: (617) 432-2843 
Email: laaron@sdac.harvard.edu 
 
Protocol Pharmacist 
Katherine Shin, PharmD 
DAIDS/NIAID/NIH 
Pharmaceutical Affairs Branch 
5601 Fishers Lane 
Room 9D30A, MSC 9829 
Bethesda, MD 20892-9829 
Phone: (240) 627-3047 
Fax: (240) 627-3112 
Email: kashin@niaid.nih.gov 
 
Protocol Data Manager 
Bonnie Zimmer, BS 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY  14226-1056 
Phone: (716) 834-0900 x7260 
Fax: (716) 834-8432 
Email: zimmer@fstrf.org 
 
Amanda Golner, BS 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY  14226-1056 
Phone: (716) 834-0900 x7382 
Fax: (716) 834-8432 
Email: golner@fstrf.org 
 
Protocol Virologist 
Grace Aldrovandi, MD 
Associate Professor, Virology Lab 130 
Children’s Hospital of Los Angeles 
4546 Sunset Blvd 
Los Angeles, CA 90027 
Phone: (323) 361-8501 
Fax: (323) 361-8599 
Email: gracea@mac.com 
 
Protocol Host Genetics 
Stephen A. Spector, MD 
University of California, San Diego  
Stein Research Building  
9500 Gilman Drive  
La Jolla, CA 92093-0672 
Phone: (858) 534-7170  
Fax: (858) 534-7411  
Email: saspector@ucsd.edu 
 
Protocol Pharmacologists 
Francesca Aweeka, PharmD 
University of California, San Francisco 
Clinical Pharmacy  
521 Parnassus Avenue, C152  
P.O. Box 0622  
San Francisco, CA  94143-0622 
Phone: (415) 476-0339 
Fax: (415) 476-0307 
Email: faweeka@sfghsom.ucsf.edu 
 


IMPAACT P1078 PROTOCOL TEAM ROSTER 
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28 October 2015 
Protocol Pharmacologists (cont) 
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  
 
Investigator 
Jyoti S. Mathad, MD, MSc 
Weill Cornell Medical College 
402 East 67th Street, 2nd floor 
New York, New York 10065 
Phone: (646) 962-8140  
Fax: (646) 962-0285 
Email: jsm9009@med.cornell.edu 
 
Protocol Immunologists 
Savita G. Pahwa, MD 
University of Miami School of Medicine  
Batchelor Research Institute, Room 712  
1580 Northwest 10th Avenue  
Miami, FL 33136 
Phone: (305) 243-7732 
Fax: (305) 243-7211 
Email: spahwa@med.miami.edu 
 
Susanne Doblecki-Lewis, MD 
University of Miami School of Medicine 
1400 NW 10th Avenue, Suite 813A (D-90A) 
Miami, FL 33136 
Phone: (305) 243-7618 
Fax: (305) 243-7621 
Email: sdoblecki@med.miami.edu 
Protocol 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  
 
Central Laboratory Specialists 
Susan Fiscus, PhD 
UNC School of Medicine 
Chapel Hill, NC 27599-7290 
Phone: (919) 942-6978 
Email: susan_fiscus@med.unc.edu  
 
Central Laboratory Specialists (cont.) 
Amy James Loftis, BS 
University of North Carolina at Chapel Hill 
116 Manning Drive 
Chapel Hill, NC 27599 
Phone: (919) 966-6867 
Fax: (919) 966-9873 
Email: amjames@med.unc.edu  
 
Diane G. Costello, BS 
Children’s Hospital of Los Angeles 
4546 W. Sunset Blvd 
Los Angeles, CA 90027 
Phone: (703) 862-0820  
Email: dcostello@impaactlabcenter.org  
 


IMPAACT P1078 PROTOCOL TEAM ROSTER 
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28 October 2015 
Protocol Field Representatives 
Joan Coetzee 
Ward J8-KID CRU, Tygerberg Hospital 
Francie van Zijl Dr. 
Parow Valley, Cape Town 
South Africa, 7700 
Phone: 27 21 938-4157 
Fax: 27 21 938-4179 
Email: joan@sun.ac.za  
 
Andrea Jurgrau, MS, CPNP 
New York Presbyterian Hospital 
VC4 East Room 412 
622 West 168th Street 
New York, NY 10032 
Phone: (212) 305-5000 
Fax: (212) 305-7400 
Email:  jurgrau@nyp.org  
 
Westat Clinical Research Associate 
Scott Watson, RN 
Westat Inc. 
1441 W. Montgomery Ave. 
Rockville, MD 20850 
Phone: (415) 494-5575 
Fax: (415) 859-9029 
Email: scottwatson@westat.com  
 
Laboratory Data Managers 
Carrie Fry, BS 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road  
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7437 
Fax: (716) 834-0655 
Email: cfry@fstrf.org 
 
Rachael Henderson, BS 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road  
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7331 
Fax: (716) 834-0655 
Email: henderso@fstrf.org 
IMPAACT Community Advisory Board 
(ICAB) Representative 
Ujwala Kadam 
Byramjee Jeejeebhoy Medical College 
Sassoon General Hospitals 
Pathology Museum, 1st Floor 
Jai Prakesh Narayan Road 
Pune, Maharashtra 411001 India 
Phone: 91-20-26052419 
Fax: 91-20-26125432 
Email: soudaminigroup@yahoo.co.in   
 
Community Program Manager 
Cheryl D. Cokley, BS, PMD Pro 
IMPAACT Operations Center, FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701, USA 
Phone: (919) 544-7040 x11359 
Email: ccokley@fhi360.org   
 
Consultants 
Vivian Rexroad, PharmD 
Johns Hopkins University  
600 North Wolfe Street, Carnegie 180  
Baltimore, MD 21287-6180 
Phone: (410) 955-4505 
Fax: (410) 614-8074 
Email: vrexroa@jhmi.edu 
 
Jussi J. Saukkonen, MD 
TB Trials Consortium, Pulmonary Center 
Boston University School of Medicine 
80 E. Concord Street, R-304 
Boston, MA 02118 
Phone: (617) 638-6120 
Fax: (617) 536-8093 
Email: jsaukk@bu.edu 
 
Monica Gandhi, MD, MPH 
University of California, San Francisco 
Division of HIV/AIDS, Box 1352 
405 Irving Street, 2nd floor 
San Francisco, CA 94114 
Phone: 415-502-6285 
Fax: 415-476-8528 
Email: monica.gandhi@ucsf.edu 


IMPAACT P1078 SITE INVESTIGATOR ROSTER 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
 
Aisa Shayo, MD, MMED, DTM&H 
KCMC CRS 
KCMC-Duke Collaboration 
Box 3010, KCMC 
Moshi, Tanzania 
Phone: 255 754 298894 
Fax: 255 272 754381 
Email: dustesha@yahoo.com 
 
Samuel K. Sinei, MBChB, MMED 
Kenya Medical Research Institute/Walter 
Reed Project CRS 
HIV Program 
P.O. Box 1357 – 20200 
Hospital Road, Kericho, Kenya 
Phone: 254 52 2030686 
Fax: 254 52 2030662 
Email: samuel.sinei@usamru-k.org 
 
Avy Violari, MD 
Soweto CRS 
Perinatal HIV Research Unit 
Chris Hani Baragwanath Hospital, 12th 
Floor 
Old Potch Road 
Johannesburg 
Gauteng, South Africa 
Phone: 27 11 9899707 
Fax: 27 11 989 9762 
Email: violari@mweb.co.za  
 
Mark F. Cotton, MD 
Stellenbosch University CRS 
Tygerberg Academic Hospital, Ward J8  
Francie van Zyl Drive, P.O. Box 19063  
Parow Valley  
Cape Town  
7505 South Africa 
Phone: 27 21 938 4219 
Fax: 27 21 938 4153 
Email: mcot@sun.ac.za 
 
Gaerolwe Masheto, MD, PGDip FamMed 
Gaborone Prevention/Treatment Trials CRS 
Princess Marina Hospital 
Plot 1836, North Ring Road 
Gaborone, Botswana 
Phone: 267 3930335 
Fax: 267 3971051 
Email: gmasheto@bhp.org.bw 
 
Aida Asmelash, MD, MPH 
Molepolole Prevention/Treatment Trials CRS 
Scottish Livingstone Hospital 
Gaborone-Molepolole Road 
Molepolole, Botswana 
Phone: 267 3930336 
Fax: 267 3901284 
Email: aasmelash@bhp.org.bw 
 
Jean Pape, MD 
GHESKIO CRS 
33 Boulevard Harry Truman 
Port-au-Prince, Haiti HT-6110 
Phone: 011 509 2940 1430 
Email: jwpape@gheskio.org  
 
Philippa Musoke, MB, ChB 
Makarere University JHU Research 
Collaboration CRS 
MUJHU Research House 
Upper Mulago Hill Road 
Kampala, Uganda 
Phone: 256 41 4541044 
Email: pmusoke@mujhu.org  
 
Carolyne Onyango, MBChB, MS 
Makarere University JHU Research 
Collaboration CRS 
MUJHU Research House 
Upper Mulago Hill Road 
Kampala, Uganda 
Phone: 256 414 541044 
Email: carolonyango@mujhu.org 
 


IMPAACT P1078 SITE INVESTIGATOR ROSTER 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
Newton Kumwenda, MPH, PhD 
College of Medicine JHU CRS 
Queen Elizabeth Central Hospital 
Chipatala Avenue 
Blantyre, Malawi 
Phone: 265 1875129 
Fax: 265 1870132 
Email: nkumwenda@jhu.medcol.mw 
 
Bonus Makanani, MBBS, FCOG(SA) 
College of Medicine JHU CRS 
Queen Elizabeth Central Hospital 
Chipatala Avenue 
Blantyre, Malawi 
Phone: 265 1875129 
Fax: 265 1870132 
Email: bmakanani@jhu.medcol.mw 
 
Tsungai Chipato, MBChB, FRCOG, MCE 
St. Mary’s and Harare Family Care CRSs 
UZ-UCSF Collaborative Research Program 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: 263 4701717 
Fax: 263 470 8267 
Email: tchipato@zol.co.zw 
 
Lynda Stranix-Chibanda, MBChB, MMED 
Seke North CRS 
UZ-UCSF Collaborative Research Program 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: 263 4704890 
Fax: 263 4704897 
Email: lynda@uz-ucsf.co.zw  
 
Vidya Mave, MD 
BJ Medical College CRS 
BJ Medical College and Sassoon General 
Hospitals 
Jai Prakash Narayan Road 
Pune, Maharastra, 411001 India  
Phone: 91 20 260 52419 
Fax: 91 20 261 25432 
Email: vidyamave@gmail.com  
 
Ramesh Bhosale, MD 
BJ Medical College CRS 
BJ Medical College and Sassoon General 
Hospitals 
Jai Prakash Narayan Road 
Pune, Maharastra, 411001 India 
Phone: 91 20 26128000, Ext. 311 
Email: drrameshbhosale@yahoo.com 
 
Virat Sirisanthana, MD 
CMU HIV Treatment CRS 
Research Institute for Health Sciences, 
Chiang Mai University 
110 Inthavaroros Road 
Chiang Mai, 50200 Thailand 
Phone: 66 5394 6148 ext. 446 
Fax: 66 5322 1849 
Email: vsirisan@rihes.org  
 
Anneke C. Hesseling, MD, PhD  
Desmond Tutu TB Centre, Stellenbosch 
University CRS 
Clinical Building, Faculty of Medicine and 
Health Sciences 
Stellenbosch University 
Francie van Zyl Drive, Parow, 7505 
Tygerberg, South Africa 
Phone: 27 21 9389173 
Fax: 27 21 9389719 
Email: annekeh@sun.ac.za  


 
 
IMPAACT P1078 – Version 2.0 
viii 
28 October 2015 
STUDY MANAGEMENT 
 
For additional guidance on study management questions and communications, please see the IMPAACT 
P1078 Manual of Procedures (MOP). 
 
Protocol Registration Questions:  Email protocol@tech-res.com or call (301) 897-1707.  Protocol 
registration material can be sent electronically to epr@tech-res.com or via FAX at 1-800-418-3544 or 
(301) 897-1701.  
 
Email the Computer Support Group at the Data Management Center (DMC) (user.support@fstrf.org) to 
have relevant site personnel added to the protocol email group (impaact.protp1078@fstrf.org).  Inclusion 
in the protocol email group will ensure that sites receive important information about the study during its 
implementation and conduct. 
 
General Questions:  Email questions concerning any aspect of protocol interpretation and/or study 
implementation not listed below, including administrative, ethical, regulatory, counseling, data, and 
laboratory operations, to impaact.teamp1078@fstrf.org.  See Section 1 of the P1078 MOP for more 
information on communication with the P1078 protocol team.   
 
Clinical and Toxicity Management Questions and Notifications:  Email questions concerning clinical 
management of study participants and adverse experiences to the study Clinical Management Committee 
(CMC) at impaact.p1078cmc@fstrf.org.  See the P1078 MOP for more information on communication 
with the P1078 CMC. 
 
Questions related to participant eligibility, potential enrollment of an ineligible participant, and/or 
deviation from other protocol requirements for screening and enrollment should be directed to the Core 
team (impaact.corep1078@fstrf.org).  Email questions related to co-enrollment in P1078 and other 
studies to the Core team.  See the P1078 MOP for more information on communication with the Core 
team. 
 
Randomization:  For randomization questions or problems and study identification number (SID) lists, 
email rando.support@fstrf.org or call the DMC Randomization Desk at (716) 834-0900 x7302. 
 
Computer and Screen Problems:  For computer and screen problems, email user.support@fstrf.org or call 
the DMC at (716) 834-0900 x7302. 
 
Product Package Inserts or Investigator Brochures:  Product package inserts or investigator brochures 
may be accessed on the DAIDS Regulatory Support Center (RSC) website: http://rsc.tech-res.com.   
 
Study Drug:  For questions or problems regarding study drug, dose, supplies, records, and returns, contact 
the DAIDS Protocol Pharmacist at Kashin@niaid.nih.gov or call (240) 627-3047. 
 
Study Drug Orders:  Email the Clinical Research Products Management Center 
(bio.crpmc.ph@thermofisher.com) or call (301) 294-0741. 
 
Expedited Adverse Event (EAE) Reporting/Questions:  Contact the DAIDS RSC Safety Office via email 
(RSCSafetyOffice@tech-res.com) or phone (1-800-537-9979 or +1-301-897-1709) or fax (1-800-275-
7619 or +1-301-897-1710).  For questions about the DAIDS Adverse Experience Reporting System 
(DAERS), email DAIDS-ESSupport@niaid.nih.gov.  Questions may also be sent within the DAERS 
application. 
 


 
 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
TABLE OF CONTENTS 
GLOSSARY................................................................................................................................. XI 
SCHEMA, P1078 TB APPRISE ...................................................................................................1 
1.0 
INTRODUCTION..............................................................................................................4 
1.1 
Background ..............................................................................................................4 
1.2 
Rationale ..................................................................................................................5 
2.0 
STUDY OBJECTIVES ....................................................................................................15 
2.1 
Primary Objective ..................................................................................................15 
2.2 
Secondary Objectives .............................................................................................15 
2.3 
Exploratory Objectives ..........................................................................................16 
3.0 
STUDY DESIGN ..............................................................................................................16 
3.1 
Pharmacokinetic Testing ........................................................................................17 
3.2 
Immunologic Testing .............................................................................................17 
3.3 
Screening for Active TB at the Screening Visit .....................................................18 
3.4 
Enrollment and Randomization Phase ...................................................................19 
3.5 
Intensified TB Case Finding ..................................................................................19 
3.6 
Standard of Care for Women and Infants Enrolled in the Study ...........................19 
3.7 
Unblinding Participants .........................................................................................19 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS .......................................20 
4.1 
Inclusion Criteria ...................................................................................................20 
4.2 
Exclusion Criteria ..................................................................................................21 
4.3 
Concomitant Medication Guidelines .....................................................................22 
4.4 
Screening Procedures .............................................................................................23 
4.5 
Enrollment Procedures ...........................................................................................23 
4.6 
Co-enrollment Procedures .....................................................................................24 
5.0 
STUDY TREATMENT ...................................................................................................25 
5.1 
Regimens, Administration, and Duration of Regimen...........................................25 
5.2 
Product Formulation ..............................................................................................28 
5.3 
Product Supply, Distribution, and Pharmacy .........................................................28 
6.0 
PARTICIPANT MANAGEMENT.................................................................................29 
6.1 
Toxicity Management, Mothers .............................................................................29 
6.2 
Toxicity Management, Infants ...............................................................................38 
6.3 
Criteria for INH/Placebo for INH Treatment Discontinuation ..............................38 
6.4 
Criteria for INH/Placebo for INH Treatment Re-initiation ...................................38 
6.5 
Criteria for Study Discontinuation .........................................................................38 
7.0 
EXPEDITED ADVERSE EVENT REPORTING ........................................................39 
7.1 
Adverse Event Reporting to DAIDS......................................................................39 
7.2 
Reporting Requirements for This Study ................................................................39 
7.3 
Grading Severity of Events ....................................................................................39 
7.4 
Expedited AE Reporting Period .............................................................................40 


 
 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
8.0 
STATISTICAL CONSIDERATIONS ...........................................................................40 
8.1 
General Design Issues ............................................................................................40 
8.2 
Outcome Measures.................................................................................................41 
8.3 
Randomization and Stratification ..........................................................................44 
8.4 
Sample Size and Accrual .......................................................................................44 
8.5 
Monitoring .............................................................................................................48 
8.6 
Analyses .................................................................................................................50 
9.0 
CLINICAL PHARMACOLOGY PLAN .......................................................................56 
9.1 
Pharmacology Objectives ......................................................................................56 
9.2 
Study Design, Modeling, and Data Analysis .........................................................57 
10.0 
HUMAN SUBJECTS .......................................................................................................59 
10.1 
Institutional Review Board and Informed Consent ...............................................59 
10.2 
Participant Confidentiality .....................................................................................60 
10.3 
Study Discontinuation ............................................................................................60 
11.0 
PUBLICATION OF RESEARCH FINDINGS .............................................................60 
12.0 
BIOHAZARD CONTAINMENT ...................................................................................60 
13.0 
REFERENCE LIST .........................................................................................................61 
 
APPENDICES 
I-A:  
Schedule of Evaluations for All Women ...........................................................................66 
I-B:  
Schedule of Evaluations for Infant Follow-up ...................................................................72 
II:  
Brief Peripheral Neuropathy Screening (BPNS) ...............................................................75 
III:  
Modified Grading Table for Hepatotoxicity ......................................................................76 
IV-A:  P1078 Informed Consent Glossary ....................................................................................77 
IV-B:  Sample Informed Consent..................................................................................................78 
IV-C:  Pharmacokinetic Analysis of Isoniazid (INH) Intensive Pharmacokinetic Subset 
Consent ..............................................................................................................................95 
IV-D:  Supplement to Appendix IV-B, Sample Informed Consent: For sites where INH is 
routinely provided to HIV-infected pregnant women ........................................................99 
 


 
 
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Glossary 
 
ACTN 
AIDS Clinical Trials Network 
AE/EAE 
Adverse Event / Expedited Adverse Event 
AFB 
Acid-fast bacillus 
ALT (SGPT) 
Amino Alanine Transferase (Serum Glutamate Pyruvate Transaminase) 
ART/ARV 
Antiretroviral Therapy / Antiretroviral 
AST (SGOT) 
Aspartate Amino Transferase (Serum Glutamic Oxalacetic Transaminase) 
ATS 
American Thoracic Society 
AUC 
Area Under the Curve 
BCG 
Bacille Calmette-Guérin 
BPNS 
Brief Peripheral Neuropathy Screen 
CAP 
College of American Pathologists 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence Interval 
CL/F 
Clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CMC 
Clinical Management Committee 
CMI 
Cell-Mediated Immunity 
CONSORT 
Consolidated Standards for Reporting Trials 
CPQA 
Clinical Pharmacology Quality Assurance 
CRC 
Clinical Research Center 
CRF 
Case Report Form 
CRPMC 
Clinical Research Products Management Center 
CRS 
Clinical Research Site 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS, NIAID 
DAIDS PRO 
DAIDS Protocol Registration Office 
DMC 
Data Management Center 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
EFV 
Efavirenz 
ELISPOT 
Enzyme-linked Immunosorbent Spot 
ERC 
Endpoint Review Committee 
FDA 
Food and Drug Administration 
GCLP 
Good Clinical Laboratory Practice 
HAART 
Highly Active Antiretroviral Therapy 
HBsAg 
Hepatitis B Surface Antigen 
HHS 
(US Department of) Health and Human Services 
HIV/AIDS 
Human Immunodeficiency Virus / Acquired Immunodeficiency Syndrome 
ICF 
Informed Consent Form 
IGRA 
Interferon Gamma Release Assay 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IND 
Investigational New Drug 
INH 
Isoniazid 
IPT 
INH-Preventive Therapy 
IRB 
Institutional Review Board 


 
 
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ITT 
Intent-To-Treat 
IUGR 
Intrauterine Growth Restriction 
LAR 
Legally Authorized Representative 
LFT 
Liver Function Test 
LPC 
Laboratory Processing Chart 
LTBI 
Latent Tuberculosis Infection 
MMWR 
Morbidity and Mortality Weekly Report 
MOH 
Ministry of Health 
MOP 
Manual Of Procedures 
M.tb. 
Mycobacterium tuberculosis 
MVI 
Multivitamins 
NAT2 
N-acetyltransferase 2 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral Blood Mononuclear Cell 
PCP 
Pneumocystis jiroveci (previously Pneumocystis carinii) Pneumonia  
PCR 
Polymerase Chain Reaction 
PEPFAR 
President’s Emergency Plan for AIDS Relief 
PHQ 
Patient Health Questionnaire 
PI 
Predicted Interval 
PID/SID 
Patient Identification Number / Study Identification Number 
PK 
Pharmacokinetics 
PMTCT 
Prevention of Mother To Child Transmission 
PN 
Peripheral Neuropathy 
QGIT 
QuantiFERON Gold-In Tube 
RE 
Regulatory Entity 
RNA 
Ribonucleic Acid 
RSC 
Regulatory Support Center 
SAE 
Serious Adverse Event 
SDAC/SDMC 
Statistical Data Analysis Center / Statistical and Data Management Center 
SERC 
Secondary Endpoint Review Committee 
SES 
Subject Enrollment System 
SIP 
Study or Site Implementation Plan 
SOE 
Schedule of Evaluations 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB  
Tuberculosis  
TST 
Tuberculin Skin Test 
UCSF 
University of San Francisco 
ULN 
Upper Limit of Normal 
USA 
United States of America 
WHO 
World Health Organization 
 
For this protocol, QGIT and TB ELISPOT are both included under the term IGRA.  IGRA will 
be the term used for those tests except where a more specific test is noted. 
 


 
 
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Schema, P1078 TB APPRISE 
 
A Phase IV Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Safety of 
Immediate (Antepartum-Initiated) Versus Deferred (Postpartum-Initiated) Isoniazid Preventive 
Therapy Among HIV-Infected Women in High TB Incidence Settings  
 
“TB APPRISE” Stands for TB Ante vs. Postpartum Prevention with INH in HIV Seropositive 
mothers and their Exposed infants  
 
Design: 
Phase IV, randomized, double-blind, placebo-controlled study 
 
Sample Size: 
950 women and their infants (475 women per study arm)  
 
Population: 
Mother-infant pairs; HIV-infected pregnant women ≥ 14 weeks through ≤ 34 
weeks (34 weeks, 6 days) gestation  
 
Randomization: At study entry, randomization will be in a 1:1 ratio to Arm A (immediate INH 
treatment) OR Arm B (deferred INH treatment) 
 
Randomization will be balanced at each clinical research site (CRS). 
 
Stratification: 
Pregnant women will be stratified by gestational age in each arm as follows: 
Stratum a: 
≥ 14 to < 24 weeks gestational age at study entry 
Stratum b: 
≥ 24 through ≤ 34 weeks (34 weeks, 6 days) gestational age at 
study entry 
 
There will be no limits on the number of women in each stratum. 
 
Regimen: 
Women in Arm A (Immediate INH) will be given: 
 INH 300 mg – initiated at study entry and continued for 28 weeks 
THEN 
 Placebo for INH – initiated after 28 weeks of INH treatment and continued 
until 40 weeks postpartum 
 
Women in Arm B (Deferred INH) will be given: 
 Placebo for INH – initiated at study entry and continued until 12 weeks 
postpartum 
THEN 
 INH 300 mg – initiated at 12 weeks postpartum and continued until 40 
weeks postpartum 
 
Women in Arm A and Arm B will be given: 
Open-label Pyridoxine (vitamin B6) and prenatal multivitamins from study entry 
until 40 weeks postpartum.  Pyridoxine and prenatal multivitamins will be 
obtained locally by the site. 
 


 
 
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Study Duration: From enrollment through 48 weeks post-delivery 
 
Pharmacokinetic Studies:  An intensive pharmacokinetic (PK) subset analysis will be performed 
on a limited number of women who are receiving both INH/placebo for INH plus HAART.  
Population PK will be done on all women, except those who participate in the intensive PK 
study.  As a biomarker of adherence and exposure, small hair samples for the measurement of 
ART and INH concentrations will be collected and analyzed at relevant study visits. 
 
Immunology Studies:  Immunology studies, including IGRA (QGIT and TB ELISPOT) and 
TST, will be performed on women and infants throughout the study; sera, plasma, and PBMCs 
will also be collected and stored on a subset of women and infants to be used for future TB/HIV-
related testing.  QGIT results will be blinded to the clinical site staff.  
 
For this protocol, QGIT and TB ELISPOT are both included under the term IGRA.  IGRA will be 
the term used for those tests except where a more specific test is noted. 
 
Primary Objective:  To compare overall safety and toxicity of immediate versus deferred INH 
preventive therapy in HIV-infected pregnant women enrolled at ≥ 14 through ≤ 34 weeks 
gestation (34 weeks, 6 days) 
 
Secondary Objectives: 
1. To compare safety and toxicity of INH in utero exposure and on infants on study 
2. To compare TB incidence and all-cause mortality in HIV-infected women and their infants 
enrolled on study 
3. To compare overall safety and hepatotoxicity, as well as evaluate risk factors for these 
outcomes, during pregnancy and immediate postpartum in women on immediate versus 
deferred INH therapy 
4. To evaluate for INH resistance among M.tb. isolates from HIV-infected women and infants 
who develop TB while on study 
5. To evaluate the intensive pharmacokinetics of INH and selected ARV drugs in a subset of 
HIV-infected pregnant and postpartum women receiving HAART 
6. To evaluate and compare the performance characteristics of IGRA (TB ELISPOT and QGIT) 
with TST in HIV-infected women and their infants 
7. To compare adherence in women initiating immediate versus deferred INH preventive 
therapy via self-report and pill counts 
 
Exploratory Objectives: 
1. To evaluate population pharmacokinetics and pharmacogenomics of INH and efavirenz 
(EFV) in HIV-infected pregnant and postpartum women 
2. To assess the effects of INH preventive therapy on the functional characteristics of TB 
specific T-cell responses measured by TB ELISPOT in HIV-infected women and their 
infants on study 
3. To evaluate adherence and exposure to INH and EFV using drug levels in hair and analyze 
the association between these drug levels and adverse effects 
4. To compare the two arms with respect to the overall (risk:benefit) clinical outcomes of the 
mother-infant pairs 


 
 
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5. To explore associations of maternal and infant specific TB responses and novel biomarkers 
with risk of maternal and infant TB infection and disease 
6. To explore the neurotoxicity of INH in combination with EFV in a subset of women  
 
Study Schema 
 
 
 
1All women will receive a TB exposure history, World Health Organization (WHO) TB 
symptom screen, any available TB screening procedures as per local standard of care and 
complete physical exam at screening. 
 
2All women will receive standard of care + prenatal multivitamin + Pyridoxine (vitamin B6) from 
study entry to 40 weeks postpartum in addition to INH/Placebo for INH.  All women will also 
receive a TB exposure history, WHO TB symptom screen and targeted physical exam at each 
study visit.  All infants will also receive standard of care. 
 
HIV-infected pregnant women ≥ 14 weeks through 
≤ 34 weeks (34 weeks, 6 days) gestation
TB Screening-Rule out active TB1
Active TB Suspected OR Documented
Refer to local TB 
program for 
evaluation and TB 
treatment; not 
eligible for study
Women meets other 
eligibility criteria
Study drugs (INH/placebo for INH), open-label Pyridoxine (vitamin B6) and 
open-label prenatal multivitamin terminated at 40 weeks postpartum
End of study 48 weeks postpartum
Arm A
Immediate INH
(INH x 28 weeks then 
placebo for INH)2
Arm B
Deferred INH
(placebo for INH until 
postpartum week 12 
then INH x 28 weeks)2
No
Yes
Enrollment and 
Randomization


 
 
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1.0 
Introduction 
 
1.1 
Background 
 
Tuberculosis (TB) is the most important cause of morbidity and mortality among HIV-infected 
persons residing in high TB burden settings such as sub-Saharan Africa and India.  TB 
predominantly affects women of reproductive age, and when it occurs during pregnancy or early 
postpartum, it can result in adverse maternal outcomes and infant TB and death.  Infant TB is 
very challenging to diagnose.  It is estimated that up to a half of infant TB cases are due to 
maternal TB disease.  While there is no controversy about the need and benefit of treating active 
TB during pregnancy or benefit of isoniazid (INH) preventive therapy (IPT) to HIV-infected 
adults, particularly those who are tuberculin skin test (TST) positive, data on the safety and 
efficacy of administering IPT to HIV-infected pregnant women in the era of antiretroviral 
therapy (ART) are not available. 
 
There have been a number of clinical trials involving IPT in HIV-infected adults and HIV-
infected or HIV-exposed children.  Current guidelines from the World Health Organization 
(WHO) recommend that all HIV-infected persons residing in low- and middle-income regions 
where TB is endemic receive at least 6 months of IPT [1].  The guidelines have removed the 
prior requirement of a positive TST due to difficulties in implementation and have now included 
a recommendation of IPT to pregnant women and children.  However, none of the more than 13 
adult IPT trials has included HIV-infected pregnant women, a population that may have a higher 
risk of adverse events (AEs) and drug-induced liver injury.  There remains limited data regarding 
highly active antiretroviral therapy (HAART) initiation in close approximation with INH but a 
pragmatic trial conducted in South Africa suggested IPT + HAART was beneficial irrespective 
of TST status.  Pregnant women, however, were excluded from this trial as well. [2] 
 
The optimal timing of IPT in pregnancy remains unknown and this knowledge gap is 
acknowledged in the WHO guidelines.  The US Centers for Disease Control and Prevention 
(CDC) guidelines and literature to date acknowledge that there is increased toxicity risk of IPT in 
pregnancy and within 3 months postpartum.  Pregnant women also have increased risk of 
adverse antiretroviral drug toxicity and increased risk of hepatic dysfunction from pregnancy 
itself.  Currently the US Food and Drug Administration (FDA) categorizes INH as category C, 
meaning that animal reproduction studies have shown an adverse effect on the fetus and there are 
no adequate and well-controlled studies in humans, but potential benefits may warrant use of the 
drug in pregnant women despite potential risks.  Although the WHO guidelines recommend use 
of IPT in HIV-infected pregnant women, in the absence of safety data, it is unclear if this 
recommendation will be followed.  Furthermore, safety data specific to IPT initiation among 
pregnant women also initiating HAART are lacking but needed.  Small studies have observed 
that continuing IPT when women become pregnant or initiating IPT in pregnancy is not 
associated with severe adverse events. [3, 4]  However, the Lesotho study, for example, had only 
liver function test data for 20 of 160 women of whom only a small number were on HAART.  
HAART is known to have an independent effect on reducing TB incidence but prospective data 
on the risks and benefits of combining IPT with HAART in pregnancy is unknown.  Since some 
HIV-infected pregnant women may not have latent TB infection (LTBI) and, therefore, may not 


 
 
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have significant benefit from IPT, it is important to evaluate the safety of IPT in pregnancy, the 
optimal timing of IPT in this population, as well as overall efficacy, risk and benefits. 
 
The goal of IMPAACT P1078 is to evaluate whether initiating IPT is safe in HIV-infected 
pregnant women who may be receiving HAART.  This study will also assess the tolerability of 
IPT in the context of HAART during pregnancy and as secondary objectives include assessment 
of efficacy of INH, pregnancy and infant outcomes, adherence to INH and ART via hair 
sampling, pharmacology of INH/HAART and performance of latent TB diagnostics.  In addition, 
the data and samples from this study may allow for novel and important immunologic studies 
that will provide insights into Mycobacterium tuberculosis (M.tb)-specific responses, LTBI, risk 
of maternal disease, and risk of infection and disease among infants born to women who have 
received INH antepartum versus postpartum. 
 
1.2 
Rationale 
 
TB: Major Cause of Morbidity and Mortality in HIV-infected Women in Low-income Countries 
 
An estimated 2 billion individuals are latently infected with Mycobacterium tuberculosis (M.tb.) 
and over 9 million cases of active TB occur each year globally with an estimated 3.8 million 
cases occurring in women [5]. HIV is an important contributor to the TB epidemic, most notably 
in sub-Saharan Africa.  TB disease is the most common HIV-related opportunistic infection and 
is the most important cause of morbidity and mortality in HIV-infected adults in low-income 
settings [6].  Even in the era of HAART, significant rates of TB disease persist [7, 8].  The 
greatest burden of HIV and TB among women occurs during the childbearing years (15-49 
years).  Active TB seems particularly prevalent during pregnancy, delivery, and the postpartum 
period [9-14].  Active TB in women with HIV co-infection is an independent factor for non-
obstetric maternal mortality.  In a study of maternal mortality in South African teaching 
hospitals, mothers with TB and HIV had a 3.2 fold increased risk of death compared to mothers 
with TB without HIV; 54% of maternal deaths due to TB disease were attributable to HIV co-
infection [15].  In a study in Zambia, TB accounted for 25% of non-obstetric deaths and most of 
these deaths occurred in HIV/TB co-infected women [16].  Similar studies in Zimbabwe, India, 
and Tanzania have identified TB as a major cause of maternal non-obstetric deaths (within first 
1-2 years postpartum) in HIV-infected women [13, 17, 18].  
 
Maternal TB has Negative Impact on Young Infants 
 
Data indicate that infants born to HIV-infected mothers with active TB have higher rates of 
prematurity, low birth weight, and intrauterine growth retardation (IUGR) [10].  Furthermore, 
newborn and young infants exposed to HIV-infected mothers with active TB are at high risk for 
tuberculosis morbidity, all-cause mortality, and HIV infection [17, 19].  In IMPAACT P1041, A 
Randomized Double Blind Placebo Controlled Trial to Determine the Efficacy of Isoniazid in 
Preventing Tuberculosis Disease and Latent Tuberculosis Infection Among Infants with Perinatal 
Exposure to HIV, infants experienced very high rates of TB exposure (nearly 10% during the 
first 3-4 months of life); HIV-infected mothers accounted for the majority of this exposure [20].  
Similarly high prevalence of TB infection has been reported in Kenyan infants [21].  It is well 
documented in natural history studies conducted prior to the 1950’s (when INH became widely 


 
 
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available) and more recent observational studies [22] that infants are likely to develop 
progressive TB disease following primary infection.  
 
IPT in HIV-infected Individuals 
 
Strategies to reduce TB burden are critical to ensuring successful clinical management of HIV-
infected individuals.  IPT reduces incident TB in HIV-infected adults by 33% and in those with a 
positive TST by 62% as well as in HIV-infected children [23, 24].  IPT has also been associated 
with a mortality benefit in HIV-infected infants and there may be a reduction in mortality among 
adults particularly if they are TST-positive (20% reduction, 4 trials pooled).  None of these 
studies included pregnant women. 
 
A study of IPT in HIV-exposed infants 3 months of age or older, was conducted as IMPAACT 
P1041.  This study was stopped early because no benefit was identified [25-27].  P1041 excluded 
infants whose mothers had TB disease or any other documented TB exposure.  It also excluded 
infants less than 3 months of age, a population at particularly high risk for active TB.  P1041 
identified maternal TB as the major source of TB exposure in infants and a risk factor for infant 
TB in at least 50% of cases [20].  Given that an important risk factor for infant TB and all-cause 
mortality is incident TB in the mother, a strategy that targets IPT in infants does not appear to be 
effective and does not address TB risk in the mother.  Therefore, it is important to demonstrate 
that IPT given during pregnancy is a safe and effective maternal-child health intervention in the 
HAART era. 
 
INH Resistance 
 
A concern that has been raised with use of INH to HIV-infected persons residing in low- and 
middle-income countries with high TB burden is the risk of INH resistance.  A review of 13 IPT 
trials in non-pregnant, HIV-infected and uninfected populations with approximately 35,000 
participants showed low risk of selecting for INH resistance [28].  
 
To avoid INH resistance, cases of active TB will be excluded using best available approaches.  
Studies have shown that the absence of cough, fever, weight loss, or night sweats have the 
highest negative predictive value for TB (>98%) [29-31].  Sites will also be encouraged to use 
additional diagnostics, such as Xpert (Xpert MTB RIF Assay or similar rapid NAAT-based test) 
and shielded chest radiograph, when readily available.  The current WHO guidelines also 
recommend this approach to rule out TB and initiate IPT.  
 
As a secondary objective, INH resistance will be assessed in participants who develop active TB 
while on the study.  Furthermore, women and infants will be screened for active TB at each visit.  
Those with a positive symptom screen will be further assessed with sputa for AFB smear, 
radiography, AFB cultures, and/or additional TB diagnostics, as recommended by local and 
WHO guidelines.  M.tb. isolates will be tested for INH resistance. 
 


 
 
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INH and Highly Active Antiretroviral Therapy (HAART) 
 
In adults, HAART without INH has been associated with a 60% reduction in TB incidence and 
HAART after INH receipt was found to reduce TB incidence by 80% in one retrospective cohort 
in Brazil and by 89% in a prospective cohort in South Africa [32, 33].  However, these studies 
did not prospectively assess the combination of HAART and IPT given around the same time.  A 
recent pragmatic study of IPT and HAART in South Africa found reduction in TB incidence 
irrespective of LTBI test status [2].  Being female, pregnant and obese are risk factors associated 
with increased drug-induced hepatotoxicity [34].  Nevirapine-containing HAART, which is 
sometimes used in pregnant and postpartum women, carries an additional risk of hepatotoxicity; 
therefore, it is imperative to assess the risks and benefits of combining INH with HAART 
whether used for PMTCT or maternal HIV treatment.   
 
Another IPT and HAART consideration is recent PK data from South African HIV-infected 
pregnant women found that INH for prophylaxis or for treatment reduced EFV clearance, 
especially among those with slow NAT2 acetylator status.  INH influences EFV concentrations 
via inhibition of CYP-2A6 [35, 36].  Whether this INH/EFV interaction results in increased EFV 
toxicity in pregnancy needs further study.  Several assessments will be used to inform this 
exploratory analysis.  A nine-item assessment tool (Patient Health Questionnaire 9, PHQ-9) that 
has been internationally validated and is available in most languages will be used as a tool to 
capture depression in pregnancy or postpartum that may or may not be related to slow INH and 
slow efavirenz (EFV) metabolism [37].  A three-item neurocognitive impairment tool [38] as 
well as several questions from the Pittsburgh Sleep Quality Index [39] will also be assessed.  
Depression and other neuropsychiatric toxicities are also captured by the DAIDS AE toxicity 
reporting requirements. 
 
INH Safety Data 
 
Hepatotoxicity 
 
INH is cleared predominantly by the liver, primarily by acetylation of N-acetyl transferase 2 
(NAT2) as discussed below.  Hepatotoxicity due to IPT in US settings has been summarized in 
the American Thoracic Society (ATS) 2006 guidelines [40] and by a recent MMWR which 
assessed severe INH-associated liver injuries for LTBI treatment in the US from 2004-2008 [41].  
Up to 20% of persons who receive IPT may experience low-grade, transient, asymptomatic 
transaminase elevations, much of which is attributed to “hepatic adaptation,” a nonprogressive 
injury to hepatocyte cell structures.  INH hepatotoxicity is mostly asymptomatic, but 
symptomatic hepatotoxicity can occur at varying transaminase levels.  Generally, INH 
hepatotoxicity occurs within weeks to months (60% in first 3 months).  The ATS recommends 
defining hepatotoxicity as one of the following: 1) amino alanine transferase (ALT) that are three 
times the upper limit of normal (ULN) or greater with clinical symptoms compatible with 
hepatitis (e.g., nausea, vomiting, abdominal pain, jaundice or unexplained fatigue); or 2) ALT 
that is at least five times the ULN in the absence of symptoms.  The FDA definition of drug-
induced hepatotoxicity for pre-market evaluation of new drugs consists of the following: ALT of 
8 X ULN or ALT > 3 X ULN  with a total bilirubin > 2 X ULN; as well as 1) the liver injury is 
hepatocellular in nature and there is no prominent cholestatic component; 2) there are no other 


 
 
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causes of hepatotoxicity, such as acute viral hepatitis A or B, or other acute liver disease; and 3) 
the drug causes more frequent hepatocellular injury as shown by ALT elevations > 3 X ULN in 
the treated group relative to the group on control treatment.  In P1078, both of these 
hepatotoxicity definitions will be assessed as secondary analyses. 
 
Risk factors for hepatotoxicity include pregnancy and being within 3 months postpartum among 
others.  The data come from two US studies conducted in the pre-HIV era.  Both studies were 
retrospective and had problems such that their results have to be interpreted with caution.  One 
study found a non-significant 2.5-fold increased risk of hepatotoxicity and a 4-fold increased risk 
of death in pregnant women.  However, there was significant loss to follow up (1,030 of 3,681 
women who began IPT never returned and only 46% completed 6 months of IPT).  Also, the 
numbers of events were small (5 pregnant women developed INH hepatitis and 2 died) [42].  A 
second study described 20 deaths in California over 14 years from INH-induced hepatitis; four 
were women who started IPT in pregnancy [43].  Supporting the notion that INH may have 
increased toxicity during pregnancy and early postpartum is the fact that both periods are 
independently associated with increased risk of hepatotoxicity due to other drugs, including 
ARVs [44].  
 
Rates of grade 3 or higher hepatotoxicity in persons receiving IPT in US range from 0.1% to 4% 
but varying definitions of hepatotoxicity have been used as well as varying degrees of adherence 
to INH.  All IPT trials in HIV-infected persons done to date have excluded pregnant women.  
One South African trial assessing novel latent TB regimens compared with INH was 
predominantly among HIV-infected women (83%) and 99.5% were Black African.  The overall 
rate of Grade 3 or 4 events was 9% in the INH arm (hepatotoxicity not specifically reported).  
Twenty six women became pregnant on IPT and 10 chose to continue IPT and no specific 
toxicity concerns were noted but numbers were small [45].   
 
Other Toxicities of IPT 
 
Peripheral neuropathy is the most common side effect of INH, occurring in about 20% of 
patients receiving 300 mg per day without supplemental pyridoxine (vitamin B6).  The side 
effects appear to be dose related and may be prevented with concomitant pyridoxine therapy.  
Patients with alcoholism, cancer, uremia, chronic liver disease, advanced age, or pregnancy may 
be predisposed to neurotoxicity from INH because they often have subclinical deficiencies of 
pyridoxine.  Neuropathy also occurs most often in “slow-acetylators,” malnourished patients, and 
diabetics [46]. 
 
Toxicities other than drug-induced liver injury and peripheral neuropathy are rare.  Cutaneous 
hypersensitivity occurs in less than 1% and hematologic abnormalities are rare.  The incidence of 
INH-induced toxic fever is estimated at 1%.  Fever usually occurs within 6 to 47 days after 
starting INH therapy; upon re-challenge fever usually reappears within 2 to 5 hours [46].  
 


 
 
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Use of INH in Pregnant and Breastfeeding Mothers and Data from Animal Reproductive 
Toxicology Studies 
 
INH is a FDA category C drug due to limited information in pregnant women.  INH is used in 
pregnancy to treat active TB, where its benefit clearly exceeds the risk.  INH is known to cross 
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 [47-49]. 
 
Animal studies show an increased rate of growth retardation in rats thought to be secondary to an 
insult to the yolk sac blood vessel walls [50, 51].  No increase in malformations was observed in 
mice pups or rabbits whose mothers received as much as 60 times the dose used in humans.  
There, however, was a modest increase in skeletal malformations in rats [52-54].  Chick embryo 
studies observed demyelination and degeneration of the central nervous system after a single 
dose of INH at different days of incubation however supplementation with vitamin B6 reversed 
these effects completely [55, 56].  Doses 30 times the usual human dose during pregnancy and 
lactation increased frequency of pulmonary adenocarcinomas in murine offspring, although a 
large case-control study of 11,169 children with cancer found no association with maternal INH 
during pregnancy (only a small number of mothers in either group took INH).  No neoplasms 
were noted in 660 children 1 to 13 years of age born to women who received INH during 
pregnancy [57-59].  An association between INH and hemorrhagic disease of the newborn was 
seen in one study but not confirmed in others; some recommend prophylactic administration of 
vitamin K at birth but this is not commonly done in practice [50].  
 
Safety 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 100 mg [60].  It can reduce pregnancy-
associated nausea and in combination with other vitamins in B complex, C and E, it has been 
associated with reduced HIV disease progression in pregnant women in Tanzania [61].  In 
P1078, open-label vitamin B6 from study Entry until Week 40 postpartum will be administered.  
In addition, the study will provide open-label prenatal multivitamins (MVI) to all women during 
pregnancy and until 40 weeks postpartum as part of standard of care.  Prenatal MVI will contain 
less than 5 mg of vitamin B6; therefore, the doses of vitamin B6 to be used in our study will be 
well within the safe range. 
 
Hair Concentrations of INH and ART as Markers of Adherence and Cumulative Exposure 
 
In a manner analogous to glycosylated hemoglobin A1C (HbA1C) providing information on 
average glucose levels over long periods of time [62], the concentration of medications in hair 
reflects drug uptake from the systemic circulation over weeks to months [63]. Drug levels in hair 
provide an advantage over single plasma ARV concentrations – where marked day-to-day 
variation limits their utility in therapeutic drug monitoring [64, 65] – in estimating an average or 
long-term measure of medication exposure [63].  Moreover, average adherence to ARVs may be 


 
 
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a better predictor of virologic suppression than duration or frequency of missed doses (captured 
by single plasma levels) [66]. 
 
The PROMISE 1077BF and 1077FF protocols have collaborated with a group at the University 
of California, San Francisco (UCSF) to incorporate a novel measure of assessing long-term 
adherence and exposure to ART in the study using hair samples.  Methods have been developed 
to extract and analyze tenofovir and emtricitabine, lopinavir/ritonavir, atazanavir, darunavir, 
nevirapine, efavirenz, and raltegravir from small scalp hair samples [67-71].  Hair concentrations 
of ARVs have been demonstrated to be the strongest independent predictor of virologic success 
in large prospective cohorts of HIV-infected patients [68, 69, 72-78], serving as stronger 
predictors of treatment outcomes than self-reported adherence [69, 73, 79, 80] or single plasma 
ARV concentrations [72].  Given concerns about waning adherence to ARVs in the postpartum 
period, incorporating an objective biomarker of ART adherence for participants in Arm A and 
Arm B of the study will further investigate this finding.  
 
The UCSF Drug Studies Unit has also recently developed a method to analyze INH in small hair 
samples as a biomarker of adherence/exposure and this study will similarly incorporate hair 
collection into P1078 to assess INH adherence among participants randomized to Arm A or B of 
the study. 
 
Pharmacology 
 
Pharmacokinetics, Pharmacogenetics, and Hepatotoxicity of INH 
 
INH is metabolized via hepatic acetylation to the N-acetyl transferase-2 (NAT2) enzyme to 
acetylisoniazid, which is further converted via oxidation by cytochrome P450 2E1 to hepatotoxic 
metabolites [81, 82].  Genetic polymorphisms of NAT2 correlate with fast, slow, and 
intermediate acetylation phenotypes.  Rapid acetylators convert 90% to acetylisoniazid while 
slow acetylators convert 67% to acetylisoniazid.  The remaining portion is excreted in urine as 
unchanged drug.  The influence of acetylation rate on INH hepatotoxicity remains controversial.  
Although it has been expected that rapid acetylators may exhibit more toxicity (greater 
conversion to hepatotoxic metabolites), studies have suggested slow acetylators have higher rates 
of hepatotoxicity than fast acetylators (26 vs. 11%).  A paper by Possuelo et al. reported that 
5.5% of 254 INH treated TB patients developed hepatotoxicity.  Of these 14 patients, nine 
(64.3%) were slow acetylators and five (35.7%) were fast acetylators indicating that slow 
acetylator status seems to be a risk factor for hepatotoxicity [83], although the mechanism 
remains obscure.  For NAT2, the rate of slow acetylation (as per diminished NAT2 activity) has 
been reported to range from 10 to 62% and there is substantial inter- and intraethnic variability in 
NAT2 polymorphisms with higher rates observed in Indian and Caucasians, moderate rates in 
South African blacks, Hispanics and lower rates in East Asians [84, 85].  However, these 
observations depend on which NAT2 polymorphisms are assessed, what method is used, and 
how ethnicity is classified.  The frequency of 2E1 variants, (including the CYP2E1*1 variant 
associated with altered 2E1 function) have been reported to be as high as 20%, but its impact on 
a population level has not been well studied [86]. 
 


 
 
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Figure 1: Schematic of INH metabolism 
 
INH and ART Pharmacokinetics in Pregnancy and Breastfeeding 
 
Data on INH pharmacokinetics in pregnancy is largely from the 1950’s and 1960’s, prior to the 
HIV epidemic.  There is a potential effect of pregnancy on NAT2 activity, using the urinary ratio 
of metabolites to caffeine suggests a slight decrease in NAT2 activity during pregnancy.  There 
are also ethnic/geographic variations in the prevalence of fast and slow acetylator status.  Given 
the potential increased toxicity risk there is a need to evaluate the pharmacokinetics of INH 
among HIV-infected women, especially in those areas where TB is endemic.  INH penetrates 
into breast milk but the concentrations achieved in infants are very low and below any level of 
concern based on available data.  The potential dose that an infant would be exposed to from 
breast milk is reported to be around 2 mg/kg/day [87]; roughly 10-20% of the usual therapeutic 
dose of 10-20 mg/kg/day advised in infants.  
 
In addition, limited information is available on ART pharmacokinetics in pregnant women at risk 
for TB in resource-limited settings.  ART exposure in the context of INH therapy may also 
contribute to the overall risk of toxicity.  As described above, INH may also impact levels of 
ART, for example, EFV [36].  In a subset of pregnant women on EFV and INH, higher levels of 
EFV were measured compared to those on EFV alone.  These women were both slow 
metabolizers of EFV and INH.  This study, however, did not capture any data on these 
interactions that were clinically significant.  In P1078, the study will capture whether any clinical 
evidence of increased EFV or INH toxicity, including the assessment of neurotoxicity through 
the use of the PHQ-9 instrument, a neurocognitive impairment assessment, several modified 
questions from the Pittsburgh Sleep Quality Index, and AE reports.  In P1078, both an intensive 
PK and a population PK study are included to assess variation between third trimester and early 
postpartum periods.  Moreover, as summarized above, ARV and INH exposure will be assessed 
when relevant via the analysis of concentrations in small hair samples.   
 
Diagnosis of LTBI in Women and Children 
 
TST screening is unreliable in patients with HIV/AIDS.  In addition to its suboptimal sensitivity, 
TST has other limitations: 1) it requires a return visit ideally within 2-3 days for interpretation [9, 
88]; and 2) it has reduced specificity in settings where atypical mycobacterial infections are 
common and where Bacille Calmette-Guérin (BCG) vaccine is routinely given.  Due to these 
limitations and the fact that LTBI (as measured by a positive TST) is difficult to diagnose, the 
Isoniazid 
acetylisoniazid 
acetylhydrazine 
NAT2 
CYP2E1 
hepatotoxins 


 
 
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current WHO guidelines do not require TST screening prior to initiation of IPT in HIV-infected 
individuals.  The 2011 WHO Guidelines for TB conditionally recommended the use of at least 
36 months of IPT for people living with HIV in high TB-prevalence and transmission settings, 
based on unpublished studies [1]; in 2015, the WHO provided an update to this recommendation, 
which provided a conditional recommendation to provide IPT to people living with HIV, with 
unknown or positive TST status.  However, the quality of evidence was rated as low [89]. 
 
Novel tests such as interferon gamma release assays (IGRAs) have been developed which may 
aid in the diagnosis of LTBI in pregnancy.  In non-pregnant HIV-infected populations, IGRAs 
(e.g., QuantiFERON Gold in Tube [QGIT] and TB ELISPOT) are associated with increased 
specificity (and possibly sensitivity) to identify LTBI, although they fail to make the crucial 
distinction between LTBI and active disease [90].  There are some data to suggest that IGRA 
may be more sensitive than TST in pregnancy [91].  IGRAs may have better predictive value 
than TST in HIV-infected individuals [92].  These tests are not standard of care in developing 
countries and further evaluation of IGRAs in the context of HIV infection and pregnancy is 
needed and will be done in this study.  
 
In P1078, there are other areas of uncertainty with respect to QGIT and TB ELISPOT in HIV-
infected pregnant and postpartum women that need to be addressed with high priority [8, 9, 90], 
including the cell type that mediates the response measured by IGRA and the effect of TST and 
of IPT on IGRA.  IFN is a relatively ubiquitous cytokine produced by multiple cells of the 
immune system including memory and effector T-cells.  TB-specific effector cells, which have a 
limited life span, may become undetectable after eradication of latent TB.  Conversely, memory 
T-cells typically persist after eradication of the antigen that originally elicited a response.  It is 
unclear whether IGRAs measure memory or effector cell-mediated immunity (CMI) and how to 
interpret their results after TST or IPT.  In this study, there is a unique opportunity to address 
these questions by performing TB ELISPOT before and after TST; before and after IPT; and by 
assessing the CD4- and CD8-mediated production of IFN and IL2 in response to M.tb. antigenic 
stimulation. 
 
The study will also compare IGRA with TST in infants born to HIV-infected mothers enrolled in 
P1078.  This will be of particular interest, because precise diagnosis of M.tb. infection in infants 
is very difficult in the absence of an accepted gold standard [22].  Several investigators have 
noted high discordance rates between IGRAs and TST in infants and young children.  Many 
children with strongly positive TST have been reported with negative IGRAs and vice versa, 
even in the absence of BCG vaccination [93-95].  Whether this is due to increased specificity of 
the IGRAs or increased sensitivity of TST remains uncertain.   
 
The study design of P1078 involves following a cohort of HIV-exposed infants from birth with 
careful assessment for TB disease in the first year of life.  Testing of infants with both IGRA and 
TST combined with the clinical endpoints of TB disease and/or documented TB exposure will 
allow a comparison of the total infant TB infection and/or disease burden by one year of life and 
determine if there is any difference between infants whose mothers received antepartum versus 
postpartum IPT.  In addition, because both TST and IGRA testing will be performed, 
concordance and clinical relevance of these tests results will be assessed. 
 


 
 
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The study will compare responses to mycobacterial antigens by TB ELISPOT measuring IFN-γ 
and IL-2 at 12 weeks for approximately 460 infants.  The response by TST and IGRA (QGIT) 
will also be compared for all infants at 44 weeks and retest the subset of 460 infants by TB 
ELISPOT.  The paucity of IGRA data in infants and lack of comparative studies with TST have 
limited the understanding of the utility of these tests.  Additionally, there is no information 
regarding the cell type that mediates the response detected by IGRA in infants.  Understanding 
the immune basis for these tests in infants is a high priority.  Lastly, storage of samples from 
infants will also allow for future exploration of the relationships between maternal immune 
responses to LTBI, INH, infant BCG responses, and infant TB responses, some of which have 
been recently shown to be important [96]. 
 
TB Disease Diagnosis and Outcomes in HIV-exposed Young Children 
 
The natural history of disease demonstrates that age and immune status are the most important 
variables that determine a child’s risk to develop TB following primary M. tuberculosis 
infection [22].  Infants are at highest risk with up to 50% progressing to active disease following 
documented TB exposure/infection, with a significant number developing disseminated disease 
[97, 98].  HIV infection dramatically increases a child’s risk to develop TB in TB endemic areas 
[99, 100].  HIV-exposed uninfected children, who should form the vast majority of children in 
the study given the provision of optimal PMTCT, also seem vulnerable to multiple pathogens 
[101, 102].  A secondary objective of P1078 is to compare infant TB and outcomes between 
those born to HIV-infected mothers who initiated INH during pregnancy and those who initiated 
it at 3 months postpartum. 
 
Diagnosis of TB in infants is challenging because sputum specimens for smear and/or culture, 
the “gold standard” used in adults, is hampered by 1) the inability of young children to 
expectorate and 2) the poor bacteriological yield in children with pauci-bacillary TB [103], 
therefore, P1078 will use the IMPAACT Network’s pediatric TB case definition that includes a 
combination of symptomatic presentation and either bacteriologic confirmation or radiographic 
certainty.  
 
Specific Study Design Issues 
 
All women and their infants will receive standard of care for HIV infection, PMTCT, and co-
infection treatment according to WHO guidelines.  More information on WHO guidelines 
and in-country standard of care can be found at: 
http://www.who.int/hiv/pub/mtct/advice/en/index.html 
 
As standard of care may vary between sites, provided care will be recorded as standard of 
care for study purposes.   
 
For this study, at least 6 months (WHO guidelines) has been translated into 28 weeks ± 2 weeks 
of INH prophylactic therapy.  As women are coming every 4 weeks for clinic visits, a 28-week 
duration will be most feasible to implement. 
 


 
 
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Rationale for Deferring IPT to Three Months Postpartum 
 
HIV-infected pregnant and early postpartum women have a higher risk of hepatotoxicity and it is 
thought that beyond 12 weeks (3 months) postpartum this risk returns to the non-pregnant 
baseline risk (30).  Recognizing that women may be at increased risk for active TB in pregnancy 
and early postpartum, it is important to balance the risks of drug toxicity with the benefits of 
earlier INH initiation.  This study will compare the INH toxicity initiated in HIV-infected 
women during pregnancy versus at 12 weeks after delivery to determine the risk of earlier 
initiation of INH in the era of HAART.  The study will also measure the effectiveness (e.g., 
incidence of maternal-infant TB or death) as a secondary objective. 
 
Equipoise for Study and for Use of Placebo 
 
Pregnancy, delivery, and the postpartum period are important entry points into the healthcare 
system for HIV-infected women and may provide the best opportunity to educate and screen for 
TB and initiate IPT [9, 104, 105].  The current WHO guidelines for IPT in HIV-infected persons 
recommend IPT to all HIV-infected persons, including pregnant women.  The guidance for 
pregnant women has been based on expert opinion and not on any clinical trial evidence as none 
of the IPT trials included HIV-infected pregnant women.  The WHO also issued further guidance 
in 2015 to clarify that IPT should be provided for individuals with HIV-infection, with an 
unknown or positive TST; this guidance is noted to have a low quality of evidence [89].  
Furthermore, the WHO guidelines to provide IPT to HIV-infected persons has been in place 
since 1998 and < 0.01% of HIV-infected adults have been receiving it, largely because of safety 
and lack of effectiveness concerns on part of providers.  In an IMPAACT site survey, none of the 
12 interested sites in Africa or India were routinely providing IPT to pregnant or postpartum 
women.  The lack of IPT data specific to HIV-infected pregnant women in the HAART era will 
likely continue to be a deterrent to initiation of IPT during pregnancy.  The goal of this study is 
to provide the necessary safety information that supports the premise that IPT can be safely 
initiated in HIV-infected women during pregnancy.  It will also address the question of optimal 
timing of IPT, an issue the WHO guidelines acknowledge remains unanswered.  In light of this, 
the study is designed primarily as a non-inferiority study to show that providing IPT during 
pregnancy does not result in significantly more drug-related toxicities than delaying initiation to 
12 weeks postpartum.  The study will assess the risk of hepatotoxicity, the possible 
additive/synergistic toxicities of HAART with IPT, and model the estimated incremental 
risks/benefits in TB prevention afforded by HAART plus IPT.  In this study, all women will 
receive IPT, be counseled about adherence to IPT and other important health measures, and be 
provided prenatal MVI.  Furthermore, both the women and their infants will be closely 
monitored and will be actively screened for signs and symptoms of TB at each visit.  It is 
therefore anticipated that women and their infants in the study will be receiving significantly 
enhanced standard of care than what they would be receiving outside the study.  
 
To best assess whether IPT initiation in pregnancy is safe the study will compare adverse effects 
with those of IPT initiated 12 weeks postpartum.  Since many women will be on various types of 
ART as well as treatment and/or prophylaxis for Pneumocystis jiroveci [previously Pneumocystis 
carinii Pneumonia (PCP)], malaria and possibly other illnesses, these therapies could impact 
safety and toxicity.  The use of a placebo is therefore critical to understand the true incidence of 


 
 
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AEs associated with IPT.  Furthermore, it is not anticipated that women with CD4 < 200 or 
< 350 cells/mm3 will be at substantial increased risk if they are randomized to early receipt of 
placebo as they will be on HAART or will be initiated on HAART.  As discussed earlier, 
HAART has a significant impact on reducing TB incidence and mortality.  There has been a call 
for research to see the relative risks and benefits of initiating HAART + IPT in patients with 
advanced HIV [106].  The protocol investigators therefore feel justified for randomizing this 
group to early receipt of placebo.  
 
Study data will address the research gap for HIV/TB care for pregnant women and their infants 
in TB endemic areas and provide much needed evidence to optimize policies and programs for 
these vulnerable populations. 
 
In light of the current WHO INH preventive therapy guidelines for HIV-infected persons, in 
which INH has been recommended for all HIV-infected persons, including pregnant women, the 
P1078 team resurveyed the IMPAACT sites that expressed strong interest in P1078.  All sites 
remain very interested in the study. 
 
2.0 
Study Objectives 
 
2.1 
Primary Objective 
 
To compare overall safety and toxicity of immediate versus deferred INH preventive therapy in 
HIV-infected pregnant women enrolled at ≥ 14 through ≤ 34 weeks gestation (34 weeks, 6 days) 
 
2.2 
Secondary Objectives 
 
 To compare safety and toxicity of INH in utero exposure and on infants on study 
 To compare TB incidence and all-cause mortality in HIV-infected women and their infants 
enrolled on study 
 To compare overall safety and hepatotoxicity, as well as evaluate risk factors for these 
outcomes, during pregnancy and immediate postpartum in women on immediate versus 
deferred INH therapy 
 To evaluate for INH resistance among M.tb. isolates from HIV-infected women and infants 
who develop TB while on study 
 To evaluate the intensive pharmacokinetics of INH and selected ARV drugs in a subset of 
HIV-infected pregnant and postpartum women receiving HAART 
 To evaluate and compare the performance characteristics of IGRA (TB ELISPOT and QGIT) 
with TST in HIV-infected women and their infants 
 To compare adherence in women initiating immediate versus deferred INH preventive 
therapy via self-report and pill counts 
 


 
 
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2.3 
Exploratory Objectives 
 
 To evaluate population pharmacokinetics and pharmacogenomics of INH and EFV in HIV-
infected pregnant and postpartum women 
 To assess the effects of INH preventive therapy on the functional characteristics of TB 
specific T-cell responses measured by TB ELISPOT in HIV-infected women and their 
infants on study 
 To evaluate adherence and exposure to INH and EFV using drug levels in hair and analyze 
the association between these drug levels and adverse effects 
 To compare the two arms with respect to the overall (risk:benefit) clinical outcomes of the 
mother-infant pairs 
 To explore associations of maternal and infant specific TB responses and novel biomarkers 
with risk of maternal and infant TB infection and disease 
 To explore the neurotoxicity of INH in combination with EFV in a subset of women 
 
3.0 
Study Design 
 
P1078 is a Phase IV, randomized, double-blind, placebo-controlled non-inferiority study to 
determine overall safety as well as the other risks and benefits of immediate versus deferred INH 
in HIV-infected pregnant women and their infants, enrolled at ≥ 14 through ≤ 34 weeks (34 
weeks, 6 days) gestation, at high risk for TB (i.e., reside in high TB prevalence area defined as 
having 60 TB cases per 100,000 population in the WHO TB annual report or documented local 
burden) infection and disease. 
 
Enrollment 
Week 28 Post-Entry Visit 
Week 12 Postpartum Visit 
 
ARM A 
INH 300 mg until Week 28  
Post-Entry visit 
ARM A 
Placebo for INH until Week 40  
Postpartum visit 
ARM A 
Continue current therapy 
 
OR 
 
 
 
ARM B 
Placebo for INH until Week 12  
Postpartum visit 
ARM B 
Continue current therapy 
ARM B 
INH 300 mg until Week 40  
Postpartum visit 
 
NOTE: 
- 
Week 12 Postpartum visit can occur at the same time, before, or after the Week 28 Post-Entry visit, 
depending on the gestational age at enrollment and delivery week. 
- 
Both arms will receive 28 weeks of INH 300 mg. 
 
 The basis for the non-inferiority design is the hypothesis that IPT can be safely initiated in 
HIV-infected women during pregnancy. 
 The information on the treatment regimen assigned at each of the visits shown above for each 
participant will be in a Pharmacist Prescription List generated by the DMC.  See Section 
5.1.1 for details regarding the Pharmacist Prescription List. 


 
 
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 For some participants in both arms, the study Week 28 Post-Entry visit and the Week 12 
postpartum visit will coincide.  When this occurs, mothers in both arms will have their 
therapy switched in a blinded fashion (i.e., mothers in Arm A will switch to Placebo for INH 
and mothers in Arm B will switch to INH 300 mg). 
 In addition, all women (Arm A and Arm B) will receive: 
 
Intensified TB case finding defined as eliciting a TB exposure history, WHO TB 
symptom screen (see P1078 MOP), and targeted physical exam at each study visit. 
 
Open-label Pyridoxine (vitamin B6) and prenatal multivitamin from study entry until 
postpartum Week 40 
 
Standard of care (defined as PMTCT and standard of care for HIV-infected pregnant 
women according to WHO guidelines) 
 All study-provided medications (INH or Placebo for INH) will be initiated at study entry 
within 72 hours of randomization.  Locally-obtained Pyridoxine (vitamin B6) and prenatal 
multivitamin will also be started in close proximity to INH/Placebo for INH. 
 Mother-infant pairs will be followed for 48 weeks post-delivery. 
 Infants of enrolled women will also receive standard of care according to WHO guidelines 
for HIV infection, PMTCT, and other maternal-child health measures. 
 
Sites should refer to Appendix I for a complete description of clinical and laboratory evaluations 
to be performed. 
 
3.1 
Pharmacokinetic Testing 
 
 Samples for intensive PK will be obtained at two time points in 36 women who are on 
HAART.  Only women who are at ≥ 28 weeks age of gestation at entry into the study will be 
eligible to participate in the intensive PK.  The samples will be collected from the same 
group of 36 women during the third trimester of pregnancy ≥ 2 weeks after start of 
INH/Placebo for INH and at the Week 16 postpartum visit.   
 Samples for population PK will be obtained at two time points on all women except those 
who participate in the intensive PK study.  These population PK samples will be collected 
during the third trimester of pregnancy and at the Week 16 postpartum visit. 
See Section 9.0 for the intensive PK substudy and population PK assessments.   
 
3.2 
Immunologic Testing 
 
Throughout the study, women and their infants will have several types of immunologic testing, 
including TST and IGRA (QGIT and TB ELISPOT).  Specimens will be collected, tested, and/or 
stored, as follows below.  Also note that PBMCs will be cryopreserved at selected sites and all 
QGIT will be performed in a blinded fashion (i.e., results will not be disclosed to the study 
clinical staff).  QGIT testing may be performed in real time or batch tested within 90 days of 
collection, per the QGIT manufacturer’s instructions, the P1078 MOP, and the P1078 LPC. 
 At entry, all women will have IGRA (QGIT) done and plasma stored for future tests.  QGIT 
supernatants will also be stored.  Approximately 700 women will have PBMCs stored.  
IGRA (TB ELISPOT) will be done in 460 women and the remaining samples will be stored 
for future testing. 


 
 
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 At delivery, all women will have TST performed and IGRA (QGIT) done; QGIT 
supernatants will also be stored in the first 260 women.  If TST is not obtained at the Labor 
and Delivery visit, sites may administer at the Week 4 postpartum visit. 
 At postpartum Week 12, approximately 460 women and their infants will have PBMCs 
stored for IGRA (TB ELISPOT) and will also have plasma stored for future tests.  Ideally, 
these will be the same women and infants who contributed PBMC for IGRA at entry and 
their infants, if feasible. 
 At postpartum Week 44, all women and their infants will have TST and IGRA (QGIT) 
performed and plasma stored for future tests.  QGIT supernatants will also be stored in the 
first 260 women.  Approximately 460 women and their infants will have PBMCs stored for 
IGRA (TB ELISPOT).  Ideally, these will be the same 460 women and infants who 
contributed PBMC for IGRA at entry and postpartum Week 12.  
 At postpartum Week 48, approximately 260 women will have PBMCs stored for IGRA (TB 
ELISPOT) and will also have plasma stored for future tests.  Ideally, these will be the same 
women who contributed PBMC for IGRA at entry, postpartum Week 12, and postpartum 
Week 44. 
 At the suspected active TB visit for women, IGRA (QGIT) will be performed and additional 
plasma, QGIT supernatants, and PBMCs will be obtained and stored for IGRA (TB 
ELISPOT).  At the suspected active TB visit for infants, TST will be done, as well as plasma 
and PBMC stored for future TB/HIV-related studies, for example, IGRA (TB ELISPOT).  
 
Ideally, TST should be read 2-3 days after placement.  However, it can be read by a trained 
observer up to 7 days from administration. 
 
Assays will be performed on cryopreserved PBMCs obtained from the mothers including 
IFN/IL2 ELISPOT using whole and CD8-depleted PBMC.  These assays will determine the 
relative participation of CD4 and CD8 cells and of memory cells in the IGRA result.  T cell 
activation and inflammatory biomarkers will also be studied.  Infants will have IFN/IL2 
ELISPOT performed in PBMC only. 
 
3.3 
Screening for Active TB at the Screening Visit 
 
All women will be screened for active TB using the current WHO recommended standardized 
TB symptom screen (see P1078 MOP) for any cough, fever, self-reported weight loss, or night 
sweats.  Additional questions will include failure to have adequate weight gain in pregnancy and 
duration of symptoms.  They will also have a standardized TB risk and exposure questionnaire 
administered and undergo a complete physical exam.  Any additional TB diagnostics, such as 
shielded chest radiograph, AFB culture, and/or Xpert, will be performed as per local standard of 
care or as indicated by the site investigator.  A woman who has a positive finding on the TB 
symptom screening evaluation, or is suspected or diagnosed with active TB, will be excluded 
from the study.   
 


 
 
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3.4 
Enrollment and Randomization Phase 
 
All women with a negative TB screening assessment who meet the inclusion criteria (Section 
4.1) and do not meet any exclusion criteria (Section 4.2) will be randomized either to receive 
INH within 72 hours of randomization (Arm A) or to have INH deferred to start at Week 12 
postpartum (Arm B).   
 
3.5 
Intensified TB Case Finding 
 
At every scheduled visit, a standardized TB exposure history to determine if any new known TB 
exposure has occurred since the last visit will be done.  In addition, the WHO-recommended TB 
symptom screen, other symptom assessment, and targeted physical examination will also be 
performed.  Women will be educated about the signs and symptoms of active TB and be asked to 
come to the clinic should any of the symptoms develop during the course of the study.  Infants 
born to these women will also be assessed at each visit for TB exposure and signs and symptoms 
suggestive of TB disease.  Infants may also have TST done at a suspected active TB visit.  
Ideally, TST should be read 2-3 days after placement.  However, it can be read by a trained 
observer up to 7 days from administration.   
 
3.6 
Standard of Care for Women and Infants Enrolled in the Study 
 
The best available local standard of care will be provided to women and their infants.  For 
women who develop TB, they will be referred for TB treatment according to local standard of 
care.  Infants of these mothers who develop TB will also be referred for initiation of TB 
preventive therapy as per local pediatric TB guidelines.  Infants who are suspected to have or 
who are diagnosed with TB will also be referred for TB treatment per local guidelines.  Infant 
feeding, prevention and treatment of HIV, and other co-morbidities will also be according to 
local standard of care.   
 
3.7 
Unblinding Participants 
 
Participants will be unblinded after follow-up is complete on all enrolled participants and the 
clinical and laboratory databases have been reviewed and finalized for analysis.  Once this date 
has been determined by the Protocol Team, unblinding lists for each site will be distributed as 
outlined in IMPAACT network policies.  See Section 6.1 for details on unblinding participants 
during the study. 
 


 
 
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4.0 
Selection and Enrollment of Participants 
 
4.1 
Inclusion Criteria 
 
4.1.1 Documented HIV-1 Infection 
Documentation of HIV-1 infection is defined as positive results from two samples 
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.  
 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 charts.  Source 
documentation (participant’s medical record/chart, Ministry of Health (MOH) 
registers, laboratory results, etc.) must be available if requested. 
 Sample #2 must be performed in a CAP/CLIA-approved laboratory or in a laboratory 
that operates according to GCLP guidelines, participates in appropriate external 
quality assurance program, and is approved by the IMPAACT Laboratory Center. 
 
Sample #1 may be tested using any of the following: 
 Two rapid antibody tests from different manufacturers or based on different 
principles and epitopes 
 One EIA OR Western Blot OR immunofluorescence OR chemiluminescence 
 One HIV DNA PCR 
 One quantitative HIV RNA PCR (above the limit of detection) 
 One qualitative HIV RNA PCR 
 One total HIV nucleic acid test 
 
If Sample #1 is positive, then collect and test Sample #2. 
 
Sample #2 may be tested using any of the following: 
 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. 
 One EIA OR Western Blot OR immunofluorescence OR chemiluminescence 
 One HIV DNA PCR 
 One quantitative HIV RNA PCR (above the limit of detection) 
 One qualitative HIV RNA PCR 
 One total HIV nucleic acid test 
 
4.1.2 Documented HIV treatment, according to WHO guidelines, for PMTCT and standard of 
care for HIV infection 
 
4.1.3 Pregnant females age > 18 years 
 


 
 
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4.1.4 Pregnant females between ≥ 13 and < 18 years who are able and willing to provide signed 
informed consent under local law, or pregnant females unable to consent under local law 
whose parents/legal guardians provide consent or “minimum age of consent according to 
locally applicable laws or regulations.” 
 
4.1.5 Pregnancy gestational age confirmed by best available method at site to be ≥ 14 weeks 
through ≤ 34 weeks (34 weeks, 6 days) 
 
4.1.6 Weight ≥ 35 kg at screening 
 
4.1.7 The following laboratory values obtained within 30 days prior to study entry: 
 Absolute neutrophil count (ANC) ≥ 750 cells/mm3 
 Hemoglobin ≥ 7.5 g/dL 
 Platelet count ≥ 50,000/mm3 
 AST (SGOT), ALT (SGPT), and total bilirubin ≤ 1.25 times the upper limit of normal 
(ULN) (Note: If participant is taking atazanavir, direct bilirubin may be used to 
determine eligibility.) 
 
4.1.8 Intent to remain in current geographical area of residence for the duration of the study 
 
4.2 
Exclusion Criteria 
 
4.2.1 Any woman with a positive TB symptom screen per WHO guidelines, including any one 
or more of the following: any cough, fever, self-reported weight loss, or night sweats 
(Note: If a potential participant is found to be negative for TB upon further testing, the 
participant may be re-screened for the study.) 
 
4.2.2 Any positive AFB smear, Xpert, or any other rapid TB screening test or culture from any 
site within the past 12 weeks, or chest radiograph (x-ray) with findings suggestive of 
active TB, or clinician suspects active TB 
 
4.2.3 Known exposure to AFB smear-positive active TB case within past 12 weeks prior to 
study entry 
 
4.2.4 Reported INH exposure (> 30 days) in the past year prior to study entry 
 
4.2.5 Receipt of any TB or atypical mycobacteria therapy for > 30 days in the past year 
 
4.2.6 Evidence of acute hepatitis, such as jaundice, dark urine (not concentrated urine), and/or 
acholic stools sustained for > 3 days within 90 days prior to entry (Note: A positive 
HBsAg does not exclude a participant from joining the study.) 
 
4.2.7 ≥ Grade 1 peripheral neuropathy (Note: Grading of peripheral neuropathy will be 
determined using the Brief Peripheral Neuropathy Screen (BPNS), discussed in Section 
6.1.3, Appendix II and the P1078 MOP.) 
 


 
 
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4.2.8 History of acute systemic adverse reaction or allergy to INH  
 
4.2.9 Known current heavy alcohol use (> 2 drinks per week) or alcohol exposure that, in the 
investigator’s opinion, would compromise participation and the outcome of this study 
 
4.2.10 Presence of new AIDS-defining opportunistic infection that has been treated less than 30 
days prior to study entry 
 
4.2.11 Receipt of an investigational agent or chemotherapy for active malignancy within 30 days 
prior to study entry 
 
4.2.12 Any clinically significant diseases (other than HIV infection) or clinically significant 
findings during the screening medical history or physical examination that, in the 
investigator’s opinion, would compromise participation and the outcome of this study 
 
4.3 
Concomitant Medication Guidelines  
 
To avoid adverse drug interactions, package inserts of anti-TB agents, ARTs, and other 
concomitant medications should be referred to whenever a concomitant medication is initiated or 
dose changed.  The following medications should be avoided, if possible, and alternative 
treatments sought: 
 Chronic acetaminophen (such as paracetamol) use defined as > 1 gram per day for ≥ 4 weeks  
 Chronic aminosalicyclic acid (aspirin) use defined as a dosage of  ≥ 1 tablet per day for ≥ 4 
weeks  
 Stavudine (d4T) or Didanosine (ddI) 
 Carbamazepine 
 Chlorzoxazone 
 Disulfiram 
 Ketoconazole 
 Phenytoin 
 
The list above is not exhaustive.  Participants may be on other medications not included in the 
list that may be known to result in AEs and toxicity in pregnant women.   
 


 
 
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4.4 
Screening Procedures 
 
All participants who sign the informed consent form must have a Screening Checklist entered 
and must obtain a screening number through the Data Management Center (DMC) Subject 
Enrollment System (SES). 
 
Participants who meet eligibility criteria will be randomized to the study according to standard 
data management procedures.  For all participants from whom informed consent is obtained, but 
who are deemed ineligible or who do not enroll into the protocol for any reason, a Screening 
Failure Results case report form must be completed and keyed into the database.  The screening 
failure data will be collected in accordance with the Consolidated Standards for Reporting Trials 
(CONSORT) 2010 Statement, which provides guidelines for reporting randomized controlled 
trials [107]. 
 
4.5 
Enrollment Procedures 
 
4.5.1 A Study/Site Implementation Plan (SIP) will be required from each site participating in 
the study.  The SIP will be reviewed and approved by members of the protocol team and 
sites will be notified that authorization to participate has been granted.  The SIP will 
collect data on the following issues:  
 
Laboratory capacity including TB diagnostics 
 
Enrollment and retention plans 
 
Willingness to participate in PK study 
 
Local standard of care for HIV-infected women and infants 
 
Local standard of care for active TB treatment and infant TB prophylaxis 
 
Pharmacy procedures for study drug 
 
4.5.2 Prior to implementation of this protocol, and any subsequent full version amendments, 
each site must have the protocol and the protocol consent form(s) approved, as 
appropriate, by their local institutional review board (IRB)/ethics committee (EC) and 
any other applicable regulatory entity (RE).  Upon receiving final approval, sites will 
submit all required protocol registration documents to the DAIDS Protocol Registration 
Office (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. 
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by the 
DAIDS PRO and sites will receive an Initial Registration notification from the DAIDS 
PRO that indicates successful completion of the protocol registration process.  A copy of 
the Initial Registration Notification should be retained in the site’s regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, 
sites should implement the amendment immediately.  Sites are required to submit an 
amendment registration packet to the DAIDS PRO at the RSC.  The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all the required 
documents have been received.  Site-specific ICF(s) WILL NOT be reviewed and 


 
 
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approved by the DAIDS PRO and sites will receive an Amendment Registration 
Notification when the DAIDS PRO receives a complete registration packet.  A copy of 
the Amendment Registration Notification should be retained in the site’s regulatory files. 
 
For additional information on the protocol registration process and specific documents 
required for initial and amendment registrations, refer to the current version of the 
DAIDS Protocol Registration Manual. 
 
Written informed consent must be obtained before any study-specific screening or 
enrollment procedures are performed.  The woman will be asked to read and sign the 
consent forms.  If the woman is unable to read, the process for consenting illiterate 
participants, as defined or approved by the local IRB/EC, should be followed.  After 
screening is completed and if eligibility criteria are met, the woman (and her unborn 
infant) will be enrolled and randomized into P1078. 
 
Subject enrollment is done through the DMC’s SES.  The appropriate enrollment screen 
for this component is identified as P1078.  Screening laboratory tests can be performed as 
early as 10 weeks gestation; however, where noted above in the inclusion and exclusion 
criteria, the specimens/assessments on which eligibility determination is based must be 
obtained within 30 days prior to study entry (earliest study entry is 14 weeks gestation).  
Re-assessment may be required, for example, if too much time (> 30 days) passes after 
the initial specimens/assessments were obtained. 
 
Note: Mothers and their infants are randomized at the same time, to the same study arm.  
In the case of a multiple birth, the additional infants will be manually assigned to the 
same study arm.  All infants will be followed in the same manner. 
 
4.6 
Co-enrollment Procedures 
 
Co-enrollment will be considered on a case-by-case basis.  Please contact the Core protocol 
team, impaact.corep1078@fstrf.org, for co-enrollment questions. 
 


 
 
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5.0 
Study Treatment 
 
Study treatment is defined as isoniazid (INH) and Placebo for isoniazid (INH).  Both will be 
provided through the study. 
 
Pyridoxine (vitamin B6) and prenatal MVI will not be provided through the study and will be 
obtained locally by the site. 
 
5.1 
Regimens, Administration, and Duration of Regimen 
 
Women will be randomized in a 1:1 ratio to Arm A (immediate INH then Placebo for INH) OR 
Arm B (Placebo for INH then deferred INH). 
 
Arm A  
Women in Arm A will initiate INH once daily by mouth at study entry.  After receiving 28 
(± 2) weeks of INH (i.e., Week 28 Post-Entry), women in Arm A will be switched to Placebo 
for INH.  The women in this arm will take Placebo for INH until the Week 40 postpartum 
visit (± 2 weeks). 
 
 
Arm B  
Women in Arm B will initiate Placebo for INH once daily by mouth at study entry and 
continue until the Week 12 postpartum visit (± 2 weeks).  At the Week 12 postpartum visit, 
women in Arm B will be switched to INH.  The women in this arm will take INH for 28 
weeks until the Week 40 postpartum visit (± 2 weeks). 
 
Along with either INH or Placebo for INH, all women will be on the open-label prenatal 
multivitamin once daily by mouth and pyridoxine (vitamin B6) 25 to 50 mg orally once daily, 
self-administered from entry until the Week 40 postpartum visit.  The pyridoxine dose (vitamin 
B6) may be increased up to 100 mg once daily for management of peripheral neuropathy by the 
site investigator, as described in Section 6.1.3. 
 
5.1.1 Regimen 
 
Upon randomization, a participant SID will be provided to the site (clinic) as well as the 
information necessary for the clinic to send an Entry Prescription to the Pharmacy in the P1078 
Pharmacist Prescription List. 
 
ENTRY 
 
Women in both arms will receive: 
 Prenatal multivitamins once daily by mouth until the Week 40 postpartum visit. 
 Pyridoxine (vitamin B6) 25 to 50 mg tablet orally once daily until the Week 40 postpartum 
visit. 
 


 
 
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Women will be randomized (1:1) to one of the following two arms: 
 Arm A – Immediate INH 
Women will start INH ≤ 72 hours after randomization to maintain blinding. 
 
Isoniazid (INH) 300 mg tablet once daily by mouth, self-administered for 28 (± 2) weeks 
(until the Week 28 Post-Entry visit).  
 
 Arm B – Deferred INH 
Women will start Placebo for INH ≤ 72 hours after randomization to maintain blinding. 
 
Placebo for INH tablet once daily by mouth, self-administered until the Week 12 postpartum 
visit (± 2 weeks). 
 
WEEK 28 POST-ENTRY VISIT 
 
All women (Arms A and B) must receive a new written prescription indicating “Week 28 Post-
Entry Visit” for the pharmacist to dispense the Week 28 Post-Entry visit study drugs.  Upon 
receipt of the new prescription, the site pharmacist should refer to the P1078 Pharmacist 
Prescription List to determine whether the participant should remain on the current treatment 
regimen or switch.  This P1078 Pharmacist Prescription List will be generated by the DMC in 
such a fashion as to instruct the pharmacist on the treatment regimen to dispense while at the 
same time maintaining the blinding of the clinic staff and participant. 
 Arm A 
Women will receive Placebo for INH 300 mg tablet once daily by mouth, self-administered 
until the Week 40 postpartum visit. 
 
 Arm B 
Women will not change study therapy at their Week 28 Post-Entry visit; however, to 
maintain blinding, a new prescription will be required.   
 
WEEK 12 POSTPARTUM VISIT 
 
All women (Arms A and B) must receive a new written prescription indicating “Week 12 
Postpartum Visit” for the pharmacist to dispense the Week 12 postpartum visit study drugs.  
Upon receipt of the new prescription, the site pharmacist should refer to the P1078 Pharmacist 
Prescription List to determine whether the participant should remain on the current treatment 
regimen or switch.   
 
 Arm A 
Women will not change study therapy at their Week 12 postpartum visit, unless Week 12 
postpartum visit is the same as the Week 28 Post-Entry visit (see note below).  To maintain 
blinding, a new prescription will be required. 
 
 Arm B 
Women will receive INH 300 mg tablet once daily by mouth, self-administered for 28 (± 2) 
weeks (until the Week 40 postpartum visit). 


 
 
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Note:  The Week 28 Post-Entry visit and the Week 12 postpartum visit may not necessarily occur 
in that order for each woman.  In the event that the Week 12 postpartum visit and the Week 28 
Post-Entry visit occur at the same time, the P1078 Pharmacist Prescription List will provide the 
correct instructions for the pharmacist.  The prescription list will contain the treatment regimen 
associated with the assigned SID for each woman at the following time points: Entry, Week 28 
Post-Entry visit, and Week 12 postpartum visit.  
 
It is left up to the pharmacy SOP whether a new prescription will be sent to the pharmacist at all 
other study visits except those at Entry, Week 28 Post-Entry and Week 12 postpartum.  If Week 
28 Post-Entry and Week 12 postpartum occur at the same time, both prescriptions should be sent 
to the pharmacist. 
 
Sites (clinic) will complete a multi-part case report form (CRF) that will include the following 
information: 
 Entry date (new prescription required) 
 Delivery date 
 Week 28 Post-Entry date (new prescription required) 
 Week 12 postpartum date (new prescription required) 
 
This CRF will be completed at the Entry visit, the Week 28 Post-Entry visit, and the Week 12 
postpartum visit.  A copy of this CRF will be provided to the pharmacy along with the new 
prescription at Entry, Week 28 Post-Entry, and Week 12 postpartum. 
 
5.1.2 Administration 
 
INH 300 mg one tablet or matching Placebo for INH one tablet will be administered orally once 
daily without food (1 hour before or 2 hours after meals).  
 
Pyridoxine (vitamin B6) 25 to 50 mg will be administered orally once daily with or without food.  
The pyridoxine dose (vitamin B6) may be increased up to 100 mg once daily for management of 
peripheral neuropathy by the site investigator, as described in Section 6.1.3. 
  
Prenatal multivitamins will be administered orally once daily with or without food.  
 
5.1.3 Duration 
 
Women randomized to Arm A (immediate INH) will receive INH for 28 (± 2) weeks and then 
will receive Placebo for INH until Week 40 postpartum visit (± 2 weeks).  
 
Women randomized to Arm B (deferred INH) will receive Placebo for INH until the Week 12 
postpartum visit (± 2 weeks) and then receive INH until Week 40 postpartum visit (± 2 weeks).  
 
All women in both Arm A and Arm B will receive pyridoxine (vitamin B6) and prenatal 
multivitamin until Week 40 (± 2 weeks) postpartum visit. 
 


 
 
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5.2 
Product Formulation 
 
 
INH 300 mg tablets: store at room temperature below 30°C (86°F).  Store in the original 
container.  
 
Placebo for INH tablets: store at room temperature below 30°C (86°F).  Store in the original 
container. 
 
Pyridoxine (vitamin B6) tablets must be purchased by the site locally and stored as directed 
by the manufacturer. 
 
Prenatal multivitamins must not have more than 5 mg of vitamin B6 and 400 IU of vitamin D.  
Prenatal MVI will be prescribed to women as part of standard of care and must be purchased 
by the site locally and stored as directed by the manufacturer.  All oral formulations of 
prenatal multivitamins (e.g., tablet, capsule, chewable tablet, or liquid) are acceptable for use 
in this study as long as they meet the above requirements. 
 
5.3 
Product Supply, Distribution, and Pharmacy 
 
5.3.1 Study Product Supply 
 
INH and Placebo for INH are manufactured by Macleods Pharmaceuticals Limited. 
 
Pyridoxine (vitamin B6) and prenatal multivitamins will be obtained locally by the site as part of 
standard of care. 
 
5.3.2 Study Product Acquisition and Distribution  
 
INH 300 mg and Placebo for INH tablets will be available through the NIAID Clinical Research 
Products Management Center (CRPMC).  The IMPAACT site pharmacist can obtain the study 
products for this protocol by following the instructions in the manual, Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks, in the section Study Product Control. 
 
Women will come to the clinic every four weeks and be provided sufficient number of doses of 
INH or Placebo for INH to last until the next scheduled visit.  No study products will be supplied 
after the Week 40 postpartum visit. 
 
BCG vaccination for the infant follow-up will not be provided through the study.   
 
Cotrimoxazole or ART drugs will not be provided by the study. 
 
5.3.3 Study Product Accountability 
 
The IMPAACT site pharmacists are required to maintain complete records of all study products 
received from the CRPMC and dispensed.  Non-US sites will receive instructions regarding the 
final disposition of any remaining study products.  The procedures to follow for accountability 
can be found in the manual, Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks, in the section, Study Product Management Responsibilities. 
 


 
 
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6.0 
Participant Management 
 
6.1 
Toxicity Management, Mothers 
 
Except for peripheral neuropathy and hepatotoxicity grading, which are provided in Appendix II 
and III and discussed in Sections 6.1.3 and 6.1.4, respectively, the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), 
Version 1.0, dated December 2004, Clarification August 2009, must be used for all AE grading 
and is available on the RSC website (http://rsc.tech-res.com).  Management of adverse 
experiences will be according to the local standard of care and the judgment of the site 
investigator, except when noted below. 
 
INH or Placebo for INH dose will not be reduced for toxicity; it will be continued at protocol 
specified dose, held, or discontinued.  The site investigator should attempt to confirm any Grade 
3 or greater clinical or laboratory findings as soon as possible.  Abnormal clinical and laboratory 
findings should be followed until resolution to < Grade 2. 
 
Women discontinuing study treatment will not be unblinded to their treatment unless the 
information is critical for making immediate therapeutic decisions for the participant (e.g., if 
withholding the treatment information would put the participant at risk of serious adverse events 
(SAEs) or death).  If a participant does need to be unblinded, then the site should notify the study 
Chairs and Medical Officers and, with their approval, submit a request to the DMC using the 
Unblinding Request Program on the DMC website, as outlined in IMPAACT network policies.  
See Section 3.7 for details on unblinding participants after completion of follow-up. 
 
All toxicity management questions and notifications should be emailed to the study Clinical 
Management Committee (CMC): impaact.p1078cmc@fstrf.org.  
 
All AEs identified in this study will be source documented.  Among other details, source 
documentation will include the severity of each event and its relationship to study drug 
(INH/Placebo for INH), 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. 


 
 
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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 
7.0 for more information on EAE reporting. 
 
6.1.1 General Toxicity Management, Mothers 
 
Clinical or laboratory AEs that are definitely unrelated to INH/Placebo for INH will generally 
not result in INH/Placebo for INH interruption, except as when defined below.  For women who 
are not receiving study-provided INH/Placebo for INH at the time of the event, toxicity 
management including decision about non-study drug discontinuation should be at the discretion 
of the site investigator and should be according to local standard of care.  Site investigators must 
report all SAEs to their local IRB/EC as per their guidelines.  
 
Toxicity management of Pyridoxine (vitamin B6), prenatal MVI, and/or concomitant medications 
should be managed at the discretion of the site investigator and should be according to the local 
standard of care.  As vitamin B6 is being provided to decrease the risk of peripheral neuropathy, 
potentially due to INH, it is typically expected that vitamin B6 will be held/discontinued if 
INH/Placebo for INH is held/discontinued.  Consultation with the P1078 Clinical Management 
Committee (CMC) is available but not required for questions related to vitamin B6, prenatal 
multivitamins, or concomitant medications, including ARVs. 
 
Toxicity management will be as outlined below (Section 6.1.2) for all qualifying events 
EXCEPT for the following toxicities: 
 Peripheral neuropathy (see Section 6.1.3) 
 Hepatic toxicity, with directions for asymptomatic elevations in liver enzymes and for 
symptomatic hepatitis (see Section 6.1.4) 
 
Whenever a repeat assessment reveals a toxicity of a different grade than the initial toxicity, the 
management outlined for that toxicity grade will apply unless otherwise specified.  If 
INH/Placebo for INH are restarted following a temporary hold, a repeat assessment should 
generally be done within one week, except as when defined below. 
 
Participants should be counseled and educated on side effects and risks of INH at each study 
visit, particularly related to non-specific signs or symptoms of hepatotoxicity, per site 
procedures. (See Appendix  I-A) These symptoms include new or worsening loss of appetite, 
nausea, vomiting, fatigue, yellowing of skin or eyes, and/or right upper quadrant tenderness. 
 
Inform the CMC of any maternal death while on study, regardless of attribution to INH/Placebo 
for INH, as soon as possible and within 3 days of site awareness. 


 
 
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6.1.2 Adverse events other than elevated liver enzymes (AST, ALT, total bilirubin), symptomatic hepatitis or peripheral neuropathy 
for women receiving INH/Placebo for INH 
 
GENERAL ADVERSE EVENTS 
CONDITION AND SEVERITY 
USE of INH/PLACEBO FOR INH 
FOLLOW-UP AND MANAGEMENT 
Grade 1 and 2 
Continue INH/Placebo for INH 
Follow SoE. 
 
Grade 3 (probably not or 
definitely not related to 
INH/Placebo for INH) 
Continue INH/Placebo for INH 
Confirm assessment generally within 3 working days of site awareness 
or as soon as possible.  Consultation with the CMC is available but not 
required.  
 
Grade 3 (possibly, probably, 
or definitely related to 
INH/Placebo for INH) 
Continue or hold INH/Placebo 
for INH at discretion of site 
investigator 
Confirm assessment generally within 3 working days of site awareness 
or as soon as possible.  Inform the CMC if repeat assessment confirms 
initial ≥ Grade 3. 
 
If confirmed, follow condition weekly for 21 days and then at regular 
intervals at the discretion of the site investigator until resolved. 
 
If INH/Placebo for INH was held and condition recurs after restarting 
INH/Placebo for INH, permanently discontinue INH/Placebo for INH. 
 
Grade 4 (probably not or 
definitely not related to 
INH/Placebo for INH) 
Continue or hold INH/Placebo 
for INH at discretion of site 
investigator 
Confirm assessment generally within 3 working days of site awareness 
or as soon as possible.  Inform the CMC if repeat assessment confirms 
initial ≥ Grade 4. 
 
Grade 4 (possibly, probably, 
or definitely related to 
INH/Placebo for INH) 
Hold INH/Placebo for INH 
Confirm assessment generally within 3 working days of site awareness 
or as soon as possible.  Inform the CMC if repeat assessment confirms 
initial ≥ Grade 4. 
 
If confirmed, permanently discontinue INH/Placebo for INH. 
 
 
 


 
 
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6.1.3 Peripheral Neuropathy (PN), Mothers 
 
Peripheral neuropathy is associated with the use of INH although it is uncommon at doses of 300 mg per day.  To decrease the risk of 
peripheral neuropathy, pyridoxine (vitamin B6) 25 – 50 mg will be given with each dose of INH.  Site investigators may increase 
dosing of pyridoxine (vitamin B6) up to 100 mg for management of peripheral neuropathy, as described below.  As study clinicians 
will be blinded to whether women are on INH or Placebo for INH, pyridoxine (vitamin B6) will be provided from study entry through 
the Week 40 postpartum visit to all women.  It is also recommended that concomitant stavudine (d4T) or didanosine (ddI) be avoided 
as they increase the risk of PN and are associated with other complications.  Women who are prescribed d4T or ddI should be closely 
monitored.  
 
In P1078, the Brief Peripheral Neuropathy Screen (BPNS) grading system will be used instead of the DAIDS neuropathy grading 
system; signs/symptoms should be present for at least two weeks to be considered peripheral neuropathy (see Appendix II and P1078 
MOP for additional details on how to perform the BPNS). 
 


 
 
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PERIPHERAL NEUROPATHY 
CONDITION AND 
SEVERITY 
USE of INH/PLACEBO FOR INH 
FOLLOW-UP AND MANAGEMENT 
Grade 1 
Continue INH/Placebo for INH 
Assess for other causes and follow SOE. 
 
Grade 2 
Hold INH/Placebo for INH 
Confirm assessment within 14 days. 
 
If confirmed, continue hold and follow condition as clinically indicated until 
resolved.  If condition resolves to ≤ Grade 1 within 4 weeks, INH/Placebo for 
INH may be restarted.  Continuation of vitamin B6 or increase to up to 100 mg 
once daily, and the duration, is at the discretion of the site investigator. 
 
If condition does not resolve to ≤ Grade 1 within 4 weeks, permanently 
discontinue INH/Placebo for INH and follow condition as clinically indicated 
until resolved. 
 
Grade 3 
 
Hold INH/Placebo for INH 
Confirm assessment within 14 days.  Inform the CMC if repeat assessment 
confirms initial ≥ Grade 3. 
 
If confirmed, permanently discontinue INH/Placebo for INH and follow 
condition as clinically indicated until resolved.  Continuation of vitamin B6 or 
increase to up to 100 mg once daily, and the duration, is at the discretion of the 
site investigator. 
 
 
 


 
 
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6.1.4 Hepatotoxicity, Mothers 
 
Women should be monitored for the development of non-specific prodromal signs and symptoms of hepatitis, which include 
unexplained anorexia, nausea or vomiting, right upper quadrant tenderness (i.e., liver tenderness or hepatomegaly), acholic stools, 
bilirubinuria, or jaundice, with or without initially abnormal ALT, AST, or total bilirubin.  Malaise and new or worsening fatigue are 
often common in pregnancy but should also be assessed in relation to potential acute hepatotoxicity. 
 
Clinical history and assessment for causality and confounding causes, such as concomitant prescribed medications, herbal and other 
complementary medications, alcohol, illicit drugs, over-the-counter medications, lactic acidosis syndrome, pre-eclampsia, acute fatty 
liver of pregnancy, and viral hepatitis should be undertaken in instances of suspected hepatotoxicity.  If the suspected hepatotoxicity is 
considered more likely to be due to one of these factors, standard management should be undertaken and INH/Placebo for INH may be 
restarted once the adverse events have resolved to ≤ Grade 1, in consultation with the CMC.  Reintroduction of potential hepatotoxic 
non-study concomitant medications, including ARVs, is at the discretion of the site investigator and the study participant.   
 
Management instructions for INH/Placebo for INH and for continued follow-up of adverse events related to hepatotoxicity are 
described below in the tables as follows: 
 Asymptomatic elevations in ALT, AST, and total bilirubin 
 Symptomatic hepatitis 
If a participant develops any signs or symptoms of hepatitis, management should follow the table for symptomatic hepatitis, regardless 
of ALT, AST, or total bilirubin levels. 
 
The grading criteria for hepatotoxicity assessment (i.e., AST, ALT, total bilirubin, symptoms) are shown in Appendix III and all 
abnormal liver enzymes (AST, ALT, or total bilirubin) should be followed until resolution to < Grade 1. 
 
NOTE: If a woman is on Atazanavir, then the total bilirubin thresholds described below are not diagnostic.  In lieu of total bilirubin, a 
direct bilirubin measurement will be used to assess and grade toxicity in women using Atazanavir.  Toxicity grading using direct 
bilirubin will follow the grading levels for total bilirubin in the Modified Grading Table for Hepatotoxicity (Appendix III). 
 
NOTE: For any other scenarios not described below, consult the CMC on management of INH/Placebo for INH and frequency of 
repeat assessments. 
 
 


 
 
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ASYMPTOMATIC ELEVATIONS in ALT, AST, and Total Bilirubin 
CONDITION 
AND SEVERITY 
USE of INH/ 
PLACEBO FOR INH 
FOLLOW-UP AND MANAGEMENT 
Grade 1 
Asymptomatic 
Continue INH/ 
Placebo for INH 
Assess ALT, AST, and total bilirubin and clinical assessment within 14 working days of site 
awareness.  Reinforce participant awareness and knowledge about signs and symptoms of 
hepatotoxicity. 
 
If confirmed, follow SoE. 
 
*If a participant develops any signs or symptoms of hepatitis, management should follow the 
table for symptomatic hepatitis, regardless of ALT, AST, or total bilirubin levels. 
 
Grade 2 
Asymptomatic 
 
Continue INH/ 
Placebo for INH 
Assess ALT, AST, and total bilirubin and clinical assessment as soon as possible and within 14 
working days of site awareness.  Reinforce participant awareness and knowledge about signs and 
symptoms of hepatotoxicity. 
 
If confirmed, management is at the discretion of the site investigator and should generally follow 
SoE. 
 
*If a participant develops any signs or symptoms of hepatitis, management should follow the 
table for symptomatic hepatitis, regardless of ALT, AST, or total bilirubin levels. 
 


 
 
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ASYMPTOMATIC ELEVATIONS in ALT, AST, and Total Bilirubin 
CONDITION 
AND SEVERITY 
USE of INH/ 
PLACEBO FOR INH 
FOLLOW-UP AND MANAGEMENT 
Grade 3 
Asymptomatic 
Hold INH/  
Placebo for INH 
Assess ALT, AST, and total bilirubin and clinical assessment as soon as possible and within 3 
working days of site awareness.  Inform the CMC if repeat assessment confirms initial ≥ Grade 
3.  Reinforce participant awareness and knowledge about signs and symptoms of hepatotoxicity. 
 
If confirmed, continue to hold INH/Placebo for INH.  Repeat testing weekly.   
 
If resolves to Grade ≤ 2 in ≤ 21 days, INH/Placebo for INH may be restarted and repeat testing 
should be done one week after resumption.  If ≥ Grade 3 recurs after restarting INH/Placebo for 
INH, permanently discontinue INH/Placebo for INH and follow condition as clinically indicated 
until resolved. 
 
If condition does not resolve to Grade ≤ 2 in ≤ 21 days, permanently discontinue INH/Placebo 
for INH and follow condition as clinically indicated until resolved. 
 
* If a participant develops any signs or symptoms of hepatitis, management should follow the 
table for symptomatic hepatitis, regardless of ALT, AST, or total bilirubin levels. 
 
Grade 4  
Asymptomatic 
Hold INH/  
Placebo for INH 
Assess ALT, AST, and total bilirubin and clinical assessment as soon as possible and within 3 
working days of site awareness.  Inform the CMC if repeat assessment confirms initial ≥ Grade 
4.  Reinforce participant awareness and knowledge about signs and symptoms of hepatotoxicity. 
 
If confirmed, permanently discontinue INH/Placebo for INH and follow condition as clinically 
indicated until resolved. 
 
*If a participant develops any signs or symptoms of hepatitis, management should follow the 
table for symptomatic hepatitis, regardless of ALT, AST, or total bilirubin levels. 
 
 


 
 
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SYMPTOMATIC HEPATITIS 
CONDITION AND 
SEVERITY 
USE of INH/ 
PLACEBO FOR INH 
FOLLOW-UP AND MANAGEMENT 
Signs and 
symptoms of 
hepatitis 
Hold INH/  
Placebo for INH 
Participants should be advised to immediately hold study drugs if they develop any signs or 
symptoms concerning for hepatitis: new or worsening nausea, vomiting, unexplained loss of 
appetite; yellowing of the skin or eyes; increased weakness or fatigue; pain in the upper 
abdomen (liver tenderness or hepatomegaly); pale or clay-colored stools; and/or unexplained 
weight loss.  Participants should be advised to seek immediate medical attention and contact 
the site as soon as possible. 
 
Immediately assess ALT, AST and total bilirubin; assess INR if available at the site.  Follow 
weekly until symptoms resolve.  Inform the CMC if any signs or symptoms are confirmed 
≥ Grade 3. 
- 
If ALT, AST, and total bilirubin are ≤ Grade 1, seek alternate causes of symptoms; 
INH/Placebo for INH may be restarted at discretion of site investigator. 
- 
If ALT, AST, or total bilirubin is ≥ Grade 2, permanently discontinue INH/Placebo for 
INH. 
 


 
 
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6.2 
Toxicity Management, Infants 
 
Infants of women participating in P1078 are not actively provided with study drugs but may be 
exposed to INH 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 7.0 as well as to the local IRBs/ECs, according to prevailing local law 
and Good Clinical Practices.  All protocol-specific reportable events and SAE will be recorded 
on CRFs. 
 
Laboratory normal ranges will be the institutional values.  However, if a site does not have an 
age-specific normal range/value for a particular laboratory evaluation, the site should use the 
latest edition of the Harriet Lane Handbook: a manual for pediatric house officers by Jason W. 
Custer and Rachel E. Rau-Mosby for normal ranges/values and document this for monitoring 
purposes.  Clinical management of toxicities in the infant should follow local standard of care. 
 
6.3 
Criteria for INH/Placebo for INH Treatment Discontinuation 
 
 Woman has developed active TB. 
 Woman is started on open-label INH for any reason. 
 Drug toxicity that requires permanent study drug discontinuation as defined in Section 6.1. 
 Repeat pregnancy during study follow-up, at site investigator’s discretion. 
 
In the event of treatment discontinuation, women and their infants will remain on-study but off 
study treatment for follow-up visits to complete follow-up through 48 weeks postpartum.  Sites 
should refer to Appendix I-A for a complete description of clinical and laboratory evaluations to 
be performed for participants who are off study treatment but remain on study.  
 
6.4 
Criteria for INH/Placebo for INH Treatment Re-initiation 
 
If a woman had her INH/Placebo for INH study drug discontinued because active TB was 
suspected but was subsequently determined to not have active TB, the woman will be allowed to 
have her INH/Placebo for INH study drug re-initiated if the duration of anti-tubercular therapy 
(e.g., 4-drug anti-TB treatment) is < 21 days. 
 
6.5 
Criteria for Study Discontinuation 
 
 The participant or legal guardian refuses further treatment and/or follow-up evaluations. 
 The investigator determines that further participation would be detrimental to the 
participant’s health or well-being. 
 The participant fails to comply with the study requirements so as to cause harm to 
him/herself or seriously interfere with the validity of the study results. 
 Study is cancelled at the discretion of the FDA, IMPAACT, the IRB or EC, OHRP, NIAID, 
NICHD, or other country-specific governmental agencies. 
 


 
 
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7.0 
Expedited Adverse Event Reporting  
 
7.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of AEs are outlined in Version 
2.0 of the DAIDS EAE Manual, which is available on the RSC website at: http://rsc.tech-
res.com/safetyandpharmacovigilance/manualforexpeditedreporting.aspx.  
 
The DAIDS Adverse Experience Reporting System (DAERS) 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. 
 
Sites where DAERS has not been implemented 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/expeditedreportingdaers.aspx.  For questions 
about EAE reporting, please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
7.2 
Reporting Requirements for This Study 
 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be 
used for this study. 
 
The study agents for which expedited reporting is required are: INH/Placebo for INH.  Open-
label Pyridoxine (vitamin B6) and prenatal multivitamin are not to be considered for EAE 
reporting. 
 
In addition to the SAE Reporting Category identified above, other AEs that must be reported 
in an expedited manner are: fetal deaths (of any gestational age). 
 
7.3 
Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Version 1.0, dated December 2004, Clarification August 2009, 
must be used and is available on the RSC website at http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_Pediatri
c_Adverse_Events.pdf. 
 
The Supplemental Toxicity Table for Grading Severity of ALT/AST/Total Bilirubin (Appendix 
III) and the Supplemental Toxicity Table for Grading Severity of Peripheral Neuropathy Adverse 
Events (Appendix II) will also be used.  The parameters specified in these tables supersede the 
DAIDS Toxicity Table when grading these events. 
 


 
 
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7.4 
Expedited AE Reporting Period 
 
 
The expedited AE reporting period for this study is the entire study duration for an individual 
participant (from study enrollment until study completion or discontinuation of the 
participant from study participation for any reason).  
 
After the protocol-defined 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). 
 
8.0 
Statistical Considerations 
 
8.1 
General Design Issues 
 
This is a double-blind, placebo-controlled, randomized study designed to determine the safety of 
immediate (antepartum) initiation of INH compared to deferred (postpartum) initiation of INH.  
Secondary objectives include comparisons of these two strategies with respect to maternal as 
well as infant TB incidence, mortality, and morbidity (i.e., efficacy).  Nine hundred and fifty 
mother/infant pairs will be followed from study entry during pregnancy until 48 weeks 
postpartum.  Women will be stratified by gestational age (≥ 14 - < 24 weeks versus ≥ 24 through 
≤ 34 weeks [34 weeks, 6 days]).  Due to the developing changes in WHO guidelines since 
approval of protocol Version 1.0, HAART use among HIV-infected pregnant women has 
increased over the years regardless of CD4 count status.  It is thus expected that almost all 
women enrolled in this study will be on HAART at study entry.  In light of this, HAART use has 
been removed as a stratification factor during randomization in this protocol version (Version 
2.0), but post-stratification analysis by HAART use will be performed, if feasible.  The study 
will be opened at sites in high TB prevalence (≥ 60 cases per 100,000 population/year) settings, 
as defined by the WHO TB annual report or documented local burden.   
 
The primary safety endpoint as defined in this study is the common basis for assessment of 
safety of INH preventive therapy in published studies [23].  It should be noted that since it 
depends on subjective attribution to INH/Placebo for INH, then potential bias may occur in the 
estimation of the event rates.  The use of a double-blind, placebo-controlled design will minimize 
potential bias in the comparison of rates between these arms.  Additionally, to check for bias in 
the analysis of the primary safety endpoint, a parallel analysis will be performed based on all 
Grade ≥ 3 AEs (regardless of attribution to INH/Placebo for INH). 
 
Blood samples will be obtained for IGRA (QGIT and/or TB ELISPOT) to determine latent TB 
status at entry.  Results will not be made available until the end of study to avoid introducing any 
biases into the clinical management.  However, results will be used in a supplementary analysis 
that will compare the different strategies in INH prophylaxis (pregnancy versus postpartum) on 
incident TB in IGRA-positive (strong evidence of latent TB infection) versus IGRA-negative (no 
evidence of latent TB infection) women.  TST and IGRA (QGIT) will be performed on all 
enrolled women at delivery.  The study team suspects only a negligible number of crossovers (if 
ever) among women in the deferred arm who test TST-positive at this point since everyone 


 
 
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enrolled would either already be on active INH therapy at delivery or expect to start active INH 
in 12 weeks. 
 
Sites will complete a Screening Failure Results CRF for all participants for whom informed 
consent was obtained, but who are deemed ineligible or who do not enroll into the protocol for 
any reason.  The screening failure data will be collected in accordance with the Consolidated 
Standards for Reporting Trials (CONSORT) 2010 Statement, which provides guidelines for 
reporting randomized controlled trials.  
 
8.2 
Outcome Measures 
 
8.2.1 Primary Endpoint 
 
Grade ≥ 3 AEs possibly, probably, or definitely associated with INH/Placebo for INH or 
permanent discontinuation of INH/Placebo for INH due to an adverse reaction in women after 
randomization until 48 weeks postpartum. 
 
8.2.2 Secondary Endpoints and Outcome Measures: 
 
8.2.2.1 In utero exposure and infant outcomes: 
 
 Fetal death 
 Small for gestational age 
 Premature birth (< 37 weeks gestation) 
 Low birth weight (< 2500 mg) 
 Congenital anomalies 
 Grade 3 or higher clinical or laboratory AEs (all AEs and possibly, probably, or definitely 
related to INH/Placebo for INH) 
 HIV infection 
 Hospitalization 
 
8.2.2.2 Any of the following endpoints: 
 
 Maternal TB (probable or confirmed – see Appendix 100 for definitions) 
 Infant TB (probable or confirmed, as defined in Appendix 100, and congenital TB, as defined 
using the Cantwell criteria) 
 Death of infant 
 Death of mother 
 Combined endpoint of maternal TB or maternal death 
 Combined endpoint of infant TB or infant death 
 Combined endpoint of maternal TB, maternal death, infant TB, or infant death 
 
NOTE: Appendix 100 will be the basis for adjudication of the TB endpoint by the Secondary 
Endpoint Review Committee (SERC).  Appendix 100 is available in the CRF Appendix Codes 
section of the Frontier Science IMPAACT Portal; the web link to portal is in the MOP.  Cantwell 
criteria for Congenital TB are in the MOP and will be collected on the P1078 CRF.  Separate 


 
 
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secondary analysis can be performed to evaluate alternate definitions/classifications of TB and 
will be defined prospectively if available or applied retrospectively, as far as the study data 
collection strategy allows.  (In special circumstance, a particular TB definition/classification 
introduced after the first SERC meeting could be used as the primary definition if concurred by 
the Core study team, the SERC and the DSMB and supported by existing data collection).  In 
addition, changes to the data collection form when needed to enhance data collection of a 
predefined endpoint may not require formal protocol changes. 
 
8.2.2.3 Occurrence of each of the following safety outcomes in HIV-infected women during 
pregnancy up to: (i) delivery (antepartum) and (ii) 12 weeks postpartum 
 
 Grade ≥ 3 AEs possibly, probably, or definitely related to INH/Placebo for INH or permanent 
discontinuation of INH/Placebo for INH due to an adverse event 
 Grade ≥ 3 AEs (all-cause) 
 Hepatotoxicity possibly, probably, or definitely related to INH/Placebo for INH 
 Hepatotoxicity (all-cause) 
 
Each of the definitions of hepatotoxicity will be studied: (i) having ≥ Grade 3 LFTs (ALT > 5 X 
ULN or ALT > 3 X ULN with bilirubin > 2 X ULN) or ALT > 3 X ULN with persistent, 
symptomatic clinical hepatitis); and (ii) using DAIDS grading.   
 
8.2.2.4 Resistance outcomes: 
 
 Resistance to INH in isolates of M.tb from mothers who develop culture-confirmed TB  
 Resistance to INH in isolates of M.tb from infants who develop culture-confirmed TB 
 
8.2.2.5 Intensive pharmacokinetic outcomes as specified in Section 9.2 
 
8.2.2.6 Latent TB Diagnostic Outcome Measures: 
 
 IGRA assay result (positive, negative, indeterminate) in women 
 IGRA assay result (positive, negative, indeterminate) in infants 
 TST result (positive or negative) in women; TST positive if ≥ 5 mm 
 TST result (positive or negative) in infants; TST positive if ≥ 10 mm in HIV-negative infants 
and if ≥ 5 mm in HIV-positive infants 
 
8.2.2.7 Adherence to INH/Placebo for INH among women, assessed by self-report and pill count 
 
For the self-report and pill counts, adherence will be considered as a continuous, ordinal 
categorical, or a binary variable.  When presented as a continuous variable, adherence is defined 
as the percentage of expected doses/pills taken during the entire treatment period (28 weeks).  
When presented as an ordinal variable, excellent adherence is defined as taking at least 90% of 
doses/pills during the entire treatment period; good adherence as ≥ 80% to < 90%; reasonable 
adherence as ≥ 60% to < 80%; and poor adherence as < 60% of doses, as reported in any of the 
scheduled adherence evaluations.  When presented as a binary variable (completer versus non-
completer), a completer is defined as having excellent adherence. 


 
 
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8.2.3 Exploratory Outcome Measures 
 
8.2.3.1 Population Pharmacokinetics  
 
 Primary:  Area under the plasma versus time curve (AUC) at each of two time points 
(antepartum and postpartum) in women.  
 Secondary:  Cpeak, half-life (t1/2), volume of distribution (Vd) and apparent clearance (CL/F) 
 
Pharmacogenetics 
 Presence of genetic variants to NAT2 and 2E1, PK of INH and EFV based on sparse 
sampling during pregnancy and postpartum  
 
8.2.3.2 Immunologic Outcome Measures 
 
 Functional and phenotypic characteristics of TB specific T-cell responses in women 
 Functional characteristics of TB specific T-cell responses in infants 
 
8.2.3.3 INH and EFV drugs levels in women’s hair samples; adverse events are as defined Grade 
3 or higher adverse events in women until 48 weeks postpartum 
 
8.2.3.4 An overall ordinal measure of clinical outcomes in the mother-infant pair, which assigns 
a score to the mother-infant pair according to severity of totality of clinical outcomes 
(clinical outcomes include maternal death, maternal TB, maternal safety events, infant 
death, infant TB, infant safety events); the measure will be formulated in consultation 
with the study team and details will be included in the statistical analysis plan (SAP). 
 
8.2.3.5 Maternal and infant specific TB responses and novel biomarkers 
 
 Anti-mycobacterial antibody responses in maternal plasma at all weeks when samples are 
collected 
 Anti-mycobacterial antibody responses in infant plasma at all weeks when samples are 
collected 
 Inflammation and immune activation markers (and other potential biomarkers) measured 
from maternal plasma/PBMC samples at all available time points 
 Inflammation and immune activation markers (and other potential biomarkers) measured 
from infant plasma/PBMC samples at all available time points 
 
8.2.3.6 Depression scores determined from the PHQ-9 instrument; responses to neurocognitive 
impairment questions and Pittsburgh Sleep Quality Index subset questions  
 


 
 
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8.3 
Randomization and Stratification 
 
Pregnant women who meet the eligibility criteria will be randomized 1:1 to either Arm A: 
immediate INH therapy or Arm B: deferred INH therapy.  Randomization will be done using a 
dynamic permuted block system and will be balanced by treatment arm at each site.  
 
In order to balance factors thought to be strongly associated with the primary outcome, HIV-
infected pregnant women will be stratified by gestational age in each arm as follows: 
 
Stratification Factor:  Gestational age 
Stratum a:  ≥ 14 to < 24 weeks gestational age at study entry   
Stratum b:  ≥ 24 through ≤ 34 weeks (34 weeks, 6 days) gestational age at study entry 
 
There will be no limits on the numbers of women enrolled in each stratum. 
 
8.4 
Sample Size and Accrual 
 
The study plans to enroll 950 women-infant pairs (approximately 475 women per arm) over a 
period of 96 weeks.  The primary objective is to compare the safety of using an immediate INH 
strategy versus deferred INH in HIV-infected pregnant women by estimating the absolute 
difference in the rates of the primary endpoint (Grade ≥ 3 AEs possibly, probably or definitely 
associated with INH/Placebo for INH or permanent discontinuation of INH/Placebo for INH due 
to adverse reactions) between women in the two arms of the study from the time of 
randomization to 48 weeks postpartum.  Determination of study sample size is based on absolute 
differences in rates, based on simple estimates for proportions using the normal approximation as 
shown below: 
 
 
 
 
It is anticipated that 90-100% of women enrolled will be on HAART at least during their 
pregnancy and this could contribute to the primary safety outcome measure.  Based on AEs and 
effect size information found in the literature [23, 45, 108-110], it is estimated that the true 
primary endpoint rate in the deferred INH arm (control arm) would range from about 3%-12%.  
The team agreed that non-inferiority of the immediate arm (no excess toxicity) will be concluded 
if the upper boundary of the 95% CI of the difference in rates (immediate arm rate – deferred 
arm rate) is lower than 5%.  A total sample size of 950 provides at least 90% power to conclude 
non-inferiority in an intent-to-treat analysis, assuming the true primary endpoint rate in the 
deferred arm (the control arm) is 5% and after adjusting for one interim analysis and a 10% loss 
to follow-up rate.   
 
Simulations were used to investigate power to conclude non-inferiority under varied true 
conditions of the safety parameters of interest.  5000 simulations were run with 427 (475 minus 
10% expected lost to follow-up) participants in each arm and a variety of true rates assumed for 
both the immediate and deferred arms, selected non-inferiority margins and with a type I error 
set as 100.0% - 95.0% = 5.0%.  For example, 5000 simulations were performed with the true rate 


 
 
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set to 5.0% in both arms, and with a non-inferiority margin of 5%.  From these, 5000 CIs were 
computed, with 91.6% of them having upper confidence limits below 5% (highlighted in red in 
Figure 2).  With available information on the 10% expected lost to follow-up included in the 
primary analysis (as censored data), 91.6% would be the estimated minimum power to conclude 
non-inferiority under this set of conditions. 
 
 
 
 
Using the simulation method described above, Table 1 shows the estimated power to conclude 
non-inferiority for varying true primary endpoint rates in the immediate and deferred arms, and 
for varying non-inferiority margins (expressed in terms of absolute difference in rates, which is 
the main parameter of interest). 
 
Figure 2: Predicted interval plot PA= 0.05, PB= 0.05 


 
 
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Table 1: Power Calculations* for Non-inferiority (no excess toxicity) in Primary Safety 
Endpoint 
 
True Safety Endpoint** 
Rate In Deferred Arm 
Maximum Acceptable 
True Safety Endpoint** 
Rate in Immediate Arm 
Margin for Non-inferiority 
(in terms of absolute  
difference in rates)*** 
Power for 
N=950 
3.0% 
3.6% 
0.6% 
8.3% 
4.5% 
1.5% 
26.7% 
5.4% 
2.4% 
54.4% 
6.0% 
3.0% 
72.1% 
5.0% 
6.0% 
1.0% 
10.2% 
7.5% 
2.5% 
40.0% 
9.0% 
4.0% 
75.3% 
10.0% 
5.0% 
91.6% 
7.5% 
10.3% 
2.8% 
34.3% 
11.3% 
3.8% 
55.8% 
13.5% 
6.0% 
91.2% 
15.0% 
7.5% 
98.6% 
10.0% 
12.0% 
2.0% 
17.2% 
15.0% 
5.0% 
68.5% 
18.0% 
8.0% 
97.3% 
20.0% 
10.0% 
99.8% 
12.0% 
14.4% 
2.4% 
19.3% 
18.0% 
6.0% 
76.2% 
21.6% 
9.6% 
99.1% 
24.0% 
12.0% 
>99.9% 
* Adjusted for interim analysis and 10% loss to follow-up 
**Grade ≥ 3 INH/Placebo for INH related adverse events or drug discontinuation due to adverse effects 
from randomization to 48 weeks postpartum 
***corresponds to 20%, 50%, 80% and 100% relative increase  
 
A key secondary objective is to examine efficacy of providing immediate INH compared to 
deferred INH, where efficacy is assessed in terms of development of maternal TB, infant TB, all-
cause maternal death, all-cause infant death, or any of these events.  Depending on the efficacy 
endpoint being explored, the anticipated rate in the deferred arm ranges from about 2.5% to 
12.5%.  Table 2 provides power calculations for detecting a significant decrease in the endpoint 
rate by using immediate INH under varying true rates in the deferred and immediate arms.  For 
example, if the true endpoint rate in the deferred arm is 5%, then there is about 68% power to 
detect a significant decrease in the event rate in the immediate arm if the true rate in the 
immediate arm is 2% (corresponding to an absolute decrease of 3% or a relative decrease of 
60%).  These are adjusted for one interim analysis and 10% loss to follow-up. 
 


 
 
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Table 2: Power* Calculations for the secondary Efficacy Endpoint Based on a Two-Sided 
Confidence Interval for the Difference in Proportions Between the Two Study Arms 
 
True Efficacy Endpoint Rate 
In Deferred Arm 
 
True Efficacy Endpoint Rate 
In Immediate Arm** 
(True Absolute Decrease) 
Power for 
N=950 
 
2.5% 
0.5% (2.0%) 
70.8% 
1.0% (1.5%) 
40.0% 
1.5% (1.0%) 
18.3% 
2.0% (0.5%) 
8.1% 
5.0% 
1.0% (4.0%) 
95.6% 
2.0% (3.0%) 
67.6% 
3.0% (2.0%) 
32.7% 
4.0% (1.0%) 
10.9% 
7.5% 
1.5% (6.0%) 
99.5% 
3.0% (4.5%) 
84.7% 
4.5% (3.0%) 
45.9% 
6.0% (1.5%) 
14.4% 
10.0% 
2.0% (8.0%) 
99.9% 
4.0% (6.0%) 
94.7% 
6.0% (4.0%) 
58.5% 
8.0% (2.0%) 
17.7% 
12.5% 
2.5% (10.0%) 
>99.9% 
5.0% (7.5%) 
98.1% 
7.5% (5.0%) 
68.8% 
10.0% (2.5%) 
21.6% 
* Adjusted for one interim analysis and 10% loss to follow-up 
**corresponds to 80%, 60%, 40% and 20% relative decrease 
 
Finally, for the immunology objective of assessing agreement among the different diagnostics 
tests for latent TB infection, a sample size of approximately 460 will be used.  PBMC samples 
from 460 enrolled women (PBMC collection will be site-restricted) will be obtained for TB 
ELISPOT and will be compared with the corresponding TST and QGIT results in the same 
women.  Studies report test agreement in the fair to moderate range (0.40 ≤ Kappa ≤ 0.60) 
among HIV-infected persons in low/middle income countries [111].  A sample size of 200 
participants will be needed to be able to detect agreement higher than Kappa = 0.20 with at least 
80% power using a 5% significance level, and assuming the true agreement is at least Kappa = 
0.40 and each of the tests shows a positive result on 30% of the participants.  The sample size is 
inflated to 460 to account for about 40% attrition rate due to lost or non-evaluable samples or 
participant loss to follow-up. 
 


 
 
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8.5 
Monitoring 
 
8.5.1 Routine Monitoring 
 
Routine monitoring will be done by the P1078 Core team, which consists of the study chair, 
vice-chairs, medical officers, statisticians, data manager, and the clinical trials specialists (email 
group is impaact.corep1078@fstrf.org).  All reports to team will be pooled across treatment 
arms. 
 
The study statisticians and data manager will prepare administrative reports twice a year.  These 
reports will include baseline information and will address protocol execution issues such as 
accrual, eligibility, co-enrollment, endpoint evaluability, and data completeness.  Endpoint 
reviews will be performed at least every 3 months.  An independent Endpoint Review 
Committee (assigned by the Tuberculosis Scientific Committee) will be assigned to review and 
adjudicate the primary safety endpoint, where data will be pooled across arms and no treatment 
assignment information will be provided; similarly for selected secondary endpoints.  Review of 
the primary safety endpoint will be done monthly as needed and will include all new Grade 3 or 
4 signs, symptoms, laboratory events and diagnoses, as well as deaths. 
 
The study statisticians and data managers will not report any safety data (including primary 
endpoint and aggregate data) to the study team.  However, since this study will be conducted 
under an FDA IND, the study NIH medical officer, or other NIH designee in charge of safety 
oversight and designated in the form FDA 1571, may review periodically aggregate safety data 
blinded to treatment assignment and to relationship attribution compiled by the endpoint review 
committee.  Such review (as well as other safety reviews that may be required per sponsor 
procedures) will be performed independently of the study team and will insure compliance with 
sponsor obligations for safety oversight. 
 
Accrual Rate Monitoring 
For P1078, it is expected that 950 mother-infant pairs will be enrolled over a 96-week period.  
Accrual will be reported to the protocol team and reviewed on monthly calls with the expectation 
of approximately 38-42 enrollees per month, and a target of 238 enrollments every 6 months.  
Monitoring will begin 3 months after the first site has received its site activation notice.  If the 
accrual is slower than expected or if two of the 6-month targets are missed, then a re-assessment 
of barriers to enrollment, site participation, sample size and eligibility criteria will be considered 
and suggestions of the Tuberculosis Scientific Committee and IMPAACT Network leadership 
will be solicited. 
 
8.5.2 Interim Analyses 
 
The study will be monitored by an NIAID-sponsored Data Safety Monitoring Board (DSMB).  
The DSMB reviews will address at least the following issues: 
 Administrative issues such as accrual 
 Safety of INH 
 Potential need for sample size re-assessment or futility of the study  
 


 
 
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The DSMB will review the study at least annually after the first woman is enrolled.  The number 
and timing of interim reviews will be conducted in consultation with the DSMB.   
 
At each interim DSMB-scheduled analysis of the primary safety endpoint (including the early 
safety monitoring procedure described in Section 8.5.3), repeated confidence intervals (RCIs) (or 
hypothesis tests, if applicable) with a simultaneous coverage probability of 95% will be used.  
Nominal alpha values will be based on the Haybittle-Peto spending criteria.  Based on the theory 
of repeated CIs, a 99.9% CI will be calculated for the difference in the primary safety outcome 
rates between the immediate arm and the deferred arm in each interim analysis.  If the lower 
bound of the confidence interval is greater than 5% this will constitute evidence that immediate 
INH therapy is inferior and grounds for considering stopping the study early.  If the upper bound 
of the computed interval is less than 5%, then this would suggest non-inferiority and stopping the 
trial may also be considered.  The team recommends that consideration for stopping the trial 
based on the above guidelines may be done only during a full DSMB review, and based on the 
following computed estimates:   
 Kaplan-Meier estimates at 48 weeks postpartum, where censoring occurs at the last clinic 
visit prior to loss to follow-up, death not associated with primary endpoint or permanent 
discontinuation of INH/Placebo for INH for TB preventive therapy for any reason other than 
adverse reaction to INH/Placebo for INH; estimate will be based on data from all enrolled 
women who would have reached 48 weeks postpartum at time of interim analysis; and 
 Simple proportions, restricted to those reaching 48 weeks postpartum at time of interim 
analysis. 
However, additional monitoring for safety, per Section 8.5.4, may be used.  
 
If the trial continues, the final analysis will use a 95% CI that will result in 95% simultaneous 
coverage probability. 
 
Predicted intervals (PIs) [112] will also be computed at the time of interim analysis and will be 
used to provide information regarding effect size estimates and precision. The results will be 
examined by the DSMB.  Based on the prediction of the trial results upon trial continuation, the 
DSMB may provide timely recommendations such as sample size adjustments, discontinuation 
of a treatment arm due to futility, or continuation of the trial as planned. 
 
Data on the secondary endpoints of maternal TB, maternal all-cause mortality, infant TB, infant 
all-cause mortality, or any of these endpoints may be presented to the DSMB as part of the 
interim analysis to help guide decisions on whether to continue the study or whether study 
modifications are needed. 
 
Results of an interim analysis or results from another trial may trigger a recommendation from 
the DSMB to terminate or unblind the study arms.  Please refer to the DAIDS SOP “Termination 
of a Trial or a Single Treatment Arm” for details. 
 


 
 
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8.5.3 Early Interim Analysis for Safety 
 
In collaboration with the DSMB, the following procedure will be used to monitor early safety 
data in this study: 
(a) The first analysis of primary endpoint data will take place when 25 women in the immediate 
arm have completed INH therapy or 15 endpoint events have occurred in the two arms 
combined, whichever happens earlier. 
(b) The data will consist of primary endpoint data on both arms.  
(c) Differences in the proportions of the cumulative number of events will be compared using 
Fisher’s exact test, and the analysis will also include exact confidence intervals for the 
proportions of events in the individual treatment arms.  Interpretation of the result should be 
done with caution, as the average time on INH between the two arms may (and will likely) 
not be identical at this point. 
(d) A confidence interval for the relative risk comparing the two arms will also be computed.  
Interpretation of the result should be done with caution as the constant hazard rate 
assumption may (and will likely) not be true for this comparison. 
(e) The analysis will be reviewed by a subgroup of the DSMB, including the Chair, at least one 
clinician, and at least one statistician.  The DSMB subgroup will determine whether the 
analysis warrants a full DSMB review. 
(f) After the initial analysis, the DSMB will recommend the timing of future monitoring. 
 
Since unanticipated serious adverse reactions are not expected, enrollment will continue while 
the early safety review is taking place. 
 
8.5.4 Additional Monitoring for Safety 
 
In addition to the monitoring scheme specified in this protocol, additional monitoring of safety 
data (which may include additional or revised statistical guidelines) may be implemented based 
on DSMB recommendations during the conduct of the study.  Details of such additions or 
changes will be included in the study monitoring plan. 
 
8.6 
Analyses 
 
The primary analysis will be conducted on an intent-to-treat (ITT) basis; i.e., study participants 
will be analyzed according to their assigned study arm, regardless of whether or not they took 
their assigned prophylaxis regimen.  However, given that this is a non-inferiority study, a per-
protocol analysis, which will include and compare only participants who completed the regimen 
they actually received (24 to 28 weeks of INH preventive therapy), as well as an as-treated 
analysis, which will compare participants according to actual treatment received, will also be 
performed as part of the supplementary analyses. 
 
Since standard of care is allowed to vary from site to site, supplementary analyses will consider 
site differences and their influence on the findings. 
 


 
 
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8.6.1 Primary Objective 
 
To compare overall safety and toxicity of immediate versus deferred INH preventive therapy in 
HIV-infected pregnant women enrolled at ≥ 14 through ≤ 34 weeks gestation (34 weeks, 6 days) 
 
Safety of INH will be assessed primarily by comparing rates of Grade ≥ 3 events possibly, 
probably or definitely associated with INH/Placebo for INH or permanent discontinuation of 
INH/Placebo for INH due to an adverse reaction between women in the immediate and deferred 
arms by 48 weeks postpartum.  Events, which are defined as probably not related, will be 
analyzed in the not related category.  For the primary analysis, a 95% confidence interval for the 
absolute difference in primary endpoint rates will be calculated from Kaplan-Meier curves 
stratified by gestational age.  Post-stratified analysis by HAART use will also be performed, if 
feasible.  Un-weighted (i.e., ignoring stratification by gestational age) estimates for the 
difference in rates will also be reported.  Data will be censored at the latest clinic visit when the 
endpoint status was ascertained prior to or at the earliest of the following times:  (1) date when 
lost to follow-up for any reason, (2) date of death due to reasons definitely not related to 
INH/Placebo for INH, (3) date of permanent discontinuation of INH/Placebo for INH as TB 
preventive therapy for any reason (other than an adverse reaction) including initiation of open 
label TB preventive therapy or treatment of presumed active TB disease. 
 
Sensitivity analyses will be done to assess the impact of coding deaths of unknown cause and all 
deaths as events.  Supplementary analyses will include estimation of the difference in primary 
endpoint rates between the two arms based on simple estimates of proportions stratified by 
gestational age, where strategies such as complete case analysis (only participants who 
completed study will be analyzed), worst case analysis (all cases lost to follow-up or who 
developed maternal TB coded as having reached endpoint), best case analysis (all cases lost to 
follow-up or who developed maternal TB coded as not reaching endpoint), will be considered. 
Un-weighted (i.e., ignoring stratification by gestational age) estimates for the difference in rates 
will also be reported.  Multivariate analyses to adjust for maternal characteristics such as age, 
duration on HAART, CD4 count, gestational age at study entry, IGRA positivity at study entry in 
all women, and other potential confounders such as HBsAg serology status at entry will be 
performed using logistic regression modeling. 
 
Finally, similar analyses will be performed on all Grade ≥ 3 AEs (regardless of INH/Placebo for 
INH attribution) as a way to check for bias in the primary endpoint analysis. 
 


 
 
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8.6.2 Secondary Objectives  
 
8.6.2.1 To compare safety and toxicity of INH in utero exposure and on infants on study 
 
Safety and toxicity of INH in utero exposure and on infants in the two treatment arms will be 
compared.  Specifically the proportion of infants who are small for gestational age, have low 
birth weight, congenital anomalies, Grade 3 or higher events and laboratory abnormalities, HIV 
infection status, and stillbirths (fetal death) during study participation will be compared between 
study arms.  Statistical analyses similar to that described in Section 8.6.1 will be performed for 
the comparison.  Potential confounders relevant to these in utero exposure/infant outcomes will 
be considered in the multivariate modeling. 
 
8.6.2.2 To compare TB incidence and all-cause mortality in HIV-infected women and their 
infants enrolled on study   
 
Maternal TB, maternal death, infant TB, and infant death will be analyzed separately and as 
combined events (as listed in Section 8.2.2.2).  Efficacy of INH will be assessed primarily by 
comparing event rates between women in the immediate and deferred arms by 48 weeks 
postpartum, using a 95% confidence interval for the absolute difference in event rates using 
Kaplan-Meier stratified by gestational age.  Post-stratified analysis by HAART use will also be 
performed, if feasible.  Un-weighted (i.e., ignoring stratification by gestational age) estimates for 
the difference in rates will also be reported.  Strategies for censoring will vary depending on the 
efficacy outcome of interest.  For analyses of maternal TB, any maternal death not caused by TB 
will be not be considered an event and any maternal death of unknown cause will be considered 
an event.  Similarly, for analyses of infant TB, any infant death not caused by TB will not be 
considered an event and any infant death of unknown cause will be considered an event.  
Sensitivity analysis to assess the effect of this strategy includes coding death due to unknown 
cause as a non-event. 
 
Supplementary analyses will include estimation of differences in these individual/combined 
endpoint rates between the two arms based on simple estimates for proportions, where strategies 
such as complete case analysis, worst-case analysis or best-case analysis will be considered.  
Other supplementary analysis may explore an expanded TB definition (e.g., adding “possible” 
TB as an endpoint and/or treating initiation of anti TB treatment as an endpoint).  Multivariate 
analyses to adjust for potential confounders, such as age of mother, gestational age at enrollment, 
duration on HAART of mother, CD4 count of mother, IGRA positivity of mother at study entry, 
adherence to INH, infant HIV status and breastfeeding status, whenever applicable, will also be 
performed. 
 
Additional similar analysis on these events will be performed, this time only for events up to 12 
weeks postpartum. 
 


 
 
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8.6.2.3 To compare overall safety and hepatotoxicity, as well as evaluate risk factors for these 
outcomes, during pregnancy and immediate postpartum in women on immediate versus 
deferred INH therapy 
 
A 95% confidence interval for the absolute difference in rates will be calculated from Kaplan-
Meier curves stratified by gestational age.  Post-stratified analysis by HAART use will also be 
performed, if feasible.  Un-weighted (i.e., ignoring stratification by gestational age at study 
entry) estimates for the difference in rates will also be reported.  Data will be censored at the 
latest clinic visit when the endpoint status was ascertained prior to or at the earliest of the 
following times: (1) date when lost to follow-up for any reason and (2) date of death. 
 
Supplementary analyses will include estimation of the difference in rates between the two arms 
based on simple estimates of proportions stratified by gestational age, where strategies such as 
complete case analysis, worst-case analysis and best-case analysis will be considered.  Un-
weighted (i.e., ignoring stratification by gestational age) estimates for the difference in rates will 
also be reported.  Multivariate analyses to adjust for maternal characteristics such as age, 
duration on HAART, CD4 count, INH levels in hair, gestational age at study entry, and other 
potential confounders such as HBsAg serology status at entry will be performed using logistic 
regression modeling. 
 
Endpoint rates at each pregnancy stage (second trimester, third trimester) will also be estimated; 
rates for endpoints that occurred during the second trimester will be assessed only within women 
enrolled during their second trimester of pregnancy.  Differences in rates of endpoints occurring 
during the third trimester by gestational age strata will also be assessed; similarly, for endpoints 
that occurred during the immediate postpartum period (delivery up to 12 weeks postpartum). 
 
Safety endpoint rates between the two arms will also be compared during the 28-week period 
that the participant was on INH.  These comparisons will be done using the same statistical 
methods described above. 
 
8.6.2.4 To evaluate INH resistance among M.tb. isolates from HIV-infected women and infants 
who develop TB while on study 
 
The proportion of women with culture confirmed M.tb. who have INH resistance will be 
compared between the two arms using Fisher’s exact test.  Similar comparisons will be 
performed among infants with culture confirmed M.tb.  
 
8.6.2.5 To evaluate the intensive pharmacokinetics of INH and selected ARV drugs in a subset of 
HIV-infected pregnant and postpartum women receiving HAART 
 
To evaluate whether INH affects the pharmacokinetics of selected ARV drugs in HIV-infected 
women during pregnancy and postpartum, comparison of antepartum and postpartum mean AUC 
for the ARV drugs between the selected subset of women in the immediate versus deferred arms 
will be performed using both parametric (two-sample t-test) and nonparametric (Wilcoxon rank 
sum test) methods.  Similar unpaired comparisons with respect to the additional parameters Cpeak, 
half-life (t½), volume of distribution (Vd) and apparent clearance (CL/F) will also be performed.   


 
 
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To evaluate whether pharmacokinetic parameters of INH and selected ARV drugs differ between 
antepartum and postpartum, within-subject paired comparisons of antepartum and postpartum 
mean pharmacokinetic parameters for INH (only for women in Arm A) as well as the selected 
ARV drugs among the selected subset of women will be performed when feasible.  
 
8.6.2.6 To evaluate and compare the performance characteristics of IGRA (TB ELISPOT and 
QGIT) with TST in HIV-infected women and their infants 
 
Contingency tables showing results of TST with IGRA will be constructed.  Degree of 
concordance of results between the IGRA (QGIT, TB ELISPOT) and TST tests for the women 
and their infants at week 44, and between IGRA and TST test results for the women at delivery, 
will be assessed using the Kappa measure of agreement.  Test results will also be stratified by 
HIV infection status of the infant, if there are enough data in each stratum.  Data from these tests 
will be compared by using the McNemar chi-square test. 
 
Serial TB infection status (study Entry, Labor and Delivery/Birth visits, and Weeks 12, 44, and 
48 postpartum) using QGIT and/or TB ELISPOT, as available in a subset of women and infants, 
will also be assessed using generalized linear modeling that will adjust for important covariates.  
Reversion and conversion rates will be estimated using observed proportions with corresponding 
95% exact confidence intervals. 
 
8.6.2.7 To compare adherence in women initiating immediate versus deferred INH preventative 
therapy via self-report and pill counts 
 
Proportion of women adherent to INH (completers) will be compared between the two arms via 
the two adherence measures (self-report, pill counts) using Fisher’s exact test.  Logistic 
regression of adherence to IPT will be performed, with duration on HAART at study entry as one 
of the independent variables included in the model.  Supplementary analyses will consider 
adherence as continuous or ordinal categorical variables.  When used as a continuous outcome, 
the percentage of doses/pills taken will be compared between the two arms using either Student’s 
two-sample t-test or Wilcoxon’s rank sum test, as appropriate.  Linear or quantile regression (as 
appropriate) of percentage of doses/pills taken will be performed with duration on HAART at 
study entry as one of the independent variables in the model. 
 


 
 
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8.6.3 Exploratory Objectives 
 
8.6.3.1 To evaluate population pharmacokinetics and pharmacogenomics of INH and EFV in 
HIV-infected pregnant and postpartum women 
 
Comparison of antepartum and postpartum mean AUC for EFV among women will be 
performed using methods for unpaired samples, considering both parametric (unpaired t-test) and 
nonparametric (Mann Whitney U test) methods.  Similar unpaired comparisons with respect to 
the additional parameters Cpeak, half-life (t½), volume of distribution (Vd) and apparent clearance 
(CL/F) will also be performed.   
 
DNA will be collected in all participants and banked until toxicity data are collected.  
Associations between presence of NAT2/2E1 variants, PK parameters, and INH hepatotoxicity 
will be evaluated using Fisher’s exact test based on data from a nested case-control design.  
Conditional logistic regression of INH hepatotoxicity will also be performed, with presence of 
NAT2 variants and presence of 2E1 variants as variables in the model, and adjustments for 
potential confounders will be considered. 
 
8.6.3.2 To assess the effects of INH preventive therapy on the functional characteristics of TB 
specific T-cell responses measured by TB ELISPOT in HIV-infected women and their 
infants on study 
 
Change from baseline (study entry) to selected follow-up time points (for example, 12 weeks 
postpartum and/or 44 weeks postpartum) in different functional characteristics of TB T-cell 
responses will be compared between the two arms using two-sample tests for the mean. 
 
Multiple regression analysis will also be performed to adjust for potential confounders. 
 
8.6.3.3 To evaluate adherence and exposure to INH and EFV using drugs levels in hair and to 
analyze the association between these drug levels and adverse effects 
 
INH levels will be measured in hair samples obtained throughout the study as indicated in the 
Schedule of Evaluations.  The study will assess the association of adverse effects with a 
composite measure of hair INH levels over all of each woman’s samples while on INH, as well 
as with a composite measure of hair EFV levels over all of each woman’s samples while on 
EFV, while controlling for time on INH, time on EFV, concomitant drugs including HAART, 
pregnancy status, and adherence by self-report or pill count.  The study will perform multiple 
logistic regression with Grade 3 or higher safety events as response variable and INH levels in 
hair as primary exposure variable, adjusting for potential confounders such as concomitant 
drugs/regimen including HAART, pregnancy status, and adherence by self-report or pill count. 
 
8.6.3.4 To compare the two arms with respect to the overall (risk:benefit) clinical outcomes of 
the mother-infant pairs 
 
To be specified in the statistical analysis plan (SAP) 
 


 
 
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8.6.3.5 To explore associations of maternal and infant specific TB responses and novel 
biomarkers with risk of maternal and infant TB infection and disease 
 
Maternal and infant specific TB responses or biomarkers at baseline (study entry for mothers, at 
birth for infants) will be assessed as potential correlates of maternal/infant TB infection and 
disease.  Generalized linear mixed modeling, Cox proportional hazards modeling, or Kaplan-
Meier estimation (with antibody responses or biomarkers as covariates) will be performed, 
depending on the outcome or composite outcome of interest.  A case-cohort design may be used 
to accommodate multiple outcomes of interest. 
 
Trends of antibody responses and biomarker profiles over time will also be assessed in a subset 
of mothers and infants where plasma samples are collected longitudinally. 
 
8.6.3.6 To explore the neurotoxicity of INH in combination with EFV in a subset of women  
 
Incidence rates of neurotoxicity among women on EFV will be estimated in each arm using 
Kaplan-Meier estimates with 95% confidence intervals around these rates.  The two arms will be 
compared by computing a 95% confidence interval of the difference in Kaplan-Meier estimates 
between these arms.  
 
9.0 
Clinical Pharmacology Plan 
 
9.1 
Pharmacology Objectives 
 
9.1.1 To evaluate the pharmacokinetics (PK) of INH and HAART during pregnancy and in the 
early postpartum period 
 
9.1.1.1 Intensive PK of INH/Placebo for INH during pregnancy 
9.1.1.2 Intensive PK of HAART during pregnancy 
9.1.1.3 Intensive PK of INH/Placebo for INH post-delivery (Week 16) 
9.1.1.4 Intensive PK of HAART post-delivery (Week 16) 
9.1.1.5 Population PK INH/Placebo for INH during pregnancy 
9.1.1.6 Population PK INH/Placebo for INH post-delivery (Week 16) 
 
9.1.2 To evaluate the pharmacogenomics and associated toxicities using NAT2, 2E1, and 
CYP2B6 genotypes, and relate genetic variants to the pharmacokinetics of INH (using 
sparse sampling in all women) in HIV-infected pregnant and postpartum women. 
 


 
 
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9.2 
Study Design, Modeling, and Data Analysis 
 
The overall goal of objective 9.1.1 is to determine the disposition of INH and HAART in the 
context of pregnancy and compare this to the pharmacokinetics (PK) of INH and HAART 
postpartum.   
 
Intensive PK Assessment 
 
A sufficient number of women will be enrolled to assure there are 18 evaluable women (total 
N=36) with antepartum and postpartum intensive PK assessments.  Only women who are at ≥ 28 
weeks age of gestation at entry into the study will be eligible to participate in the intensive PK.  
Each participant will be required to undergo serial pharmacokinetic sampling around 
administration of the dose of INH/Placebo for INH.  Participants should have been on 
INH/Placebo for INH at a stable dose for at least 2 weeks to assure steady-state conditions.  PK 
evaluations will occur during the third trimester of pregnancy (≥ 2 weeks after start of 
INH/Placebo for INH) during which time the greatest impact of pregnancy on drug disposition is 
likely to occur.  PK evaluations must be repeated in the same women postpartum with these 
visits occurring at the Week 16 postpartum visit (± 4 weeks).  Only women at selected sites and 
who are on stable HAART ante- and postpartum will be eligible for this set of intensive PKs. 
 
On the day of each PK evaluation, each participant must hold her dose of INH/Placebo for INH 
and come to clinic (or clinical research site (CRS) if available).  Timing of the dose should be 
scheduled so that it occurs close to 24 hours after the previous day’s dose as possible and will not 
be given until after the baseline (0 time) blood sample is collected.  HAART dosing should also 
be as close to ideal schedule as possible (e.g., every 12 or 24 hours).  HAART administration on 
the day when intensive PK sampling is scheduled should ideally occur at the same time as INH 
administration.  This assures PK sampling for both INH and HAART at appropriate times post-
dosing.  After arrival in clinic, a venous catheter will be placed in the participant’s arm vein to 
permit collection of serial blood samples.  Blood samples (4 mL each) will be collected in EDTA 
tubes prior to the dose (0 time) and then 1, 2, 4, 6, 8, and 12 hours post-dose.  It is imperative 
that the precise time of dose administration (and the time of dose administration for the two 
preceding doses) and the time for each PK blood sample collection be noted and recorded on the 
P1078 PK CRFs.   
 
Blood samples will be centrifuged at 800 G for 10 minutes and plasma will be harvested and 
aliquoted into 3 cryovials and immediately frozen at -70°C to await further processing.   
 
Due to the marginal stability of INH at room temperature, each blood sample should be 
processed within 1 hour of collection and immediately stored in the freezer.   
 
Samples will be analyzed for INH and selected ARV drugs via liquid chromatography tandem 
mass spectrometry methods within an IMPAACT-approved Pharmacology Laboratory using a 
CPQA approved analytical method.  Selection of ARV drugs for analysis will depend on 
available plasma and prioritizing of drugs will be based on which drugs a) have limited 
information in pregnancy, b) have the potential to contribute to hepatotoxicity, c) are commonly 
used among women enrolled in the intensive PK cohort, and d) are of high interest to the 


 
 
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investigators.  See the Laboratory Processing Chart (LPC) for P1078 and any related 
information, on the P1078 study site of the IMPAACT website: 
http://www.impaactnetwork.org/studies/P1078.asp.   
 
Non-compartmental PK analysis (using WinNonlin®) will be used to estimate the area under the 
plasma concentration versus time curve (AUC) during pregnancy and postpartum and other PK 
parameters as specified in 8.6.2.5.  Estimation of a 24-hour AUC (for INH and as appropriate for 
ART) will be estimated using the 0 hour concentration as also the 24-hour concentration since 
participants will be at steady-state.  Enrollment of 36 women will permit paired comparison of 
the AUC for INH in women receiving active drug antepartum versus postpartum and permit 
detection of a 40% difference in AUC; a difference deemed clinically significant.  AUC 
estimates calculated will be dose corrected since variable INH doses (based on mg/kg weight) 
are permitted by the study.  Likewise, AUC estimates for ART (12 or 24 hours depending on the 
regimen) will also be dose corrected in the event variable ART doses are administered.  The 
study is powered to determine a significant difference in INH antepartum versus postpartum as 
women may receive variable HAART regimens.  
 
The overall goal of objective 9.1.2 is to assess the relationship between genetic variants to 
NAT2, 2E1, and INH induced hepatotoxicity.   
 
NAT2 and 2E1 genotype DNA will be collected in all participants and banked until toxicity data 
are collected.  After hepatotoxicity data has been collected for the P1078 participants, women 
with hepatotoxicity and a control group of women without hepatotoxicity will be evaluated for 
the presence of NAT2 and 2E1 variants.  It is assumed that variant frequencies for NAT2 and 
2E1 range from 15 to 34 % (see Section 1.2) and INH hepatotoxicity rates are at least 10% (e.g., 
9% of participants had INH associated hepatotoxicity defined as ALT 3 X ULN with either 
bilirubin > 2 X ULN or symptoms suggestive of hepatitis or ALT or bilirubin > 5 X ULN).  
Genetic variants will also be related to INH PK exposure as determined through intensive PK 
assessments and random samples collected in all women (see Appendix I-A).  INH sampling will 
only be done once for all women during pregnancy and then only once for all women 
postpartum. 
 
Population PK Assessment 
 
All women, except those participating in the intensive PK, will be asked to provide a single 
random blood sample collected between two and twelve hours post INH/Placebo for INH dosing 
for population PK analysis and, for those women also on EFV, between ten and fourteen hours 
post-EFV dose (if not possible to collect post-EFV dose within this timeframe, collect pre-dose).  
This will be done during the third trimester (28 to 40 weeks gestation) and repeated at the Week 
16 postpartum visit.  Sample analysis will only occur at the end of the study for the women 
undergoing pharmacogenetic testing.  Population samples will be analyzed using standard 
nonlinear mixed-effect modeling techniques.  Correlations between hair concentrations of INH at 
these time points and plasma levels of INH will be performed. 
 


 
 
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Table 4:  Pharmacogenetic Subsample Proportions 
 
Number of 
cases: controls 
True proportion with 
NAT2 variants among controls 
Minimum detectable proportion 
with NAT2 variants among cases 
80:120 
5% 
18.8% 
15% 
33.1% 
25% 
45.1% 
35% 
56.1% 
60: 140 
5% 
19.6% 
15% 
34.2% 
25% 
46.5% 
35% 
57.5% 
40: 160 
5% 
21.9% 
15% 
37.2% 
25% 
49.7% 
35% 
60.8% 
 
Table 4 shows the minimum detectable proportions of women with, say, NAT2 variants among 
those with INH hepatotoxicity if comparisons were made using Fisher’s exact test with 5% 
significance level and 80% power, under varying true proportions with NAT2 variants among 
women without INH hepatotoxicity and varying ratios of controls to cases.  For example, if a 
ratio of 1.5 controls to one case (that is, 80 women with INH hepatotoxicity and 120 women 
without INH hepatotoxicity) is used and it is assumed to have 15% relative frequency with 
NAT2 variants among women without INH hepatotoxicity, then with 80% power, a difference in 
proportions between the case versus the control group can be detected if the true proportion with 
NAT2 variants among women with INH hepatotoxicity were no less than 33.1%. 
 
Genetic testing will be carried out at a selected IMPAACT laboratory.  Please refer to the LPC 
for sample processing and shipping information.  
 
10.0 
Human Subjects 
 
10.1 
Institutional Review Board and Informed Consent 
 
This protocol, the sample informed consent documents (Appendices IV-B, IV-C, and IV-D), and 
any subsequent modifications must be reviewed and approved by the IRB and/or EC responsible 
for oversight of the study.  Written informed consent must be obtained from the parents or legal 
guardians of participants who cannot consent for themselves, such as those below the legal age.  
The informed consent will describe the purpose of the study, the procedures to be followed, and 
the risks and benefits of participation.  A copy of the consent form will be given to the 
participant (or parent or legal guardian). 
 
Each site which receives US HHS funding and follows the United States Code of Federal 
Regulations Title 45-Public Welfare, Part 46-Protection of Human Subjects (also known as the 
Common Rule) should have on record at the site a plan that detects and addresses any change in 
guardianship occurring in pediatric participants and determines when a study participant must 


 
 
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have a consent process which involves a legally authorized representative (LAR) other than a 
family member with guardianship.  The plan will include how the site determines when a LAR is 
initially or no longer needed and how frequently the LAR re-signs the consent.  The plan should 
follow all national, local, and state guidelines.  The plan should be documented and filed in the 
appropriate regulatory file at the site but not submitted to DAIDS PRO.  
 
10.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will be identified only by 
a coded number to maintain participant confidentiality.  All records will be kept in a secured 
area.  All computer entry and networking programs will be done with coded numbers only.  
Clinical information will not be released without written permission of the participant, or the 
participant’s parent or legal guardian, except as necessary for monitoring by the US FDA, the 
host country regulatory authorities, the Office for Human Research Protections (OHRP), the 
NIAID, NICHD, and local IRB or EC. 
 
10.3 
Study Discontinuation 
 
The study may be discontinued at any time by the US FDA, IMPAACT Network, NIAID, 
NICHD, the IRB or EC, OHRP, or other country-specific governmental agencies as part of their 
duties to ensure that research participants are protected.   
 
11.0 
Publication of Research Findings 
 
Publication of the results of this trial will be governed by IMPAACT policies.  Any presentation, 
abstract, or manuscript will be made available for review by the sponsors prior to submission. 
 
12.0 
Biohazard Containment 
 
As the transmission of HIV and other blood borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study, as currently recommended by the Centers for Disease Control and 
Prevention and any host country public health guidelines. 
 
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) for specific instructions and to the AIDS Clinical Trials Network 
(ACTN) Guidelines for Shipment and Receipt of Category B Biological Substance Shipment and 
ACTN Instruction for Overnight Shipments documents at  
http://www.hanc.info/labs/labresources/procedures/Pages/actnShippingDemo.aspx. 
 
Infection control for active TB cases and good laboratory practices for TB isolation and storage 
of M.tb. isolates will be according to WHO guidance and best practices locally to minimize TB 
transmission. 


 
 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
 
13.0 
Reference List 
 
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70. Huang, Y., et al., Sensitive analysis of anti-HIV drugs, efavirenz, lopinavir and ritonavir, in human 
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Appendix I-A: Schedule of Evaluations for All Women 
 
 
ANTEPARTUM 
 
POSTPARTUM 
Suspected   
Active TB 3 
Early Discontinuation 
Or last study visit,  
Week 48 (± 2 wks) 4 
Screen 1 
Entry 
4 weeks after entry 
(± 2 wks) 
8 weeks after entry 
(± 2 wks) 
Every 4 weeks 
(± 2 wks) 
Labor & Delivery 2 
(+ 5 days) 
4 weeks 
(± 2 wks) 
8 weeks 
(± 2 wks) 
12 weeks 
(± 2 wks)  
16 wks  
(± 2 wks) 
Every 4 weeks 
(± 2 wks) 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical exam 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral neuropathy 
screening tool 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Obstetrical exam 8 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
Adherence training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adherence assessments and 
pill count 9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pill dispensing 10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TST assessment 11 
 
 
 
 
 
X 
X11 
 
 
 
Wk 44 
 
 
Contraceptive counseling 12 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Study medicine counseling 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation/Documentation of 
HIV infection 1 
(6 mL) 
 
 
 
 
 
 
 
 
 
 
 
 
CD4/CD8 lymphocyte subsets 13 
3 mL 
 
 
 
 
3 mL 
 
 
 
 
 
 
3 mL 
Hematology 14 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Chemistries 15 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
HIV RNA RT-PCR 16 
 
6 mL 
 
 
 
 
 
 
 
 
 
6 mL 
 
Pregnancy test 
 
 
 
 
 
 
Urine (5 mL) or serum (1 mL blood in SST or NON tube) test is acceptable.   
Only collected/performed when pregnancy is suspected or considered clinically 
indicated by the study site clinician. 
Plasma (Heparin) 17 
 
15 mL 
 
 
 
 
 
 
20 mL 
 
4 or  
20 mL 
(Wk 44) 
20 mL 
20 mL 
(Wk 48) 


 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
 
ANTEPARTUM 
 
POSTPARTUM 
Suspected   
Active TB 3 
Early Discontinuation 
Or last study visit,  
Week 48 (± 2 wks) 4 
Screen 1 
Entry 
4 weeks after entry 
(± 2 wks) 
8 weeks after entry 
(± 2 wks) 
Every 4 weeks 
(± 2 wks) 
Labor & Delivery 2 
(+ 5 days) 
4 weeks 
(± 2 wks) 
8 weeks 
(± 2 wks) 
12 weeks 
(± 2 wks)  
16 wks  
(± 2 wks) 
Every 4 weeks 
(± 2 wks) 
Viable PBMC 18 
 
from 
above 
 
 
 
 
 
 
from 
above 
 
from 
above 
from  
above 
from  
above 
Serum (SST or NON) 19 
 
1 mL 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B Surface Antigen 
(HBsAg) testing 20 
 
2 mL 
 
 
 
 
 
 
 
 
 
 
 
Interferon Gamma Release 
Assay (IGRA) and supernatant 
storage 21 
 
3 mL 
 
 
 
3 mL 
 
 
 
 
3 mL 
(Wk 44) 
3 mL 
 
Hair collection 
 
 
 
At the visits that coincide with 8 and 28 wks post-entry  
and Wks 20 & 40 postpartum 
 
 
Total Blood Volume (mL) 
excluding PK studies 
5 – 11 mL 29 mL 
2 mL 
2 mL 
2 mL 
8 mL 
2 – 3 mL 
2 – 3  
mL 
2 – 23 mL 
2 – 3 mL 
2 – 26 mL 
31 – 32 
mL 
5 – 26 mL 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
Population PK (all women 
except those participating in the 
Intensive PK) 22 
 
 
4 mL 
 
 
 
 
4 mL 
(± 4 wks) 
 
 
 
Intensive PK (0, 1, 2, 4, 6, 8, 
and 12 hrs post-dose; 4 mL at 
each time point) 23 
 
 
28 mL 
 
 
 
 
28 mL 
(± 4 wks) 
 
 
 
Blood for DNA and 
pharmacogenetic variants  
(all women) 24 
 
 
 
3 mL, at the visit that coincides with  
8 wks post-entry 
 
 
 
 
 
 
Total Blood Volume (mL)  
for PK substudies 
 
 
3 – 31 mL 
3 mL 
3 mL 
 
 
4 or 
 28 mL 
 
 
 
 


 
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For insufficient blood draws, priorities are as follows:  
 At screening: HIV test (if required), hematology, liver enzymes and other chemistries, CD4 
 At Entry and follow-up visits: 
1) Safety (liver enzymes, hematology)  
2) TB diagnostics 
3) TB immunology 
4) Pharmacokinetics  
5) Virology 
 
The volume of blood drawn shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week period. 
 
1. 
Evaluations should be completed within 30 days prior to study entry.  The screening visit may take place on the same day as the entry 
visit, as long as all screening results are obtained prior to study randomization.  If sufficient documentation of HIV status as specified 
in Section 4.1.1 is not available, HIV diagnostic testing is to be done according to the specified algorithm. 
2. 
The target visit window for the Labor & Delivery visit is up to 5 days postpartum, with an allowable visit window of up to 2 weeks.  
Every effort should be made to conduct the visit within the target visit window. 
3. 
Suspected Active TB Visits: 
Diagnosis of incident active TB will be made using definitions in Appendix 100.  A complete TB evaluation documenting recent 
exposures/ill contacts, clinical history of illness (i.e., duration of signs/symptoms), and workup performed to make diagnosis will be 
completed and samples for AFB smear(s) x 2 (induced if necessary), and/or Xpert, and/or culture(s) as well as any other TB 
diagnostics will be performed on appropriate clinical samples for any enrolled women at this visit.  Culture-confirmed M.tb. isolates 
will be stored for drug susceptibility testing.  If the woman is seen for a Suspected Active TB visit, the infant should also have a 
Suspected Active TB visit for evaluation and recommendation for TB prophylaxis care or treatment per Appendix I-B.  See P1078 
MOP for the suggested work-up for women suspected of having active TB. 
4. 
For women who permanently stop study treatment and refuse any further study follow-up, i.e., off treatment/off study, OR postpartum 
Week 48.  Women who meet a toxicity/intolerance endpoint will be considered off treatment/on study and will follow the usual 
schedule of study visits but will not undergo study procedures that are specific for women on INH/Placebo for INH (i.e., adherence 
assessment, pill count, PK samples, hematologies, chemistries) but will come in to clinic for routine evaluation and blood draws as 
scheduled (CD4, QGIT, stored sample, incident TB, and last study visit).  If a toxicity endpoint is reached, follow-up testing needs to 
be done until resolution of the toxicity (see Section 6.1 for details).  
5. 
General medical history, TB history, medications, obstetrical history, allergies, counseling on signs and symptoms of hepatitis, and 
assessment of signs & symptoms for active TB disease.  WHO clinical staging for HIV to be assessed at Screening only.  Signs and 
symptoms of neurocognitive impairment (including depression, sleep, and memory) will also be assessed at entry, every 12 weeks 
during the antepartum period, and postpartum Weeks 4, 12, 24, 36, and 48. 


 
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6. 
Complete physical exam includes vital signs (temperature, pulse, blood pressure, and respiration), assessment of general appearance, 
lymph node exam, and liver and spleen size, when feasible.  Height will be assessed at the entry visit only and weight will be 
measured at every study visit (so BMI and change in weight can be calculated).  Mid-Upper Arm Circumference (MUAC) will be 
performed at the Entry visit only (see P1078 MOP). 
7. 
Validated ACTG brief peripheral neuropathy screen will be utilized (see P1078 MOP for peripheral neuropathy screen information). 
8. 
Obstetrical exam includes gestational age assessment at the Entry visit (as defined by local investigator), fundal height, and fetal heart 
tones at all antepartum visits. 
9. 
Adherence assessments using the standardized ACTG adherence questionnaire and pill counts will be completed at each indicated 
study visit until Week 40 postpartum.  INH/Placebo for INH and pyridoxine (vitamin B6) will be assessed.  
10. 
Pill dispensing will be done up to postpartum Week 36 visit only; participants will receive study treatment until Week 40 postpartum 
only.  
11. 
Tuberculin skin testing (TST) will be performed using standardized methods (see P1078 MOP) and will be done in all women at the 
Labor & Delivery and postpartum Week 44 visits, after the blood draw for plasma and IGRA.  If TST is not obtained at the Labor & 
Delivery visit, sites may obtain at the Week 4 visit.  Ideally, TST should be read 2-3 days after placement.  However, it can be read by 
a trained observer up to 7 days from administration.  A TST is defined in women in P1078 as positive if ≥ 5 mm. 
12. 
See P1078 MOP for contraception counseling guidelines and guidance on signs and symptoms of INH side effects. 
13. 
CD4/CD8 lymphocyte subsets must be performed at DAIDS-IQA certified laboratories.  Dual platform labs only must have a WBC 
and differential to complete lymphocyte subset testing. 
14. 
Hematology assessments (complete blood count, cell differential, and platelet count) to be completed from blood collected for 
CD4/CD8 lymphocyte subsets at indicated visits and as clinically indicated. 
15. 
Liver enzyme tests will be done per the table below: 
Study Visit 
Chemistry Assessment(s) 
Targeted Women 
Screen 
AST, ALT, total bilirubin (or direct bilirubin, if on 
atazanavir), glucose, and creatinine 
All women 
Entry and all other specified 
study visits 
ALT 
All women 
As needed per Section 6.1 
AST, ALT, and total bilirubin (or direct bilirubin, if 
on atazanavir) 
Women with Grade 1 or higher ALT 
result 
16. 
Every effort should be made to avoid drawing viral load determinations within 14 days of vaccination, systemic infection, or genital 
HSV outbreak, because of the potential for a transient increase in viral load in response to vaccination or infection.  Quantitative HIV-
1 RNA PCR must be performed at DAIDS-VQA certified laboratories using a VQA/DCLOT approved method.  It is recommended 
that the same HIV RNA test be used through all protocol visits.  Note: All participants should have an Entry visit viral load.  If HIV 
viral load is completed at the Screen visit to confirm HIV infection, then that result can be used for both confirmation and Entry 
assessments. 


 
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17. 
Plasma in Heparin should be stored at the specified visits for future HIV-related and TB-related testing (e.g., baseline vitamin D 
levels; baseline immune profiles [e.g., immune activation markers] or metabolomic biosignatures among TB cases and non-cases for 
biomarker discovery; future HIV and TB studies).  Blood should ideally be drawn prior to placement of TST. 
Study Visit 
Volume 
Targeted Population 
Entry 
15 mL 
Plasma – All women 
PBMCs – Approximately 700 women.  TB ELISPOT will only be performed in 
approximately 460 women and the remaining samples will be stored for future testing 
Postpartum Week 12 
20 mL 
Plasma & PBMCs – Approximately 460 women (same women who contributed samples 
for TB ELISPOT at Entry, if feasible) 
Postpartum Week 44 
20 mL 
Plasma & PBMCs – Approximately 460 women (same women who contributed samples 
for TB ELISPOT at Entry and Postpartum Week 12, if feasible) 
4 mL 
Plasma – Remaining women  
Postpartum Week 48 
20 mL 
Plasma & PBMCs – Approximately 260 women (same women who contributed samples 
for TB ELISPOT at Entry, Postpartum Week 12, and Postpartum Week 44, if feasible) 
Suspected Active TB 
Visit 
20 mL 
Plasma & PBMCs – Women who are evaluated for suspected active TB 
18. 
TB ELISPOT will be performed on cryopreserved viable PBMCs (as described in the table above) at the end of the study.  Collection 
of PBMCs will be site restricted.   
19. 
Collect and store as indicated above and in the LPC.  This specimen will be stored for future use in TB biomarker, antibody, 
inflammation, nutrition, or other TB/HIV related studies. 
20. 
Enrollment should not be delayed until the results are available since HBsAg is not part of the inclusion or exclusion criteria.  Women 
with positive HBsAg and their infant(s) should receive best available local standard of care. 
21. 
QGIT: See the P1078 MOP and LPC for information on performing QGIT.  Testing should not be performed on participants with 
suspected or confirmed TB, if prior to the indicated visit.  At all indicated visits, QGIT will be performed in a blinded fashion in all 
women and blood should be drawn prior to TST placement, if applicable.  If results are not obtained or are indeterminate, the test 
should be repeated within 4 weeks.  Repeat tests should be minimized as much as possible to avoid interference of the TST with the 
QGIT results.  Refer to Section 3.2, the MOP, and LPC for details regarding QGIT testing. 
Study Visit 
Assessment(s) 
Targeted Women 
Entry 
Blinded QGIT, Stored QGIT supernatants 
All women 
Labor & Delivery 
Blinded QGIT 
All women 
Stored QGIT Supernatants 
Subset of 260 women, as in P1078 LPC 
Week 44 Postpartum 
Blinded QGIT 
All women 
Stored QGIT Supernatants 
Subset of 260 women, as in P1078 LPC 
Suspected TB visit 
Blinded QGIT 
Women with whom this visit is conducted 
Stored QGIT Supernatants 
Women with whom this visit is conducted 


 
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22. 
Collect during the third trimester of pregnancy and then at the Week 16 postpartum visit (± 4 weeks). 
23. 
Collect for women randomized to this collection on HAART, during the third trimester of pregnancy, and ≥ 2 weeks after start of 
INH/Placebo for INH and at the Week 16 postpartum visit (± 4 weeks). 
24. 
DNA and Pharmacogenetic variant samples will be batch shipped.


 
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Appendix I-B: Schedule of Evaluations for Infant Follow-up 
 
 
Birth 1 
(+ 5 days) 
4 Weeks 
(± 2 weeks) 
8 Weeks 
(± 2 weeks) 
12 Weeks 
(± 2 weeks) 
24 Weeks 
(± 4 weeks) 
36 Weeks 
(± 4 weeks) 
44 Weeks 
(± 2 weeks) 
Suspected 
Active TB 2 
Early 
Discontinuation  
Or last study visit, 
48 Week 
(± 2 weeks) 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
 
History 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
Hematology 5  
1 mL 
1 mL 
 
1 mL 
1 mL 
 
 
1 mL 
1 mL 
ALT 
1 mL 
1 mL 
 
1 mL 
1 mL 
 
 
1 mL 
1 mL 
HIV Nucleic Acid Test (NAT) 6 
3 mL 
 
 
 
 
 
 
3 mL 
3 mL 
TST 7 
 
 
 
 
 
 
X 
X 
 
IGRA 8 
 
 
 
 
 
 
3 mL 
 
 
Plasma 9 
3 mL 
 
 
8 mL 
3 mL 
 
8 mL 
8 mL 
 
Viable PBMC 9 
 
 
 
from 
above 
 
 
from 
above 
from 
above 
 
Hair Collection 
X 
 
 
 
X 
 
 
 
 
Total Infant Blood Volume 
8 mL 
2 mL 
0 mL 
10 mL 
5 mL 
0 mL 
11 mL 
13 mL 
5 mL 
 
For insufficient blood draws, priorities are as follows:  
1) Safety (hematology, chemistries)  
2) TB diagnostics 
3) TB immunology 
4) Virology   
 
No more than 5 mL/kg may be drawn for research purposes in a single day.  No more than 9.5 mL/kg may be drawn over any eight-week 
period. 
 


 
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1. 
The target visit window for the Birth visit through day 5 of life, with an allowable visit window of up to 2 weeks.  Every effort should 
be made to conduct the visit within the target visit window. 
2. 
Suspected Active TB Visits: 
If the infant is suspected to have active TB, if the mother is seen for a Suspected Active TB visit, or if the infant is exposed to a TB 
source case, the infant should have a Suspected Active TB visit.  Diagnosis of incident active TB will be made using definitions in 
Appendix 100.  A complete TB evaluation documenting recent exposures/ill contacts, clinical history of illness (i.e., duration of 
signs/symptoms), and TST in infants will be performed using standard algorithms and definitions.  If gastric washing is done as part of 
TB diagnosis work-up, a separate specimen should be collected and stored for future TB testing.  Culture-confirmed M. tb. isolates 
will be stored for drug susceptibility testing.  See P1078 MOP for the suggested work-up for infants suspected of having TB or 
exposed to known TB case. 
3. 
History: TB exposure, diagnoses, medications, signs and symptoms, method of infant feeding, immunization record. 
4. 
Birth Physical Exam: Birth/newborn exam, birth weight and length, gestational age, congenital abnormalities, gender and race. 
Follow-up Physical Exam: Weight, length, vital signs (temperature, heart rate, blood pressure and respirations), and examination of 
neurological status, lymph nodes, lungs and abdomen.  Collection of infant blood pressure is optional; follow local standard of care. 
5. 
Hematology: CBC with differential and platelets. 
6. 
Infant HIV infection status will be assessed by HIV nucleic acid test.  HIV DNA PCR is preferred; if not available HIV RNA PCR can 
be used.  Infants with one initial positive HIV NAT test must have a specimen drawn on a different day than the sample that originally 
tested positive to confirm the results and infection status.  Must be performed in a laboratory that operates according to GCLP 
guidelines and participates in the appropriate external quality assurance (EQA) program.  Store any remaining sample for repeat 
testing. 
7. 
The TST will be performed after the QGIT/ELISPOT assay blood draw.  Ideally, TST should be read at 2-3 days after placement.  
However, it can be read by a trained observer up to 7 days from administration.  A TST is defined as positive as ≥ 10 mm in HIV-
negative infants and as ≥ 5 mm in HIV-positive infants.  See P1078 MOP for standardized TST method. 
8. 
QGIT: blood will be drawn for QGIT prior to placement of TST (see P1078 MOP) at the Week 44 study visit.  If results are not 
obtained or are indeterminate, the test should be repeated within 4 weeks.  Repeat tests should be minimized as much as possible to 
avoid interference of the TST with the QGIT results.  Refer to the Section 3.2, the MOP, and LPC for details regarding QGIT testing.  
TB ELISPOT will be performed on stored PBMCs as described in footnote 9 below. 


 
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9. 
Plasma and PBMCs will be collected and stored at the specified visits for future HIV-related and TB-related testing (e.g., TB 
biomarker, antibody, inflammation, or nutrition studies).  Blood volumes will be according to age appropriate guidelines.  Blood 
should be drawn prior to placement of TST at the Week 44 and Suspected TB visits.  See P1078 MOP and LPC for collection, 
processing, and shipment instructions. 
Study Visit 
Targeted Population 
Birth 
Plasma – All infants  
Week 12 
Plasma and PBMCs – Infants of the approximately 460 women from whom plasma and PBMCs are collected at 
postpartum Week 12 
Week 24 
Plasma – All infants for future HIV diagnostic testing that is not done as part of local standard of care.  If HIV 
DNA PCR or HIV RNA PCR is done as part of local standard of care, the plasma will be used for other HIV or 
TB related future testing 
Week 44 
Plasma – All infants 
PBMCs – Infants of the approximately 460 women from whom PBMCs is collected at postpartum Week 44 
Suspected Active 
TB visit 
Plasma and PBMCs – Infants who are evaluated for suspected active TB 


 
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Appendix II: Brief Peripheral Neuropathy Screening (BPNS) 
 
A Brief Peripheral Neuropathy Screening will be done on all mothers at every visit while on 
study.  The screening will evaluate: 
 
1. Symptoms in the feet and legs 
2. Vibration perception through the interphalangeal bone of the great toe 
3. Deep tendon reflexes in the Achilles tendon 
 
The table below will be used to determine the grade of Peripheral Neuropathy at each visit based 
on the final BPNS score.  
 
Grading of BPNS 
Grade 
Final BPNS score 
 
0 
11 or 00 
Normal or Currently Absent 
1 
1 – 3 
Mild PN 
2 
4 – 6 
Moderate PN 
3 
7 – 10 
Severe PN 
 
Please refer to the P1078 MOP for detailed instructions on how to perform and grade the Brief 
Peripheral Neuropathy Screening.   


 
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Appendix III: Modified Grading Table for Hepatotoxicity 
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT (SGPT) 
>1.25 - ≤3 X ULN 
>3 - ≤5 X ULN 
>5 - ≤10 X ULN 
>10 X ULN 
AST (SGOT) 
>1.25 - ≤3 X ULN 
>3 - ≤5 X ULN 
>5 - ≤10 X ULN 
>10 X ULN 
Total bilirubin† 
>1.25 - ≤2 X ULN 
>2 - ≤3 X ULN 
>3 - ≤10 X ULN 
>10 X ULN 
Symptoms* 
As per DAIDS grading criteria 
† In lieu of total bilirubin, a direct bilirubin measurement will be used to assess and grade toxicity 
in women using Atazanavir.  Toxicity grading using direct bilirubin will follow the grading levels 
for total bilirubin. 
* Symptoms or signs suggestive of hepatotoxicity include unexplained anorexia, nausea or 
vomiting, liver tenderness or hepatomegaly, acholic stools, bilirubinuria, or jaundice.  Malaise 
and new or worsening fatigue are often included but are common in pregnancy.  All these 
symptoms in isolation are non-specific for hepatotoxicity but should be graded and monitored as 
per Section 6.1.4. 


 
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Appendix IV-A: P1078 Informed Consent Glossary 
 
Adherence assessment 
A way to check how well you are taking your medication 
Adherence training 
To help you correctly take your medication 
Blood Chemistries 
Blood tests that check your blood sugar and how your kidneys are working 
CBC (Hematology tests)   
A complete blood count that shows how many red and white blood cells that you 
have 
CD4 cell count 
A measure of the T-cell, a type of white blood cell in the immune system that helps 
protect the body from infections.  The test is a way of measuring how much damage 
has been done to your immune system. 
CD4/CD8 cell count 
A measure of the number of white blood cells (T-cells) in the immune system that 
fight infection.  The test shows how strong your immune system is. 
Contraceptive counseling 
Discussion of ways to help you prevent getting pregnant 
Gastric washing 
A test used to find out if the TB bacteria are present in mucous that is swallowed 
and is taken from the stomach 
Genetic testing 
Blood test to check the genes that are related to the purpose of the study 
HBV (Hepatitis B screening)  
A blood test to determine if you have the liver disease hepatitis B 
HIV Nucleic Acid Test 
A number of HIV tests that are used to identify the genetic material of the HIV virus 
(the building blocks that make up the virus) in the body, such as in the different parts 
of the blood and in tissues. 
HIV DNA PCR 
A blood test to check if the HIV virus is present in your blood 
HIV-1 RNA or HIV Viral Load 
A blood test which measures the amount of HIV in your blood 
IGRA (Interferon Gamma 
Release Assay) 
Special blood tests for tuberculosis.  The tests are used to check if you may have 
TB.  They are also used to check if you have the TB bacteria even if you are not 
feeling sick (or the TB bacteria are asleep). 
Liver enzymes  
Blood tests that check how your liver is working 
M. tb. 
Mycobacterium tuberculosis, the bacteria that causes Tuberculosis or TB 
M. tb. smear  
A test for tuberculosis, that uses some of the mucous you can cough up, to 
determine if you have tuberculosis (TB) 
PK (Pharmacokinetics) 
     - Population PK 
     - Intensive PK 
Blood tests to measure medication levels 
     - In a specific group of people taking the same medication 
     - Over a certain time period 
Suspected TB visit 
A visit that will be done if you may have tuberculosis (TB) 
TST (Tuberculin skin test)  
A test placed on the skin of your arm using a small needle that can help determine if 
you have been exposed to tuberculosis (TB) 
Note: This glossary should be given to each individual who is considering participating in the 
study along with the informed consent.


 
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Appendix IV-B: Sample Informed Consent 
 
DIVISION OF AIDS (DAIDS) 
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS 
NETWORK (IMPAACT) 
 
SAMPLE INFORMED CONSENT 
 
P1078: A Phase IV Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Safety 
of Immediate (Antepartum-Initiated) Versus Deferred (Postpartum-Initiated) Isoniazid 
Preventive Therapy Among HIV-infected Women in High TB Incidence Settings 
 
SHORT Name: “TB APPRISE” Stands for TB Ante vs. Postpartum Prevention with INH in HIV 
Seropositive mothers and their Exposed infants 
 
SHORT TITLE FOR THE STUDY: P1078: TB APPRISE 
 
Version 2.0, dated 28 October 2015 
 
INTRODUCTION 
 
You and your baby are being asked to take part in this research study because you are infected 
with HIV (the virus that causes AIDS) and you are pregnant.  You live in an area where an 
infection called tuberculosis (TB) is common, and are not taking anti-TB drugs.  You do not 
have active TB.  This study is sponsored by the National Institutes of Health (NIH) in the United 
States.  The investigator in charge of this study at this site is: (insert name of Principal 
Investigator).  Before you decide if you want to be a part of this study, we want you to know 
about the study. 
 
This is a consent form.  It gives you information about this study.  The study staff will talk with 
you about this information.  You are free to ask questions about this study at any time.  If you 
agree to take part in this study, you will be asked to sign this consent form.  You will be offered 
a copy to keep. 
 
There is a separate list of special words used in this consent form, and the list includes an 
explanation of the words.  A copy of the list will be given to you by the study staff to help you 
understand the special words in this consent form.  
 
WHY IS THIS STUDY BEING DONE? 
 
The main reason for this study is to see if INH (Isoniazid, a medication commonly used to treat 
or prevent TB) is safe in HIV positive pregnant and postpartum (after delivery) women.  We 
want to see if INH protects pregnant women and their babies from getting TB.  This study will 
also try to find out if starting INH during pregnancy is as safe as waiting until after delivery for 
your newborn baby.  There have been many studies of INH in HIV positive people but few in 
pregnant and postpartum women.  This study will also try to find out other ways to diagnose TB 


 
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in both mothers and their babies; it will look at how INH can affect the way the immune system 
reacts to TB or the TB vaccine, Bacille Calmette-Guérin (BCG) and will check INH levels in 
mothers’ blood. 
 
The study medication used in this study is an anti-TB medication called isoniazid or INH.  INH 
has been used for treatment and for preventing TB since the 1950s.  It has been well studied in 
adults with and without HIV; however, there are limited data for the use of INH in pregnancy, 
particularly when used in combination with HAART.  INH is associated with side effects such as 
damage to your liver, nerve problems in your hands and feet (called peripheral neuropathy), and 
in rare instances can cause death.  Being pregnant or having recently delivered may increase 
some of these side effects.  Close monitoring of participants on INH will reduce the risk of 
adverse side effects, which will be done in this study, but it is important to know that these side 
effects can occur.  The vitamins used in this study are prenatal multivitamins and pyridoxine 
(called vitamin B6).  This study will provide the study medication, multivitamins, and pyridoxine 
(vitamin B6) to you.  During this study, you will continue your anti-HIV therapy, however the 
anti-HIV medications will not be provided by the study.  You will need to continue to obtain 
them from your primary care doctor as you have been doing. 
 
HIV positive people have a weakened immune system, they are less able to fight tuberculosis 
(TB) infection and are more likely to develop active TB.  As a result, the current World Health 
Organization (WHO) guidelines are recommending that all children and adults living with HIV, 
including pregnant women, those receiving antiretroviral treatment (ART), and living in areas 
where there is a high rate of TB should take INH prevention therapy.  The recommendation is 
that INH should be taken for 6 to 36 months or as a life-long treatment in settings where HIV 
and TB are very common.  Additionally, HIV infected people who may have TB symptoms 
should be tested for active TB or other conditions so that they are able to access the appropriate 
treatments. 
 
Based on the WHO recommendations, your primary care doctor no longer needs to do a 
Tuberculin Skin Test (TST) to check if you have been exposed to TB before starting you on an 
INH regimen.  Since the current recommendation for INH treatment during pregnancy is based 
on information learned before the time of HIV and use of anti-HIV medications, the correct time 
to start INH in pregnant women is not included in these new WHO recommendations because 
this information is not known.  There is also no information at this time on how safe INH is for 
pregnant women, especially pregnant women who are also taking anti-HIV medications.  This 
study has been developed to try to answer the following important questions: 
 
 How safe is INH in HIV infected pregnant and postpartum women? 
 What are the bad and good effects of INH given at the same time as anti-HIV medications on 
HIV infected pregnant and postpartum women? 
 What is the best time to start INH in HIV infected pregnant and postpartum women? 
 Will INH protect HIV infected pregnant women and their babies from getting TB? 
 How safe is INH in the unborn and newborn baby if INH is given to HIV infected pregnant 
women? 
 


 
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To make the answers to these questions easier to find in this study, participants will be assigned, 
by chance, to either a group receiving INH during pregnancy as per WHO recommendations, or 
a group receiving INH only after 12 weeks after the delivery of the baby.  In other words, there is 
a 1 in 2 chance (or 50%) that the INH treatment you get will not follow the WHO 
recommendations.  All women are expected to receive at least 6 to 7 months of INH by the end 
of their participation in the study.  However, INH/Placebo for INH may need to be stopped 
earlier if you experience any severe side effects.  Your doctor will discuss this with you. 
 
It is important that you understand that even if you choose not to participate in this study, you 
can still be treated with INH if your primary care doctor says you need to, or if advised by your 
country/local public health office, or if after knowing of these new WHO recommendations you 
decide that is what you want to do.  You will get INH the same way you get other medicines 
from your primary care doctor. 
 
WHAT DO I AND MY BABY HAVE TO DO AS PART OF THIS STUDY? 
 
After you have read and signed this consent form, you will have a screening visit to see if you 
can be in the study. 
 
Screening Visit: 
[Sites: add local information regarding how long the screening visit will take.] 
 
The purpose of screening is to see if you are eligible for the study, including screening to see if 
you have active TB.  If you do not have active TB, you may be able to take part in the study.   
 
If you do have active TB, you cannot be in the study, but you will be referred to your primary 
care doctor so that you can receive the care that you need.   
 
You will have the following done at the screening visit: 
 
Your medical history: You will be asked to answer many questions.  These questions will be 
about your medical history in general, your pregnancy, your medical history as related to TB, 
how you have been feeling for the past 30 days, medications you are taking now, medications 
you have taken in the past, and your lowest ever CD4 cell count (the number of a type of 
white blood cells that helps protect the body from infections).  You will also be asked if you 
had close contact in the last few weeks with someone who is confirmed to have active TB.  
You may also be asked questions about your sexual history and any drug and alcohol use.  
Any information provided about drug usage will not be shared with law enforcement. 
 
Counseling about signs and symptoms of INH side effects 
 
A physical exam:  This will include weight, tests for nerve problems in your hands and feet 
(peripheral neuropathy), and an exam for pregnant women (obstetrical exam).  You will also 
be educated about the signs and symptoms of active TB and be asked to come in for a visit if 
any of the symptoms of active TB develop during the study. 
 
Blood tests: About 5 mL (1 teaspoon) of blood will be taken from a vein for routine safety 
tests (Complete Blood Count or CBC, blood chemistries and liver enzymes, and to measure 
the number of white blood cells that fight infection or CD4/CD8 cell count).  


 
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 
A confirmation of your HIV infection:  We may also take up to 6 mL of blood to test you to 
confirm your HIV status. 
 
You will be told the results of these blood tests as soon as they are available.  
 
If you do not enroll into the study: 
If you do not take part in this study for any reason, we would still like to use some of your 
information.  As part of the screening visit, some demographic (such as age, gender, race), 
clinical (such as disease condition, diagnosis), and laboratory (such as CD4 cell count) 
information will be collected so that IMPAACT researchers may help find out if there are 
patterns or common reasons why people do not join a study.  
 
If you are eligible and decide to enroll in the study, you will have an entry visit within a month 
after screening.   
 
Enrollment and Follow-up Visits: 
You will be randomized (like the flip of a coin) to have an equal chance of starting INH 
immediately or waiting until 12 weeks after you deliver your baby to start INH.  If you are not 
randomized to start INH immediately, you will start a placebo (a tablet that looks like INH but 
does not have any real medicine in it) and will be switched to INH 12 weeks after you deliver.  If 
you are randomized to INH immediately, you will receive it for 28 weeks and then switch to 
Placebo for INH.  You and the site staff will not know at which point you are receiving INH or 
Placebo for INH while you are in the study.  This means you and the site staff are “blinded” to 
the treatment.  All pregnant women entering the study will receive INH or Placebo for INH once 
a day until their baby is born.  All women will receive INH or Placebo for INH up to 40 weeks 
after delivery, and then be followed in the study for 8 more weeks after finishing the study 
medication.  
 
In addition to receiving INH or Placebo for INH, you will also be given vitamin B6 and prenatal 
multivitamins to be taken by mouth once a day until 40 weeks after your baby is born. 
 
You will come to the clinic about every 4 weeks while you are in the study.  The study staff will 
let you know about how long the study visits and procedures will take.  The study staff will also 
let you know if you need to come back to the clinic for additional visits to complete all of the 
study evaluations.  This study has up to 21 visits for some women.  
 
If you have any problems or have any new signs or symptoms, you should call the study 
investigator as soon as possible.  The study staff will tell you about some of the specific risks 
from INH or Placebo for INH in the sections below.  The study staff will also tell you what you 
should do if you develop any signs or symptoms from INH toxicity.   
 


 
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Table 1 
 
Entry 
Every 4 Weeks 
Before Delivery 
Labor & 
Delivery 
Every 4 Weeks 
After Delivery 
Sick Visit 
Final Visit 
History and review of medications 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
Obstetrical Exam 
X 
X 
 
 
 
 
Peripheral Neuropathy Exam 
X 
X 
X 
X 
X 
X 
Pill Dispensing  
X 
X 
X 
X 
 
 
Pill Count 
 
X 
X 
X 
X 
X 
Adherence Assessment 
 
X 
X 
X 
X 
X 
CBC 
 
 
X 
 
 
 
CD4/CD8 
 
 
X 
 
 
X 
Viral Load 
X 
 
 
 
X 
 
Liver Enzymes 
X 
X 
X 
X 
X 
X 
 
 
At your entry visit you will have: 
[Sites: add local information regarding how long the entry visit will take]. 
 
The examinations and tests shown in Table 1 under the column “Entry.”  
 
As part of your medical history, you will be asked to complete a questionnaire about any 
symptoms of depression or problems you may have with sleep, memory, or ability to focus.  
Your doctor will review your answers to this survey with you. If you have any signs or 
symptoms of depression or problems with sleep, memory, or ability to focus, or you would 
like to speak to someone about how you are feeling, your doctor will refer you to care 
according to local standards of care.  You will also be asked to complete this questionnaire 
every 12 weeks before your delivery and at your week 4, 12, 24, 36, and 48 visits after you 
deliver your baby. 
 
A physical exam, including height (at entry visit only).  
 
Adherence training. 
 
Counseling about signs and symptoms of INH side effects. 
 
Blood tests – Up to about 29 mL (about 6 teaspoons) of blood will be taken from a vein: 
 
About 10 mL (2 teaspoons) will be for the tests in Table 1 and Hepatitis B (HBV) 
screening.  Note: The site investigator will receive the results of the Hepatitis tests and 
will discuss the results with you. 
 
About 3 mL (a little more than ½ teaspoon) will be for a first type of Interferon Gamma 
Release Assay (IGRA) test (a special TB test).  This test will be done in all women.  If 
there are no results from the test, you will be asked to come back within 4 weeks to 
repeat the test. 
 
About 15 mL (3 teaspoons) will be used for the following tests: 
 For all women, a portion of the blood will be stored for future tests. 
 For around 460 women from selected sites, another portion of the blood will be used 
for a second type of IGRA test. 
 For an additional group of around 240 women from selected sites, another portion of 
the blood will be stored for future tests. 
Note: There are 2 types of IGRA tests that will be used for this study, and both are 
special TB tests.  All women will have the first type of IGRA test.  The second type of 
IGRA test will only be done in some women throughout the study.  The IGRA tests are 
for investigation only and have not been confirmed for pregnant women and adults with 
HIV.  Because the tests are for investigation only, you or the site investigator will not be 


 
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told of the results. 
The site investigator may ask you to come back to the clinic sooner than your next visit if any 
of your laboratory results are abnormal. 
 
Every 4 weeks before delivery you will have: 
[Sites: add local information regarding how long the visits will take]. 
 
The examinations and tests shown in Table 1 under the column “Every 4 Weeks Before 
Delivery.” 
 
Counseling about signs and symptoms of INH side effects. 
 
Blood tests – About 2 mL (less than ½ teaspoon) will be taken from a vein for the tests in 
Table 1. 
The site investigator may ask you to come back to the clinic sooner than your next visit if any 
of your laboratory results are abnormal. 
 
At your labor and delivery visit you will have: 
[Sites: add local information regarding how long the visit will take]. 
 
The examinations and tests shown in Table 1 under the column “Labor & Delivery.” 
 
Counseling about signs and symptoms of INH side effects. 
 
Blood tests – About 5 mL (1 teaspoon) of blood will be taken from a vein for the tests shown 
in Table 1. 
 
A Tuberculin Skin Test (TST) will also be done.  A trained clinic staff member will try to 
read the test ideally within 2-3 days but up to 7 days afterwards.  The staff will try to read the 
test while you are in the hospital after delivery.  You may have to return to the clinic within 7 
days after the TST was placed if your doctor says you can go home before the test is read.  If 
you do not have a TST test done at your labor and delivery visit, you will have a TST test 
done at your Week 4 postpartum visit. 
 
About 3 mL (a little more than ½ teaspoon) of blood will be taken for an IGRA test (the same 
IGRA test that was done at entry).  This will be done in all women. 
The site investigator may ask you to come back to the clinic sooner than your next visit if any of 
your laboratory results are abnormal. 
 
Study visits after you have your baby: 
[Sites: add local information regarding how long study visits will take]. 
After you have your baby, you will come to the clinic every 4 weeks for 48 weeks (about 1 year).  
At each visit you will have: 
 
The examinations and tests shown in Table 1 under the column “Every 4 Weeks After 
Delivery.” 
 
Blood tests – About 2 mL (less than ½ teaspoon) will be taken from a vein for the tests 
shown in Table 1. 
 
Contraceptive counseling and counseling about signs and symptoms of INH side effects. 
 
You may also be asked to give an additional 1 mL of blood or a urine sample to test for 
pregnancy if you, the site investigator, or nurse think(s) you may be pregnant. 
 
At 12 weeks after delivery, around 460 women (the same 460 women who had the second 
type of IGRA test at entry) will have 20 mL (4 teaspoon) of blood taken for another IGRA 
test and a portion stored for future tests.   
 
In addition, at 44 weeks after you have your baby you will have: 


 
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 
A TST will be done.  You will need to return to the clinic ideally within 2-3 days, but up 
to 7 days, afterwards so the TST can be read by a trained clinic staff. 
 
About 3 mL (a little more than ½ teaspoon) of blood will be taken for the first type of 
IGRA test.  If there are no results from the test, you will be asked to come back within 4 
weeks to repeat the test.  
 
In addition, about 4 – 20 mL (a little less than 1 teaspoon – 4 teaspoons) of blood will be 
taken for the following tests: 
 For around 460 women (the same 460 women who had the second type of IGRA test 
at entry and 12 weeks after having their baby), 20 mL (4 teaspoons) of blood will be 
taken.  A portion of the blood will be stored for future tests and another portion will 
be used for the second type of IGRA test. 
 If you are not part of the group of 460 women, 4 mL of blood (a little less than 1 
teaspoon) will be taken and will be stored for future tests.    
The site investigator may ask you to come back to the clinic sooner than your next visit if any of 
your laboratory results are abnormal. 
 
Sick Visit (Suspected Active TB Visit): 
If you or the site investigator thinks you may have TB at any time during the study, you will 
have the examinations and tests listed under sick visit in Table 1 under the column “Sick Visit.”   
 
In addition, you will have: 
 
A physical and, if you are pregnant, obstetrical exam. 
 
Counseling about signs and symptoms of INH side effects. 
 
You may also be asked to give an additional 1 mL of blood or a urine sample to test for 
pregnancy if you, the site investigator, or nurse think(s) you may be pregnant. 
 
Blood tests – About 31 mL (about 7 teaspoons) of blood will be taken from a vein: 
 
About 8 mL (about 2 teaspoons) will be for the tests shown in Table 1. 
 
About 3 mL (a little more than ½ teaspoon) of blood will be taken for the first type of 
IGRA test. 
 
About 20 mL (4 teaspoons) will be used for the following tests: 
 A portion of the blood will be stored for future tests. 
 Another portion of the blood will be used for the second type of IGRA test.   
 
Samples will also be taken for an M. tb.  (Mycobacterium tuberculosis, the bacteria that 
causes Tuberculosis or TB) smear to check if you have TB and a test to check what 
medications will work for your TB.   
 
Other tests may be done if the site investigator feels they are needed to diagnose TB. 
 
At your early discontinuation or last study visit you will have: 
The examinations and tests shown in Table 1 under the column “Final Visit.” 
 
Contraceptive counseling and counseling about signs and symptoms of INH side effects. 
 
Blood tests – About 5 mL (1 teaspoon) of blood will be taken from a vein for the tests shown 
in Table 1. 
 
At the last study visit or 48 weeks after delivery, around 260 women (the same women who 
had the second type of IGRA test at entry, 12 weeks after having their baby and 44 weeks 
after having their baby) will have 20 mL (4 teaspoon) of blood taken for another IGRA test 
and a portion stored for future tests.   


 
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 
You may also be asked to give an additional 1 mL of blood or a urine sample to test for 
pregnancy if you, the site investigator, or nurse think(s) you may be pregnant. 
 
Intensive Pharmacokinetics (PK) (about 36 women are needed for this special study): 
There is a special PK study (and a separate consent for it) that requires about 28 mL (a little less 
than 6 teaspoons) of blood and 12 hours of your time.  This special PK study will be done two 
times, one while you are pregnant and the other after you have your baby.  The tests will measure 
the amount of INH and the amount of some anti-HIV medications in your blood over a specific 
time period.  You must be at least 28 weeks pregnant when you enter this study to be able to 
participate in the special PK study.  Please ask the site investigator, if you are interested in this. 
 
 
The first blood sample will be taken at a scheduled visit when you are in your third trimester 
of pregnancy.   
 
The second blood sample will be taken at a scheduled visit about 16 weeks after your baby is 
born. 
 
Population Pharmacokinetics (PK) (done for all women except those that will be in the Intensive 
PK): 
You will have two blood samples taken and stored to be used later for a population PK test, one 
while you are pregnant and the other after you have your baby.  The sample will be taken at a 
time point at least 2 hours but not more than 12 hours after you receive INH or Placebo for INH. 
If you are taking the medicine efavirenz (EFV), the sample will be taken at a time point at least 
10 hours but no more than 14 hours after you have taken EFV.  The site staff will let you know 
when this sample will be taken.  You may be asked to remain in the clinic or return later in the 
day to have this blood sample taken.  The amount of blood that will be taken for both PK 
samples is about 4 mL (a little less than 1 teaspoon).  These tests will measure the amount of 
INH in your blood. 
 
 
The first blood sample will be taken at a scheduled visit when you are in your third trimester 
of pregnancy.   
 
The second blood sample will be taken at a scheduled visit about 16 weeks after your baby is 
born. 
 
Not all the blood will be tested.  The test will only be done on the samples from women who 
have some liver damage while in the study and on about the same amount of samples from a 
group of women who do not get liver damage while in the study (or the same women who will 
have the genetic testing that is described next).  The samples that will be tested will be chosen 
after the study is completed.  You or the site investigator will not be told the results because the 
test is for investigation only and will be done after the study is completed. 
 
Blood for genetic testing (done for all women): 
You will have about 3 mL (a little more than ½ teaspoon) of blood taken about 8 weeks after you 
enter the study for a test to check the genes that are related to what we are looking at in this 
study.  The blood will be stored, and the test will be done at the end of the study.  Not all the 
blood will be tested.  The test will be done on the samples from women who get some liver 
damage while in the study.  The test will also be done on about the same amount of samples from 


 
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women who do not get liver damage while in the study.  The samples that will be tested will be 
chosen after the study is completed.  You or the site investigator will not be told of the results 
because the test is for investigation only and will be done after the study is completed. 
 
Study visits for baby(ies) born to mom in the study: 
 
Table 2 
 
Birth 
4 weeks 
8 weeks 12 weeks 24 weeks 36 weeks 44 weeks 
Sick 
Visit 
Final 
Visit 
History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
X 
 
X 
X 
 
 
X 
X 
Liver Enzymes 
X 
X 
 
X 
X 
 
 
X 
X 
HIV Nucleic 
Acid Test 
X 
 
 
 
 
 
 
X 
X 
 
Your baby will be seen for the visits shown in Table 2 until you (mother) complete the 48 weeks 
on study after you have your baby.  These visits will be at the same time as yours and will be 
scheduled at the same time as your well-baby visits as much as possible.  At each scheduled 
visit: 
 
Your baby will have the examinations and tests shown in Table 2 under the column for each 
specific visit. 
 
You will be asked questions about your baby’s TB exposure, signs and symptoms that may 
mean your baby has active TB, medications, other current illnesses you have and how you 
feed your baby.  You will also be asked questions about how your baby is doing. 
 
Your baby will have blood tests – About 2 mL - 11 mL (less than ½ teaspoon to a little more 
than 2 teaspoons) of blood will be taken for: 
 
About 2 mL - 5 mL (less than ½ teaspoon to 1 teaspoon) will be for the tests at Birth, 4 
weeks, 12 weeks, and 24 weeks that are shown in Table 2.  If the result of the HIV 
Nucleic Acid Test (NAT) test at birth shows that the HIV virus is present in your baby’s 
blood, the test will be repeated on a different day to confirm the result. 
 
At birth and 24 weeks, about 3 mL (a little more than ½ teaspoon) will be for future HIV 
and TB testing if it is needed.  If future HIV testing is not needed, the blood will be used 
for other future HIV or TB related tests. 
 
At 44 weeks, about 3 mL (a little more than ½ teaspoon) will be for the first type of 
IGRA test. 
 
In addition, at 44 weeks your baby will have a TST.  Your baby will need to return to the 
clinic ideally within 2-3 days but up to 7 days afterwards so the TST can be read by a trained 
clinic staff. 
 
At 12 weeks, the babies of around 460 women (the 460 women who have the second type of 
IGRA test at entry and 12 weeks after having their baby) will have 8 mL (a little more than 1 
½ teaspoon) of blood taken for the second type of IGRA and a portion will be stored for 
future tests. 
 
At 44 weeks, an additional 8 mL (a little more than 1 ½ teaspoon) of blood will be taken and 
used for the following tests: 
 
For all babies, a portion of the blood will be stored for future HIV and TB tests. 


 
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 
For the babies of around 460 women (the 460 women who have the second type of IGRA 
test at entry, 12 weeks after having their baby and 44 weeks after having their baby), 
another portion of the blood will be used for the second type of IGRA test. 
NOTE: The IGRA tests used in this study are for investigation only and have not been 
confirmed for children and babies.  Because the tests are for investigation only, you or the 
site investigator will not be told of the results. 
 
No more than 13 mL (about 3 teaspoons) of blood will be taken from your baby for any of the 
visits in the study. 
 
Sick Visit (Suspected Active TB Visit) for the baby: 
If you or the site investigator thinks your baby may have TB at any time during the study, your 
baby will have the examinations and tests listed under “Sick Visit” in Table 2.  The following 
will also be done during the sick visit: 
 
You will be asked questions about your baby’s TB exposure, signs and symptoms that may 
mean your baby has active TB, and other current illnesses that your baby may have. 
 
Blood tests – About 13 mL (about 3 teaspoons) of blood will be taken from a vein: 
 
About 5 mL (1 teaspoon) will be for the tests shown in Table 2. 
 
About 8 mL (a little less than 2 teaspoons) will be used for the second type of IGRA test 
and will be stored for future tests. 
 
A TST will be done.  Your baby will need to return to the clinic ideally within 2-3 days but 
up to 7 days afterwards so the TST can be read by a trained clinic staff. 
 
Additional tests as needed to confirm that your baby has TB.  If a mucous sample is not 
available from your baby, a test called gastric washing may have to be done.  The test will 
check if there are any M. tb. bacteria in a sample of liquid taken from your baby’s stomach.  
The site investigator can explain how the test is done. 
 
If the M. tb. bacteria are found in a sample or samples taken from your baby, it will be used 
for a test to check what medications work with your baby’s TB. 
 
Other tests may be done if the site investigator feels it is needed to diagnose TB. 
 
If you (mother) have a sick visit because you may have TB, your baby will also have a sick visit 
to check if your baby may have TB.  If you (mother) have been started on anti-TB medications 
because you may have TB or your baby had confirmed contact with someone who may have TB, 
your baby will also have a sick visit to check if your baby may have TB.   
 
Hair collection: 
With your permission, a small sample of hair (about 100 strands) will be cut from your and your 
baby’s heads so that so that we can measure levels of INH and some anti-HIV medications in 
this small hair sample.  Your hair will be cut at 8 and 28 weeks after you enter the study and at 
20 and 40 weeks after your delivery.  Your baby’s hair will be cut at birth and 24 weeks after 
birth.  Drug levels in hair may give us a better idea of long-term exposure to a drug.  Please note, 
humans lose about 100 hairs from their head every day naturally, so this amount of hair removal 
should not be noticeable.  You or the site investigator will not be told the results of this test 
because the test is for investigation only and will be done after the study is completed. 
 


 
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You will be asked if you agree to have your and your baby’s hair collected when you sign this 
consent form.  If you do not agree to have you and your baby’s hair collected, or you change 
your mind later, you can still participate in this study. 
 
Specimen storage and future use for mother and baby: 
With your permission, some of your and your baby’s blood will be stored as described in 
previous sections of this consent form.  In addition, any leftover or unused samples that are taken 
for the tests in this study may also be stored after the tests are done instead of being destroyed.  
All the samples that will be stored may be used for future IMPAACT-approved HIV-related and 
TB-related research studies.  There will be no information that directly identifies you or your 
baby on the blood samples that will be stored.  The samples may be sent to the US or any of our 
approved IMPAACT partners for storage and testing.  You will not be told the results of these 
tests because they will be done in the future.    
 
Your and your baby’s samples may be stored at a special laboratory facility in the US called a 
repository.  Only approved researchers will have access to them.  People who work at the facility 
will also have access to your and your baby’s samples to keep track of them.  These people will 
not have information that directly identifies you or your baby.  Your and your baby’s samples 
will not be sold or directly used to produce commercial products.  All proposed research studies 
using your and your baby’s samples will be reviewed by the National Institutes of Health (NIH).  
There is no time limit on how long your or your baby’s samples will be stored.  
 
The researchers will not contact you or your baby’s primary care doctor with the results of 
studies done using your or your baby’s stored samples.  This is because research studies are often 
done with experimental procedures or may be done several years after the study has ended.  The 
results of such studies should not be used to make decisions about you or your baby’s medical 
care.  If the researchers decide that the result of a certain study provides important information 
for your or your baby’s medical care, the site investigator will be notified.  If you would like to 
be contacted with this sort of information, you must notify the study staff of any changes in your 
address or phone number.  
 
You will be asked if you agree to have your and your baby’s samples stored when you sign this 
consent form.  You may decide that you do not want your or your baby’s samples stored for 
future research studies.  You and your baby can still participate in this study even if you make 
this decision.  You may withdraw your consent for the storage and use of your or your baby’s 
samples at any time.  If you withdraw your consent, these stored samples will be destroyed. 
 
OTHER INFORMATION 
 
Information provided throughout this study about sexual history and any drug and alcohol use 
will not be shared with parents or caretakers of adolescent participants. 
[Sites should modify the preceding language about confidentiality of sexual activity and any 
drug and alcohol use to conform to their local practice, regulations and IRB/EC requirements.] 
 


 
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HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 950 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 48 weeks after you have 
your baby. 
 
Your baby will be in this study for about 48 weeks.  
 
WHY WOULD THE SITE INVESTIGATOR TAKE ME/MY BABY OFF THIS STUDY 
EARLY? 
 
The site investigator may need to take you or your baby off the study early without your 
permission if: 
 
The study is cancelled by the US Food and Drug Administration (FDA), IMPAACT 
Network, National Institute of Allergy and Infectious Diseases (NIAID), National Institute of 
Child Health and Human Development (NICHD), 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 or your baby are not able to attend the study visits as required by the study. 
 
The site investigator may also need to take you off the study medication without your permission 
if: 
 
You are diagnosed with TB disease or TB infection. 
 
Continuing the study medication may be harmful to you or your baby. 
 
You start taking the anti-TB medication INH that is provided outside of the study. 
 
You or your baby need(s) a treatment that you or your baby may not take while on the study 
medication. 
 
You are not able to take the study medication as required by the study. 
 
You become pregnant. 
 
You experience some severe side effects from the study medication. 
 
During the study: 
If you must permanently stop taking study-provided anti-TB medication (INH), prenatal 
multivitamins, and vitamin B6 before your study participation is over, the study staff will discuss 
other options that may be of benefit to you or your baby.  The site investigator may ask you and 
your baby to continue to be part of the study and return for some study visits and procedures. 
 
After the study: 
If continuing to take these or similar medications or vitamins would be of benefit to you, the 
study staff will discuss how you may be able to obtain them. 
 


 
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WHAT ARE THE RISKS OF THE STUDY? 
 
Side effects of INH  
There may be an increase in some liver function tests indicating that there may be some damage 
to the liver.  The risk may also be increased during pregnancy and within three months after you 
give birth.  The risk may also be more serious or more common if you are receiving antiretroviral 
medications for HIV, if you already have some liver damage, if you drink alcohol regularly, if 
you are older, or if you are using injection drugs.   
 
Signs of liver problems may include: loss of appetite, weight loss, nausea (feeling sick to the 
stomach) and vomiting; pain in upper abdomen; stools lighter in color; increased weakness and 
fatigue; and/or yellowing of eyes or skin.  Other signs of liver problems may include: changes in 
the color of urine; loose or watery stools; skin rash; or fever.   
 
These side effects are usually temporary.  However, in rare cases, liver damage from INH can be 
very serious or even cause death.   
 
PLEASE NOTE: If you experience any of these symptoms, immediately stop taking INH or 
Placebo for INH, seek immediate medical attention, and contact the site investigator as soon as 
possible. 
 
INH can sometimes cause nerve damage.  Signs of nerve damage may include tingling and 
numbness in the hands and feet.  This is the most common side effect. 
 
Other side effects may include: memory loss, confusion, trouble sleeping, changes in behavior or 
mood, changes in vision, clumsiness, unsteadiness or dizziness, seizures, low blood counts, high 
blood sugar, joint pain, and lower vitamin B6 levels.  (Vitamin B6 is a vitamin that helps with 
many functions in your body.) 
 
Some medications used to treat TB may also cause diarrhea (loose or watery bowels), including 
bloody diarrhea, which may be serious. 
 
Side Effects of Placebo for INH 
Placebo for INH side effects may include mild nausea and the feeling of being sick to your 
stomach. 
 
Tuberculosis 
If you develop or your baby develops TB, you and your baby will be followed as part of clinical 
care.  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.  
 
There is a risk of resistance to INH and that this anti-TB medication may not work as well, if you 
do develop TB. 
 


 
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Risks of Blood Draws 
In this study, there are risks from drawing blood.  You or your baby may feel some discomfort 
when blood is drawn for this study.  Other risks may include bleeding, bruising, and swelling or 
a small blood clot may form where the needle enters the body.  There is a small risk of a minor 
infection where the needle for blood drawing enters the body.  In rare cases lightheadedness or 
fainting can occur. 
 
Other risks 
There may be other risks to taking part in this study that are not known at this time.  For your and 
your baby’s safety, you must tell the site investigator or nurse about all medications you and 
your baby are taking/getting 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 site investigator or nurse before you or your 
baby enrolls in any other clinical trials while on this study. 
 
If you join this study, some hospital staff and all study staff will know that you have HIV.  These 
workers are very serious about your privacy (see CONFIDENTIALITY).  Study staff will make 
every possible effort to be sure that others do not learn your HIV status.  However, sometimes if 
you receive special treatment or attend a special clinic, it may make others wonder if you have 
HIV. 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known if the anti-TB medication (INH) may harm unborn babies.  After you have your 
baby, you must agree not to become pregnant again, while taking INH or Placebo for INH.  You 
and your partner must use reliable birth control that you discuss with the site investigator and/or 
the study staff.   
 
You must continue to use the birth control until 1 month after stopping the anti-TB medication.  
 
Breastfeeding 
If you are breastfeeding your baby, he or she can get some of the anti-TB and multivitamin 
medicines that you are taking from the breast milk.  It is unknown whether the anti-TB 
medication may cause harm to your baby. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your and your baby’s personal information confidential.  We cannot 
guarantee absolute confidentiality.  Your and your baby’s personal information may be disclosed 
if required by law.  Any publication of this study will not use your and your baby’s name or 
identify you and your baby personally. 
 
Your records and your baby’s records may be reviewed by the US 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, and host country regulatory authorities. 


 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
 
A description of this clinical trial will be available on ClinicalTrials.gov as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will 
include a summary of the results.  You can search this website at any time. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you and your baby take(s) part in this study, there may be a direct benefit to you and your 
baby, but no guarantee can be made.  Taking an anti-TB medication like INH may be of benefit 
to you and your baby.  Taking a prenatal multivitamin and 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 you and your baby may receive no benefit from being in this study.  
Information learned from this study may help others who have HIV. 
 
WHAT OTHER CHOICES DO I/DOES MY BABY HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
Continuing standard of care for you and your baby. 
 
Treatment with other anti-TB medications available to you or your baby, if necessary.  INH 
is an option in addition to other anti-TB medications. 
 
Treatment with experimental drugs, if you or your baby qualify. 
 
Please talk to the site investigator about these and other choices available to you and your baby.  
The site investigator will explain the risks and benefits of these choices. 
 
[Note: For sites where INH is routinely provided to HIV-infected pregnant women, please 
complete the SIC addendum in Appendix IV-D.] 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company.  In some 
cases, it is possible that your insurance company will not pay for these costs because you and 
your baby are taking part in a research study.   
[Sites: modify or delete language regarding insurance as appropriate for your site and insert 
appropriate language for local costs] 
 
WILL I RECEIVE ANY PAYMENT? 
 
You and your baby may receive reimbursement for some expenses for this study.  You and/or 
your baby may receive payment for transportation or meals.  [Site-specific-TBD] 
 
WHAT HAPPENS IF I AM/MY BABY IS INJURED? 
 
If you and/or your baby are 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 


 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
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 take part/not to allow 
your baby to take part in this study or leave this study/take your baby out of the study at any 
time.   
 
Your decision will not have any impact on your or your baby’s participation in other studies and 
will not affect your access to medical care.  We will tell you about new information from this or 
other studies that may affect your or your baby’s health, welfare, or willingness to stay in this 
study.  If you want the results of the study, let the study staff know. 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
name of the investigator or other study staff 
 
telephone number of above  
 
For questions about your or 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 P1078 – Version 2.0 
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28 October 2015 
SIGNATURE PAGE   
 
If you have read this consent form (or had it read and explained to you), all of your questions 
have been answered, and you agree for you and your baby to take part in this study, please 
indicate your choices and sign your name below. 
 
A parent or legal guardian that agrees for a minor pregnant woman to take part in the study and 
signs below also agrees and signs for the newborn infant to participate in the study. 
 
Stored specimens, including blood, plasma, and serum: 
____ Yes ____ No You agree to the storage and use of your stored specimens and your baby’s 
stored specimens for future tests as discussed in this consent form, 
including genetic testing.  
 
_____ Yes ____ No You agree to the storage and use of your stored specimens and your baby’s 
stored specimens for future tests as discussed in this consent form, 
EXCEPT for genetic testing. 
 
Hair: 
____ Yes ____ No You agree to the storage and use of your and your baby’s hair as discussed 
in this consent form. 
 
 
 
Participant’s Name (print) 
 
 
 
Participant’s Signature and Date 
Participant’s Legal Guardian (print)  
(As appropriate) 
 
 
 
Legal Guardian’s Signature and Date 
Study Staff Conducting  
Consent Discussion (print) 
 
 
 
Study Staff’s Signature and Date 
Witness’s Name (print) 
(As appropriate)  
 
 
 
Witness’s Signature and Date 
Father’s Name (if reasonably available) 
 
 
Father’s Signature and Date  
(if reasonably available) 
 
 
 


 
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Appendix IV-C: Pharmacokinetic Analysis of Isoniazid (INH) Intensive Pharmacokinetic 
Subset Consent 
 
PHARMACOKINETIC ANALYSIS OF ISONIAZID (INH) 
 
INTENSIVE PHARMACOKINETIC SUBSET CONSENT 
 
P1078: A Phase IV Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Safety 
of Immediate (Antepartum-Initiated) Versus Deferred (Postpartum-Initiated) Isoniazid 
Preventive Therapy Among HIV-infected Women in High TB Incidence Settings 
 
SHORT Name: “TB APPRISE” Stands for TB Ante vs. Postpartum Prevention with INH in HIV 
Seropositive mothers and their Exposed infants 
 
SHORT TITLE FOR THE STUDY: P1078: TB APPRISE 
 
Version 2.0, dated 28 October 2015 
 
WHY IS THIS STUDY BEING DONE? 
 
You have agreed to be in a study to see if the anti-TB medication Isoniazid (INH) may prevent 
you and your (unborn) baby from becoming ill or infected with tuberculosis (TB).  To help us 
determine whether or not the INH dose that you are taking makes a difference in the amount of 
illness you or your baby has, you will have repeat blood samples taken while you are pregnant 
and after you have your baby, to measure the amount of INH in your blood.  This is called a 
pharmacokinetics or PK study.   
 
WHAT DO I HAVE TO DO TO TAKE PART IN THIS INTENSIVE PHARMACOKINETICS 
(PK) STUDY?  
 
If you are at least 28 weeks pregnant when you enter the main part of the study, you may be 
selected to take part in an intensive PK study if you are on highly active antiretroviral medication 
(HAART) and INH or Placebo for INH.  You will have to stay at the clinic or hospital for over 
12 hours and have blood drawn at 7 time-points for the PK study.  A total of 36 women are 
needed for the intensive PK study.  
 
Intensive PK study (while you are pregnant AND after you have your baby) 
 
The first blood sample will be taken while you are in the third trimester of your pregnancy at 
least 2 weeks after you start INH or Placebo for INH.   
 
The second blood sample will be taken at a scheduled visit about 16 weeks after your baby is 
born. 
 
At each of the two visits, you will have a little less than 1 teaspoon of blood (4 mL) taken before 
you take your medications (time 0).  While in the clinic, you will be given your dose of INH or 
Placebo for INH, prenatal multivitamin and vitamin B6 without food (either fasting 1 hour before 
a meal or 2 hours after a meal).  You will also be given your HAART medication at the same 


 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
time that you are given your dose of INH or Placebo for INH.  At 1, 2, 4, 6, 8, and 12 hours after 
you have taken your anti-TB and HAART medications, a little less than 1 tsp of blood (4 mL) 
will be taken at each time point to measure the amount of INH in your blood during the day.  
Sometimes a heparin-lock is used when more than one blood sample is taken over a period of 
time.  A heparin-lock is a small tube left in the vein until all of the blood samples have been 
taken.  Then it is removed.  This allows blood to be taken from a vein many times without 
sticking you again.  A little less than 6 teaspoons (about 28 mL) of blood will be taken in all, for 
the PK tests.   
 
HOW LONG WILL I BE IN THIS PK STUDY? 
 
You will be in the intensive PK study as part of a scheduled visit, for the main study.  The 
intensive PK study will take more than 12 hours, on that visit day.  The 12 hour study will be 
done once during your third trimester of pregnancy at least 2 weeks after you start INH or 
Placebo for INH, and again about 16 weeks after your baby is born. 
 
HOW MANY WOMEN WILL TAKE PART IN THIS PK STUDY? 
 
About 36 women are needed for this intensive PK study.    
 
WHAT ARE THE RISKS OF THIS PK STUDY? 
 
Blood drawing may cause some pain, discomfort, bleeding, or bruising where the needle enters 
the skin.  Blood drawing may also cause a lightheaded feeling, and in rare cases, fainting.  A 
small blood clot may form at the site where the needle enters the skin or swelling of the 
surrounding skin may occur.  There is also a small risk of a minor infection at the blood draw 
site. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential.  We cannot guarantee 
absolute confidentiality.  Your personal information may be disclosed if required by law.  Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the US 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, and host 
country regulatory authorities. 
 
A description of this clinical trial will be available on ClinicalTrials.gov as required by U.S. 
Law.  This website will not include information that can identify you. At most, the website will 
include a summary of the results.  You can search this website at any time. 
 


 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
ARE THERE ANY BENEFITS TO TAKING PART IN THIS STUDY? 
 
You will receive no benefit from taking part in this study but the results may let us learn if INH 
works differently in the same women, when they are pregnant and after their baby is born. 
 
WILL I RECEIVE ANY PAYMENT? 
 
You will be reimbursed for expenses such as childcare and travel to take part in the intensive PK 
study.  [Site-specific-TBD] 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
name of the investigator or other study staff 
 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
 
telephone number of above   
 


 
IMPAACT P1078 – Version 2.0 
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28 October 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 to take part in this study.  Please sign your name below. 
 
All other information that is contained in the main study consent you signed also applies to this 
addendum consent. 
 
 
 
 
 
Participant’s Name (print) 
 
Participant’s Signature and Date 
Participant’s Legal Guardian (print)  
(As appropriate) 
 
 
Legal Guardian’s Signature and Date 
Study Staff Conducting  
Consent Discussion (print)  
 
 
Study Staff’s Signature and Date 
Witness’s Name (print)  
(As appropriate) 
 
 
Witness’s Signature and Date 
 


 
IMPAACT P1078 – Version 2.0 
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28 October 2015 
Appendix IV-D: Supplement to Appendix IV-B, Sample Informed Consent: For sites where 
INH is routinely provided to HIV-infected pregnant women 
 
P1078: A Phase IV Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Safety 
of Immediate (Antepartum-Initiated) Versus Deferred (Postpartum-Initiated) Isoniazid 
Preventive Therapy Among HIV-infected Women in High TB Incidence Settings 
 
SHORT Name: “TB APPRISE” Stands for TB Ante vs. Postpartum Prevention with INH in HIV 
Seropositive mothers and their Exposed infants 
 
SHORT TITLE FOR THE STUDY: P1078: TB APPRISE 
 
Version 2.0, dated 28 October 2015 
 
Isoniazid (INH) may be immediately available to individuals infected with HIV, including 
pregnant women, through the study site or through the local government clinic that cares for 
people who have or could get TB.  This is one option available to you to receive INH without 
participating in this study.  Please see the study doctor or your own doctor if you would like to 
learn more about this. 
 
If you decide to participate in the study and complete the study, you may also be able to receive 
up to 36 months of INH through the local government clinic or the study site. 
 
If you understand that you have other ways of receiving INH without being in the study and you 
are still interested in participating in the study, please sign the consent below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
Participant’s Signature and Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant’s Legal Guardian (print)  
 
Legal Guardian’s Signature and Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting Consent  
 
  
Study Staff’s Signature and Date  
Discussion (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness’ Name (print) 
 
 
 
Witness’ Signature and Date  
(As appropriate) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Father’s Name 
 
 
 
 
Father’s Signature and Date 
(If father’s signature is required) 
 
 
(If father’s signature is required) 
 
 

SAP_000.pdf: 
P1078 Statistical Analysis Plan  Version 2.0                                                                                        
 
IMPAACT P1078 Statistical Analysis Plan 
Final Version 2.0 (Primary Analysis) 
 
A Phase IV Randomized Double-Blind Placebo-Controlled Trial to 
Evaluate the Safety of Immediate (Antepartum-Initiated) Versus 
Deferred (Postpartum-Initiated) Isoniazid Preventive Therapy Among 
HIV-Infected Women in High TB Incidence 
NCT 01494038  
 
 
  November 2, 2017 
 
This is IMPAACT P1078 SAP Version 2.0 with names of authors, 
names of publication writing team members, and appendices 
redacted. 
 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
TABLE OF CONTENTS 
INTRODUCTION .......................................................................................................................... 3 
1.1 Purpose of the Statistical Analysis Plan (SAP) 
3 
1.2 Study Design (Protocol Version 2.0) 
3 
2 
STUDY OBJECTIVES (PROTOCOL VERSION 2.0) ............................................................. 4 
2.1 Primary Objective 
4 
2.2 Secondary Objectives 
4 
2.3 Exploratory Objectives 
4 
3 
OUTCOME MEASURES ........................................................................................................ 5 
3.1 Primary Endpoint 
5 
3.2 Secondary Endpoints 
6 
3.3 Other Outcomes 
7 
4 
STATISTICAL METHODS ...................................................................................................... 9 
4.1 Analysis of the Primary Objective 
9 
4.1.1 
Sensitivity analyses of the primary objective ................................................. 10 
4.2 Analysis of Secondary Objectives 
10 
5 
REPORT COMPONENTS .................................................................................................... 11 
5.1 Accrual 
11 
5.2 Study Status 
11 
5.2.1 
Maternal .............................................................................................................. 12 
5.2.2 
Infant ................................................................................................................... 12 
5.3 Maternal Baseline Characteristics 
12 
Validation: No validation of the analysis programs is required. ....................................... 12 
5.3.1 
Demographics ................................................................................................... 12 
5.3.2 
Health Status ..................................................................................................... 13 
5.3.3 
Antiretroviral (ARV) Regimen .............................................................................. 13 
5.3.4 
Laboratory Values ............................................................................................. 13 
5.4 Maternal Safety 
14 
5.5 Maternal Hepatotoxicity 
14 
5.6 Peripheral neuropathy 
15 
5.7 Maternal Mortality 
15 
5.8 Treatment Intolerability 
15 
5.9 Primary Endpoints and Analysis 
16 
5.10 In utero exposure and infant outcomes 
17 
5.10.1 Summary of pregnancy outcomes ................................................................... 17 
5.10.2 Infant baseline characteristics ......................................................................... 17 
5.10.3 Summary of adverse pregnancy outcomes .................................................... 18 
5.10.4 Summary of HIV infection status ..................................................................... 18 
5.10.1 Summary of safety and mortality ..................................................................... 18 
5.11 Maternal and Infant TB 
19 
5.12 Changes in ARV regimen 
20 
5.13 Vital Status of Participants Lost to Follow-up 
20 
5.14 Report Appendices 
20 
APPENDICES ............................................................................................................................. 21 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
Introduction 
1.1 
Purpose of the Statistical Analysis Plan (SAP) 
This statistical analysis plan has been developed to (1) provide a structured time-frame for 
database completion and preparation of the final primary analysis report; (2) facilitate discussion 
of the key statistical analysis components amongst the study team; (3) provide agreement 
between the study team and statisticians regarding the statistical analyses to be performed; and 
(4) aid in setting priorities relating to the data cleaning and development of statistical analysis 
programs.  
The statistical analysis plan contains details of all statistical analyses that will be completed for 
the final primary analysis report. 
1.2 
Study Design (Protocol Version 2.0)  
This study is a randomized, double-blind, placebo-controlled non-inferiority trial designed to 
assess the overall safety and toxicity of 28 weeks of isoniazid (INH) preventive therapy (IPT) 
initiated during pregnancy versus deferred initiation of IPT at 12 weeks postpartum in HIV-
infected pregnant women and their infants at high risk for TB infection and disease. The study 
will also assess the efficacy of these strategies in the women and their infants, safety and 
toxicity of INH in utero and on infants, INH resistance among Mycobacterium tuberculosis 
(M.tb.) isolates among participants who develop TB while on study, intensive PK of INH and 
ARV drugs among HIV-infected women on HAART, adherence to INH during pregnancy and 
postpartum, and performance characteristics of IGRA with TST among HIV-infected pregnant 
women and their infants.  
A target of 950 HIV-infected pregnant women at ≥14 to  ≤34 weeks (34 weeks, 6 days) of 
gestation and living in high TB incidence areas, defined as having 60 TB cases per 100,000 
population in the WHO TB annual report, will be enrolled. Women who are suspected of having 
TB with a positive WHO TB symptom screen, have reported recent exposure to an active TB 
case, have received INH or TB treatment for >30 days in the past year, have evidence of acute 
hepatitis within 90 days prior to study entry, or have ≥Grade 1 peripheral neuropathy will not be 
eligible. 
Participants will be stratified based on gestational age at entry, and will be randomized in equal 
proportions to one of the following two groups: 
 
ARM A: Maternal INH at study entry for 28 weeks and then switched to placebo for INH 
until 40 weeks postpartum (immediate IPT), or 
 
ARM B: Maternal placebo for INH from study entry until 12 weeks postpartum and then 
switched to INH for 28 weeks until 40 weeks postpartum (deferred IPT) 
Each maternal participant will also receive vitamin B6 and multivitamins from study entry until 40 
weeks postpartum, as well as intensified TB case finding, and will be followed up to 48 weeks 
postpartum.  Each infant participant will be followed from birth until 48 weeks postpartum with 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
intensified TB case finding. 
The primary hypothesis is that initiation of IPT during pregnancy among HIV-infected pregnant 
women is as safe as deferring IPT to 12 weeks postpartum. 
2 Study Objectives (Protocol Version 2.0) 
The primary analysis report will include the primary objective and secondary objectives 1-4 
(listed in sections 2.1 and 2.2 below).  Secondary objectives 5-7 and the exploratory objectives 
(section 2.3) will be addressed in separate analysis plans. 
2.1 
Primary Objective 
To compare overall safety and toxicity of immediate versus deferred INH preventive therapy in 
HIV-infected pregnant women enrolled at ≥14 through ≤34 weeks gestation (34 weeks, 6 days) 
2.2 
Secondary Objectives 
1. To compare safety and toxicity of INH in utero exposure and on infants on study  
2. To compare TB incidence and all-cause mortality in HIV-infected women and their 
infants enrolled on study  
3. To compare overall safety and hepatotoxicity, as well as evaluate risk factors for these 
outcomes, during pregnancy and immediate postpartum in women on immediate versus 
deferred INH therapy 
4. To evaluate for INH resistance among M.tb. isolates from HIV-infected women and 
infants who develop TB while on study 
5. To evaluate the intensive pharmacokinetics of INH and selected ARV drugs in a subset 
of HIV-infected pregnant and postpartum women receiving HAART 
6. To evaluate and compare the performance characteristics of IGRA (TB ELISPOT and 
QGIT) with TST in HIV-infected women and their infants 
7. To compare adherence in women initiating immediate versus deferred INH preventive 
therapy via self-report and pill counts 
2.3 
Exploratory Objectives  
1. To evaluate population pharmacokinetics and pharmacogenomics of INH and EFV in 
HIV-infected pregnant and postpartum women 
2. To assess the effects of INH preventive therapy on the functional characteristics of TB 
specific T-cell responses measured by TB ELISPOT in HIV-infected women and their 
infants on study   
3. To evaluate adherence and exposure to INH and EFV using drug levels in hair and 
analyze the association between these drug levels and adverse events 
4. To compare the two arms with respect to the overall (risk:benefit) clinical outcome of the 
mother-infant pairs 
5. To explore associations of maternal and infant specific TB responses and novel 
biomarkers with risk of maternal and infant TB infection and disease 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
6. To explore the neurotoxicity of INH in combination with EFV in a subset of women 
 
 
A brief description of the important study time points is shown in the following table:  
Evaluations 
Time points of interest 
Adverse events in mothers (for 
primary safety analysis) 
Up to week 48 postpartum 
Adverse events in infants 
Up to week 48 from birth 
Adverse pregnancy outcomes 
Delivery to week 48 from birth 
Maternal TB 
Up to week 48 postpartum 
Infant TB 
Up to week 48 from birth 
Intensive and sparse PK in mothers 
Antepartum (third trimester) and 
week 16 postpartum 
TST in mothers 
Delivery (or Week 4 postpartum 
if not done at delivery) and 
Week 44 postpartum 
TST in infants 
Week 44 from birth 
IGRA in mothers 
Entry, delivery and Week 44 
postpartum 
IGRA in infants 
Week 44 from birth 
 
 
3 Outcome Measures 
3.1 
Primary Endpoint 
Grade ≥ 3 AEs possibly, probably, or definitely associated with INH/Placebo for INH or 
permanent discontinuation of INH/Placebo for INH due to an adverse reaction in women after 
randomization until 48 weeks postpartum. 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
Study drug attribution is based on adjudication by an Independent Endpoint Review Committee 
(IERC), which consists of OB/GYN and pediatric specialists who are not members of the study 
team. Refer to the Endpoint Review Process document for details of the review process. 
Adverse events include laboratory results, signs/symptoms, or diagnoses reported in the study 
database. Note that for hematology results, only those collected at delivery are considered in 
the primary endpoint since testing at other study visits specified in protocol Version 1.0 was 
discontinued in Version 2.0. Except for the following, diagnoses are based on Appendix 100 
definitions and grading of adverse events is based on the DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events (Version 1.0, dated December 2004) grading criteria:  
 
As stated in Section 6.1.4 of the protocol, grading for ALT (SGPT), AST (SGOT) and 
total bilirubin (or direct bilirubin for women taking Atazanavir) are based on the modified 
grading table for hepatotoxicity in Appendix III of the protocol.  
 
As stated in Section 6.1.3 of the protocol, the Brief Peripheral Neuropathy Screen 
(BPNS) grading criteria (see Appendix II of protocol) will be used instead of the DAIDS 
grading criteria; signs/symptoms should be present for at least two weeks to be 
considered peripheral neuropathy. 
3.2 
Secondary Endpoints 
 
In utero exposure and infant endpoints: 
o Fetal death 
o Small for gestational age 
o Premature birth (< 37 weeks gestation) 
o Low birth weight (< 2500 gm) 
o Congenital anomalies 
o Grade 3 or higher clinical or laboratory AEs  
 all AEs  
 possibly, probably, or definitely related to INH/Placebo for INH 
o HIV infection 
o Hospitalization 
 
 
Any of the following endpoints: 
o Maternal TB (probable or confirmed – see Appendix 100 for definitions) 
o Infant TB (probable or confirmed, as defined in Appendix 100, and congenital TB, 
as defined using the Cantwell criteria) 
o Death of infant 
o Death of mother 
o Combined endpoint of maternal TB or maternal death 
o Combined endpoint of infant TB or infant death 
o Combined endpoint of maternal TB, maternal death, infant TB, or infant death 
 
NOTE: TB endpoints and infant cause of death will be reviewed by a Secondary Endpoint 
Review Committee (SERC), which consists of maternal and pediatric TB specialists who may be 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
members of the study team. Refer to the Endpoint Review Process document for details of the 
review process.  Appendix 100 will be the basis for adjudication of the TB endpoint by the SERC 
and is available in the CRF Appendix Codes section of the Frontier Science IMPAACT Portal; 
the web link to portal can be found in the MOP.  Cantwell criteria for Congenital TB are in the 
MOP and will be collected on the P1078 CRF.   
Deaths of enrolled women will receive external review by the IERC for adjudication of study 
treatment attribution and will also be reviewed by the SERC.  The SERC will consider if the 
cause of death (COD) is due to unrecognized active TB (expected to be rare), from a known 
cause other than active TB, or from an unknown cause.  
 
Occurrence of each of the following safety outcomes in HIV-infected women: 
during pregnancy up to: (i) delivery (antepartum) and (ii) 12 weeks postpartum 
o Grade ≥ 3 AEs possibly, probably, or definitely related to INH/Placebo for INH or 
permanent discontinuation of INH/Placebo for INH due to an adverse event 
o Grade ≥ 3 AEs (all-cause) 
o Hepatotoxicity possibly, probably, or definitely related to INH/Placebo for INH 
o Hepatotoxicity (all-cause) 
 
Note: Each of the definitions of hepatotoxicity will be studied: (i) having ≥ Grade 3 LFTs (ALT > 
5 X ULN or ALT > 3 X ULN with bilirubin > 2 X ULN) or ALT > 3 X ULN with persistent, 
symptomatic clinical hepatitis); and (ii) using DAIDS AE grading criteria, Version 1.0.   
 
 
Resistance outcomes: 
o Resistance to INH in isolates of M.tb from mothers who develop culture-confirmed 
TB  
o Resistance to INH in isolates of M.tb from infants who develop culture-confirmed TB 
 
 
3.3 
Other Outcomes 
 
Latent TB Diagnostic Outcome Measures 
o IGRA assay result (positive, negative, indeterminate) in women 
o IGRA assay result (positive, negative, indeterminate) in infants 
o TST result (positive or negative) in women; TST positive if ≥ 5 mm 
o TST result (positive or negative) in infants; TST positive if ≥ 10 mm in HIV-
negative infants and if ≥ 5 mm in HIV-positive infants 
 
 
Adherence to INH/Placebo for INH among women, assessed by self-report and pill 
count 
o For the self-report and pill counts, adherence will be considered as a continuous, 
ordinal categorical, or a binary variable.  When presented as a continuous 
variable, adherence is defined as the percentage of expected doses/pills taken 
during the entire treatment period (28 weeks).  When presented as an ordinal 
variable, excellent adherence is defined as taking at least 90% of doses/pills 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
during the entire treatment period; good adherence as ≥ 80% to < 90%; 
reasonable adherence as ≥ 60% to < 80%; and poor adherence as < 60% of 
doses, as reported in any of the scheduled adherence evaluations.  When 
presented as a binary variable (completer versus non-completer), a completer is 
defined as having excellent adherence. 
 
 
Population Pharmacokinetics  
o Primary:  Area under the plasma versus time curve (AUC) at each of two time points 
(antepartum and postpartum) in women.  
o Secondary:  Cpeak, half-life (t1/2), volume of distribution (Vd) and apparent clearance 
(CL/F) 
 
 
Pharmacogenetics 
o Presence of genetic variants to NAT2 and 2E1, PK of INH and EFV based on sparse 
sampling during pregnancy and postpartum  
 
 
Immunologic Outcome Measures 
o Functional and phenotypic characteristics of TB specific T-cell responses in women 
o Functional characteristics of TB specific T-cell responses in infants 
 
 
Drug Levels in Hair 
o INH and EFV drugs levels in women’s hair samples; adverse events are as defined 
Grade 3 or higher adverse events in women until 48 weeks postpartum 
 
 
Risk-benefit Outcome 
o An overall ordinal measure of clinical outcomes in the mother-infant pair, which 
assigns a score to the mother-infant pair according to severity of totality of clinical 
outcomes (clinical outcomes include maternal death, maternal TB, maternal safety 
events, infant death, infant TB, infant safety events); the measure will be formulated 
in consultation with the study team prior to release of final analysis results to the 
team, and details will be included in the statistical analysis plan (SAP) for this 
secondary analysis. 
 
 
Maternal and infant specific TB responses and novel biomarkers 
o Anti-mycobacterial antibody responses in maternal plasma at all weeks when 
samples are collected 
o Anti-mycobacterial antibody responses in infant plasma at all weeks when samples 
are collected 
o Inflammation and immune activation markers (and other potential biomarkers) 
measured from maternal plasma/PBMC samples at all available time points 
o Inflammation and immune activation markers (and other potential biomarkers) 
measured from infant plasma/PBMC samples at all available time points 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
 
 
Neurotoxicity 
o Depression scores determined from the PHQ-9 instrument; responses to 
neurocognitive impairment questions and Pittsburgh Sleep Quality Index subset 
questions 
 
4 Statistical Methods 
4.1 
Analysis of the Primary Objective 
 
Safety of INH will be assessed primarily by comparing rates of Grade ≥ 3 events possibly, 
probably or definitely associated with INH/Placebo for INH or permanent discontinuation of 
INH/Placebo for INH due to an adverse reaction between women in the immediate and deferred 
arms by 48 weeks postpartum.   
 
For the final primary analysis, a confidence interval for the absolute difference in primary 
endpoint rates will be presented as study entry gestational age-stratified Mantel-Haenszel 
estimates with the confidence interval computed using the method of Greenland and Robins 
(Biometrics 1985;41:55-68), and will use the rounded value of 5% significance level given that 
sequential monitoring with a Haybittle-Peto use function boundary (alpha-value) was used for 
interim analyses. Non-inferiority of immediate IPT in HIV-infected pregnant women with regards 
to safety will be demonstrated if the upper bound of this confidence interval is less than 5%.  
Unweighted (i.e., ignoring stratification) estimates for the difference in rates will also be 
reported. (Note: Although HAART use at study entry was a stratification factor in Version 1.0 of 
the protocol, and removed as stratification factor in Version 2.0, analyses will not stratify by 
HAART use at study entry because all women enrolled - except one - were on HAART at study 
entry.) 
 
Data will be censored at the latest clinic visit (or contact with the participant while) on study 
when the endpoint status was ascertained prior to or at the earliest of the following times: (1) 
date when lost to follow-up for any reason, (2) date of death due to reasons not related to 
INH/Placebo, (3) date of permanent discontinuation of INH/Placebo as TB preventive therapy 
for any reason (other than an adverse reaction) including initiation of open label TB preventive 
therapy or treatment of presumed active TB disease, (4) date of last observed clinic visit or 
communication with the participant (on or before week 48 postpartum visit window). Participants 
who were lost to follow-up had their last date of clinic visit (or site contact) while on study before 
the week 48 postpartum visit window. 
The primary safety analysis will be intent-to-treat, with participants analyzed according to 
randomized study arm. 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
4.1.1 Sensitivity analyses of the primary objective 
The following sensitivity analyses will be performed: (i) per-protocol, which will include and 
compare only participants who initiated and completed the regimen to which they were 
randomized according to the protocol (ie. completed study treatment or discontinued due to 
death or toxicity); and (ii) as-treated, which will compare participants according to the actual 
treatment received (ie. participants in the deferred arm who started INH in the antepartum 
period will be analyzed in the immediate arm). 
Sensitivity analyses will be done to assess the impact of coding deaths of unknown cause and 
all deaths as events.  Supplementary analyses will include estimation of the difference in 
primary endpoint rates between the two arms based on simple estimates of proportions 
stratified by gestational age, where endpoints will be assessed based on available data (i.e. if 
participant discontinued the study early and did not experience an endpoint up until that point, 
then assume no endpoint was reached). Un-weighted (i.e., ignoring stratification by gestational 
age) estimates for the difference in rates will also be reported. 
Multivariable analyses to adjust for maternal characteristics such as treatment arm, age, 
duration on HAART, CD4 count, gestational age at study entry, IGRA positivity at study entry in 
all women, and other potential confounders such as HBsAg serology status at entry will be 
performed using Poisson regression modeling. 
Finally, similar analyses will be performed on all Grade ≥ 3 AEs (regardless of INH/Placebo for 
INH attribution) as a way to check for bias in the primary endpoint analysis. 
4.2 
Analysis of Secondary Objectives 
 
Maternal TB, maternal death, infant TB and infant death will be analyzed separately and as 
combined events.  Efficacy of INH will be assessed primarily by comparing event rates between 
women in the immediate and deferred arms by 48 weeks postpartum.  
A 95% confidence interval for the absolute difference in event rates will be computed using 
study entry gestational age-stratified Mantel-Haenszel estimates. Unweighted (i.e., ignoring 
stratification) estimates for the difference in rates will also be reported.  
 
Strategies for censoring will vary depending on the efficacy outcome of interest. For analyses of 
maternal TB, any maternal death not caused by TB will not be considered an event and any 
maternal death of unknown cause will be considered an event. Similarly, for analyses of infant 
TB, any infant death not caused by TB will not be considered an event and any infant death of 
unknown cause will be considered an event. Sensitivity analysis to assess the effect of this 
strategy includes coding death due to unknown cause as a non-event. 
 
This will be a modified intent-to-treat analysis, with participants analyzed according to 
randomized study arm, excluding those who were determined to have active TB at entry. 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
For final analyses, supplementary analyses will include estimation of differences in these 
individual/combined endpoint rates between the two arms based on simple estimates for 
proportions.  
5 Report Components 
Notes:  
 
Unless otherwise indicated, all outputs will be by treatment arm. 
 
Data presented on individual participants will be identified by Public ID. 
 
Validation requirements per CBAR SOPs: 
o All programs that generate permanent study-specific derived datasets that 
contribute to the generation of reports for final analyses that either contain or are 
supportive of the analyses of the primary or secondary objectives will be 
validated; all such programs will undergo code review and execution checks, and 
the primary safety outcome measures will have results verification (double 
programming)    
o All programs that conduct key analyses for primary or secondary objectives will 
be validated; all such programs will undergo code review and execution checks, 
and those programs that conduct the analyses for the primary objective 
( maternal safety) will have results verification (double programming). The 
following analyses are considered key: Study/Treatment Status, Study 
Discontinuation prior to Evaluation of Primary Outcome, Maternal Safety, Infant 
Safety, Maternal TB, Infant TB. The level of validation required for each of the 
key analyses is specified below in the respective subsections. 
5.1 
Accrual 
Validation: No validation of the analysis programs is required. 
 
 
Table of site activation dates and date of first enrollment 
 
Table of accrual by month with dates of first and last enrollment will be indicated as a 
footnote [STATUS] 
 
Table of accrual by site [STATUS] 
 
Table of accrual by HAART stratification factor and site [STATUS] 
 
Table of accrual by gestational age stratification factor and site [STATUS] 
 
Table of accrual by sub-cohort (intensive PK, PBMC collection, none) and site [STATUS] 
 
5.2 
Study Status  
Validation: The analysis programs for Study Status and Premature Study 
Discontinuation will be validated, but not double-programmed. 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
5.2.1 
Maternal 
 
CONSORT diagram, including number of women randomized to each treatment arm 
(reasons not randomized), number who initiated study treatment (reasons not initiated), 
and number who completed study (reasons not completed). [STATUS] 
 
Listing of participants with eligibility violations, including blinded ID, treatment arm, and 
description of violation [STATUS] 
 
Table of stratification errors: number (%) by strata [STATUS] 
 
Table of off-study reasons: number (%) [F1601]  
 
Table of off-study reasons: number (%) by month and phase of pregnancy (entry to < 
delivery, delivery to < week 12 PP, week 12 PP to week 48 PP) [F1601] 
 
Listing of participants not initiating randomized treatment, including blinded ID,  
treatment arm, and reason [ADM0021]  
 
Listing of participants who initiated randomized treatment more than 3 days after study 
entry, including blinded ID,  treatment arm, and day of initiation [ADM0021] 
 
Duration of follow-up defined as time (weeks) from randomization date to last clinic visit 
(or last contact) while on study: mean (s.d.), min, max, median (Q1-Q3).  [STATUS, 
F1601] 
 
If more than 10% of participants prematurely discontinue the study, generate the 
following: 
o Figure of time-to-last clinic visit from randomization date, with comparison by 
treatment group using log rank test. [STATUS, F0010] 
o Figure of time-to-last clinic visit from randomization date by gestational age 
stratum with comparison by treatment group using log rank test. [STATUS, 
F0010] 
5.2.2 
Infant 
 
Table of deliveries: number (%) by month [STATUS, EVW0292] 
 
Table of off-study reasons: number (%) [F1601]  
 
5.3 
Maternal Baseline Characteristics 
Validation: No validation of the analysis programs is required. 
5.3.1 Demographics 
 
Age (years): N, N missing, mean (s.d.), min, max, median (Q1-Q3); number (%) by age 
group (eg. <24, 24-<29, 29-<34, ≥34) with years rounded down [STATUS] 
 
Self-reported race/ethnicity: number (%) by category [STATUS] 
 
Country: number (%) [STATUS] 
 
Gestational age (weeks) at entry: N, N missing, mean (s.d.), min, max, median (Q1-Q3); 
number (%) by category (14-<24, 24-34) [OBW0006] 
o Note: Gestational age is determined based on best available method, with methods 
prioritized as (i) ultrasound, (ii) last menstrual period, (iii) fundal height, and may 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
not match the level used for stratification if the site defined best available method 
differently.   
5.3.2 Health Status  
 
Entry HIV-1 RNA (copies/ml): Number (%) by category (eg. <50 cp/ml, 50-<200 cp/ml, 
≥200 cp/ml) and detectable vs. undetectable (<LLQ).  Note: HIV-1 RNA is performed by 
a “licensed assay” so the limit of quantification could differ by assay type. [RNALDMS] 
 
Screening CD4 counts (cells/uL): N, N missing, mean (s.d.), min, max, median (Q1-Q3); 
number (%) by category (eg. <350, 350-<500, 500-<650, ≥650) [LBW0054]Entry weight 
(kg): N, N missing, mean (s.d.), min, max, median (Q1-Q3) [F0031] 
 
Entry BMI (kg/m2): N, N missing, mean (s.d.), min, max, median (Q1-Q3) 
[F0031,EVW0247] 
o BMI=(weight/(height*height/10000)) 
 
Entry WHO clinical staging for HIV: Number (%) by clinical stage (I, II, III, IV) [PE0043] 
 
Prior TB treatment (>30 days): number (%) by response (yes, no, unknown) [HXW0166]  
 
Entry IGRA positivity: Number (%) by status (positive, negative, indeterminate) 
[TBW0060] 
 
Entry HBsAg serology: Number (%) by status (positive, negative, indeterminate) 
[SRW0026] 
 
Entry hepatitis C serology: Number (%) by status (positive, negative, indeterminate) 
[SRW0026] 
5.3.3 Antiretroviral (ARV) Regimen 
 
Entry ARV regimen: number (%) by HAART category (HAART, not on HAART) and by 
actual regimen [PE0412] 
 
Efavirenz-containing ARV regimen at entry: number (%) by EFV use (yes, no) [PE0412] 
5.3.4 Laboratory Values  
 
ALT: number (%) by grade; mean (s.d.), min, max, median (Q1-Q3) 
 
AST: number (%) by grade [PE6817] 
 
Total Bilirubin: number (%) by grade [PE6817] 
 
ANC (cells/mm3): number (%) by grade [PE6812] 
 
Hemoglobin (g/dl): number (%) by grade [PE6812] 
 
Platelet count (cells/mm3): number (%) by grade [PE6812] 
 
Note: Grading will be based on Appendix III of protocol for ALT, AST and total bilirubin and by 
DAIDS Version 1.0 toxicity grade otherwise.  Baseline laboratory evaluations were done at 
screening, except for ALT, which was done at screening and entry. Baseline ALT is calculated 
as the mean of screening and entry values if both are available. 
 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
5.4 
Maternal Safety  
Validation: The analysis programs in this section will be validated, but not double-
programmed. 
 
Tables of new grade 3 or 4 labs and signs/symptoms: number (%) by SOC and grade. 
[STATUS, PE6812, PE6817, PE6832] 
 
Table of new grade 3 or 4 diagnoses: number (%) by MedDRA code [EVENTS]. 
 
Table of new grade 3 or 4 primary adverse events (labs, signs/symptoms, and 
diagnoses): number (%) by MedDRA code [EVENTS] 
 
Table of serious adverse events (SAEs): number (%) by MedDRA code [EVENTS] 
Note: The highest grade experienced by a given participant for each safety event is included. 
 
5.5 
Maternal Hepatotoxicity 
Validation: The analysis programs in this section will be validated, but not double-
programmed. 
 
Table of grade 1, 2, 3, and 4 LFTs (ALT, AST, TBIL): number (%) by highest grade 
[PE6817] 
 
Table of hepatotoxicity by type, assuming protocol grading and DAIDS grading, 
separately: number (%) with Fisher’s exact tests with mid-p adjustment (Lydersen et al, 
2009, Statistics in Medicine)  [PE6817]: 
o Grade 3 ALT (highest grade) 
o Grade 4 ALT (highest grade) 
o Grade 3 ALT, AST, or TBIL (highest grade) 
o Grade 4 ALT, AST, or TBIL (highest grade) 
o Grade ≥2 ALT and grade ≥2 TBIL 
o Grade ≥2 ALT with symptomatic clinical hepatitis 
o Any hepatotoxicity (defined as any of the above) 
Note: Symptomatic clinical hepatitis will be identified based on blinded review 
(pooled over study arms) by selected protocol team members (at end of study follow-
up and prior to data freezing for final analysis).  Substitute direct bilirubin for TBIL for 
participants on atazanavir. 
 
Create the following by treatment arm and efavirenz use at entry, separately [PE6817, 
ADM0040]: 
o Peak ALT: min, max, mean (SD), median (Q1-Q3), Wilcoxon rank sum test  
o Table of participant ALT levels (U/L) at scheduled study visits by stage of 
pregnancy (weeks AP/PP): N, mean (s.d.), median (Q1-Q3) 
o Table with number (%) of participants by ALT grade at scheduled study visits and 
stage of pregnancy (weeks AP/PP)  


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
o Plot of median (Q1,Q3) ALT level at scheduled study visits by stage of pregnancy 
(weeks AP/PP)  
 
Table of estimates (with 95% confidence intervals) of difference in incidence rates 
between arms, based on stratified Mantel-Haenszel estimates  (primary) and simple 
proportions (sensitivity) at week 48 postpartum, for the following endpoints 
[STATUS,PE4005,TRAC]: 
o Any hepatotoxicity, possibly, probably, or definitely related to study treatment 
o Any hepatotoxicity, all cause 
 
Kaplan-Meier plot of time to endpoint from randomization date by study arm and by 
gestational age, with number of events and number at risk for the following endpoints 
o Any hepatotoxicity, possibly, probably, or definitely related to study treatment 
o Any hepatotoxicity, all cause 
 
Table of analysis of difference in endpoint rates between arms up to (i) delivery and (ii) 
12 weeks postpartum, based on stratified Mantel-Haenszel  estimates (primary) and 
simple proportions (sensitivity), for the following endpoints [STATUS,PE4005,TRAC]: 
o Any hepatotoxicity, possibly, probably, or definitely related to study treatment 
o Any hepatotoxicity, all cause 
5.6 
Peripheral Neuropathy 
Validation: The analysis programs in this section will be validated, but not double-
programmed. 
 
Table with ≥grade 1 peripheral neuropathy: number (%) by highest grade [NE6056] 
 
Table of BPNS final score: min, max, mean (SD), median (Q1-Q3), Wilcoxon rank sum 
test [NE6056] 
5.7 
Maternal Mortality 
Validation: The analysis programs in this section will be validated, but not double-
programmed. 
 
Listing of maternal deaths including public ID, treatment arm, weeks on study, stage of 
pregnancy, site assessment of primary COD and treatment attribution, and IERC 
treatment attribution [STATUS, PE1414, TRAC]  
 
Listing of maternal deaths including the following peak lab values: ALT, AST, total 
bilirubin, alkaline phosphatase, GGT, INR, total protein, and albumin [PE6812, PE6817]   
5.8 
Treatment Intolerability 
Validation: The analysis programs in this section will be validated, but not double-
programmed. 
 
Table of treatment discontinuation: number (%) of enrolled women discontinuing study 
treatment prematurely (discontinued study treatment prior to week 40 postpartum, which 
is the end of study treatment period for both arms) by reason [PE4005] 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
 
Table of permanent treatment discontinuation due to toxicity: number (%) of enrolled 
women discontinuing study treatment prematurely due to toxicity by type of toxicity 
[PE4005, TXW0221] 
 
Listing of participants who permanently discontinued study drug due to toxicity but did 
not have a grade 3 or higher AE related to study treatment, including: blinded ID; 
treatment arm, actual week of treatment discontinuation, and off-treatment reason 
[PE4005, TRAC] 
5.9 
Primary Endpoints and Analysis 
Validation: The analysis programs in this section will be validated, and primary analysis will 
be double-programmed. 
 
Cross-tabulation of participants with at least one adverse event at least possibly related 
to study treatment based on IERC assessment and participants with at least one 
adverse event at least possibly related to study treatment based on site assessment: 
number (%) [TRAC]  
 
Table of most severe safety outcome related to study treatment among participants 
experiencing primary safety endpoints: number (%) of each of the following 
[STATUS,PE4005,TRAC]: 
o Grade 3 AE related to study treatment  
o Grade 4 AE related to study treatment 
o Death related to study treatment  
o Permanent discontinuation of study treatment due to toxicity but no grade 3 or 
higher AE related to study treatment 
 
Table of primary analysis of difference in endpoint rates between arms, based on 
stratified Mantel-Haenszel estimates at week 48 postpartum (primary) and simple 
proportions (sensitivity), for the following endpoints [STATUS,PE4005,TRAC]: 
o Primary safety endpoint 
o Any Grade ≥ 3 AE (all cause) 
 
Table of per-protocol and as-treated sensitivity analyses of difference in endpoint rates 
between arms, based on stratified Mantel-Haenszel estimates at week 48 postpartum 
and simple proportions, for the following endpoints [STATUS,PE4005,TRAC]: 
o Primary safety endpoint 
o Any Grade ≥ 3 AE (all cause) 
 
Table of sensitivity analysis coding deaths of unknown cause and all deaths as primary 
endpoints (if death or a prior AE experienced by the participant who died were not 
already considered to be a primary endpoint) 
 
Kaplan-Meier plot of time to endpoint from randomization date by study arm and by 
gestational age, with number of events and number at risk for the following endpoints 
o Primary safety endpoint 
o Any Grade ≥ 3 AE (all cause) 
 
Table of analysis of difference in endpoint rates between arms up to (i) delivery and (ii) 
12 weeks postpartum, based on stratified Mantel-Haenszel estimates (primary) and 
simple proportions (sensitivity), for the following endpoints [STATUS,PE4005,TRAC]: 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
o Primary safety endpoint 
o Any Grade ≥ 3 AE (all cause) 
 
Multivariable Poisson regression model for the primary safety endpoint adjusted for 
treatment arm and the following baseline characteristics: maternal age, duration on 
HAART (from start date of HAART to randomization date), CD4 count, gestational age, 
IGRA positivity, and HBsAg serology status 
Per NIH policy for Phase III and pivotal Phase II and IV studies, NIH requires primary analyses 
of treatment comparisons to be summarized by sex and by race and treatment interactions with 
sex and race to be tested. These analyses are required so do not represent multiple 
comparisons and are presented in the primary study analysis regardless of power issues.  As 
P1078 maternal analyses are restricted to women, the primary analysis will be presented by 
race but not by sex. 
 
Table of primary analysis of difference in primary safety endpoint rates between arms, 
based on stratified Mantel-Haenszel estimates at week 48 postpartum, by race 
[STATUS,PE4005,TRAC] 
 
Logistic regression of the primary safety endpoint on the interaction term for treatment 
and race 
5.10 In Utero Exposure and Infant Outcomes  
Validation: The analysis programs in this section will be validated, but not double-
programmed. 
Note: Exact categorical tests (with mid-p adjustment for the case of Fisher’s exact tests) will 
be employed to compare the difference in outcomes between arms. 
 
 
5.10.1 Summary of pregnancy outcomes 
 
Table with number (%) of pregnancies by outcome type (eg. live birth, stillbirth, 
spontaneous abortion, induced abortion, discordant birth outcomes) and number of 
fetuses (singleton, twins) 
 
5.10.2 Infant baseline characteristics 
 
Gender: number (%) by category [EVW0292] 
 
Gestational age at birth (weeks): N, N missing, min, max, median (Q1-Q3); number (%) 
by category (<34, 34 -<37, ≥37)  
o Note: The calculation of gestational age at birth will be based on three sources, 
prioritized as follows: newborn exam [PE5896], pregnancy outcome evaluation 
[EVW0292] and mother’s gestational age at enrollment [OBW0006] plus number of 
weeks to delivery. 
 
Birth weight (grams): N, N missing, min, max, median (Q1-Q3); number (%) by category 
(<1500, 1500 -<2500, ≥2500) [PE5896] 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
 
Apgar score at 1 minute: N, N missing, min, max, median (Q1-Q3); number (%) by 
category (0-3, 4-6, 7-10) [PE5896] 
 
5.10.3 Summary of adverse pregnancy outcomes 
Note: The evaluations of small for gestational age, premature birth, low birth weight and 
congenital anomalies are based on live births.  Multiple births with both live birth and 
stillbirth outcomes will be counted as pregnancies with stillbirths and other adverse 
pregnancy outcomes that may have been observed. Pregnancy outcome of induced 
abortion will be excluded from adverse pregnancy outcome summaries. 
 
Table with number (%) of pregnancies resulting in each of the following adverse 
pregnancy outcomes: 
o Fetal demise (stillbirth, spontaneous abortion) 
o Premature birth (<37 weeks gestation) 
o Low birth weight (<2,500 grams) 
o Congenital anomalies 
o Any adverse pregnancy outcome excluding congenital anomalies (defined as any 
of the above excluding congenital anomalies) 
o Any adverse pregnancy outcome (defined as any of the above)  
 
 
Table with number (%) of pregnancies resulting in each of the following severe adverse 
pregnancy outcomes: 
o Fetal demise (stillbirth, spontaneous abortion) 
o Premature birth (<34 weeks gestation) 
o Low birth weight (<1,500 grams) 
o Any severe adverse pregnancy outcome (defined as any of the above)   
5.10.4 Summary of HIV infection status 
 
Table with infant HIV infection status (positive, negative, indeterminate, unknown) 
 
Note: To be reviewed at end of study follow-up and prior to data freezing for final 
analysis by selected protocol team members (pooled over study arms). 
 
5.10.1 Summary of safety and mortality 
 
Tables of new grade 3 and 4 labs and signs/symptoms: number (%) by SOC and grade 
[STATUS, PE6812, PE6817, PE6832] 
 
Table of new grade 3 and 4 diagnoses: number (%) by MedDRA code [EVENTS]. 
 
Table of new grade 3 and 4 clinical and laboratory events: number (%) by MedDRA code 
[EVENTS] 
 
 
 
Listing of infant/neonatal deaths, including blinded ID, treatment arm, age at death 
(weeks on study), gestational age at birth, primary cause of death, narrative of etiology 
of death [PE1414] 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
 
Table of infant safety summary: number (%) with any grade 3 or 4 adverse event; grade 
3 or 4 adverse event definitely, probably or possibly related to study treatment based on 
site assessment; hospitalization; infant/neonatal death (overall, within 0-7 days of birth, 
within 0-28 days of birth) [EVENTS,PE9905,PE1414] 
 
5.11 Maternal and Infant TB  
Validation: The analysis programs in this section will be validated, but not double-
programmed. 
Note: Mother-infant pairs will be excluded if the mother had TB diagnosis at study entry. 
 
Listing of active TB events, including blinded ID, treatment arm, event week, site 
diagnosis, SERC decision, event grade and INH resistance testing results (if available), 
shown separately for mothers and infants   
 
Table of SERC-assessed TB and death endpoints: number (%) by arm of the following:  
o Maternal TB cases by type (PULMONARY: 220021-CONFIRMED, 220022-
PROBABLE; EXTRAPULMONARY: 220031-CONFIRMED, 220032-PROBABLE)  
o Infant TB cases by type (PULMONARY: 220021-CONFIRMED, 220022-
PROBABLE, POSSIBLE; EXTRAPULMONARY: 220031-CONFIRMED, 220032-
PROBABLE; CONGENITAL TB. 
o Death of infant 
o Death of mother 
o Maternal TB or maternal death 
o Infant TB or infant death 
o Maternal TB, maternal death, infant TB, or infant death 
As event numbers warrant: 
 
Table of intent-to-treat analysis of difference in endpoint rates between arms, based on 
stratified Mantel-Haenszel estimates at week 48 postpartum (primary) and simple 
proportions (sensitivity), stratified by gestational age, for the following endpoints: 
o Maternal TB 
o Infant TB 
o Death of infant 
o Death of mother 
o Maternal TB or maternal death 
o Infant TB or infant death 
o Maternal TB, maternal death, infant TB, or infant death 
 
 
Kaplan-Meier plot of time to endpoint from randomization date by study arm and by 
gestational age, with number of events and number at risk for the following endpoints: 
o Maternal TB 
o Infant TB 
o Death of infant 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
o Death of mother 
o Maternal TB or maternal death 
o Infant TB or infant death 
o Maternal TB, maternal death, infant TB, or infant death 
5.12 Changes in ARV regimen 
Validation: The analysis programs in this section will be validated, but not double-
programmed. 
 
Table of ARV discontinuation: number (%) discontinuing at least one component of 
baseline ARV regimen by category (EFV-based regimen vs. non-EFV ARV regimen) 
[PE0421] 
 
Table of changes in EFV use: number (%) with the following changes in EFV use, by 
phase of pregnancy (entry to < delivery, delivery to < week 12 PP, week 12 PP to week 
48 PP) [STATUS, PE0421]:  
o Switched from an EFV-containing regimen at entry to a non EFV-containing 
regimen 
o Switched from a non EFV-containing regimen at entry to an EFV-containing 
regimen 
5.13 Vital Status of Participants Lost to Follow-up 
Validation: The analysis programs in this section will be validated, but not double-
programmed. 
 
Table of number (%) of participants lost to follow-up with vital status data and source of 
information by category (participant, family member, neighbor, medical records, other) 
[VSW0024] 
 
Table of number (%) of mothers who experienced the following since last seen on study 
[VSW0024]: 
o Death 
o Hospitalization 
o TB diagnosis 
o  Delivery by pregnancy outcome 
 
Table of number (%) of infants who experienced the following since last seen on study 
[VSW0024]: 
o Death 
o Hospitalization 
o TB diagnosis 
 
5.14 Report Appendices 
 
Listing by arm of enrolled women who experienced primary safety endpoint, including: 
blinded ID; adverse event and grade associated with safety endpoint; week of event; 


P1078 Statistical Analysis Plan  Version 2.0                                                                                        
whether treatment was temporarily discontinued, permanently discontinued, or not; week 
of treatment discontinuation  [STATUS, PE4005, TRAC]