Clinical trial NCT02412436
Conditions: HIV-1 Infection Tuberculosis
Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Start date: 2015-11-03; Completion date: 2017-06-15
Enrollment: 62 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study was done to evaluate the effect of HIV and TB treatment on a commonly used birth control method. It enrolled women who were infected with HIV and TB and were taking efavirenz (EFV; Sustiva®; an anti-HIV medication), rifampicin (RIF; an anti-TB medication), and isoniazid (INH; an anti-TB medication). The purpose of this study was to find out the best frequency to give depot medroxyprogesterone acetate (DMPA; a hormonal birth control method that is given as a shot every 3 months) in these women. This study also tried to find out if a 150 mg injection of DMPA was effective in preventing ovulation, the process by which the ovaries (the ovaries are part of the female reproductive system) release an egg for fertilization, for 12 weeks in women who are taking EFV and RIF. Another purpose of this study was to find out if it is safe to take RIF, EFV and DMPA at the same time.

Detailed description:
Globally, women comprise 52% of all people living with human immunodeficiency virus (HIV). Decisions about contraception in a population of women infected with both tuberculosis (TB) and HIV are of paramount importance. In the setting of the treatment of active TB, preventing pregnancy becomes even more important because it allows women to attain a level of health that will support healthy future pregnancies. Treatment options for TB may be limited in pregnancy because of concerns about teratogenicity. Millions of women around the world use depot medroxyprogesterone acetate (DMPA, trade name Depo-Provera) for prevention of pregnancy. DMPA is an intermediate-acting progesterone-only injectable contraceptive with a high efficacy rate. Unfortunately, DMPA's safety and effectiveness among women co-infected with TB and HIV is unknown since the interactions of TB treatment, combination ART (cART), and DMPA have not been well studied. The results of this study are likely to be applicable to women receiving RIF-containing TB treatment who are not being treated concurrently with EFV as well, given that addition of EFV to RIF is unlikely to increase induction of metabolizing enzymes significantly beyond the induction achieved with RIF alone.

The study population included premenopausal women, 18 to 46 years of age, who were co-infected with HIV and TB. To be eligible to enroll in the study, participants must have been on EFV 600 mg once daily plus two or more nucleoside reverse transcriptase inhibitors (NRTIs) for at least 28 days prior to study entry with no plans to change therapy for the 12 weeks of the study. Women must have been on the continuation phase of active TB treatment (with a minimum of 12 weeks remaining) taking RIF 8-12 mg/kg orally and INH 4-6 mg/kg orally on a 5-day or more per week schedule (or as directed by national guidelines for TB treatment). At study entry/week 0, DMPA 150 mg was administered intramuscularly as a single dose.

Study duration was 12 weeks. Visits occurred at weeks 0, 2, 4, 6, 8, 10, and 12. The key evaluations included physical examination, clinical assessments, hematology, chemistry, HIV RNA, pregnancy testing, plasma progesterone levels, and plasma DMPA concentration levels.

The sample size was 46 participants, of which 42 had to be evaluable. Participants who missed two successive visits prior to week 8 and those who did not complete the week 10 and week 12 clinic visits with available DMPA concentrations and progesterone levels were not evaluable and replaced in the sample size. The final number of participants enrolled was 62 participants, with only 42 evaluable.

Arms: arm 1: At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV).
Interventions: intervention 1: Depot medroxyprogesterone acetate
Intervention descriptions: intervention 1: Depot medroxyprogesterone acetate intramuscular injection

Protocol documents:
Prot_ICF_000.pdf: 
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
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A5338
An Open-Label, Non-Randomized Study of Pharmacokinetic 
Interactions Among Depot Medroxyprogesterone Acetate 
(DMPA), Rifampicin (RIF), and Efavirenz (EFV) in Women 
Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)
A Limited Center Trial of the AIDS Clinical Trials Group 
(ACTG)
DAIDS ES #11982
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Letter of Amendment #2 
          Page 1 of 2 
25 January 2016 
ACTG A5338 Protocol Version 1.0 
 
 
Letter of Amendment #2 for: 
 
A5338 
 
An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among 
Depot Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz 
(EFV) in Women Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)  
 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
 
DAIDS ES # 11982 
 
Letter of Amendment Date: 25 January 2016 
 
 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
 
 
 
 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
 
 
 
 
Fax: 
(301) 628-3302 
Silver Spring, MD  20910 
 
 
LETTER OF AMENDMENT 
 
DATE:  
January 25, 2016 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5338 Protocol Team  
 
SUBJECT: 
Letter of Amendment #2 for Protocol A5338, Version 1.0, 12/12/14 entitled “An 
Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among 
Depot Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz 
(EFV) in Women Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)” 
 
 
The following information impacts the A5338 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by your 
IRB/EC before implementation.  
 
The following information may also impact the Sample Informed Consent (SIC). Your 
IRB/EC is responsible for determining the process of informing subjects of the contents of 
this LOA. 
 


 
Letter of Amendment #2 
          Page 2 of 2 
25 January 2016 
ACTG A5338 Protocol Version 1.0 
 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory 
Support Center. Sites will receive a registration notification for the LOA once the DAIDS 
PRO verifies that all the required LOA registration documents have been received and are 
complete. An LOA registration notification from the DAIDS PRO is not required prior to 
implementing the LOA. A copy of the LOA registration notification along with this letter and 
any IRB/EC correspondence should be retained in the site’s regulatory files. 
 
The following are changes to A5338, Version 1.0, 12/12/14 (noted in strikethrough and bold): 
 
1. In the required TB treatment regimen (Section 5.1.1), the following changes are made: 
 
Required TB treatment (not provided through study): 
 
Rifampicin (RIF) 600 mg 8 – 12 mg/kg orally once daily or as directed by 
the national guidelines for TB treatment. 
 
Isoniazid (INH) 300 mg 4 – 6 mg/kg orally once daily or as directed by the 
national guidelines for TB treatment. 
 
2. In Section 9.1, General Design Issues, the following changes are made in the 2nd 
paragraph: 
 
A woman is eligible for this study if she is premenopausal between the ages of 18 
and 46 and co-infected with HIV and TB.  Women must be on: (1) both RIF- and 
(600 mg once daily) INH-containing TB treatment, and (2) EFV (600 mg once daily) -
based cART at least 4 weeks before study entry. (The participant must be on EFV-
based cART for at least 4 weeks before study entry.) The dose of INH, RIF, and 
EFV is defined in section 5.1.1. 
 
 
The above information will be incorporated into the next protocol version as necessary if the 
protocol is amended. 
 


Clarification Memo #2            Page   1 of 2 
3 August 2016 
ACTG A5338 Protocol Version 1.0 
Clarification Memo #2 for: 
A5338 
An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among 
Depot Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz 
(EFV) in Women Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)  
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 11982 
Clarification Memo Date: 3 August 2016 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
Telephone: 
301-628-3000 
8757 Georgia Avenue, 12th Floor 
Fax:  
 
301-628-3302 
Silver Spring, MD  20910 
CLARIFICATION MEMO 
DATE: 
August 3, 2016 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5338 Protocol Team  
SUBJECT: 
Clarification Memo # 2 for Protocol A5338, Version 1.0, 12/12/14, entitled “An 
Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among 
Depot Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz 
(EFV) in Women Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)” 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your institutional 
review board (IRB); however, as always, you must follow your IRB's policies and 


Clarification Memo #2 
          Page   2 of 2 
3 August 2016 
ACTG A5338 Protocol Version 1.0 
procedures. If IRB review of clarification memos is required at your site, please submit 
this document for review. 
Each site should file a copy of this clarification memo with the protocol for reference. 
The protocol clarifications contained in this memo should be implemented immediately. 
These updates will be included in the next version of the A5338 protocol if it is amended 
at a future date. 
The following are clarifications to A5338, Version 1.0, 12/12/14: 
The use of ethambutol (EMB) does not exclude a woman from participating in the study. This is 
supported by the following sections of the protocol: 

Inclusion criterion 4.1.4: Currently receiving RIF and Isoniazid (INH)-based TB therapy
on at least 5 days per week schedule after completion of the intensive phase of TB
treatment (minimum of 8 weeks of TB treatment) and expected to be on TB treatment for
a minimum of 12 weeks after enrollment.
This criterion does not exclude the use of EMB during the study.

Exclusion criterion 4.2.3: Use of any drugs other than RIF and EFV known to: 1) induce
CYP3A4 system within 30 days and to 2) inhibit the CYP3A4 system with one week prior
to study entry.
Because EMB does not induce or inhibit the CYP3A4 system, its use is consistent with
the language in the protocol.
Although the use of EMB is not prohibited, the sites are reminded to follow their country's TB 
treatment guidelines and to use EMB only if it is part of local standard of care for TB treatment. 
Sites should inform the team if other TB medications will be used in the study. All TB 
medications used in the study should be recorded on study case report forms (CRFs). 
Please contact the A5338 team at ACTG.COREA5338@fstrf.org with any questions. 


Clarification Memorandum #1 
          Page 1 of 2 
27 April 2015 
ACTG A5338 Protocol Version 1.0 
Clarification Memo #1 for: 
A5338 
An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among 
Depot Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz 
(EFV) in Women Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)  
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 11982 
Clarification Memo Date: 27 April 2015 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
Fax:  
(301) 628-3302 
Silver Spring, MD 20910 
CLARIFICATION MEMO 
DATE: 
April 27, 2015 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5338 Protocol Team  
SUBJECT: 
Clarification Memo # 1 to the A5338 Protocol, Version 1.0, 12/12/14 entitled “An 
Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among 
Depot Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz 
(EFV) in Women Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)” 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your IRB; however, 
as always, you must follow your IRB's policies and procedures. If IRB review of 
clarification memos is required at your site, please submit this document for review. 
Each site should file a copy of this clarification memo with the protocol for reference. 


Clarification Memorandum #1 
          Page 2 of 2 
27 April 2015 
ACTG A5338 Protocol Version 1.0 
The protocol clarifications contained in this memo should be implemented immediately.  
These updates will be included in the next version of the A5338 protocol if it is amended 
at a future date. 
The following are clarifications (noted in either strikethrough or bold font) to protocol A5338, 
Version 1.0, 12/12/14: 
1.
Sites Participating in the Study, 2nd paragraph
This is a limited site study, open to select non-US sites. The approved sites are listed on
the Protocol-Specific Web Page (PSWP).
2.
Doses of ARV and TB medications to be collected in the CRF prior to PK in Section 10.2, 1st
paragraph, 1st sentence
Doses of all ARV and TB medications EFV, RIF, and INH taken for over 48 hours prior to
PK will be collected on the CRF at weeks 0, 2, 4, 6, 8, 10, and 12.


Letter of Amendment #1 
          Page 1 of 4 
16 October 2015 
ACTG A5338 Protocol Version 1.0 
Letter of Amendment #1 for: 
A5338 
An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among 
Depot Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz 
(EFV) in Women Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)  
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 11982 
Letter of Amendment Date: 16 October 2015 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
Phone: (301) 628-3000 
8757 Georgia Avenue, 12th Floor 
Fax: 
(301) 628-3302 
Silver Spring, MD  20910 
LETTER OF AMENDMENT 
DATE: 
October 16, 2015 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5338 Protocol Team  
SUBJECT: 
Letter of Amendment #1 for Protocol A5338, Version 1.0, 12/12/14 entitled “An 
Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among 
Depot Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz 
(EFV) in Women Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)” 
The following information impacts the A5338 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by your 
IRB/EC before implementation.  
The following information may also impact the Sample Informed Consent (SIC). Your 
IRB/EC is responsible for determining the process of informing subjects of the contents of 
this LOA. 


Letter of Amendment #1 
          Page  2 of 4 
16 October 2015 
ACTG A5338 Protocol Version 1.0 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory 
Support Center. Sites will receive a registration notification for the LOA once the DAIDS 
PRO verifies that all the required LOA registration documents have been received and are 
complete. An LOA registration notification from the DAIDS PRO is not required prior to 
implementing the LOA. A copy of the LOA registration notification along with this letter and 
any IRB/EC correspondence should be retained in the site’s regulatory files. 
The following are changes to A5338, Version 1.0, 12/12/14 (noted in strikethrough and bold 
font): 
1.
In the Exclusion Criteria (Section 4.2), the following changes are made:
a.
Section 4.2.1 is revised to:
Receipt of DMPA and or any other injectable contraceptive contraceptives within 
180 days prior to study entry.  
b.
Section 4.2.8 is revised to:
Any previous Breast breast cancer diagnosis. 
2.
In Pharmacy: Product Supply, Distribution, and Accountability (Section 5.3), the following
changes are made to allow sites the option to use locally available depot
medroxyprogesterone acetate (DMPA) instead of study-provided DMPA:
a.
The following paragraph is added as the 3rd paragraph in Section 5.3.1
Sites may use locally available DMPA if drug importation issues or delays are 
anticipated or encountered. The locally available DMPA must be approved by 
the A5338 Core Team before it can be used for the study. No additional funding 
will be provided to sites for purchasing DMPA locally, and participants and the 
participants' insurers must not be billed for the product. 
b.
Section 5.3.2
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC or any other source and subsequently dispensed. 
All unused study products must be returned to the NIAID CRPMC (or as otherwise 
directed by the sponsor) Study product not obtained from the CRPMC should be 
disposed of in accordance with the disposal standard operating procedures at 
the site after the study is completed or terminated. The site pharmacist at non-US 
Clinical Research Sites (CRSs) must follow the instructions in the manual Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks in the section Study 
Product Management Responsibilities for the destruction of unused study 
products obtained from the CRPMC. 
3.
In the noncompliance criteria for premature study discontinuation (Section 8.1), the following
changes are made to clarify the criteria for missed doses and pharmacokinetic (PK)
sampling:


Letter of Amendment #1 
          Page  3 of 4 
16 October 2015 
ACTG A5338 Protocol Version 1.0 
a.
Section 8.1.3
Missed 2 or more of the RIF and/or EFV doses within one week prior to PK sampling 
at week 2, 4, 6, or 8 and did not return with acceptable adherence (ie, missed 2 or 
more of the RIF and/or EFV doses) for the rescheduled PK sampling for 2 
consecutive study weeks. 
b.
Section 8.1.4
Missed 2 or more of the RIF and/or EFV doses within one week prior to PK sampling 
at week 10 or 12 and did not return with acceptable adherence (ie, missed 2 or more 
of the RIF and/or EFV doses) for the rescheduled PK sampling. 
4.
In Section 9.5, the following changes are made to add review by an independent Study
Monitoring Committee (SMC) to the planned team monitoring:
The study team will monitor participant accrual to ensure the target number of evaluable 
participants is enrolled. Study sites will be required to report all participant dropouts and 
noncompliance, including missing PK sample times/visits to the study team as soon as 
they occur. The study team will make decisions on participant’s replacement on 
conference calls or by emails. The study team will also review data availability 
reports prepared by the study statisticians and/or laboratory data manager 
regularly, to ensure that samples for primary and secondary analyses are 
collected as anticipated. 
During the study, the safety and tolerability of the study medications will be monitored by 
means of adverse events reports representing laboratory and clinical data, such as 
Toxicity Summary reports or Phase I/II reports provided by ACTG DMC. It is required for 
study sites to enter these data into the DMC database within a specified time period for 
data entry. The study team will discuss these reports on regularly scheduled conference 
calls or by email. It is the responsibility of the study team to interpret the adverse event 
data and make any decisions needed to protect study participants from undue risk. Any 
concerns will be presented to the DAIDS Clinical Representative. 
An ACTG-appointed Study Monitoring Committee (SMC) review will take place at 
the earliest of (a) approximately 50% accrual to the study, (b) 6 months after 
enrollment of the first participant, or (c) if two or more participants become 
pregnant on study treatment.  Subsequent reviews will occur annually for as long 
as there are participants in follow-up. 
5.
In Pharmacology Study Design (Section 10.2), the following changes are made in the 1st and
2nd paragraphs to clarify the criterion for rescheduling a visit for PK sampling and the
schedule of the medroxyprogesterone acetate (MPA) PK and plasma progesterone
evaluations:
Doses of all ARV and TB medications taken for 48 hours prior to PK will be collected on 
the CRF at weeks 2, 4, 6, 8, 10, and 12. The participant should be contacted one week 
prior to the scheduled visit to reinforce the importance of 100% adherence to RIF and 
EFV and of her upcoming appointment. A participant who misses 2 or more doses of RIF 
and/or EFV within one week prior to the scheduled PK sampling at weeks 2, 4, 6, 8, 10, 
and 12 will have the visit rescheduled to one week later. For the week 10 and week 12 
visits, the rescheduled PK sampling should be strictly within the original visit window for 


Letter of Amendment #1 
          Page  4 of 4 
16 October 2015 
ACTG A5338 Protocol Version 1.0 
that visit. The schedule for the remaining visit weeks should not be changed. The rules 
for replacing participants who do not complete the PK are described in sections 8.1 and 
9.5.  
A single 4 mL blood sample for PK will be collected just prior to DMPA injection at week 
0 and at the scheduled visits at weeks 2, 4, 6, 8, 10, and 12. The blood sample will be 
centrifuged within 1 hour of collection to separate the plasma which will be stored at -
70°C or colder until assay for MPA and/or progesterone. 
6.
In the Sample Informed Consent (SIC), the following changes are made in the “Why Would
The Doctor Take Me Off This Study Early?” section to clarify the criteria for missed visits and
missed doses that would lead to premature study discontinuation:
a.
1st bullet
You miss two study visits in a row or you miss either the week 10 or week 12 visit. 
b.
2nd bullet
You do not take the RIF and/or EFV medications as you are supposed to and you 
then do not take the RIF and/or EFV prior to your rescheduled visit to collect the 
blood sample to measure the level of DMPA in your blood. 
The above information will be incorporated into the next protocol version as necessary if the 
protocol is amended. 


 
 
 
 
 
A5338 
 
 
An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among 
Depot Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz 
(EFV) in Women Co-Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB)  
 
 
A Limited Center Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
The National Institute of Allergy 
and Infectious Diseases 
 
 
non-IND Protocol 
 
 
 
 
 
 
 
The ACTG Tuberculosis Transformative  
Science Group:  
 
 
 
 
Richard Chaisson, MD, Chair 
 
Protocol Chair: 
Rosie Mngqibisa, MBChB 
 
 
Protocol Vice Chairs: 
Susan E. Cohn, MD, MPH 
 
Jennifer Robinson, MD, MPH 
 
DAIDS Clinical Representative: 
Catherine Godfrey, MD 
 
Clinical Trials Specialists: 
Laura Moran, MPH  
 
Jhoanna C. Roa, MD 
 
 
 
 
 
 
Final Version 1.0 
December 12, 2014 


A5338 
 
 
Final Version 1.0 
 
 
12/12/14 
 
 
 
 
CONTENTS 
 
 
Page 
 
SITES PARTICIPATING IN THE STUDY ..................................................................................... 4 
PROTOCOL TEAM ROSTER ....................................................................................................... 5 
STUDY MANAGEMENT ............................................................................................................... 8 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ...................................................................... 10 
SCHEMA ..................................................................................................................................... 11 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES .................................................................... 12 
1.1 
Hypothesis ........................................................................................................... 12 
1.2 
Primary Objectives .............................................................................................. 12 
1.3 
Secondary Objectives ......................................................................................... 12 
1.4 
Exploratory Objectives ........................................................................................ 12 
2.0 
INTRODUCTION ............................................................................................................. 13 
2.1 
Background ......................................................................................................... 13 
2.2 
Rationale ............................................................................................................. 19 
3.0 
STUDY DESIGN ............................................................................................................. 20 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS ........................................................ 21 
4.1 
Inclusion Criteria .................................................................................................. 21 
4.2 
Exclusion Criteria ................................................................................................ 23 
4.3 
Study Enrollment Procedures .............................................................................. 24 
4.4 
Coenrollment Guidelines ..................................................................................... 25 
5.0 
STUDY TREATMENT ..................................................................................................... 26 
5.1 
Regimen, Administration, and Duration ............................................................... 26 
5.2 
Study Product Formulation and Preparation ....................................................... 27 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ............................... 27 
5.4 
Concomitant Medications .................................................................................... 28 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ............................................................ 29 
6.1 
Schedule of Events ............................................................................................. 29 
6.2 
Timing of Evaluations .......................................................................................... 30 
6.3 
Instructions for Evaluations ................................................................................. 31 
7.0 
CLINICAL MANAGEMENT ISSUES ............................................................................... 37 
7.1 
Toxicity ................................................................................................................ 37 
7.2 
Pregnancy ........................................................................................................... 37 
7.3 
Breastfeeding ...................................................................................................... 38 
8.0 
CRITERIA FOR PREMATURE STUDY DISCONTINUATION ........................................ 38 
9.0 
STATISTICAL CONSIDERATIONS ................................................................................ 39 
9.1 
General Design Issues ........................................................................................ 39 
9.2 
Outcome Measures ............................................................................................. 39 


A5338 
 
 
Final Version 1.0 
 
 
12/12/14 
CONTENTS (Cont’d) 
Page 
 
9.3 
Randomization and Stratification ......................................................................... 40 
9.4 
Sample Size and Accrual .................................................................................... 41 
9.5 
Monitoring ............................................................................................................ 42 
9.6 
Analyses .............................................................................................................. 42 
10.0 
PHARMACOLOGY PLAN ............................................................................................... 44 
10.1 
Pharmacology Objectives .................................................................................... 45 
10.2 
Pharmacology Study Design ............................................................................... 45 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis ............................... 46 
10.4 
Anticipated Outcomes ......................................................................................... 46 
10.5 
Pharmacogenomics – Host Genetic Analysis ...................................................... 47 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 47 
11.1 
Records to Be Kept ............................................................................................. 47 
11.2 
Role of Data Management .................................................................................. 47 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 47 
11.4 
Expedited Adverse Event Reporting to DAIDS.................................................... 48 
12.0 
HUMAN PARTICIPANTS ................................................................................................ 49 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 49 
12.2 
Participant Confidentiality .................................................................................... 49 
12.3 
Study Discontinuation .......................................................................................... 49 
13.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 49 
14.0 
BIOHAZARD CONTAINMENT ........................................................................................ 49 
15.0 
REFERENCES ................................................................................................................ 50 
 
APPENDIX I: SAMPLE INFORMED CONSENT 
 
 


 
4 
A5338 
Final Version 1.0 
 
 
12/12/14 
 
SITES PARTICIPATING IN THE STUDY 
 
This is a limited site study.  The sites were selected based on the availability of potentially 
eligible subjects, close proximity of the site to a Tuberculosis (TB) clinic, integrated HIV/TB 
programs and interest in the study according to responses to a site feasibility survey.  
 
The approved sites are listed on the Protocol-Specific Web Page (PSWP). 
 
 
 
 
 


 
5 
A5338 
Final Version 1.0 
 
 
12/12/14 
PROTOCOL TEAM ROSTER 
 
Chair 
Rosie Mngqibisa, MBChB 
Durban Adult HIV CRS 
Enhancing Care Foundation 
Durban 
4001  
SOUTH AFRICA 
Phone:  27-31-5663933 
Fax:  
27-86-6184343 
E-mail:  mngqibisa@ecarefoundation.com 
 
Vice Chairs 
Susan E. Cohn, MD, MPH  
Northwestern University Feinberg School of 
Medicine 
Northwestern University CRS  
Infectious Diseases Division 
645 North Michigan Avenue, Suite 900, 
Room 926 
Chicago, IL 60611 USA 
Phone:  312-926-3693 
Fax:  
312-695-5088 
E-mail:  susan-cohn@northwestern.edu 
 
Jenny Robinson, MD, MPH 
Division of Clinical Pharmacology  
Johns Hopkins University School of 
Medicine 
600 North Wolfe Street, Osler 527 
Baltimore, MD 21287 USA 
Phone:  410-550-0336 
Fax:  410-550-0196 
E-mail: jrobin87@jhmi.edu 
 
DAIDS Clinical Representative 
Catherine Godfrey, MD 
HIV Research Branch  
TRP, DAIDS, NIAID, NIH 
MSC 9830 
5601 Fishers Lane 
Bethesda, MD 20892-9830 USA 
Phone:  240-627-3074 
Fax:  
301-432-9282 
E-mail:  cgodfrey@niaid.nih.gov 
 
 
 
Clinical Trials Specialists 
Laura Moran, MPH  
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc.  
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 USA 
Phone:  301-628-3373 
Fax:  
301-628-3302 
E-mail:  lmoran@s-3.com 
 
Jhoanna C. Roa, MD 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc.  
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 USA 
Phone:  301-628-3196 
Fax:  
301-628-3302 
E-mail:  jroa@s-3.com 
 
Statisticians 
Yoninah Cramer, MS 
Statistical & Data Analysis Center 
Harvard School of Public Health and 
Frontier Science & Technology Research 
Foundation 
900 Commonwealth Avenue, 2nd Floor  
Boston, MA  02215 USA 
Phone:  617-632-5901  
Fax:  
617-632-2001 
E-mail:  cramer@sdac.harvard.edu   
 
Susan L. Rosenkranz, PhD  
Statistical and Data Analysis Center 
Harvard School of Public Health 
900 Commonwealth Avenue, 2nd Floor 
Boston, MA 02215 USA 
Phone:  617-632-5915 
Fax:  
617-632-2001 
E-mail:  sue@sdac.harvard.edu 
 
 
 
 
 
 
 
 


 
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PROTOCOL TEAM ROSTER (Cont'd) 
12/12/14 
 
Data Manager 
Kristine Coughlin, BA 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 USA 
Phone:  716-834-0900 Ext. 7239 
Fax:  
716-834-8432 
E-Mail:  coughlin@fstrf.org 
 
DAIDS Pharmacist 
Michelle Wildman, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9E15  
Rockville, MD 20852 USA 
Phone:  240-627-3058 
Fax:  
240-627-3112 
E-mail:  michelle.wildman@nih.gov  
 
Pharmacologist  
Helen McIlleron, MBChB, PhD  
Division of Clinical Pharmacology 
University of Cape Town 
K-45 Old Main Building 
Groote Schuur Hospital  
Observatory 
Cape Town 
7925  
SOUTH AFRICA 
Phone:  27-21-4066292 
Fax:  
27-21-4481989 
E-mail:  helen.mcilleron@uct.ac.za 
 
Pharmacogenomics Specialist 
David Haas, MD 
Vanderbilt Therapeutics Clinical  
Research Site  
Vanderbilt Health-One Hundred Oaks 
719 Thompson Lane, Suite 47183 
Nashville, TN 37204 
Phone:  615-936-8594 
Fax:  
615-936-2644 
E-mail:  david.w.haas@vanderbilt.edu 
 
 
 
 
Investigators  
Kelly Dooley, MD, PhD 
Johns Hopkins Adult AIDS CRS 
Johns Hopkins University 
600 North Wolfe Street, Osler 527 
Baltimore, MD 21287 USA 
Phone:  443-287-0517 
Fax:  
410-614-9978 
E-mail:  kdooley1@jhmi.edu 
 
Cynthia Firnhaber, MD 
Wits HIV CRS 
Clinical HIV Research Unit 
Perth Road 
Westdene 
Johannesburg, Guateng  
2092  
SOUTH AFRICA 
Phone:  27-11-2768800 
Fax:  
27-11-4822130 
E-mail:  cfirnhaber@witshealth.co.za 
 
Gary Maartens, MBChB, MMed 
University of Cape Town 
Division of Clinical Pharmacology 
Observatory 
Anzio Road 
Cape Town  
7925  
SOUTH AFRICA 
Phone:  27-21-4066286 
Email:  gary.maartens@uct.ac.za  
 
Zephne Van Der Spuy, MBChB, PhD 
Department of Obstetrics and Gynecology 
University of Cape Town 
P.O. Box 34584 
Groote Schuur, Cape Town, 7937  
SOUTH AFRICA 
Phone:  27-21-6504987 
Fax:  
27-21-4486921 
Email:  Zephne.VanDerSpuy@uct.ac.za    
 
 
 
 
 
 


 
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PROTOCOL TEAM ROSTER (Cont'd) 
12/12/14 
 
Field Representatives 
Ian S. Mugisa, BDS, MSD 
Joint Clinical Research Center 
(JCRC)/Kampala CRS 
Ring Road, Butikiro House-Mengo 
P.O. Box 10005 
Kampala 256 
UGANDA 
Phone:  256-714992428 
Email:  mugisaian@yahoo.co.uk  
 
Asuman Ssentamu, BSN, MBA 
Joint Clinical Research Center 
(JCRC)/Kampala CRS 
Plot 893 Ring Road, Butikiro House 
P.O. Box 10005 
Kampala 256 
UGANDA 
Phone:  256-414342521 
Fax:  
256-414342632 
Email:  asenta2001@yahoo.com  
 
Laboratory Technologist 
Vandana Kulkarni, MSc 
BJ Medical College CRS 
Jai Prakash Narayan Road, 1st Floor 
Pune 411 001, Maharashtra 
INDIA 
Phone:  91-98-90647587 
Fax:  
91-20-26125432 
E-Mail:  Vandana@jhumitpune.com 
 
Community Scientific Subcommittee (CSS) 
Representative 
Flavia Nakayima Miiro, MSc 
THETA African Solutions for African 
Challenges 
P.O. Box 25757 
Old Kira Road Bukoto 
Kampala  
UGANDA 
Phone:  256-702506386 
Email:  flatmiiro@gmail.com  
 
 
 
 
 
International Site Specialist 
Akbar Shahkolahi, PhD 
ACTG Network Coordinating Center (NCC)  
Social & Scientific Systems, Inc.  
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 USA 
Phone:  301-628-3318 
Fax:  
301-628-3302 
E-mail:  ashahkolahi@s-3.com  
 
Laboratory Data Managers 
Rachael Henderson, BS 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 USA 
Phone:  716-834-0900 Ext. 7331 
Fax:  
716-834-0655 
Email:  henderso@fstrf.org  
 
Amanda Zadzilka, BS 
Frontier Science & Technology Research 
Foundation 
 4033 Maple Road 
Amherst, NY 14226 USA 
Phone:  716-834-0900 Ext. 7284 
Fax:  
716-834-0655 
Email: zadzilka@fstrf.org 
 
 


 
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STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.coreA5338@fstrf.org via e-mail. 
The appropriate team member will respond with a "cc" to actg.coreA5338@fstrf.org.  A 
response should generally be received within 24 hours (Monday-Friday). 
 
Protocol E-mail Group 
Sites should contact the Computer Support Group at the Data Management Center (DMC) as 
soon as possible to have the relevant personnel at the site added to the actg.protA5338 e-mail 
group. Include the protocol number in the e-mail subject line.  
 
Send an e-mail message to actg.user.support@fstrf.org.   
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the protocol team. Send an e-mail message to actg.coreA5338@fstrf.org. 
Include the protocol number, patient identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to pharmacologic laboratory tests, contact the protocol 
pharmacologist. Send an e-mail message to actg.coreA5338@fstrf.org (ATTN:  Helen 
McIlleron). 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), 
the CRF schedule of events, randomization/registration, delinquencies, and other data 
management issues, contact the data manager. CRFs can be downloaded from the FSTRF 
website at www.fstrf.org. 
 
For transfers, reference the Patient Transfer from Site to Site SOP 119, and contact Kristine 
Coughlin directly.  
 
For other questions, send an e-mail message to actg.coreA5338@fstrf.org (ATTN: Kristine 
Coughlin).   
 
Include the protocol number, PID, and a detailed question. 
 
Participant Registration 
For participant registration questions or problems and study identification number SID lists.  
 
Send an e-mail message to rando.support@fstrf.org. Call the Statistical and Data 
Analysis Center (SDAC)/DMC Randomization Desk at 716-834-0900 x7301.    
 
Computer and Screen Problems  
Contact the SDAC/DMC programmers. 
 
Send an e-mail message to actg.support@fstrf.org  or call 716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialist. Send an e-
mail message to actg.coreA5338@fstrf.org (ATTN: Jhoanna Roa and Laura Moran). 
 
 
 


 
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STUDY MANAGEMENT (Cont'd) 
 
Copies of the Protocol 
To request a hard copy of the protocol, send a message to ACTGNCC@s-3.com (ATTN: Diane 
Delgado) via e-mail. Electronic copies can be downloaded from the ACTG Web site 
(https://www.actgnetwork.org). 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Michelle Wildman, protocol pharmacist, at 301-496-7913. 
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5338 team members. 
 
Send an e-mail to actg.coreA5338@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
AE 
AUC 
BMI 
cART 
COC 
CPQA 
DEXA 
DMPA 
FSH 
INH 
IUD 
LMP 
LTBI 
MPA 
NLME 
RIF 
SHIV 
STI 
 
 
adverse event 
area under the concentration-time curve 
body mass index 
combination antiretroviral therapy 
combined oral contraceptives 
clinical pharmacology quality assurance 
dual-energy x-ray absorptiometry 
depot medroxyprogesterone acetate (Depo-Provera) 
follicle-stimulating hormone 
isoniazid 
intrauterine device 
last menstrual period 
latent TB infection 
medroxyprogesterone acetate (Provera) 
nonlinear mixed-effects 
rifampicin 
simian HIV 
sexually transmitted infection 
 
 
 
 


 
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SCHEMA 
 
 
A5338 
 
An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among Depot 
Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz (EFV) in Women Co-
Infected with Human Immunodeficiency Virus (HIV) and Tuberculosis (TB)  
 
 
DESIGN 
This is a phase II open-label, single arm, multicenter, steady-state 
pharmacokinetic (PK) study of drug-drug interactions in HIV-infected 
women treated with depot medroxyprogesterone acetate (DMPA) while 
receiving an efavirenz (EFV)-based combination antiretroviral therapy 
(cART), rifampicin (RIF) and isoniazid (INH) during the treatment of active 
tuberculosis (TB).  
 
Blood samples for DMPA PK analysis will be collected at pre-dose and 
every 2 weeks post DMPA administration. Progesterone levels will be 
tested every 2 weeks post DMPA administration. 
 
 
DURATION  
All participants will be followed for 12 weeks.  
 
 
SAMPLE SIZE 
46 evaluable participants 
 
 
POPULATION 
Premenopausal women 18 to 46 years of age who are co-infected with 
HIV and TB. 
 
Women who participate in this study must be on EFV plus two or more 
nucleoside reverse transcriptase inhibitors (NRTIs) for at least 4 weeks 
and intend to continue on this regimen without modifications for the 
duration of the study. Women must be on the continuation phase of active 
TB treatment taking RIF and INH on a 5-day or more per week schedule. 
 
 
REGIMEN 
Depot medroxyprogesterone acetate (DMPA) 150 mg administered 
intramuscularly (IM) as a single-dose at study entry. 
 
An optional dose of DMPA will be available at no cost to all qualifying 
study participants after all week 12 study evaluations are completed.  
 
 
Study provided drug is DMPA only. ARV therapy and TB treatment 
medications will not be provided by this study. 
  


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
Concurrent use of efavirenz (EFV) and rifampicin (RIF) will increase the clearance of 
medroxyprogesterone acetate (MPA) in HIV and TB coinfected women, resulting in 
reduced plasma MPA concentrations and reduced contraceptive efficacy. 
 
1.2 
Primary Objectives 
 
1.2.1 To estimate the optimal dosing frequency of depot MPA (DMPA) for HIV and TB 
coinfected women taking EFV-based combination antiretroviral therapy (cART) 
and RIF-containing TB treatment based on a target MPA concentration >0.1 
ng/mL. 
 
1.2.2 To determine whether a 150 mg DMPA IM injection will be adequate to suppress 
ovulation through 12 weeks in women taking EFV-based cART and RIF-
containing TB treatment based on serial plasma progesterone concentrations. 
 
1.3 
Secondary Objectives 
 
1.3.1. To estimate the area under the concentration-time curve (AUC), trough 
concentration (Cmin), maximum concentration (Cmax), apparent clearance (CL/F), 
and half-life (t1/2) of MPA in HIV and TB coinfected women taking EFV-based 
cART and RIF-containing TB treatment.  
 
1.3.2. To estimate time and variability in time to MPA Cmin reaching 0.1ng/mL or less in 
HIV and TB coinfected women taking EFV-based cART and RIF-containing TB 
treatment.   
 
1.3.3. To estimate the proportion of participants who maintain MPA levels above the 
minimum level thought to suppress ovulation (MPA 0.1ng/mL) through 12 weeks 
after DMPA administration. 
 
1.3.4. To evaluate the toxicity and safety of concurrent RIF, EFV, and DMPA use. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To explore whether pharmacokinetic (PK) interactions between EFV, RIF, and/or 
DMPA are affected by human genetic polymorphisms that have been reported to 
affect metabolism of these drugs. 
 
1.4.2 To explore body mass index (BMI) and body fat content over time and correlate 
with DMPA levels. 
 
1.4.3 To explore relationship between DMPA and bone metabolism in the HIV and TB 
coinfected women. 
 


 
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2.0 
INTRODUCTION 
 
2.1 
Background 
 
Tuberculosis (TB) remains the most common cause of morbidity in HIV-infected patients 
in resource-limited countries. In the pre-highly active antiretroviral therapy (HAART) era, 
patients with HIV with latent TB infection (LTBI) had about a 10% risk of developing TB 
disease annually, a proportion that is most important in areas of high TB prevalence. 
HIV, due to its ability to suppress the immune system, is a significant risk factor for 
development of active TB in patients with latent TB [1, 2]. The HIV epidemic has fueled 
the resurgence of the TB epidemic leading to a dramatic increase in TB infections in the 
resource limited countries [3]. HIV infection increases the risk for TB (acquisition, 
reactivation and reinfection), alters its clinical presentation, and reduces survival 
compared to patients with TB who are not HIV infected [4, 5]. A large percentage of 
patients on TB treatment will require combination antiretroviral therapy (cART).  
 
Globally, women comprise 52% of all people living with HIV. In Sub-Saharan Africa, 
women account for approximately 57% of all people living with HIV and the prevalence 
of HIV in women between the ages of 15 and 24 years remains more than twice as high 
as young men in the same age group [6, 7]. In settings of high HIV prevalence, young 
women aged 15 to 24 years experience tuberculosis rates 1.5 to 2 times higher than 
men in the same age group [7]. Decisions about contraception in a population of women 
infected with both TB and HIV are of paramount importance. In the setting of the 
treatment of active tuberculosis, preventing pregnancy becomes even more important 
because it allows women to attain a level of health that will support healthy future 
pregnancies. Treatment options for TB may be limited in pregnancy because of 
concerns about teratogenicity. Indeed, fetal exposure to RIF, although generally 
considered safe, is associated with bleeding disorders. Treatment of TB before 
pregnancy avoids TB exposure in the neonate, a condition associated with high infant 
mortality. 
 
Millions of women around the world use DMPA (Depo-Provera), an intermediate-acting 
progesterone-only injectable contraceptive, for prevention of pregnancy because of its 
high efficacy rate and its ease and convenience of administration [8]. According to data 
from the United Nations (UN) and Africa, more than 50% of women choosing reversible 
contraception in Sub-Saharan Africa use DMPA. Unfortunately DMPA’s safety and 
effectiveness among women coinfected with TB and HIV is unknown since the 
interactions of TB treatment, cART, and DMPA have not been well studied. A 
pharmacological interaction between hormonal contraceptives and RIF was described in 
the 1970s, and unintended pregnancies reported, leading to national guidelines 
recommending alternative dosing schedules for DMPA without good evidence for these 
recommendations [9]. The requirement for a third drug (EFV) with potential interactions 
makes the contraceptive efficacy of DMPA even more difficult to predict. 
 
While some studies suggest that women using progestin-only injectable contraceptive 
may be at increased risk of transmitting HIV to an uninfected partner, most other studies 
have not shown this association except for a recent observational study which 
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uninfected partner [10]. Further work indicated that this might be due to increased genital 
tract viral load in women using this method of contraception [11]. A pigtail macaque 
model looking at the effect of DMPA on simian HIV (SHIV) showed no increase in 
plasma viral load or vaginal shedding of SHIV [12] and a recent prospective study did 
not find an association between DMPA and cervical HIV in well-suppressed women on 
ART [13]. Several studies are underway that will elucidate the relationship between 
contraceptive method choice and infectivity (Clinical Trial on the Effects of Progestin-
based Contraception in the Genital Tract of HIV-infected and Uninfected Women, 
[NCT02103660] and HIV-Target Cell Response in Women Initiating Various 
Contraceptive Methods in High HIV-Incidence Areas: Zim CHIC [NCT02038335]). A 
World Health Organization (WHO) expert group reviewed all available evidence and 
recommended that women at high risk for HIV infection and women living with HIV can 
continue to use all existing hormonal contraceptive methods including DMPA without 
restriction. Women using progesterone-only injectable contraceptive should also be 
advised to use condoms as an HIV preventive measure [14]. 
 
2.1.1 DMPA 
 
Medroxyprogesterone acetate (MPA, Provera) is a 21-carbon synthetic progestin 
with high selectivity and activity resembling those of natural progesterone. MPA 
has been used extensively in combination with estrogens for oral hormone 
replacement therapy in postmenopausal women. Relative to progesterone, MPA 
undergoes substantially less first-pass hepatic metabolism when given orally. 
MPA has a plasma half-life of 24 hours, with hepatic metabolism to various polar 
compounds and their conjugates [1]. DMPA, given as a 150 mg intramuscular 
dose, inhibits ovulation for up to 14 weeks and is therefore, given every 3 months 
to ensure continuous contraception, with a typical use failure rate of 0.3% during 
the first year [15]. The apparent half-life of DMPA is approximately 50 days after 
the intramuscular (IM) injection. Peak plasma concentration (1 to 7 ng/mL) is 
reached within 3 weeks of the injection and decreases exponentially to become 
undetectable at 120 to 200 days after dosing. MPA levels stay above the 
concentration needed to suppress ovulation (0.1 ng/mL) for approximately 3 
months [16, 17, 18]. MPA levels at 3 months (12 weeks, Cmin) after injection 
ranges from 0.04 to 1.31 ng/mL and mean MPA Cmin is 0.45 ng/mL with 
coefficient of variation (CV) of 53% when coadministered with NRTIs only and 
0.37 ng/mL with CV of 57% when co-administered with EFV-containing regimen. 
Women may not ovulate for up to 6 months after the last DMPA dosing [19]. 
 
DMPA prevents conception by inhibiting gonadotropin release, leading to 
ovulation suppression and thinning of the endometrial lining. Luteal activity and 
ovulation, as indicated by a rise in serum progesterone to >5 ng/mL, occurs when 
the MPA concentration drops to <0.1 ng/mL [17, 20, 21]. 
 
DMPA is metabolized via the cytochrome p450 enzyme system [16] and induces 
the activity of CYP3A4. When given as an injectable, MPA induces activity of 
CYP3A4 by 25% [18]. PK studies of DMPA with selected antiretroviral agents 
have not demonstrated a reduced contraceptive efficacy as assessed through 
ovulation suppression measured by progesterone levels [16, 19]. Non-NRTIs 


 
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(NNRTIs) and protease inhibitors (PIs) have demonstrated significant interactions 
with combined oral contraceptives (COC), which might lead to decreased efficacy 
of the COC [22, 23]. Studies of interactions between ART and DMPA have not 
demonstrated any clinically significant changes in the levels of either selected 
cARTs or DMPA. Cohn et al. showed that there were similar levels of DMPA in 
women on selected cART regimens (nelfinavir [NFV], nevirapine [NVP] and EFV) 
compared to women not on cART [16, 24]. Another small study done recently 
also failed to show significant changes in the PK of DMPA in HIV-infected women 
on cART with zidovudine (ZDV), lamivudine (3TC), and EFV [19]. This cART 
combination did not increase DMPA-related adverse events nor did it decrease 
the effectiveness of DMPA [19]. DMPA has not been shown to significantly alter 
the levels of antiretroviral drugs.  The levels of EFV remained unchanged 
compared to baseline in the Cohn et al. study [16]. Current guidelines do not 
recommend changes in dosing frequency for patients on EFV-containing cART 
who use DMPA.   
 
It is unknown whether simultaneous treatment of HIV and TB affected the serum 
concentration, efficacy, or adverse effects (AEs) of DMPA. 
 
There have been concerns about decreased effectiveness of DMPA in obese 
women.  No pregnancies were documented in two large phase 3 trials that 
included 193 women (of 1787 total) with a body mass index (BMI) of >30 [25]. A 
detailed study designed to assess the efficacy of DMPA in obese women 
revealed fluctuating estrogen levels consistent with follicular development, but no 
evidence of ovulation [26]. Patients being treated for both TB and HIV may 
experience even more variability in estrogen and DMPA levels. Patients treated 
for TB typically gain weight. The proportion of fat gain in that setting is variable 
and may affect DMPA metabolism. In the exploratory objective, BMI and body fat 
content will be estimated over time and compared to DMPA levels.   
 
Safety Profile:  
 
DMPA is safe in HIV infected women. There were few toxicities in the ACTG 
A5093 study related to DMPA with abnormal menstrual bleeding being the most 
frequent and similar to non-HIV-infected populations [16, 24]. Watts et al. 
demonstrated no significant changes in the levels of circulating HIV viral load in 
patients after administration of DMPA [24].  
 
The most common side effects are menstrual irregularities (bleeding or spotting), 
amenorrhoea (2.1%) abdominal pain/discomfort 11%, weight gain (37.7%), 
dizziness 6%, headache 17%, nervousness 11%, and decreased libido 6%. 
 
DMPA users were found to gain more weight than users of other forms of 
hormonal contraceptives with a >10% weight gain demonstrated in some 
populations [27]. A prospective cohort found that after 18 months of use women 
with a BMI ≥30 had a significantly higher mean weight increase (9.45 kg) 
compared to women with a BMI <25 (4.04 kg). A baseline assessment of BMI 
may predict weight gain expected with DMPA use [28]. 


 
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Other less common adverse reactions include loss of bone mineral density, 
thromboembolic disorders, insomnia, depression, acne, breast pain, and 
arthralgia. 
 
2.1.2 Rifampicin (RIF): 
 
Rifampicin is a semi-synthetic rifamycin derivative that is highly active against 
mycobacteria, most gram-positive bacteria, and some gram-negative bacteria. It 
is bactericidal for both intracellular and extracellular microorganisms. By 
inhibiting prokaryotic DNA-dependent RNA polymerase, it suppresses the early 
elongation of the nucleotide chain in RNA synthesis. It is a key component of TB 
treatment and RIF containing regimens are associated with reduced mortality 
compared to non RIF containing regimens. Studies have demonstrated that 
addition of RIF to a TB regimen shortens the duration of treatment with higher 
cure rates [29]. Menzies et al. demonstrated that regimens that contained RIF for 
only 1-2 months of TB treatment instead of 6 months had high failure rates with 
an increased chance of relapse and resistance development [30].  
  
An oral dose of RIF is absorbed completely when taken on an empty stomach, 
and after 1.5 to 2 hours, a 600 mg dose yields a peak blood level of 8 to 20 
mcg/mL. The half-life of RIF varies from 2 to 5 hours, and it is shortened by 
approximately 20 to 40% after the first week of daily treatment because of RIF’s 
auto-induction of hepatic microsomal enzymes. The half-life is unaffected by 
renal impairment but is increased by liver disease or biliary obstruction. RIF is 
deacetylated to an enterohepatically recirculated active metabolite, and 50% to 
60% is excreted in the feces. Up to 30% of a dose is excreted in the urine. 
Approximately 85% of circulating RIF is bound to plasma proteins, and is widely 
distributed throughout the body. Certain genetic polymorphisms have been 
associated with reduced concentrations of rifamycin antibiotics, including RIF 
[31].   
 
RIF is a potent inducer of multiple cytochrome P450 enzymes, such as CYP3A 
and CYP2B6, and drug transporters can accelerate clearance of drugs 
metabolized via the cytochrome p450 system, including cART [18, 19, 22] with 
potential loss of efficacy of these drugs.  
 
RIF reduces the concentrations of many antiretroviral medications, especially PIs 
like atazanavir (ATV) and lopinavir/ritonavir (LPV/r) [32], and NNRTIs like NVP. 
The effect of RIF on EFV concentrations appears to depend on the CYP2B6 
metabolizer genotype of the patient. CYP2B6 genotype not only determines the 
plasma EFV concentration at a given time point but also the long-term effects of 
EFV auto-induction on plasma exposure. Individuals with the extensive-
metabolizer phenotype tend to have a pronounced EFV auto-induction effect, 
which has influence on the long-term therapeutic outcome [33]. In patients 
coinfected with TB and HIV, EFV-metabolizing enzymes are induced maximally 
during the first 4 weeks of RIF’s use and EFV therapy does not induce the 
enzymes to any greater extent. This suggests that EFV has no significant 
additive or synergistic enzyme induction effect with on-going RIF therapy in 


 
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HIV/TB co-treated patients. That is to say, the duration of therapy influences 
long-term EFV auto-induction in the absence of RIF; however, in the presence of 
RIF, maximal induction occurs during the early stages of therapy, and prolonged 
EFV dosing does not further reduce EFV concentrations in these auto-inducers 
[34]. A study done in South Africa found no evidence of a decrease in EFV mid-
dosing interval plasma concentration in the presence of RIF, and a high 
proportion of South Africans were found to have the CYP2B6 polymorphism 
which impairs metabolism of EFV [35]. Similar results were demonstrated in a 
study in South India which concluded that RIF did not significantly alter the 
steady-state PK of EFV in HIV-infected patients [35, 36]. Globally, among HIV-
infected patients who require RIF-containing TB therapy, EFV-based cART is the 
preferred HIV regimen. 
 
Safety Profile:  
 
In the usual daily dose of 10 mg/kg (maximum 600 mg), RIF is well tolerated. It 
often causes harmless red-orange discoloration of tears, sweat, saliva, feces, 
and urine. Less than 4% of TB patients experience significant adverse reactions 
to RIF. Gastrointestinal AEs are the most common, and they include epigastric 
distress, anorexia, nausea, vomiting, cramps, and diarrhea. Hepatitis rarely 
occurs in persons who have normal baseline hepatic function. The incidence of 
hepatitis may be increased for older persons and those who have chronic liver 
disease or alcoholism, but remains substantially lower than that for pyrazinamide 
or isoniazid. RIF can cause a flu-like syndrome of fever, chills, and myalgia (felt 
to be related to the development of antirifampicin antibodies), although this is 
uncommon using the 600 mg dose given daily or thrice-weekly. In a very small 
proportion of patients the flu-like syndrome is associated with interstitial nephritis, 
acute tubular necrosis, thrombocytopenia, hemolytic anemia, and shock.  There 
may be changes in menstruation like oligomenorrhoea and amenorrhea [37]. 
 
2.1.3 Efavirenz (EFV): 
 
EFV is a potent NNRTI that is widely used in combination with other ARVs for the 
treatment of HIV-1 infection. Studies support its use for initial therapy.  
 
The single dose of the 600 mg EFV tablet administered to patients after a high-
fat/high-calorie meal and while fasting was generally well tolerated. Even though 
the US FDA approved a revised label for EFV stating that the dose should be 
increased to 800 mg daily in patients also taking rifampin who weigh over 50 kg, 
the CDC recommends use of the standard 600 mg dose of EFV in patients being 
cotreated for TB regardless of their weight. The evidence for use of a higher dose 
of EFV in this clinical scenario is inconclusive, and the higher EFV dose has 
been associated with an increased incidence of neurotoxic side effects. There is 
large inter-individual variability in EFV metabolism, such that universally 
increasing the EFV dose in participants weighing over 50 kg may increase the 
incidence of EFV-related AEs. 
 


 
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Steady-state plasma EFV clearance is known to be affected by relatively frequent 
genetic polymorphisms, primarily in CYP2B6 (esp. rs3745274 and rs28399499) 
[38, 39, 40, 41, 42], and perhaps also in CYP2A6 [43]. Genotyping of CYP2B6 
can be used to characterize individuals as belonging to slow, intermediate, and 
extensive EFV metabolizer groups. Metabolites of EFV lack anti-HIV activity. 
 
Safety Profile:  
 
The most significant AEs observed in patients receiving EFV were central 
nervous system (CNS) symptoms, psychiatric symptoms, and rash [44]. Fifty-
three percent of individuals noted CNS complaints, which may include dizziness, 
insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, 
depression, confusion, agitation, amnesia, hallucinations, stupor, abnormal 
thinking, and depersonalization. In addition, convulsions have been observed in 
the presence of known medical history of seizures. CNS symptoms usually begin 
during the first 1 or 2 days of therapy and generally resolve after the first 2 to 4 
weeks. Dosing at bedtime improves the tolerability of these symptoms and is 
recommended during the first weeks of therapy and in patients who continue to 
experience these symptoms.  
 
Serious psychiatric adverse experiences have been reported, including severe 
depression, suicidal ideation or attempts, aggressive behavior, paranoid 
reactions, and manic reactions. Rash is usually mild to moderate and occurs 
within the first 2 weeks of initiating therapy. In most persons, rash resolves with 
continuing EFV therapy within 1 month. EFV can be reinitiated in persons 
interrupting therapy because of rash. 
 
There is concern for potential teratogenic effects with EFV exposure in the first 
trimester of pregnancy. An increased incidence of neural tube defects has been 
observed in fetuses from EFV-treated monkeys that received doses resulting in 
plasma drug concentrations similar to those in humans given 600mg/day. There 
are also case reports of neural tube defects linked to first trimester EFV exposure 
in humans. Therefore, pregnancy should be avoided in women receiving EFV, 
and barrier contraceptives should always be used in combination with hormonal 
contraceptives to maximize pregnancy prevention.   
 
Most new-onset AEs were reported as mild and transient. A greater percentage 
of patients who received EFV under fed conditions (91.3%) reported AEs 
compared with patients who received EFV under fasted conditions (73.9%). 
Patients who received EFV after the meal also reported individual AEs more 
frequently. The AEs that were reported by >10% of patients under fed conditions 
included dizziness (16, 69.6%), headache (7, 30.4%), impaired concentration (6, 
26.1%), and nausea (3, 13%). The AEs that were reported by >10% of 
participants under fasted conditions included dizziness (10, 43.5%, headache (4, 
17.4%), and impaired concentration (4, 17.4%). Two (10%) patients each 
reported an AE of moderate intensity that was considered to be of possible 
(headache, fasted) or probable (abdominal pain, fed) relationship to study 
medication. There were no serious AEs or deaths reported. No clinical laboratory 


 
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results were reported as AEs by the investigator.  No one discontinued the study 
because of an AE. 
 
It is recommended that EFV be taken on an empty stomach, preferably at 
bedtime. For more information concerning EFV, refer to the most recent package 
insert. 
 
2.2 
Rationale 
 
The high burden of TB in HIV-infected women, the increased prevalence of HIV in 
women of reproductive age, and the limited data on use of DMPA in women being 
treated simultaneously for TB and HIV make it crucially important to understand the 
clinical significance of interactions among DMPA, EFV, and RIF given the significant 
number of women who could benefit from this combination of medications [45]. It is not 
known whether patients taking RIF and EFV together eliminate MPA faster than women 
taking DMPA alone. This needs to be evaluated to determine the optimal frequency of 
DMPA injections in HIV/TB co-infected patients. 
 
Given that women of reproductive potential are overrepresented in the population of 
HIV/TB coinfected individuals and given the risk to the mother and fetus if pregnancy 
occurs during co-treatment of these infections, reliable contraception for this population 
of women is especially important. While it has been shown that RIF reduces the levels of 
both oral estrogen and progesterone [46, 47], its effect on injectable progestin has not 
been clearly characterized. Because MPA is extensively metabolized in the liver, largely 
by CYP3A, it is likely that RIF will reduce MPA concentrations when DMPA and RIF are 
coadministered [15]. Some country guidelines, including the 2004 South African 
guidelines, have recommended shortening the dosing interval of DMPA from 12 weeks 
to 8 weeks in patients concurrently taking RIF [48]. Even though these guidelines were 
revised in December 2012 to recommend use of DMPA with the 12-week dosing interval 
in patients on rifampicin, there has been no new data on the effectiveness of DMPA in 
these patients. Australian Centre for Disease Control (CDC) guidelines for control of 
Tuberculosis in the Northern Territory recommend use of methods of contraception in 
patients on RIF other than DMPA and COC [49]. Some country guidelines, however, 
recommend use of DMPA keeping the 12-week dosing interval, even though the effects 
on pregnancy risk are unknown in patients coinfected with TB. The WHO document, 
Medical Eligibility Criteria for Contraceptive Use, recommends use of DMPA but advises 
medical followup by the provider [50]. However, there are still limited data on whether 
RIF has a negative impact on the effectiveness of DMPA [51], even when DMPA is given 
more frequently, and the optimal dosing frequency for DMPA has not been established 
in this population. This study, therefore, will focus on the effects of combined RIF-
containing TB treatment and EFV-based cART on DMPA. 
 
DMPA suppresses the pituitary-ovarian-uterine axis and consequently may result in a 
hypoestrogen state which may lead to bone resorption exceeding bone formation 
resulting in reduced bone mineral density especially in adolescence and early adulthood 
before full bone maturity is attained. This loss in bone mineral density is unlikely to 
happen in the first 12 weeks and appears to be the greatest in the first 2 years of use 
and plateaus thereafter. [52, 53] In 2004, the FDA issued a black box warning that the 


 
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reduced mineral density may not be completely irreversible and its effect in increased 
risk of osteoporotic bone fractures later in life is unknown [54]. Currently, bone mass 
measurement heavily relies on x-ray like DEXA scan which are expensive and not easily 
accessible in resource limited settings. Development of future assays for biomarkers of 
bone metabolism for early detection of reduced bone mass will be very useful. The 
mechanism for the bone loss has not been extensively studied, with very little data in 
HIV-infected women. Because of this, blood for bone biomarkers will be collected before 
and 12 weeks after receiving DMPA and future funding for analyses of these specimens 
will be sought. Of particular interest is the potential additive toxicity of tenofovir disoproxil 
fumarate (TDF)-containing regimens and other agents that increase bone resorption.  
This study is not powered to assess this interaction, but evaluation of the cART 
regimens may lead to the detection of a signal warranting further study. 
  
This study will enroll women with known TB infection during the continuation phase of 
RIF-containing TB treatment regimen who are on a stable cART regimen consisting of at 
least 2 NRTIs and EFV. Women will be given DMPA after being on EFV-based cART for 
at least 4 weeks and on RIF-containing TB treatment for at least 8 weeks. PK 
assessments for MPA will be assessed pre-dose then every 2 weeks after starting 
DMPA administration, through week 12. The rationale for giving DMPA at this time point 
is: (1) RIF and EFV concentrations are near steady state and maximal induction effect 
will be achieved; and (2) RIF dosing frequency does not change during the continuation 
phase of TB treatment (whereas frequency and concurrent TB drugs may change 
between the intensive and the continuation phases). Initiating the study treatment within 
the four weeks after completion of intensive phase TB treatment allows a 12-week 
period required for completion of the study. 
 
The results of this study are likely to be applicable to patients receiving RIF-containing 
TB treatment that are not being treated concurrently with EFV as well, given that addition 
of EFV to RIF is unlikely to increase induction of metabolizing enzymes significantly 
beyond the induction achieved with RIF alone. 
 
 
3.0 
STUDY DESIGN 
 
A5338 is an open-label, non-randomized 12-week, single-arm study to determine the PK 
of single-dose DMPA among women with TB and HIV co-infection who are receiving 
RIF-containing TB treatment plus EFV-based cART. Biomarkers of suppression of 
ovulation will also be evaluated. Participants will be HIV and TB co-infected women who 
have completed the intensive phase and are already in the continuation phase of RIF-
containing TB treatment and who have been on EFV-based cART for at least 4 weeks. 
 
Women diagnosed with TB and who are not already receiving HIV treatment at the time 
of screening for eligibility may start cART at any time between 2 and 8 weeks after TB 
treatment has been initiated, at the discretion of the treating physician and health care 
provider at the local clinic and in accordance with national and local treatment 
guidelines. Women who develop TB while on ART may also participate in the study. At 
study entry, all participants will receive a single IM injection of DMPA.  
 


 
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We will estimate individual MPA elimination rates, and then examine if any participant 
has a plasma progesterone level >5 ng/mL by the time that the estimated MPA level 
reaches 0.1 ng/mL. If data allows, a correlation between plasma progesterone levels and 
MPA concentrations observed at study weeks 10 and 12 will be investigated to better 
understand a minimum threshold of MPA concentration level to prevent ovulation using 
plasma progesterone level. If MPA clearance is induced by the co-administered drugs, 
the study week 10 and later are thought to be the times when ovulation would be most 
likely to occur, and increased plasma progesterone levels would be seen.   
 
We will estimate MPA area under the concentration-time curve (AUC) by collecting PK 
samples from baseline (week 0) pre-DMPA dosing through week 12 after DMPA dosing 
from all participants. We will determine whether potential PK interactions between EFV-
based cART with RIF and DMPA affect the suppression of ovulation as measured by the 
proportion of participants whose progesterone level is >5 ng/mL at weeks 2, 4, 6, 8, 10, 
and 12. We will also determine the proportion of women who have sub-therapeutic 
concentrations of MPA (levels <0.1 ng/mL) at different time points. Using a combination 
of both sub-therapeutic concentrations of MPA and progesterone >5 ng/mL, we will be 
able to determine whether contraception is thought to be maintained throughout the 12-
week study. Mathematical modeling will be employed to determine the optimal frequency 
of DMPA dosing in the setting of TB and HIV cotreatment. 
 
Information about demographic factors that can affect drug concentrations such as age, 
sex, ethnicity, disease state, and concomitant drug use will be collected on all 
participants. Whole blood will be collected and stored for potential pharmacogenomics 
analyses including CYP2B6 genotyping. All participants will be strongly encouraged to 
use condoms and non-hormonal contraceptives for prevention of pregnancy and 
sexually transmitted infections (STI) if engaging in behaviors that put them at risk. The 
participants will be informed that the contraceptive effect of DMPA may be attenuated 
and participants who engage in activities that could lead to pregnancy will be required to 
use another non-hormonal contraceptive. Other forms of hormonal contraceptives will be 
prohibited. Women who have had a tubal ligation or other sterilization procedure, are 
currently using a non-hormonal intrauterine device (IUD) or those whose partners have 
had a vasectomy will be eligible for the study. 
 
All participants will complete self-reported questionnaires to assess adherence to both 
TB therapy and cART, and to collect AEs commonly reported with DMPA, ie, irregular 
bleeding patterns. Adherence will also be assessed by review of patients’ TB treatment 
records and participant’s self-report. 
 
 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 


 
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other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral load. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies, or for sites located in countries other than the United States, a kit 
that has been certified or licensed by an oversight body within that country and 
validated internally. Non-US sites are encouraged to use US FDA-approved 
methods for IND studies.  
 
WHO and CDC (Centers for Disease Control and Prevention) guidelines 
mandate that confirmation of the initial test result must use a test that is different 
from the one used for the initial assessment. A reactive initial rapid test should be 
confirmed by either another type of rapid assay or an E/CIA that is based on a 
different antigen preparation and/or different test principle (eg, indirect versus 
competitive), or a Western blot or a plasma HIV-1 RNA viral load. 
 
4.1.2 Current tuberculosis infection, confirmed or probable diagnosis. 
 
Confirmed TB is defined as: 
• 
demonstration of acid fast bacilli using the Ziehl Nielson or Auramine stain 
OR 
• 
a positive culture of M. tuberculosis OR  
• 
a positive GeneXpert test in sputum, pleural and pericardial fluid, lymph node 
aspirate, cerebrospinal fluid or blood. 
 
Probable TB is based on the clinician’s judgment where acid-fast bacilli are not 
demonstrable but sufficient clinical suspicion exists to initiate empiric TB therapy. 
A probable diagnosis may be based on the presenting clinical symptoms of fever 
for more than 2 weeks, unintentional weight loss of more than 10% of body 
weight, night sweats, positive TB contacts, radiographic findings, and the 
absence of another possible diagnosis.  
 
4.1.3 Currently stable on EFV-based cART for at least 28 days. 
 
See section 5.1.1 for cART initiation if a woman is not on HIV treatment at the 
time of screening and acceptable NRTIs. 
 
4.1.4 Currently receiving RIF and Isoniazid (INH)-based TB therapy on at least 5 days 
per week schedule after completion of the intensive phase of TB treatment 
(minimum of 8 weeks of TB treatment) and expected to be on TB treatment for a 
minimum of 12 weeks after enrollment.  
 
4.1.5 Premenopausal female with presumed normal ovarian function based on normal 
menstrual history and absence of previous ovarian dysfunction diagnosis. 
 
NOTE: Clinical assessment and clinician’s opinion are acceptable for determining 
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4.1.6 Last menstrual period (LMP) ≤35 days prior to study entry.  
 
4.1.6.1 If LMP is >35 days prior to study entry, serum follicle-stimulating 
hormone (FSH) must be 40 MIU/mL. 
 
NOTE: Enrollment after the start of the monthly menstrual flow is preferred. 
 
4.1.7 Negative serum or urine-HCG pregnancy test within 30 days prior to study entry 
and negative pregnancy test at entry at any network-approved laboratory that 
operates in accordance with Good Clinical Practices and participates in 
appropriate external quality assurance programs. 
 
4.1.8 All participants must agree not to participate in a conception process (eg, active 
attempt to become pregnant or in vitro fertilization) for the duration of the study.  
 
Women of reproductive potential, who are participating in sexual activity that 
could lead to pregnancy, must agree to use an additional reliable method of 
contraception while in the study. Acceptable forms of contraceptives include: 
 
Condoms (male or female) with or without a spermicidal agent 
 
Diaphragm or cervical cap with spermicide 
 
Non-hormonal IUD 
 
Bilateral tubal ligation 
 
Male partner vasectomy 
 
4.1.9 Laboratory values within 30 days prior to study entry: 
 
Absolute neutrophil count ≥500 cells/mm3    
 
Platelet count ≥50,000 platelets/mm3  
 
Hemoglobin ≥8.0 g/dL  
 
Aspartate transaminase (AST) and alanine aminotransferase (ALT) <5 x 
upper limit of normal (ULN)  
 
Creatinine ≤1.5 x ULN   
 
Total bilirubin ≤2.0 x ULN 
 
4.1.10 Women between the ages of 18 to 46 years 
 
4.1.11 Ability and willingness to provide written informed consent 
 
4.2 
Exclusion Criteria 
 
4.2.1 Receipt of DMPA and any other injectable contraceptives within 180 days prior to 
study entry. 
 


 
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4.2.2 Receipt of other hormonal contraceptives within 30 days prior to study entry.  
 
4.2.3 Use of any drugs other than RIF and EFV known to: 1) induce CYP3A4 system 
within 30 days and to 2) inhibit the CYP3A4 system with one week prior to study 
entry. 
 
4.2.4 ≤40 kg in weight. 
 
4.2.5 Bilateral oophorectomy.  
 
4.2.6 Less than 30 days postpartum at study entry. 
 
4.2.7 Hypersensitivity to DMPA, MPA, or any of the other ingredients in DMPA. 
 
4.2.8 Breast cancer. 
 
4.2.9 Serious illness requiring systemic treatment and/or hospitalization within 21 days 
prior to study entry.  
 
4.2.10 Karnofsky performance score <70 within 14 days prior to study entry. 
 
4.2.11 Use of any immunosuppressant medication including systemic corticosteroids 
within 30 days prior to study entry. 
 
NOTE:  Use of systemic or inhaled corticosteroids, such as for acute therapy for 
Pneumocystis jiroveci pneumonia (previously called Pneumocystis carinii 
pneumonia; PCP) or asthma exacerbation or TB Immune Reconstitution 
Inflammatory Syndrome (IRIS), and prednisone ≤10 mg (or equivalent) is 
permitted as a stable or tapering dose. 
 
4.2.12 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.13 History of deep venous thrombosis or pulmonary emboli. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(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 


 
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DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant will be asked to read and sign the 
approved protocol consent form. 
 
For participants from whom a signed informed consent has been obtained, an 
ACTG Screening Checklist must be entered through the Data Management 
Center (DMC) Subject Enrollment System.  
 
4.3.2 Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database. 
At entry, participants will be registered according to standard ACTG DMC 
procedures.  
 
4.4 
Coenrollment Guidelines  
 
Sites are encouraged to coenroll participants in A5243, “Plan for Obtaining Human 
Biological Samples at Non-U.S. Clinical Research Sites for Currently Unspecified 
Genetic Analyses”. Coenrollment in A5243 does not require permission from the A5338 
protocol chairs. 
 
For specific questions and approval for coenrollment in other studies, sites should first 
check the PSWP or contact the protocol team via e-mail as described in the Study 
Management section. 
 
 


 
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5.0 
STUDY TREATMENT 
 
Study treatment is defined as a single dose of depot medroxyprogesterone acetate 
(DMPA). ARV and TB therapy are required; however they will NOT be supplied through 
the study. 
 
5.1 
Regimen, Administration, and Duration 
 
5.1.1 Regimen 
 
At study entry/week 0, participants will receive:  
Depot medroxyprogesterone acetate (DMPA) 150 mg administered 
intramuscularly (IM) as a single-dose.  
 
NOTE: An optional additional dose of DMPA will be provided at no cost to all 
study participants who successfully complete all 12 weeks of the study, 
experience no AEs from the first injection, are interested in continuing with DMPA 
outside of the protocol, and after confirmation of a negative pregnancy test.  
 
Required ARV therapy (not provided through study):  
 
Efavirenz (EFV) 600 mg orally once daily in combination with 2 or more 
NRTIs.  
 
Two or more NRTIs 
NOTES: 
a. Acceptable NRTIs include the following:  
 
zidovudine (ZDV) 
 
lamivudine (3TC) 
 
emtricitabine (FTC) 
 
didanosine (ddI) 
 
stavudine (d4T) 
 
abacavir (ABC) 
 
tenofovir disoproxil fumarate (TDF)  
b. Refer to section 5.4.2 for the prohibited NRTI combinations. 
 
Women who are not already receiving HIV treatment at the time of 
screening may initiate cART at any time between 2 and 8 weeks after 
starting TB treatment, at the discretion of the treating physician and 
health care provider at the local clinic. 
 
ARV therapy will not be provided through the study. For participants 
requiring changes in ARV therapy during the study, see sections 6.2.4 
and 8.2 for follow-up and study discontinuation. 
 
Required TB treatment (not provided through study): 
 
Rifampicin (RIF) 600 mg orally once daily. 


 
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 
Isoniazid (INH) 300 mg orally once daily. 
NOTE: Pyridoxine (vitamin B6), if recommended by local standard of 
care with INH, will not be supplied through the study and must be 
obtained locally by the site. 
 
Participants must be on the continuation phase of TB treatment with a 
minimum of 12 weeks of TB treatment remaining. 
 
5.1.2 Administration 
 
The 1 mL vial or the 1 mL pre-filled syringe of DMPA should be vigorously 
shaken just before use to ensure that the dose being administered represents a 
uniform suspension. A total of 1 mL (150 mg) of DMPA should be injected deeply 
into the gluteal or deltoid muscle.  
 
5.2 
Study Product Formulation and Preparation 
 
Depot medroxyprogesterone acetate (DMPA) is supplied in vials and pre-filled syringes, 
each containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension at a 
concentration of 150 mg/mL. The product must be stored at 20°C to 25°C (68°F to 
77°F). 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Depot medroxyprogesterone acetate (DMPA) will be supplied by Greenstone 
LLC. 
 
Study product will be available through the National Institute of Allergy and 
Infectious Diseases (NIAID) Clinical Research Products Management Center 
(CRPMC). The site pharmacist should obtain the study product(s) for this 
protocol by following the instructions in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks in the section Study Product 
Management Responsibilities.  
 
Any study product not provided by the study must comply with the NIAID 
(DAIDS) policy that outlines the process for authorizing the use of study products 
not marketed in the US in NIAID (DAIDS)-supported and/or -sponsored clinical 
trials. This policy is available on the NIAID (DAIDS) website at: 
http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Docume
nts/NonFDAapprovedProducts.pdf 
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
products must be returned to the NIAID CRPMC (or as otherwise directed by the 


 
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sponsor) after the study is completed or terminated. The site pharmacist at non-
US Clinical Research Sites (CRSs) must follow the instructions in the manual 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks in the 
section Study Product Management Responsibilities. 
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the updated ACTG Drug Interactions 
Database located at: http://tdm.pharm.buffalo.edu/home/di_search/Search. 
 
5.4.1 Required Medications 
 
 
EFV-based cART, RIF, and INH (refer to section 5.1.1) 
 
5.4.2 Prohibited Medications 
 
• 
NRTIs are allowed, however, the following NRTI combinations are 
prohibited: 
 
ZDV and d4T 
 
3TC and FTC 
 
ABC and ddI 
 
ABC and TDF 
 
3TC and d4T 
 
ddI and d4T  
 
• 
Other prohibited medications are listed on the A5338 PSWP. 
 
5.4.3 Precautionary Medications 
 
Precautionary medications are listed on the A5338 PSWP. 
 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events 
 
Evaluation 
Screening
Entry 
On-Study (Weeks) and Visit Windows 
Premature Study  
Discontinuation 
Week 0
2 
4 
6 
8 
10 
12 
±3 days ±3 days ±3 days ±3 days ±7 days ±7 days
Documentation of HIV-1 and TB infection 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Menstrual Baseline and Interval History 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medication History 
X 
 
 
 
 
 
 
 
 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence Assessments (cART and TB 
medications) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
X 
 
 
 
X 
X 
Chemistry 
X 
 
 
X 
 
 
 
X 
X 
Liver Function Tests 
X 
 
 
X 
 
 
 
X 
X 
Pregnancy Test 
X 
X 
 
X 
 
 
 
X 
X 
Plasma Progesterone Levels 
 
 
X 
X 
X 
X 
X 
X 
X 
Serum FSH (see section 6.3.8) 
X 
 
 
 
 
 
 
 
 
CD4+/CD8+ 
 
X 
 
 
 
 
 
 
 
HIV-1 RNA 
 
X 
 
 
 
 
 
X 
 
DMPA Injection 
 
X 
 
 
 
 
 
X 
 
DMPA PK 
 
X 
X 
X 
X 
X 
X 
X 
 
Whole blood for Drug Metabolism Genotype 
 
X 
 
 
 
 
 
 
 
Stored Serum for Bone Metabolism Biomarkers
 
X 
 
 
 
 
 
X 
 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant’s starting any study 
medications, treatments, or interventions. At the time of screening, participants 
must have completed the intensive phase and be in the continuation phase of TB 
treatment. Participants must require at least 12 more weeks of TB treatment at 
the time they receive the DMPA injection at study entry. 
 
Site staff are encouraged to contact/liaise with primary care physicians at TB 
clinics for identification of eligible participants prior to completion of the intensive 
phase of TB treatment. Information about the location of the ARV clinic and 
planned timing of cART initiation should be obtained. The identified participants 
will be given appointments for the research clinic as soon as they are initiated on 
cART. Site staff will obtain contact details of these potential participants to 
remind them about scheduled screening appointments. Eligible participants will 
be enrolled as soon as eligibility is determined. 
 
Screening evaluations to determine eligibility must be completed within 30 days 
prior to study entry unless otherwise specified. In addition to data being collected 
on participants who enroll into the study, demographic, clinical, and laboratory 
data on screening failures will be captured in a Screening Failure Results form 
and entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
Entry evaluations must be completed on the day of registration after eligibility is 
determined from the screening evaluations. Participant must begin treatment the 
same day of registration. Entry evaluations must be completed prior to DMPA 
administration. 
 
Enrollment and completion of entry evaluations after the start of the monthly 
menstrual flow is preferred. 
 
6.2.3 
Post-Entry Evaluations 
 
Post-entry evaluations occur after study entry and injection of DMPA. Study visits 
are scheduled as indicated in the Schedule of Events (SOE) in section 6.1. The 
final visit is the week 12 visit. 
 
The visit windows for post-entry evaluations are ±3 days for weeks 2, 4, 6, and 8, 
and ±7 days for weeks 10 and 12. The evaluations at weeks 10 and 12 should be 
performed as close as possible to the ideal visit date.  If the week 10 or week 12 
PK sampling is rescheduled, the reschedule date must be within the original visit 
window for the visit. There must be at least 3 days between the PK samples 
collected at each visit. 
 


 
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NOTE: All PK visits must be scheduled to occur following at least 2 consecutive 
doses of RIF and EFV in those participants who take TB medications <7 days a 
week. 
 
Participants who elect to receive a second dose of DMPA at week 12 (see 
section 6.3.11) will have no further follow-up after the second dose of DMPA is 
administered. 
 
Women who wish to continue receiving DMPA after completing the study will be 
referred to a family planning program or a program at their local clinic.  
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Registered Participants Who Do Not Start Study Treatment 
All case report forms (CRFs) must be completed and keyed for the period up to 
and including week 0. 
 
Premature Study Discontinuation  
Participants who prematurely discontinue from the study will have the premature 
discontinuation evaluations performed as per section 6.1 and then be taken off 
study.   
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
Web site for information about what must be included in the source document: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourced
ocappndx.pdf 
 
All stated evaluations are to be recorded on the CRF and keyed into the database 
unless otherwise specified. This includes events that meet the International Conference 
on Harmonisation (ICH) definitions for a serious adverse event. 
 
Results in death 
 
Life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity  
 
Congenital anomaly/birth defect 
 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the events listed above.   
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 1.0, December 2004 (Clarification, August 2009), which can be 
found on the DAIDS RSC Web site: http://rsc.tech-
res.com/safetyandpharmacovigilance/.  
 


 
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6.3.1 Documentation of HIV-1 and TB Infection 
 
HIV-1 Infection 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the CRF. 
 
TB Infection 
Section 4.1.2 specifies the clinical and laboratory requirements for confirmed or 
probable TB diagnosis.  The TB diagnosis (ie, date of diagnosis and confirmed or 
probable) will be recorded on the CRF; however TB documentation will not be 
recorded. 
 
6.3.2 Medical History 
 
The medical history must include all diagnoses identified by the ACTG criteria for 
clinical events and other diagnoses. In addition to reporting in the CRF all 
diagnoses within the past 30 days, the following diagnoses should be reported 
regardless of when the diagnosis was made. 
 
AIDS-defining conditions 
 
Bone fractures (verbal history accepted) 
 
Coronary heart disease 
 
Cancer (exclusive of basal/squamous cell skin cancer) 
 
Tuberculosis 
 
Documentation of hepatitis B (surface antigen and core antibody) at any time 
prior to entry 
 
Documentation of hepatitis C (antibody) at any time prior to entry 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.3 Menstrual Baseline and Interval History 
 
Baseline History 
Age of menarche and cycle length and frequency will be obtained at the 
screening visit and reported in the CRF.  
 
Interval History 
The last menstrual period (date of first day of bleeding) will be collected at every 
visit and reported in the CRF. 
 
6.3.4 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history and reported in 
the CRF.  
 


 
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Medication History Table 
 
Medication Category 
Complete History or 
Timeframe 
Antiretroviral therapy 
1 year prior to study entry 
Immune-based therapy 
1 year prior to study entry 
Tuberculosis therapy 
Complete 
Hormonal contraceptive therapies 
including barrier methods 
1 year prior to study entry 
Blinded study treatment 
30 days prior to study entry 
Prescription drugs for treatment of 
opportunistic infections 
30 days prior to study entry 
Prescription drugs for prophylaxis of 
opportunistic infections 
30 days prior to study entry 
Prescription drugs (other) 
30 days prior to study entry 
Complementary and Alternative 
therapies 
30 days prior to study entry 
Dietary supplements 
30 days prior to study entry 
Other – In Vitro Fertilization (IVF) 
30 days prior to study entry 
 
6.3.5 Clinical Assessments 
 
In addition to the visits specified in section 6.1, the clinical assessments (except 
height) should be performed when clinically indicated. 
 
Complete Physical Exam 
A complete physical examination will be conducted at screening and as part of 
clinical assessments performed when clinically indicated. The complete physical 
exam will include, at a minimum, an examination of the skin, head, mouth, and 
neck; auscultation of the chest; cardiac exam; abdominal exam; examination of 
the lower extremities for edema; and Karnofsky performance test. It will also 
include signs and symptoms, diagnoses, and vital signs (weight, height, 
temperature, pulse, respiration rate, and blood pressure). 
 
Targeted Physical Exam 
A targeted physical examination is required at all study visits after screening. The 
targeted physical exam must include vital signs (temperature, pulse, respiration 
rate, and blood pressure) and is to be driven by any previously identified or new 
signs or symptoms including diagnoses that the participant experienced. 
 
Height 
Height required to be reported on the CRF at study entry only. 
 
Weight 
Weight required at study entry and at all visits. 


 
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Waist Circumference 
Waist circumference required at study entry and all on-study visits. 
 
Signs and Symptoms 
At entry, all grades that occurred 30 days before entry must be recorded in the 
source document and CRFs.   
 
After entry: 
 
Grades 1 and 2 toxicities must be recorded in the source document.  
 
Grades 3 and 4 toxicities must be recorded in both the source document and 
CRF.  
 
Record all signs and symptoms that led to a change in treatment regardless 
of grade on both source document and CRF. Further evaluation will be 
required for those events that meet Expedited Adverse Event (EAE) or ICH 
reporting requirements. 
 
Diagnoses 
At the entry and post-entry visits, record all diagnoses identified by the ACTG 
criteria for clinical events and other diseases in the source document and CRFs. 
 
HIV and TB Treatment Modifications 
After entry, all modifications to antiretroviral medications and TB drugs including 
initial doses, subject-initiated, physician modifications and/or protocol-mandated 
interruptions, modifications, and permanent discontinuation will be recorded on 
the CRFs. 
 
6.3.6 Concomitant Medications 
 
At the entry and post-entry visits, record the new and discontinued medications in 
the source document and CRFs. 
 
6.3.7 Adherence Assessments for cART and TB Medications 
 
 
Adherence will be carefully assessed at screening, entry/day 0 and post entry 
visits using the ACTG self-report questionnaires completed by the participant or 
completed with the help of site staff (counselor- or nurse-driven). All participants 
will also have their TB treatment record reviewed to monitor adherence to 
treatment. Participants will be encouraged to maintain perfect adherence. 
Participants will be encouraged to bring documentation of TB treatment history, if 
available, TB medication, and cART at all study visits. For sites with clinics 
located at a different location from the TB and ARV clinic, study staff will be 
encouraged to work closely with TB and ARV providers for scheduling of 
participants, provision of medication, and monitoring of adherence to medication. 
 


 
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6.3.8 Laboratory Evaluations 
 
At screening and entry all laboratory values must be recorded.  For post-entry 
assessments, record all Grade 3 laboratory values. All laboratory toxicities that 
led to a change in treatment, regardless of grade, must be recorded. Further 
evaluation will be required for those events that meet EAE or ICH reporting 
requirements. All protocol required labs will be done at the DAIDS-approved local 
lab unless otherwise specified. 
 
Hematology 
Perform hemoglobin, hematocrit, white blood cell count (WBC), absolute 
neutrophil count (ANC), and platelets as clinically indicated in addition to the 
visits specified in section 6.1. 
 
Blood Chemistries 
Perform electrolytes (sodium, potassium, chloride, and bicarbonate), creatinine, 
and blood urea nitrogen as clinically indicated in addition to the visits specified in 
section 6.1. 
 
Liver Function Tests (LFTs) 
Perform total bilirubin, AST (SGOT), and ALT (SGPT), albumin as clinically 
indicated in addition to the visits specified in section 6.1. 
 
Pregnancy Test 
At screening, serum or urine -HCG (urine test must have a sensitivity of ≤25 
mIU/mL) may be used. 
 
Urine -HCG may be used at the entry, post-entry, and premature study 
discontinuation visits and when clinically indicated. 
 
There must be a negative pregnancy test within 30 days prior to study entry as 
well as at the time of study entry. 
 
Perform as clinically indicated in addition to the visits specified in section 6.1. 
 
Plasma Progesterone Levels  
This will be done at a central lab. For details, please see the LPC found on the 
A5338 PSWP. 
 
Serum FSH 
At screening must be performed on women with LMP >35 days. For details, 
please see the current laboratory processing chart (LPC) found on the A5338 
PSWP.   
 


 
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6.3.9 Immunologic Studies 
 
CD4+/CD8+ 
Obtain CD4+ and CD8+ cell counts and percentages at study entry from a 
laboratory that possesses a CLIA certification or equivalent.  
 
6.3.10 Virologic Studies 
 
Plasma HIV-1 RNA 
HIV-1 RNA must be performed by a laboratory certified by the DAIDS Virology 
Quality Assurance (VQA) Program at study entry and at week 12. 
 
6.3.11 DMPA Injection  
 
DMPA 150 mg will be administered intramuscularly (IM) as a single-dose at 
entry/week 0 after all blood samples for week 0 have been drawn.  
 
Participants who successfully completed all their study requirements will be 
offered an extra dose of DMPA at no cost after all evaluations for the week 12 
visit are completed, if in the opinion of the investigator the second DMPA dose 
does not present unnecessary risk to the participant. DMPA dose should be 
given after DMPA level and other blood work have been drawn.  
 
6.3.12 Pharmacokinetic Assays  
 
MPA Levels 
Plasma will be obtained for MPA levels. For details, please see section 10.2 and 
the LPC found on the A5338 PSWP.   
 
6.3.13 Whole Blood for Drug Metabolism Genotype 
 
A single whole blood sample will be obtained at entry from all study participants 
for human genotyping of polymorphisms that have been associated with 
metabolism and/or transport of the study drugs, including EFV (eg, CYP2B6), 
RIF (eg, SLCO1B1), and DMPA. The samples will be processed at the Vanderbilt 
DNA Resources Core Laboratory. See the LPC on the A5338 PSWP for details 
regarding processing and shipping. 
 
If at Entry/week 0 the whole blood for drug metabolism genotype it is not 
obtained, this sample may be obtained at any later visit week. 
 
6.3.14 Metabolic Studies  
 
Biomarkers of Bone Metabolism  
Serum will be collected and stored for future studies of biomarkers of bone 
metabolism. For details, please see the LPC found on the A5338 PSWP.  
 


 
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7.0 
CLINICAL MANAGEMENT ISSUES 
 
7.1 
Toxicity  
 
Toxicities will be evaluated and managed by the study team in close consultation with 
the participants’ primary care clinicians. Ongoing communication between the ACTG 
study staff and the participants’ clinicians will be encouraged. If either the study team or 
primary care clinician becomes aware of an adverse event, he/she will contact the other 
within 24 hours of awareness. 
 
For participants who experience toxicities that require treatment interruption or changes, 
a detailed letter with the results will be sent to primary care physicians by the study staff 
informing them about the toxicities and planned management from the study 
perspective.  
 
If TB medication or cART is held for toxicity by the primary care physician, participants 
must inform the study team. Information about these treatment modification/ 
interruptions must be recorded on the source document and CRF.  
 
Grades 1 and 2: can be managed as per standard of care by the study doctor. 
  
Vaginal Bleeding: ≥Grade 2 must be closely monitored and managed as per standard of 
care. 
 
Grades 3 and 4: participants must be stabilized and referred immediately if required to 
obtain treatment at local hospital.  
 
7.2 
Pregnancy  
 
If a participant becomes pregnant on study, she will continue to be followed on study and 
on cART and TB treatment, and have the study evaluations performed following the visit 
schedule in section 6.1, except the PK evaluation, until she completes the study.  After 
she completes the study, she will be followed for safety until the outcome of her 
pregnancy is known.  
 
If a woman has completed the study or chooses to discontinue from the study before the 
end of the pregnancy, then site staff should request permission to contact her regarding 
pregnancy outcomes at the end of pregnancy. If the information is obtained, pregnancy 
outcomes will be submitted on a CRF at the end of the pregnancy.  
 
Pregnancy Outcomes and Reporting 
A Pregnancy Outcomes CRF should be completed for all participants who become 
pregnant. The intrapartum complications and/or pregnancy outcome should be recorded 
on the CRFs.  
 
Sites are encouraged to report prospectively any pregnancy to The Antiretroviral 
Pregnancy Registry if such occurs during this study. More information is available at 
www.apregistry.com; Fax: 44-1628-789-666 or 910-256-0637; Phone: 910-679-1598. 


 
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7.3 
Breastfeeding  
 
Sites should follow local guidelines to prevent Mother-to-Child Transmission (MTCT) 
during breastfeeding. 
 
 
8.0 
CRITERIA FOR PREMATURE STUDY DISCONTINUATION 
 
8.1 
Participant meets one or more of the criteria for noncompliance.   
 
8.1.1 Failure by the participant to attend 2 consecutive visits at week 2, 4, 6, or 8. 
 
8.1.2 Failure by the participant to attend any of the week 10 or week 12 visit. 
 
8.1.3 Missed 2 or more of the RIF and EFV doses within one week prior to PK 
sampling at week 2, 4, 6, or 8 and did not return with acceptable adherence (ie, 
missed 2 or more of the RIF and EFV doses) for the rescheduled PK sampling 
for 2 consecutive study weeks. 
 
8.1.4 Missed 2 or more of the RIF and EFV doses within one week prior to PK 
sampling at week 10 or 12 and did not return with acceptable adherence (ie, 
missed 2 or more of the RIF and EFV doses) for the rescheduled PK sampling. 
 
NOTE: A participant who prematurely discontinues from the study due to noncompliance 
will be replaced. 
 
8.2 
Participant requires a change in the cART or TB regimen during the 12 weeks on study. 
 
8.2.1 For the purposes of this study, a cART change that will warrant replacement of 
the participant includes: 
 
Addition of another NNRTI or a PI resulting in a NNRTI/PI or any PI 
combination therapy.  
 
Any substitution within the NNRTI class. 
 
Addition of an integrase inhibitor or entry inhibitor to the regimen. 
NOTE:  Participants may stay on study if they change or discontinue one or more 
of their NRTIs since this class of medications is not thought to affect the 
metabolism of DMPA or EFV. See section 5.4.2 for the NRTI combinations that 
are not allowed in this study. 
 
8.2.2 For the purposes of this study, a TB regimen change that will warrant 
replacement of the participant includes: 
 
Stopping RIF secondary to toxicity or resistance. 
 
Addition of other TB medications to the study TB regimen of RIF and INH. 
 
8.3 
Request by the participant to withdraw. 


 
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8.4 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant. 
 
8.5 
Participant judged by the investigator to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the validity 
of the study results. 
 
8.6 
At the discretion of the IRB/Ethics Committee, NIAID, Office for Human Research 
Protections (OHRP), other government agencies as part of their duties, or investigator. 
 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
General Design Issues 
 
This is a phase II, open-label, single arm, PK study to investigate effects of 
coadministered EFV and RIF on PK of DMPA  in HIV- and TB-coinfected women and to 
evaluate whether the current dosing frequency of DMPA is adequate to suppress 
ovulation in women when taken together with an EFV- and RIF-containing regimen. 
 
A woman is eligible for this study if she is premenopausal between the ages of 18 and 
46 and co-infected with HIV and TB.  Women must be on both RIF (600 mg once daily)-
containing TB treatment and EFV (600 mg once daily)-based cART at least 4 weeks 
before study entry. 
 
After HIV- and TB-coinfected women undergo screening evaluations for study eligibility, 
PK samples for MPA concentrations from eligible women will be taken at study entry. 
After entry, PK samples for MPA concentrations will be taken every 2 weeks during the 
12-week study period. Blood samples for plasma progesterone levels will be collected 
from all the eligible women for investigating evidence of ovulation during the 12 weeks of 
DMPA administration. 
 
Eligible women will also undergo study visits for safety labs at weeks 4 and 12.  Signs 
and symptoms will be assessed at bi-weekly study visits. 
 
9.2 
Outcome Measures 
 
9.2.1 Primary Outcome Measures 
 
MPA concentration levels obtained at 2, 4, 6, 8, 10, and 12 weeks after DMPA is 
administered. The 12 week measurement will be the measurement obtained 
closest to 84 days after DMPA is administered. The allowable window for the 
measurement is ±7 days, as stated in section 6.2.3. 
 
Plasma progesterone levels obtained at 2, 4, 6, 8, 10, and 12 weeks after DMPA 
is administered. 


 
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9.2.2 Secondary Outcome Measures 
 
9.2.2.1 Estimation of MPA PK parameters in HIV and TB co-infected women 
taking EFV and RIF: 
MPA PK parameters AUC over the 12 weeks (AUC0-12wk), Cmin, Cmax, 
apparent clearance (CL/F), and half-life (t1/2) calculated using standard 
non-compartmental method: These PK parameters will be calculated 
based on the MPA concentrations obtained every 2 weeks over the 12 
weeks. MPA concentration obtained at entry (prior to DMPA 
administration) will be evaluated as confirmation that no DMPA was 
taken prior to study entry.   
 
9.2.2.2    Estimation of time and variability in time to reach MPA 0.1 ng/mL: 
Times (weeks) where elimination slopes estimated fitting loge-linear 
regression models to the individual MPA concentrations obtained in the 
elimination phase reach MPA level of 0.1 ng/mL: The exact sampling 
time (weeks) will be used. 
 
9.2.2.3    Estimation of the proportion of participants reaching MPA level <0.1 
ng/mL at specified time points: 
MPA concentration levels obtained at study weeks 6, 8, and 10. Since 
the week 12 measurements will be evaluated as the primary outcomes 
(section 9.2.1), the MPA measurements at study weeks 6, 8, and 10 
after DMPA administration will be studied for any earlier sign of MPA 
levels <0.1 ng/mL.   
 
9.2.2.4    Evaluation of toxicity and safety: 
All adverse events with toxicity Grade ≥3 from signs/symptoms and 
chemistry and hematology laboratory analyses. 
 
9.2.3 Exploratory Outcome Measures 
 
9.2.3.1 Human genetic variants/polymorphisms that are known to affect PK of 
EFV (eg, CYP2B6) and RIF (eg, SLCO1B1). 
 
9.2.3.2 Participants’ BMIs and body fat percentages collected over the study 
period of 12 weeks. Body fat percentages will be estimated using age, 
body weight, height, and waist circumference. 
 
9.3 
Randomization and Stratification 
 
Since this study has a single study arm, no randomization will be employed. There will 
be no stratification for participants. 
 


 
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9.4 
Sample Size and Accrual 
 
It is known that DMPA, EFV, and RIF drugs share some common metabolic pathways 
via the CYP3A4 enzyme system: MPA is metabolized by and induces CYP3A4 activity; 
RIF is primarily metabolized by CYP2B6 system but also by CYP3A4 and induces 
CYP3A4 and CYP2B6 enzyme activities; EFV is primarily metabolized by CYP2B6 and 
both induces and inhibits CYP3A4 enzyme activity (mixed and unpredictable activity). 
Therefore, it is anticipated that co-administration with EFV and RIF will induce clearance 
of MPA concentration, resulting in lower MPA concentrations during the elimination 
phase, compared to those seen when DMPA is administered alone. Thus, DMPA may 
need to be administered more frequently when used together with EFV and RIF.   
 
The study hypothesis is that concurrent use of EFV and RIF increases the clearance of 
MPA, resulting in reduced MPA concentrations. The study will evaluate whether more 
frequent DMPA dosing is needed when DMPA is administered in combination with EFV 
and RIF in HIV- and TB-infected women. The evaluation of dosing frequency will be 
conducted by estimating the proportion of women with MPA levels <0.1 ng/mL 12 weeks 
post-dose (at the end of the dosing cycle). The critical value 0.1 ng/mL for MPA levels 
was chosen based on published papers including studies by Mishell [17] and Smit et al. 
[55]. These studies indicate that when MPA level falls below 0.1 ng/mL, serum 
progesterone level rises and the probability of ovulation increases. 
 
In ACTG DMPA studies A5093 and A5283 in HIV-infected women, of the 79 PK 
evaluable participants, 5 women had MPA levels <0.1 ng/mL at 12 weeks after a single 
dose of DMPA was administered. None of these 5 women, however, had any evidence 
of ovulation (serum progesterone levels remained below 5 ng/mL). In a study by Smit et 
al. [56] in 94 women, all but one woman had MPA levels above 0.1 ng/mL at 12 weeks 
after DMPA administration. These 94 women had received either a single dose or 
multiple doses of DMPA. Therefore, based on the single dose studies, the proportion of 
women with MPA levels <0.1 ng/mL (sub-therapeutic MPA levels) 12 weeks post-dose is 
thought to be about 6% in normal DMPA use, although a study conducted by Trussell 
[57] showed that there is a contraceptive failure rate of about 0.3% when DMPA is used 
correctly. 
 
The primary analysis outcome will be the proportion of women with sub-therapeutic MPA 
levels (<0.1 ng/mL) at 12 weeks. A one-sided binomial test with significance level 0.05 
will be used to test the null hypothesis that the proportion of women with sub-therapeutic 
MPA level is 6% or less. A sample size of 42 women provides 90% power to reject the 
null hypothesis if the proportion of women with sub-therapeutic MPA levels in this study 
is at least 21% (this is 15% or higher increase from the 6% threshold).  With a sample 
size of 42 women, the underlying true proportion will be declared as statistically 
significant increase if 6 or more women have sub-therapeutic MPA levels at 12 weeks 
(this is equivalent to saying that 90% CI for the underlying proportion is entirely above 
the 6% threshold). Based on the results from a PK study of oral contraceptives 
containing ethinyl estradiol (estrogen) and norethindrone (progestin) which are 
metabolized by CYP3A4 enzyme [58], the study team considers that the underlying 
proportion of women with sub-therapeutic MPA levels of 21% or higher (15% or higher 


 
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increase from the 6% threshold) is plausible in the setting of coadministration with EFV 
and RIF. 
 
The statistical power was also examined to see if the sample size will achieve a 
plausible power to detect a clinically meaningful decrease (30%) in MPA concentration 
at 12 weeks (MPA Cmin) as one of the secondary objectives. With a significance level of 
0.05, a one-sided t-test showed about 91% and 84% power to detect a 30% decline 
when the coefficient of variation (CV) is 60% and 70%, respectively (in the ACTG study 
A5093, CV of MPA Cmin was approximately 57% when coadministered with EFV). We 
note that this power was examined in loge-scale since it is known that PK parameter Cmin 
has a log-normal distribution.  
 
To protect against 10% loss of the primary outcomes after study accrual is closed, the 
study will enroll a total of 46 women. (In the ACTG DMPA study, A5093, the loss of the 
primary outcomes of week 12 was 9.8% [6 of 61 participants] due to either sample 
specimen loss or assay results not available.) 
 
A participant is considered to be evaluable for the primary objective if the participant 
completes the MPA PK sampling during the study period of 12 weeks after DMPA 
administration. The participant replacement criteria are described in sections 8.1 and 
8.2. 
 
The study team anticipates that the study will enroll approximately 4 participants per 
month and it will take approximately 12 months to meet the target enrollment for the 
study. 
 
9.5 
Monitoring 
 
The study team will monitor participant accrual to ensure the target number of evaluable 
participants is enrolled. Study sites will be required to report all participant dropouts and 
noncompliance, including missing PK sample times/visits to the study team as soon as 
they occur. The study team will make decisions on participant’s replacement on 
conference calls or by emails. 
 
During the study, the safety and tolerability of the study medications will be monitored by 
means of adverse events reports representing laboratory and clinical data, such as 
Toxicity Summary reports or Phase I/II reports provided by ACTG DMC. It is required for 
study sites to enter these data into the DMC database within a specified time period for 
data entry. The study team will discuss these reports on regularly scheduled conference 
calls or by email. It is the responsibility of the study team to interpret the adverse event 
data and make any decisions needed to protect study participants from undue risk. Any 
concerns will be presented to the DAIDS Clinical Representative. 
 
9.6 
Analyses 
 
A detailed statistical analysis plan will be developed after protocol Version 1.0 is finalized 
and before the study is open to accrual. The following will provide a summary of 
analyses that will state key analysis approaches. 


 
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9.6.1 Analyses of Primary Outcome Measurements 
 
The proportion of participants with sub-therapeutic MPA levels (<0.1 ng/mL) will 
be estimated based on the participants who complete the PK sampling at 12 
weeks after DMPA administration. A 90% confidence interval (CI) will be 
provided for proportion using Clopper-Pearson exact method for binomial 
measurements. This CI will provide us reasonable evidence that the true 
proportion is greater than the threshold (6%), by determining whether the 90% CI 
is entirely above the threshold. 
 
Individual-specific MPA concentration-time curves in the elimination phase will be 
estimated by fitting loge-linear regression models to the data of MPA 
concentrations obtained at time of maximum MPA concentration and later. These 
estimated individual elimination curves will then be used to estimate the times 
(weeks) where MPA concentration levels reach at 0.1 ng/mL. We will present 
descriptive statistics of these estimated weeks including mean, SD, median, 
interquartile range, minimum and maximum. Mixed-effects model analysis 
(allowing individual elimination slope to be both fixed and random variable) with 
repeated measurements within individual participants will also be performed to 
estimate the times for comparison purposes with the results obtained using the 
log-linear regression models fitted for individual participants. These modeling 
approaches will provide the population mean estimate of the time where MPA 
concentration level reaches at 0.1 ng/mL with 90% CI, which will guide us to 
determine optimal dosing frequency of DMPA in the study population. Details of 
these modeling approaches will be described in the statistical analysis plan that 
will be generated separately and approved by study team. 
 
Descriptive statistics of plasma progesterone levels will be tabulated by study 
week. If there are participants with progesterone levels >5 ng/mL, the proportion 
and percentage of participants with progesterone levels >5 ng/mL will be 
tabulated by study week. 
 
Relationships of plasma progesterone levels with MPA concentration levels will 
be investigated by exploratory plots and using nonlinear regression models to 
better understand a lower limit of therapeutic MPA level that could prevent 
ovulation. This analysis will be based on MPA and plasma progesterone levels 
observed at week 10 and 12. If MPA clearance is truly induced by the 
coadministered drugs, MPA levels at these times may be low enough that 
plasma progesterone may have risen. We note that if plasma progesterone levels 
have not begun to rise by week 10/12, this analysis may have a poor statistical 
power.    
 
9.6.2 Analyses of Secondary Outcome Measurements 
 
9.6.2.1 Estimation of MPA PKs in presence of EFV and RIF: 
MPA PK parameters AUC0-12wk, concentration at week 12 (trough 
concentration, Cmin). Cmax, CL/F, and T1/2 will be estimated using non-


 
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compartmental approach and descriptive statistics of these PK 
parameters will be presented. For the purpose of evaluating whether 
these PK parameters are significantly different from those in women not 
on the companion drugs, those PK parameters will be compared to 
those from the historic controls (A5093 Control Arm) using 
nonparametric two-sample Wilcoxon test. GMRs in MPA PK parameters 
of co-administration over administration-alone and associated 90% CIs 
will also be presented to provide magnitude of the differences as a 
supplementary analysis. 
 
9.6.2.2 Estimation of time and variability in time to reach a MPA 0.1 ng/mL: 
Times (weeks) and variability in times to reach MPA 0.1 ng/mL will be 
estimated using the analysis methods described in section 9.6.1.    
 
9.6.2.3    Estimation of the proportion of participants reaching MPA level <0.1 
ng/mL: 
The proportion and percentage of participants with MPA concentration 
levels <0.1 ng/mL will be summarized by each of the study weeks 8 and 
10.  90% CI for proportion at each week will be presented using 
Clopper-Pearson exact method. 
 
9.6.2.4    Evaluation of toxicity and safety: 
Signs and symptoms, chemistry and hematology with toxicity Grade ≥3 
will be tabulated by study week.  
 
9.6.3 Analyses of Exploratory Outcome Measurements 
 
9.6.3.1    Inter-individual differences in PK parameters between EFV, DMPA, 
and/or RIF when stratified by human genetic variants that are known to 
predict altered pharmacokinetics of EFV (eg, CYP2B6) and RIF (eg, 
SLCO1B1) will be investigated using descriptive statistics of PK 
parameters categorized by metabolizer status (based on the human 
genetic variants) and performing an nonparametric ordered test (eg, 
Jonckheere-Terpstra trend test) in PK parameters for the priori ordering 
of metabolizer groups in the co-administration if data allows. 
 
9.6.3.2    Associations of MPA PK parameters with baseline BMI and/or body 
fat percentage will be examined using visual plots (eg, scatter plots) 
and investigated using linear or nonlinear regression models. Changes 
of BMIs and body fat percentages at study week 12 from baseline will 
be descriptively summarized. 
 
 
10.0 
PHARMACOLOGY PLAN 
 
Women stable on an EFV and 2 NRTIs-based regimens, who are on RIF and INH, and 
who have not received DMPA within the last 180 days, will receive one dose of DMPA at 


 
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study entry. An optional dose of DMPA will be available at no cost to all study 
participants, after all week 12 study evaluations are completed. Refer to section 5.1.1 for 
the allowed NRTIs and section 5.4.2 for the prohibited NRTI combinations.  
 
The primary PK analysis is described in section 9.6. The secondary PK analysis 
employing a population approach and nonlinear mixed effects modelling is described in 
this section. 
 
10.1 
Pharmacology Objectives 
 
Using nonlinear mixed-effects (NLME) modeling, the population PK of MPA will be 
described in the population in order: 
 
10.1.1 To describe the structural PK model for MPA given in the DMPA formulation. 
 
10.1.2 To identify and quantify the effects of covariates influences on PK (eg, weight 
[including total, fat and lean components], age, time on TB treatment, time on 
ART, adherence to ART and TB treatments, CYP2B6 genotype, etc.). 
 
10.1.3 To characterize between subject and random unexplained components of the PK 
variability. 
 
10.1.4 To predict the time at which the proportion of women with MPA <0.1 ng/L 
matches that at 12 weeks from historical data. 
  
10.2 
Pharmacology Study Design 
 
Doses of all ARV and TB medications taken for 48 hours prior to PK will be collected on 
the CRF at weeks 2, 4, 6, 8, 10, and 12. The participant should be contacted one week 
prior to the scheduled visit to reinforce the importance of 100% adherence to RIF and 
EFV and of her upcoming appointment. A participant who misses 2 or more doses of RIF 
and EFV within one week prior to the scheduled PK sampling at weeks 2, 4, 6, 8, 10, 
and 12 will have the visit rescheduled to one week later. For the week 10 and week 12 
visits, the rescheduled PK sampling should be strictly within the original visit window for 
that visit. The schedule for the remaining visit weeks should not be changed. The rules 
for replacing participants who do not complete the PK are described in sections 8.1 and 
9.5.  
 
A single 4 mL blood sample for PK will be collected just prior to DMPA injection at week 
0 and at the scheduled visits at weeks 2, 4, 6, 8, 10, and 12. The blood sample will be 
centrifuged within 1 hour of collection to separate the plasma which will be stored at -
70°C or colder until assay for MPA and progesterone. 
 
The ACTG Pharmacology Specialty Laboratory at the University of Cape Town will use 
liquid chromatography-tandem mass spectrometry (LC MS/MS) to measure MPA and 
progesterone in the plasma. The assay methods will be validated and submitted to 
Clinical Pharmacology Quality Assurance (CPQA) for review.  
  


 
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10.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
The concentration vs. time data for DMPA will be analyzed using NLME modelling using 
the software NONMEM (Version 7.2) [57].  
 
The modelling approach will follow a stepwise procedure to first identify the structural 
model best describing the data, and then incorporate the effect of the study covariates 
such as weight, age, and effect of concomitant anti-retroviral and anti-tuberculosis 
treatment. 
 
Various structural pharmacokinetic models will be evaluated, focusing on correctly 
characterizing the absorption after intra-muscular injection. The tested models will 
include one, two, and three compartments disposition with first-order elimination and 
zero-, first-order, or saturable absorption.  
 
Statistically significant variability and correlation estimates for the PK parameters will be 
included and the covariates of interest will be evaluated with respect to their impact on 
the PK parameters and their variability. 
 
Allometric scaling [59] will be used to account for the effect of body size on the PK 
parameters, using total body weight or fat-free mass. Other covariate effects will be 
evaluated and included if they significantly improve the ability of the model to describe 
the data. The effect of adherence to and time on ART and TB regimens, and CYP2B6 
genotype (if available), will be investigated on clearance.   
 
Concentrations below the limit of quantification will be included in the analysis and 
handled with established methods [60]. 
 
The tools used for model development and graphical and statistical diagnostics will 
include Xpose, and Perl Speaks NONMEM, and Pirana [61].  
  
The PK profiles will be analyzed using post-hoc Bayesian methods to extract information 
such as peak concentration, overall exposure (AUC), and time above target 
concentration. Simulations will be employed to explore the pharmacokinetic profiles, 
their variability in a population, and how they are affected by weight, concomitant anti-
retroviral or anti-tuberculosis treatment, other covariates found significant, and possibly 
under different dosing scenarios, and to predict the time at which the proportion of 
women with MPA <0.1 ng/L matches that at 12 weeks from historical data. 
 
10.4 
Anticipated Outcomes 
 
The anticipated outcomes are described in the section above. They are the model 
outputs: firstly the population PK of MPA will be described using the primary model 
parameters and secondary measure estimates. Covariate effects on the model 
parameters will be identified and quantified. The model will ascribe variability (due to 
fixed effects, inter individual and random unexplained variability) with accuracy. 
Secondly, simulations will predict the optimal dosing frequency to achieve a target 
trough concentration of >0.1 ng/mL in the target proportion of women. 


 
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10.5 
Pharmacogenomics – Host Genetic Analysis 
 
Inter-individual differences in host genes (eg, those that encode drug-metabolizing and 
transporter proteins) have been associated with inter-individual differences in plasma PK 
of EFV [38, 39, 40, 41, 42, 43] and RIF [62]. The study will therefore evaluate human 
genetic polymorphisms that are known to affect steady-state plasma PK of EFV and RIF. 
Among study participants that receive EFV and RIF, analyses of PK data will take into 
consideration such polymorphisms. If additional polymorphisms are reported to affect 
sex hormones, these may also be studied. 
 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Case report forms (CRF) will be provided for each participant. Participants must not be 
identified by name on any CRFs. Participants will be identified by the patient 
identification number (PID) and study identification number (SID) provided by the ACTG 
DMC upon registration. 
 
11.2 
Role of Data Management 
 
11.2.1 Instructions concerning the recording of study data on CRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
11.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
11.3 
Clinical Site Monitoring and Record Availability 
 
11.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, CRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
11.3.2 The site investigator will make study documents (eg, consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily available 
for inspection by the local IRB, the site monitors, the NIAID, and the OHRP for 
confirmation of the study data. 
 


 
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11.4 
Expedited Adverse Event Reporting to DAIDS 
 
11.4.1 Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at   http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
The DAIDS Adverse Events Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS.  In the 
event of system outages or technical difficulties, expedited AEs may be 
submitted via the DAIDS EAE Form. For questions about DAERS, please contact 
DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site queries may also be sent 
from within the DAERS application itself. 
 
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/.  For questions about EAE reporting, 
please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2  Reporting Requirements for this Study 
 
 
The SUSAR Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
 
The study agent for which expedited reporting is required is depot 
medroxyprogesterone acetate (DMPA). 
 
In addition to the EAE Reporting Category identified above, other AEs that 
must be reported in an expedited manner are: Injection related AEs. 
 
11.4.3 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, December 2004 
(Clarification, August 2009), must be used and is available on the DAIDS RSC 
Web site at http://rsc.tech-res.com/safetyandpharmacovigilance/.  This table will 
be used for all genital and menstrual symptoms. 
 
11.4.4  Expedited AE Reporting Period 
 
 
The EAE reporting period for this study is as per the EAE manual. 
 
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). 
 


 
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12.0 
HUMAN PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB or ethics committee responsible 
for oversight of the study. A signed consent form will be obtained from the participant. 
The consent form will describe the purpose of the study, the procedures to be followed, 
and the risks and benefits of participation. A copy of the consent form will be given to the 
participant, and this fact will be documented in the participant’s record. 
 
12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, NIAID, and 
OHRP, or other government agencies as part of their duties.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, NIAID, or the OHRP, 
or other country-specific government agencies as part of their duties to ensure that 
research participants are protected.  
 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies.  
 
 
14.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention and the National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  
 
 


 
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15.0 
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Depo-Provera injectable contraceptive. Available from: http://www. 
Fda.gov/bbs/topics/ANSWERS/2004/ANS0125.html.  
 
55  Smit J, Botha J, McFadyen L, Beksinska M. Serum medroxyprogesterone acetate levels in 
new and repeat users of depot medroxyprogesterone acetate at the end of the dosing 
interval. Contraception. 2004 Jan;69(1):3-7. 
 
56  Trussell J (2011). "Contraceptive efficacy". In Hatcher RA.; Trussell J; Nelson AL.; Cates W 
Jr.; Kowal D; Policar MS (eds.). Contraceptive technology (20th revised ed.). New York: 
Ardent Media. pp. 779–863. ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC 781956734. 
Table 26–1 = Table 3–2 Percentage of women experiencing an unintended pregnancy 
during the first year of typical use and the first year of perfect use of contraception, and the 
percentage continuing use at the end of the first year. United States. 
 
57  Beal SL, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM User's Guide—Introduction to 
NONMEM 7. Ellicott City: Icon Development Solutions; 2009. 
 
58  LeBel M, Masson E, Guilbert E, et al. Effects of Rifabutin and Rifampicin on the 
Pharmacokinetics of Ethinylestradiol and Norethindrone. Journal of Clinical Pharmacology. 
1998;38:1042-1050. 
 
59  Anderson BJ, Holford NH. Mechanism-Based Concepts of Size and Maturity in 
Pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303-32. 
 
60  Beal SL. Ways to fit a PK model with some data below the quantification limit. J 
Pharmacokinet Pharmacodyn. 2001 Oct;28(5):481-504. 
 
61  Keizer RJ, Karlsson MO, and Hooker A. Modeling and Simulation Workbench for NONMEM: 
Tutorial on Pirana, PsN, and Xpose CPT Pharmacometrics Syst Pharmacol. Jun 2013; 2(6): 
e50. Published online Jun 26, 2013. doi: 10.1038/psp.2013.24. 
 
62  Weiner M, Peloquin C, Burman W, et al. Effects of tuberculosis, race, and human gene 
SLCO1B1 polymporhisms on rifampin concentrations. Antimicrob Agents Chemother. 2010 
Oct;54(10):4192-200. 


 
 
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APPENDIX I 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
SAMPLE INFORMED CONSENT 
 
For protocol: 
An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Among Depot 
Medroxyprogesterone Acetate (DMPA), Rifampicin (RIF), and Efavirenz (EFV) in Women Co-
Infected with Human Immunodeficiency Virus (HIV) and Tuberculosis (TB) 
Final Version 1.0, 12/12/14 
 
 
SHORT TITLE FOR THE STUDY: DMPA in HIV/TB (PRIDE-HT), Final Version 1.0, 12/12/14 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are a woman infected with 
the human immunodeficiency virus (HIV), the virus that causes AIDS; have tuberculosis (TB); 
are taking particular anti-HIV and anti-TB medications; will continue to take TB treatment for at 
least 3 months; and are able to get pregnant.  This study is sponsored by the United States 
(US) National Institutes of Health (NIH).  The doctor in charge of this study at this site is: (insert 
name of Principal Investigator).  Before you decide if you want to be a part of this study, we 
want you to know about the study.  
 
This is a consent form. It gives you information about this study.  The study staff will talk with 
you about this information.  You are free to ask questions about this study at any time.  If you 
agree to take part in this study, you will be asked to sign this consent form. You will get a copy 
to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
This study is being done to evaluate the effect of HIV and TB treatment on a commonly used 
birth control method. This study is being done on women who are infected with HIV and TB and 
are taking efavirenz (EFV; Sustiva®; an anti-HIV medication), rifampicin (RIF; an anti-TB 
medication) and isoniazid (INH; an anti-TB medication).  The purpose of this study is to find out 
the best schedule to give depot medroxyprogesterone acetate (DMPA; a hormonal birth control 
method that is given as a shot every 3 months) in women with HIV and TB who are also taking 
EFV and RIF.  This study will also try to find out if a 150 mg injection of DMPA is effective in 
preventing ovulation, the process by which the ovaries (the ovaries are part of the female 
reproductive system) release an egg for fertilization, for 12 weeks in women who are taking EFV 
and RIF.  Another purpose of this study is to find out if it is safe to take RIF, EFV and DMPA at 
the same time. 
 


 
 
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For this study, DMPA will be provided in the form of an injection.  DMPA is approved by the 
United States Food and Drug Administration (US FDA) for prevention of pregnancy.  The list of 
risks of DMPA is included in this document; the risks are the same that would be encountered 
when DMPA is used outside of the study.   
 
This study will not provide any anti-HIV or anti-TB medications.  The anti-HIV and anti-TB 
medications that participants have to take to be in this study have been approved by the US 
FDA and are not being tested in this study. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Screening 
If you would like to be in this study, after you have read and signed this informed consent form, 
you will come to the clinic for a screening visit to make sure you meet the requirements for 
joining the study.  This visit will take about 1-2 hours.  At this visit: 
• 
Your HIV infection status will be confirmed. If there is no record available, another HIV test 
will be done.  You may have to sign a separate consent form before this is done. 
• 
Your TB infection status will be confirmed. 
• 
You will be asked about your age at the time of your first menstrual period, the first day of 
your last menstrual period, and how often and usual number of days of your menstrual 
periods. 
• 
You will be asked questions about your medical history and any medications you are taking.  
You will also be asked about any anti-TB medications you have ever taken; anti-HIV and 
hormonal birth control mediations you have taken within the last year and other medications 
you have taken within the last 30 days.   
NOTE: You must be taking EFV, RIF and INH to be eligible for the study. 
• 
You will have a complete physical exam, including obtaining your height and weight. 
• 
You will be asked about adherence to your anti-HIV and anti-TB medications (how correctly 
you are taking your medications).  
• 
You will have about 1 tablespoon (15 mL) of blood drawn for routine lab tests for safety.  
You will be told the results of these tests when they become available.  
• 
You will be asked to give a urine sample or have 1 teaspoon (5 mL) of blood drawn to see if 
you are pregnant.  This test must show that you are not pregnant for you to enroll in the 
study.  You will be told the result of the test when it becomes available. 
• 
If it has been more than 35 days since your last menstrual period, you will have an 
additional 2 teaspoons (10 mL) of blood drawn to measure the amount of follicle-stimulating 
hormone (FSH) in your blood.  In women, FSH is the hormone that helps control the 
menstrual cycle and the production of eggs in the ovaries.  You will be told the result of the 
test when it becomes available. 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information.  As part of this screening visit, some demographic (for 
example, age), clinical (for example, disease condition, diagnosis), and laboratory (for example, 
pregnancy test, FSH) information is being collected from you so that ACTG researchers may 
help determine whether there are patterns or common reasons why people do not join a study. 


 
 
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Entry 
If you are eligible for the study, you will be contacted to come in for an entry visit, ideally right 
after the start of your menses.  This visit will last about 1-2 hours.  At this visit: 
• 
You will be asked about your menstrual period and if there has been a change in your 
menstrual period since the screening visit. 
• 
You will have a brief physical exam, which will include obtaining your weight and waist 
measurement, and you will be asked about your health and any changes in your medicines 
since your last visit.  
• 
You will be asked about adherence to your anti-HIV and anti-TB medications. 
• 
You will have about 1 tablespoon (15 mL) of blood drawn to measure your viral load (the 
amount of HIV in your blood) and your CD4+/CD8+ cell count (cells that help fight infection).  
You will be told the results of these tests when they become available. 
• 
You will be asked to give a urine sample or have 1 teaspoon (5 mL) of blood drawn to see if 
you are pregnant.  This test must show that you are not pregnant for you to enroll in the 
study.  You will be told the result of the test when it becomes available. 
• 
You will have about 1 teaspoon (4 mL) of blood drawn to measure the level of DMPA in your 
blood.  You will not receive the result of this test. 
• 
You will have 2 tablespoons (30 mL) of blood drawn and stored for future study-related bone 
test (to check signs of bone health) and genetic test (a test of your DNA [genes] to better 
understand how fast your body removes the study drugs from your blood).  Genetic testing 
looks at differences in people’s genes.  Your body, like all living things, is made up of cells, 
and cells contain deoxyribonucleic acid, also known as “DNA”.  DNA is like a string of 
information put together in a certain order.  Parts of the string make up “genes”.  Genes 
contain instructions on how to make your body work and fight disease.  The testing in this 
study will only look at certain genes that are known to have an effect on how your body uses 
hormones.  The tests will not look at any other genes.  You will not receive the results of 
these tests. 
 
After all of these evaluations are completed, you will receive your DMPA injection. 
 
Study Visits 
After your entry visit, you will come to the clinic again 2, 4, 6, 8, 10, and 12 weeks after the visit 
at which you received DMPA.  These study visits will last about 30 minutes to 1 hour. 
 
During most on-study visits: 
• 
You will be asked when you had your last menstrual period. 
• 
You will have a brief physical exam, which will include obtaining your weight and waist 
measurement, and you will be asked about your health and any changes in your medicines 
since your last visit. 
• 
You will be asked about adherence to your anti-HIV and anti-TB medications. 
• 
You will have 2 teaspoons (10 mL) of blood drawn to measure the amount of progesterone 
in your blood.  Progesterone is a female hormone produced by the ovaries when a mature 
egg is released (from the ovary) and is ready to be fertilized (ovulation).  You will not receive 
the result of this test. 


 
 
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• 
You will have about 1 teaspoon (4 mL) of blood drawn to measure the level of DMPA in your 
blood. 
 
In addition, during the week 4 and week 12 on-study visits: 
• 
You will have about 1 tablespoon (15 mL) of blood drawn for routine lab tests for safety.  
You will be told the results of these tests when they become available. 
• 
You will be asked to give a urine sample or have 1 teaspoon (5 mL) of blood drawn to see if 
you are pregnant.  You will be told the result of the test when it becomes available. 
• 
At the week 12 visit only, you will have an additional 2 tablespoons (30 mL) of blood drawn 
to measure your viral load and stored for future study-related bone tests. 
 
You must inform the study doctor if your primary care physician temporarily stops any of your 
anti-HIV and anti-TB medications because of a harmful side effect while you are in the study. 
 
If You Have to Stop the Study Early 
If you leave the study early, you will be asked to come to the clinic for an additional study visit.  
This visit will last about 1 hour.  At this visit: 
• 
You will have a brief physical exam, which will include obtaining your weight, and you will be 
asked about your health and any changes in your medicines since your last visit.  
• 
You will be asked about adherence to your anti-HIV and anti-TB medications. 
• 
You will have about 1 tablespoon (15 mL) of blood drawn for routine lab tests for safety.  
You will be told the results of these tests when they become available. 
• 
You will be asked to give a urine sample or have 1 teaspoon (5 mL) of blood drawn to see if 
you are pregnant.  You will be told the result of the test when it becomes available. 
• 
You will have 2 teaspoons (10 mL) of blood drawn to measure the amount of progesterone 
in your blood. 
 
Other 
The blood samples collected for the test to measure the level of DMPA in your blood may be 
shipped for storage and testing in South Africa. 
 
The blood samples collected for future study-related bone test and genetic test may be shipped 
for storage in the United States until the tests are performed. 
 
Some of your blood that is left over after all required study testing is done may be stored (with 
usual protectors of identity) and used for ACTG-approved HIV-related research.  These leftover 
blood samples may be shipped for storage in the United States for an indefinite period of time.  
Results of testing performed on these blood samples may not be given to you. 
 
Please indicate now if you agree to have your left-over blood samples stored for future ACTG-
approved HIV-related research.  You may change your mind at any time and your samples will 
be destroyed.  
 
 
 YES 
 
 NO 
 
 


 
 
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HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 46 women will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 12 weeks (about 3 months).   
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
You miss two study visits in a row. 
• 
You do not take the RIF and EFV medications as you are supposed to and you then do not 
take the RIF and EFV prior to your rescheduled visit to collect the blood sample to measure 
the level of DMPA in your blood. 
• 
The blood sample to measure the level of DMPA in your blood could not be collected for two 
study visits in a row or at the week 10 or week 12 study visit (for example, because you 
missed the visit). 
• 
You do not take your anti-HIV and anti-TB medications as you are supposed to. 
• 
You have a severe adverse reaction to your anti-TB and anti-HIV medications and your 
primary care physician has taken you off these drugs. 
• 
You need a treatment that you may not take while on the study. 
• 
Your primary care physician no longer thinks that participating in the study is in your best 
interest or continuing in the study may cause you harm. 
• 
The doctor in charge of the study believes that you may not be able to comply with the 
study, and that this may cause you harm or injury, or may affect the results of the study. 
• 
You are not able to complete the study visits as required by the study. 
• 
The study is stopped or cancelled. 
 
If I have to permanently leave the study, how would DMPA be provided? 
If you complete all 12 weeks of the study, you may be able to receive an additional one dose of 
DMPA at no cost to you after all the evaluations at week 12 are completed. After you have 
completed your study participation, the study will not be able to continue to provide you with 
DMPA that you received on the study. If continuing to take these or similar drugs/agents would 
be of benefit to you, the study staff will discuss how you may be able to obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects please ask the medical staff at your 
site. 
 


 
 
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Risks of DMPA 
• 
Changes in menstrual periods 
• 
Conditions that may lead to the development of blood clots (thromboembolic disorders) 
involving deep veins of the legs, lung, and brain (stroke) 
• 
Headache 
• 
Nervousness 
• 
Dizziness 
• 
Difficulty falling and/or staying asleep 
• 
Depression (a mood disorder that causes a persistent feeling of sadness and loss of interest 
that interferes with your everyday life) 
• 
Swelling/water retention 
• 
Changes in vaginal secretions 
• 
Pain in the stomach area or belly 
• 
Jaundice (a yellowing of the skin) and abnormal liver function tests 
• 
Breast tenderness 
• 
Sensitive skin, hives, and rash 
• 
Acne 
• 
Loss of scalp hair 
• 
Delayed return to fertility 
• 
Weight gain 
• 
Thinning of the bones (Loss in bone density) 
• 
Joint pain 
• 
Pregnancy 
• 
Low sex drive 
 
Studies of women who have used different forms of contraception found that women who used 
DMPA over long periods of time had no increased risk of developing cancer of the breast, ovary, 
uterus, cervix or liver.  However, women under 35 years of age whose first exposure to DMPA 
was within the previous 4 to 5 years may have a slightly increased risk of developing breast 
cancer similar to that seen with oral contraceptives. 
 
At least one research study in humans has suggested an increased rate of HIV infection to the 
uninfected partners of DMPA users, while other studies have found no such relationship. A large 
clinical trial addressing the issue of DMPA and the risk of transmitting HIV is currently ongoing, 
and the WHO has issued guidelines saying that women with HIV can use DMPA without 
restrictions. 
 
If you experience any of the side effects of DMPA, you must contact the study staff who will 
advise you to come to the clinic for assessment. Depending on the severity of your symptoms, 
the study doctor will either manage your symptoms or refer you to the hospital for care. If 
symptoms are mild, the study doctor will give you treatment but for severe symptoms, you will 
be referred to the hospital immediately. 
 
Risks of Drawing Blood  
Taking blood may cause some discomfort, bleeding, bruising, and/or swelling where the needle 
enters the body, lightheadedness, and in rare cases, fainting or infection. 
 


 
 
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Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV or TB 
status secret from people close to you. This may lead to unwelcome discussions about or 
reactions to your HIV or TB status. Please talk with the study staff if you have any concerns in 
this regard. 
 
Other Information 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
Women who become pregnant while receiving DMPA may have an increased risk of delivering 
a baby that has birth defects.  For this reason, we do not recommend that you allow yourself to 
become pregnant while using this medication.  It is not known if taking DMPA together with anti-
HIV and anti-TB drugs affects the levels of DMPA in your blood. 
 
DMPA injections should not be taken during pregnancy.  Pregnant women may not join the 
study.  If you are having sex that could lead to pregnancy, you must agree not to become 
pregnant. 
 
If you decide to participate in this study, you must use at least one barrier method of birth 
control during this study because it is unknown if various combinations of anti-HIV and anti-TB 
medications make DMPA less effective.  You should NOT use DMPA as your ONLY method of 
birth control. 
 
You may choose one or more of the birth control methods listed below:  
• 
Male condom with or without spermicide (a cream or gel that kills sperm) 
• 
Female condom with or without spermicide 
• 
Diaphragm or cervical cap with spermicide 
• 
Non-hormonal intrauterine device (IUD) 
• 
Bilateral tubal ligation (surgery that involves blocking the fallopian tubes [the part of the 
female reproductive system that carries the eggs from the ovary to the uterus or womb] to 
prevent the egg from being fertilized) 
• 
Male partner vasectomy (surgery that prevents the release of sperm from the male partner) 
 
You must NOT use birth control pills during this study. 
 
If you can become pregnant, you must have a pregnancy test before you enter this study.  The 
test must be negative. If you think you may be pregnant at any time during the study, tell your 
study staff right away.  The study staff will talk to you about your choices.  Your choice will not 
affect your usual medical care provided by your doctor.  You may be allowed to join future 
research studies, if you qualify. 


 
 
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If you become pregnant while on study, you will continue taking your anti-HIV and anti-TB 
medications and continue to be seen at the scheduled study visits until you complete the study.  
You will have the study evaluations performed at each visit except the test to measure the level 
of DMPA in your blood. 
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If 
you are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to 
an international database that collects information about pregnancies in women taking anti-HIV 
drugs. This report will not use your name or other information that could be used to identify you. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, it is unlikely that there will be any direct benefit to you. It is also 
possible that you may receive no benefit from being in this study. Information learned from this 
study may help others who have HIV and TB, and improve our understanding of the use of 
DMPA in HIV-infected women. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
treatment with prescription drugs available to you or at your local clinic 
• 
treatment with experimental drugs, if you qualify  
• 
no treatment 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT 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 ACTG, Office for Human Research Protections, (insert 
name of site) institutional review board (IRB)/ethics committee (EC), National Institutes of 
Health (NIH), local National Health Organization, other government agencies, study staff, and 
study monitors. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov. This Web site will 
not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.  
 
 


 
 
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WHAT ARE THE COSTS TO ME? 
 
Study drugs, exams, and lab tests will be provided without charge. Taking part in this study may 
lead to added costs to you and your insurance company. In some cases it is possible that your 
insurance company will not pay for these costs because you are taking part in a research study.   
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Insert site-specific information on compensation to study participants] 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the National Institutes of 
Health. You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research subject, contact: 
• 
name or title of person on the IRB/EC (a local board or committee that reviews, approves 
and monitors research studies involving humans) or other organization appropriate for the 
site 
• 
telephone number of above 
 


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

SAP_002.pdf: 
Statistical Analysis Plan 
 
ACTG A5338: An Open-Label, Non-Randomized Study of 
Pharmacokinetic Interactions Among Depot Medroxyprogesterone Acetate 
(DMPA), Rifampicin (RIF), and Efavirenz (EFV) in Women Co-Infected 
with Human Immunodeficiency Virus (HIV) and Tuberculosis (TB) 
 
ClinicalTrials.gov Identifier: NCT02412436 
 
Version 1.0 
November 28, 2018 
 
 
 


Introduction 
This Statistical Analysis Plan addresses the following secondary objectives listed in the study 
protocol. 
1.3.1. To estimate the area under the concentration-time curve (AUC), trough concentration 
(Cmin), maximum concentration (Cmax), apparent clearance (CL/F), and half-life (t1/2) of MPA 
in HIV and TB coinfected women taking EFV-based cART and RIF-containing TB 
treatment. 
1.3.2. To estimate time and variability in time to MPA Cmin reaching 0.1 ng/mL or less in 
HIV and TB coinfected women taking EFV-based cART and RIF-containing TB treatment.   
Statistical Analysis Plan 
 The concentration vs. time data for DMPA will be analyzed using nonlinear mixed-
effects (NLME) modelling using the software NONMEM (version 7.4.2) (S. Beal, 
Sheiner, Boeckmann, & Bauer, 2009) pooling the data from the available studies A5338, 
A5238 and A5093.  
 The modelling approach followed a stepwise procedure to first identify the structural 
model best describing the data, and then incorporate the effect of the study covariates 
such as weight, age, and effect of concomitant anti-retroviral and anti-tuberculosis 
treatment. 
 Various structural pharmacokinetic models were evaluated, focusing on correctly 
characterizing the absorption after intra-muscular injection. The tested models included 
one and two compartments disposition, with first-order elimination and zero-, first-order, 
two parallel first order absorption. 
 Model selection was be based on changes in the NONMEM objective function value 
(ΔOFV), and visual inspection of conditional weighted residuals (CWRES) versus time, 
visual predictive checks, and basic goodness of fit plots (GOF). 
 Statistically significant variability and correlation estimates for the PK parameters were 
included and the covariates of interest were retained in the final model with respect to 
their impact on the PK parameters and their variability. Covariate selection was be based 
on the drop in objective function value (assumed to be χ-square distributed and thus using 
3.84 points drop as significant at p<0.05 for the inclusion of a single parameter), while 
scrutinizing the physiological plausibility of the effect. 
 Allometric scaling (Anderson & Holford, 2008) was USED to account for the effect of 
body size on the pharmacokinetic parameters, using total body weight. 
 
References 
1. 
Beal, S., Sheiner, L. B. L., Boeckmann, A. & Bauer, R. R. J. NONMEM User’s 
Guides. (1989-2009). (2009). 
2. 
Anderson, B. J. & Holford, N. H. G. Mechanism-Based Concepts of Size and Maturity 
in Pharmacokinetics. Annu. Rev. Pharmacol. Toxicol. 48, 303–332 (2008).  

SAP_001.pdf: 
 
 
ACTG A5338 
 
An Open‐Label, Non‐Randomized Study of Pharmacokinetic 
Interactions Among Depot Medroxyprogesterone Acetate 
(DMPA), Rifampicin (RIF), and Efavirenz (EFV) in Women Co‐
Infected with Human Immunodeficiency Virus (HIV) and 
Tuberculosis (TB) 
 
ClinicalTrials.gov Identifier: NCT02412436 
 
FINAL 
Statistical Analysis Plan 
Version 2.0 
April 30, 2018 
 
 
 
Prepared by 
Susan L. Rosenkranz, PhD, and Yoninah Cramer, MS 
Statistical and Data Analysis Center, Harvard T.H. Chan School of Public Health, Boston MA & 
Frontier Science & Technology Research Foundation, Brookline, MA 
 
 
 
 


A5338 Statistical Analysis Plan                                                Final Version 2.0, April 30, 2018 
 
Page 2 of 16 
 
Table of Contents 
1 
Study design ........................................................................................................................................... 4 
1.1 
Study Treatment ...................................................................................................................... 4 
1.2 
Evaluations ............................................................................................................................... 4 
1.3 
Definition of PK and safety populations, and about replacements .................................... 5 
1.4 
Accrual target, duration of study and anticipated time to meet accrual target ................ 5 
1.5 
SAP version history ................................................................................................................ 6 
2 
Study hypothesis and objectives .......................................................................................................... 6 
2.1 
Hypothesis ............................................................................................................................... 6 
2.2 
Primary objectives ................................................................................................................... 7 
2.2.1 
To estimate the optimal dosing frequency of DMPA for HIV and TB coinfected women 
taking EFV-based combination antiretroviral therapy (cART) and RIF-containing TB 
treatment, based on a target MPA concentration >0.1 ng/mL. ........................................ 7 
2.2.2 
To determine whether a 150 mg DMPA IM injection will be adequate to suppress 
ovulation through 12 weeks in women taking EFV-based cART and RIF-containing TB 
treatment based on serial plasma progesterone concentrations. .................................... 7 
2.3 
Secondary objectives .............................................................................................................. 7 
2.3.1 
To estimate the area under the concentration-time curve (AUC), trough concentration 
(Cmin), maximum concentration (Cmax), apparent clearance (CL/F), and half-life (t1/2) 
of MPA in HIV and TB coinfected women taking EFV-based cART and RIF-containing 
TB treatment. .................................................................................................................... 7 
2.3.2 
To estimate time and variability in time to MPA Cmin reaching 0.1ng/mL or less in HIV 
and TB coinfected women taking EFV-based cART and RIF-containing TB treatment. . 7 
2.3.3 
To estimate the proportion of participants who maintain MPA levels above the minimum 
level thought to suppress ovulation (MPA 0.1ng/mL) through 12 weeks after DMPA 
administration. .................................................................................................................. 7 
2.3.4 
To evaluate the toxicity and safety of concurrent RIF, EFV, and DMPA use. ................. 7 
2.4 
Exploratory objectives ............................................................................................................ 7 
2.4.1 
To explore whether pharmacokinetic (PK) interactions between EFV, RIF, and/or 
DMPA are affected by human genetic polymorphisms that have been reported to affect 
metabolism of these drugs. .............................................................................................. 7 
2.4.2 
To explore body mass index (BMI) and body fat content over time and correlate with 
DMPA levels. .................................................................................................................... 7 
2.4.3 
To explore relationship between DMPA and bone metabolism in the HIV and TB 


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coinfected women............................................................................................................. 7 
3 
Sample size considerations ................................................................................................................... 7 
4 
Planned analyses .................................................................................................................................... 8 
4.1 
General statistical methods .................................................................................................... 8 
4.2 
Accrual, study disposition, and demographic and baseline clinical characteristics ....... 8 
4.3 
MPA and progesterone concentrations at week 12 (primary) and other weeks 
(secondary) .............................................................................................................................. 8 
4.4 
MPA PK parameters (secondary objective 2.3.1), using noncompartmental analysis .... 9 
4.5 
Time and variability in time to MPA Cmin falling below 0.10 ng/mL (secondary objective 
2.3.2), using nonlinear mixed-effect population PK modeling ............................................ 9 
4.6 
Safety and tolerability of concurrent RIF, EFV and DMPA (secondary objective 2.3.4) .. 9 
4.7 
Concomitant medications ..................................................................................................... 10 
4.8 
Week 12 plasma HIV-1 RNA .................................................................................................. 10 
4.9 
Exploratory objectives to be address in primary analysis report .................................... 10 
4.10 
Exploratory objectives to be address in later analysis report .......................................... 10 
5 
Appendix 1, sample size considerations as stated in protocol ........................................................ 11 
6 
Appendix 2, “Pharmacology Plan” (Section 10) as stated in protocol ............................................ 13 
10.1 
Pharmacology Objectives ..................................................................................................... 13 
10.2 
Pharmacology Study Design ................................................................................................ 13 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis ............................................ 14 
10.4 
Anticipated Outcomes .......................................................................................................... 14 
10.5 
Pharmacogenomics – Host Genetic Analysis .................................................................... 14 
7 
References ............................................................................................................................................ 16 
 
 
 


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1 
Study design 
ACTG A5338 is a phase II, open‐label, single‐arm, multicenter, steady‐state pharmacokinetic (PK) study 
of drug‐drug interactions in HIV and TB co‐infected women treated with DMPA while receiving an 
efavirenz (EFV)‐based combination anti‐retroviral therapy (cART), rifampicin (RIF) and isoniazid (INH).   
The study population is premenopausal women, 18 to 46 years of age, who are co‐infected with HIV and 
TB.  To be eligible to enroll in the study, participants must be on EFV plus two or more nucleoside 
reverse transcriptase inhibitors (NRTIs) for at least 28 days prior to study entry with no plans to change 
therapy for the 12 weeks of the study.  Women must be on the continuation phase of active TB 
treatment taking RIF and INH on a 5‐day or more per week schedule. 
Additional entry criteria include: 
 
Premenopausal women with presumed normal ovarian function based on normal menstrual 
history and absence of previous ovarian dysfunction diagnosis. 
 
Last menstrual period 35 days prior to study entry.  If last menstrual period >35 days prior to 
study entry, serum follicle‐stimulating hormone (FSH) must be checked and be 40 mIU/mL to 
be  eligible  for  enrollment.    NOTE:  Enrollment  after  the  start  of  monthly  menstrual  flow  is 
preferred, but not required. 
 
Negative serum or urine‐HCG pregnancy test. 
 
No receipt of DMPA or any other injectable contraceptives within 180 days prior to study entry. 
 
No receipt of other hormonal contraceptives within 30 days prior to study entry. 
This is a limited‐site study.  The sites were selected based on the availability of potentially eligible 
participants, close proximity to a TB clinic, integrated HIV/TB programs and interest in the study 
according to responses to a site feasibility survey.  The approved sites are listed on the protocol‐specific 
Web page. 
1.1 
Study Treatment 
DMPA is the only drug provided by the study.  cART and TB treatment medications are not provided by 
this study.   
DMPA 150 mg is administered intramuscularly as a single‐dose at study entry.  
An optional dose of DMPA will be available at no cost to all study participants (after confirmation of a 
negative pregnancy test) who successfully complete all 12 weeks of the study, experience no adverse 
events (AEs) from the first injection, and are interested in continuing with DMPA outside of the protocol. 
1.2 
Evaluations 
A single PK blood sample will be collected for assay of MPA at entry (day 0), just prior to DMPA injection 
and at weeks 2, 4, 6, 8, 10 and 12 after DMPA injection.  The proportion of participants with sub‐
therapeutic MPA levels (<0.1 ng/mL) will be estimated based on the participants who complete the PK 
sampling at 12 weeks after DMPA administration.   
After entry, a participant who misses 2 or more doses of RIF or EFV within the one‐week prior to a 
scheduled PK sampling visit will have the visit rescheduled to one week later. 
Other assessments include plasma progesterone levels (weeks 2, 4 6, 8, 10 and 12); clinical assessments 
for safety (including blood chemistry and hematology tests) at each study visit and at premature 


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discontinuation; CD4+/CD8+ (entry only), plasma HIV‐1 RNA (entry and week 12); stored whole blood for 
drug metabolism genotype;and stored serum for bone metabolism biomarkers and others.   
1.3 
Definition of PK and safety populations, and about replacements 
The PK population (“evaluable for primary endpoint” per protocol language) consists of participants 
who complete the MPA PK sampling and are compliant with study dosing and evaluations.  Specifically, 
participants are excluded from the PK population, and are replaced in accrual for noncompliance with 
protocol (stated in protocol section 8.1) if: 
 
Participant fails to attend 2 consecutive visits at week 2, 4, 6, or 8. 
 
Participant fails to attend either the week 10 or week 12 visit. 
 
Participant misses 2 or more RIF and/or EFV doses within one week prior to PK sampling at week 
2, 4, 6, or 8 and did not return with acceptable adherence for the rescheduled PK sampling visit 
for 2 consecutive study weeks. 
 
Participant misses 2 or more RIF and/or EFV doses within one week prior to PK sampling at week 
10 or 12 and did not return with acceptable adherence for the rescheduled PK sampling. 
Participants are also excluded from the PK population and replaced in accrual for certain changes to the 
cART or TB regimen during the 12 weeks on study (stated in protocol section 8.2); specifically: 
 
Addition of another NNRTI or any PI.  
 
Any substitution within the NNRTI class. 
 
Addition of an integrase inhibitor or entry inhibitor to the regimen. 
 
NOTE:  Participants may stay on study if they change or discontinue one or more of their NRTIs, 
since this class of medications is not thought to affect the metabolism of DMPA or EFV. See 
section 5.4.2 for the NRTI combinations that are not allowed in this study. 
 
Stopping RIF secondary to toxicity or resistance. 
 
Addition of TB medications, to the study TB regimen of RIF and INH, of TB meds known to induce 
or inhibit the cytochrome p450 enzyme system, as identified by having study chairs review the 
complete list of all such meds. (When guidelines at the Botswana site changed to include 
Ethambutol, the team allowed the use of this drug.)  Study chairs and pharmacologist will review 
a list of such medications, identifying those of concern and not. 
The safety population (participants to be included in toxicity summaries) consists of participants to 
whom the DMPA injection was administered and had evaluations conducted during at least one post‐
baseline visit. 
1.4 
Accrual target, duration of study and anticipated time to meet accrual target 
The accrual target is a total of 46 evaluable participants. 
The duration of the study is 12 weeks from entry through the final clinic visit.   
Accrual to A5338 was anticipated to take approximately 12 months (anticipate 3‐4 participants to enroll 
per month).  The study team anticipated enrolling approximately 4 participants per month, in which case 
the accrual target was expected to be met about 12 months after the first participant enrolled. 


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1.5 
SAP version history 
Version 
Changes Made 
Effective Date 
1 
Original Version 
9/25/2017 
2 
Requirements for program validation and results verification 
were removed (to Analysis Implementation Plan).  Minor 
clarifications were made. 
4/30/2018 
 
 
2 
Study hypothesis and objectives 
2.1 
Hypothesis 
Concurrent use of efavirenz (EFV) and rifampicin (RIF) will increase the clearance of 
medroxyprogesterone acetate (MPA) in HIV and TB coinfected women, resulting in 
reduced plasma MPA concentrations and reduced contraceptive efficacy. 


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2.2 
Primary objectives 
2.2.1 
To estimate the optimal dosing frequency of DMPA for HIV and TB coinfected 
women taking EFV‐based combination antiretroviral therapy (cART) and RIF‐
containing TB treatment, based on a target MPA concentration >0.1 ng/mL. 
2.2.2 
To determine whether a 150 mg DMPA IM injection will be adequate to 
suppress ovulation through 12 weeks in women taking EFV‐based cART and RIF‐
containing TB treatment based on serial plasma progesterone concentrations. 
2.3 
Secondary objectives 
2.3.1 
To estimate the area under the concentration‐time curve (AUC), trough 
concentration (Cmin), maximum concentration (Cmax), apparent clearance 
(CL/F), and half‐life (t1/2) of MPA in HIV and TB coinfected women taking EFV‐
based cART and RIF‐containing TB treatment.  
2.3.2 
To estimate time and variability in time to MPA Cmin reaching 0.1ng/mL or less 
in HIV and TB coinfected women taking EFV‐based cART and RIF‐containing TB 
treatment.   
2.3.3 
To estimate the proportion of participants who maintain MPA levels above the 
minimum level thought to suppress ovulation (MPA 0.1ng/mL) through 12 
weeks after DMPA administration. 
2.3.4 
To evaluate the toxicity and safety of concurrent RIF, EFV, and DMPA use. 
2.4 
Exploratory objectives 
2.4.1 
To explore whether pharmacokinetic (PK) interactions between EFV, RIF, and/or 
DMPA are affected by human genetic polymorphisms that have been reported 
to affect metabolism of these drugs. 
2.4.2 
To explore body mass index (BMI) and body fat content over time and correlate 
with DMPA levels. 
2.4.3 
To explore relationship between DMPA and bone metabolism in the HIV and TB 
coinfected women. 
3 
Sample size considerations 
A5338 is a phase II, open‐label, single‐arm, PK study to estimate the optimal dosing frequency of DMPA 
for HIV‐ and TB‐coinfected women taking EFV‐based combination antiretroviral therapy (cART) and RIF‐
containing TB treatment, based on MPA and plasma progesterone concentrations measured at week 12 
(end of the dosing interval).  The primary analysis consists of reporting proportions (and associated 
confidence intervals) of participants with MPA concentrations below 0.1 ng/mL (the threshold below 
which ovulation is no longer expected to be suppressed) and with plasma progesterone above 5 ng/mL 
(indicating the return of luteal activity and ovulation). 


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For the primary analysis outcome, of women with sub‐therapeutic MPA levels (<0.1 ng/mL) at week 12, 
a one‐sided binomial test with significance level 0.05 of the null hypothesis will be conducted.  The null 
hypothesis is that the proportion of women with sub‐therapeutic MPA concentration is 6% or less. If the 
true proportion of women with sub‐therapeutic MPA levels at week 12 is at least 21% (15% or more 
above the null 6% threshold), the sample size of 42 women provides 90% power to reject the null.  
Based on the results from a PK study of oral contraceptives containing ethinyl estradiol (estrogen) and 
norethindrone (progestin) which are metabolized by CYP3A4 enzyme, the study team considers that the 
underlying proportion of women with sub‐therapeutic MPA levels of 21% or higher (15% or higher 
increase from the 6% threshold) is plausible in the setting of coadministration with EFV and RIF. 
To protect against 10% loss of data contributing to the primary outcome measures after accrual is closed 
(eg, loss of sample or inability to assay), the accrual target is a total of 46 women. 
Appendix 1 shows sample size considerations as stated in the protocol. 
4 
Planned analyses 
4.1 
General statistical methods 
See definitions of PK and safety populations in Section 1.3 herein. 
Statistical tests are considered significant if the p‐value is at/below 0.05.  Confidence intervals (CIs) are 
calculated to have 95% coverage probability.  No adjustments are made for multiple comparisons. 
PK parameters will be determined using standard non‐compartmental approach, using validated SAS 9.4 
code (SAS Institute Inc., Cary, NC, USA).  
4.2 
Accrual, study disposition, and demographic and baseline clinical characteristics 
Accrual counts by month and site will be tabulated.   
A CONSORT diagram will be used to account for all participants who enrolled in the study, showing early 
study discontinuations and losses from the safety and PK populations.   
Counts and percentages of participants by off‐treatment reason and by off‐study reason will be 
tabulated.   
Listings of premature off‐treatment and off‐study participants will give details about the 
discontinuation. 
Demographic and baseline clinical characteristics will be summarized for all participants who enrolled, 
and for the PK population participants.  Categorical characteristics will be summarized by counts and 
percentages.  Continuous characteristics will be summarized by mean, standard deviation (SD), median, 
25 and 75th percentiles (interquartile range, IQR) and minimum and maximum (range).  Categorical 
characteristics include race, ethnicity.  Continuous baseline characteristics include height, weight, BMI, 
plasma HIV‐1 RNA, and CD4+ and CD8+ counts and percentages.  Percentages of participants with 
plasma HIV‐1 RNA viral load <400 and <50 copies/mL at study entry will also be tabulated. 
4.3 
MPA and progesterone concentrations at week 12 (primary) and other weeks (secondary) 
Apart from week 0 measurements, MPA and progesterone concentrations reported as below the lower 
limit of the assay will be assigned values of half the lower limit, respectively.  Week 0 MPA 


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concentrations reported as below the lower limit of the assay will be assigned a value of zero (as MPA is 
not an endogenous chemical). 
Participant‐specific concentration‐time plots of MPA and progesterone will be created.  Separately for 
MPA and progesterone, plots of mean concentration, ± SD, by scheduled week (2, 4, 6, 8, 10, and 12) 
will be generated.  Similarly, plots of median concentration, ± IQR, concentrations by scheduled week 
will be generated. 
The primary endpoints are the percentages of participants with MPA concentrations below 0.1 ng/mL 
and with progesterone concentrations above 5, 3 and 1 ng/mL.  (Serum progesterone of 5 ng/mL or 
above indicates a return of ovulation.)  We will also report % with progesterone above 3 and above 1 
ng/mL.  The week 12 values are those obtained closest to 84 days after DMPA administration, within ±7 
days (as stated in protocol Section 6.2.3; all data will be included in population PK modeling).  Counts, 
percentages and 95% confidence intervals (CIs) around the percentages will be tabulated.  (Note that 
protocol specified that CIs would have 90% coverage, but this was stated in error.)  For calculation of CIs, 
Clopper‐Pearson exact methods for binomial measurements will be used.  (Note that this analysis also 
addresses secondary objective 2.3.3) 
For completeness, proportions below the MPA and above the progesterone thresholds at other visits 
(weeks 2, 4, 6, 8, and 10) will also be tabulated.  Week‐specific summary statistics for MPA and 
progesterone concentrations will also be tabulated (mean, SD, median, IQR, and range). 
4.4 
MPA PK parameters (secondary objective 2.3.1), using noncompartmental analysis 
Using standard non‐compartmental methods, the following participant‐specific MPA PK parameters will 
be calculated:  AUC over the 12 weeks (AUC0‐12wk, defined as the sum of trapezoids), Cmin (minimum 
observed concentration), Cmax (maximum observed concentration), apparent clearance (CL/F, dose 
amount divided by AUC0‐12wk), and half‐life (t1/2, assuming exponential decay, estimated by fitting a log‐
linear regression to the 3 or more observed concentrations that occur after [not including] Cmax; if 3 
such concentrations are not available, half‐life will not be calculated, but population PK modeling will 
yield estimates for all participants).  Descriptive statistics of these PK parameters will be tabulated, 
where descriptive statistics consist of mean, SD, median, IQR and range; for CL/F and t1/2, descriptive 
statistics consist of median, IQR and range only. 
4.5 
Time and variability in time to MPA Cmin falling below 0.10 ng/mL (secondary objective 2.3.2), 
using nonlinear mixed‐effect population PK modeling 
Estimation of time to MPA < 0.10 ng/mL is best addressed via nonlinear mixed‐effects modeling, which 
(pending funding) will be performed by Paolo Denti in Helen McIlleron’s pharmacology laboratory.  
Output of such modeling will produce the time (with 95%CI) for a typical individual to reach a 
concentration of 0.1 ng/mL, as well as the typical concentration (with 95%CI) at 84 days.  Section 
6/Appendix 2 herein shows protocol Section 10, Pharmacology Plan. 
4.6 
Safety and tolerability of concurrent RIF, EFV and DMPA (secondary objective 2.3.4) 
Signs/symptoms, blood chemistry values and hematology values of grade 3 and higher will be 
summarized for participants in the safety population.  Counts and proportions of participants (with 
Clopper‐Pearson 95% CIs around the proportions) exhibiting grade 3 toxicities, grade 4 toxicities and 
death (if any; not expected) will be tabulated, overall, by MedDRA system organ class (SOC) and by 


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MedDRA preferred term.  DMPA‐related side effects such as vaginal bleeding, cramping, and vaginal 
candidiasis, of grades 1 and 2 will also be summarized1.  A listing of such toxicities will also be provided, 
showing onset and resolution day (if resolved) relative to first dose of study drug.  In the listings, events 
will be flagged with indicators for (a) “grade is higher than that for the same event/finding present at 
baseline (if present as baseline)” and (b) whether or not the team deemed the event related to study 
drug. 
To provide information on tolerability, counts and proportion of participants prematurely discontinuing 
study drug and study participation will be tabulated, with Clopper‐Pearson 95% CIs around the 
proportions). 
The number of pregnancies believed to have begun while on study treatment (if any) will be reported. 
4.7 
Concomitant medications 
A list of reported concomitant medications will be prepared for review by the study chairs.  If 
concomitant medications are identified that have the potential for pharmacokinetic interactions with 
the study drugs, a listing of participants taking these drugs will be included in the Final Analysis Report 
(FAR),showing study days on which the concomitant medications of concern were started and stopped.  
This listing provides context for the estimated PK parameters. 
4.8 
Week 12 plasma HIV‐1 RNA 
Percentages of participants with plasma HIV‐1 RNA viral load <400 and <50 copies/mL at the week 12 
visit will be tabulated. 
4.9 
Exploratory objectives to be address in primary analysis report 
Among secondary objectives, the primary analysis report will summarize changes in plasma HIV‐1 RNA, 
body mass index2, and waist‐to‐height ratio 3 over time, and in relation to MPA concentrations.   
4.10 
Exploratory objectives to be address in later analysis report 
A secondary analysis report will summarize:  (1) relationships between EFV, RIF and MPA PK parameters 
and human genetic polymorphisms that have been reported to affect metabolism of these drugs 
(pharmacogenomics); and (2) relationships between DMPA administration and biomarkers of bone 
metabolism.   
 
 
 
 
                                                     
1 Statisticians will collaborate with Chairs to identify the MedDRA codes that correspond to DMPA‐related side effects. 
2Body mass index, BMI:   if  wtkgs eq .  then wtkgs = round( wtlbs/2.2, .1 ); if  htcm eq .  then  htcm = htin / 0.39; htmeter = htcm/100; * 
BMI = weight (in kg) / height squared (in meters).; bmi = wtkgs / (htmeter**2); 
3 Waist‐to‐height ratio, WHtR, is a measure of body fat content, calculated as 100*waist circumference/height, after converting waist 
circumference and height to common units. 


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5 
Appendix 1, sample size considerations as stated in protocol 
It is known that DMPA, EFV, and RIF drugs share some common metabolic pathways via the 
CYP3A4 enzyme system: MPA is metabolized by and induces CYP3A4 activity; RIF is primarily 
metabolized by CYP2B6 system but also by CYP3A4 and induces CYP3A4 and CYP2B6 enzyme 
activities; EFV is primarily metabolized by CYP2B6 and both induces and inhibits CYP3A4 enzyme 
activity (mixed and unpredictable activity). Therefore, it is anticipated that co‐administration 
with EFV and RIF will induce clearance of MPA concentration, resulting in lower MPA 
concentrations during the elimination phase, compared to those seen when DMPA is 
administered alone. Thus, DMPA may need to be administered more frequently when used 
together with EFV and RIF.   
The study hypothesis is that concurrent use of EFV and RIF increases the clearance of MPA, 
resulting in reduced MPA concentrations. The study will evaluate whether more frequent DMPA 
dosing is needed when DMPA is administered in combination with EFV and RIF in HIV‐ and TB‐
infected women. The evaluation of dosing frequency will be conducted by estimating the 
proportion of women with MPA levels <0.1 ng/mL 12 weeks post‐dose (at the end of the dosing 
cycle). The critical value 0.1 ng/mL for MPA levels was chosen based on published papers 
including studies by Mishell et al (1996) and Smit et al. (2004). These studies indicate that when 
MPA level falls below 0.1 ng/mL, serum progesterone level rises and the probability of ovulation 
increases. 
In ACTG DMPA studies A5093 and A5283 in HIV‐infected women, of the 79 PK evaluable 
participants, 5 women had MPA levels <0.1 ng/mL at 12 weeks after a single dose of DMPA was 
administered. None of these 5 women, however, had any evidence of ovulation (serum 
progesterone levels remained below 5 ng/mL). In a study by Smit et al. (2004), in 94 women, all 
but one woman had MPA levels above 0.1 ng/mL at 12 weeks after DMPA administration. These 
94 women had received either a single dose or multiple doses of DMPA. Therefore, based on the 
single dose studies, the proportion of women with MPA levels <0.1 ng/mL (sub‐therapeutic MPA 
levels) 12 weeks post‐dose is thought to be about 6% in normal DMPA use, although a study 
conducted by Trussell et al. (2011)showed that there is a contraceptive failure rate of about 
0.3% when DMPA is used correctly. 
The primary analysis outcome will be the proportion of women with sub‐therapeutic MPA levels 
(<0.1 ng/mL) at 12 weeks. A one‐sided binomial test with significance level 0.05 will be used to 
test the null hypothesis that the proportion of women with sub‐therapeutic MPA level is 6% or 
less. A sample size of 42 women provides 90% power to reject the null hypothesis if the 
proportion of women with sub‐therapeutic MPA levels in this study is at least 21% (this is 15% or 
higher increase from the 6% threshold).  With a sample size of 42 women, the underlying true 
proportion will be declared as statistically significant increase if 6 or more women have sub‐
therapeutic MPA levels at 12 weeks (this is equivalent to saying that 90% CI for the underlying 
proportion is entirely above the 6% threshold). Based on the results from a PK study of oral 
contraceptives containing ethinyl estradiol (estrogen) and norethindrone (progestin) which are 
metabolized by CYP3A4 enzyme(LeBel et al, 1998), the study team considers that the underlying 
proportion of women with sub‐therapeutic MPA levels of 21% or higher (15% or higher increase 
from the 6% threshold) is plausible in the setting of coadministration with EFV and RIF. 


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The statistical power was also examined to see if the sample size will achieve a plausible power 
to detect a clinically meaningful decrease (30%) in MPA concentration at 12 weeks (MPA Cmin) as 
one of the secondary objectives. With a significance level of 0.05, a one‐sided t‐test showed 
about 91% and 84% power to detect a 30% decline when the coefficient of variation (CV) is 60% 
and 70%, respectively (in the ACTG study A5093, CV of MPA Cmin was approximately 57% when 
coadministered with EFV). We note that this power was examined in loge‐scale since it is known 
that PK parameter Cmin has a log‐normal distribution.  
To protect against 10% loss of the primary outcomes after study accrual is closed, the study will 
enroll a total of 46 women. (In the ACTG DMPA study, A5093, the loss of the primary outcomes 
of week 12 was 9.8% [6 of 61 participants] due to either sample specimen loss or assay results 
not available.) 
 
 


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6 
Appendix 2, “Pharmacology Plan” (Section 10) as stated in protocol 
Women stable on an EFV and 2 NRTIs‐based regimens, who are on RIF and INH, and who have not 
received DMPA within the last 180 days, received one dose of DMPA at study entry. An optional dose of 
DMPA wad made available at no cost to all study participants, after all week 12 study evaluations are 
completed. Refer to section 5.1.1 for the allowed NRTIs and section 5.4.2 for the prohibited NRTI 
combinations.  
The primary PK analysis is described in section 9.6. The secondary PK analysis employing a population 
approach and nonlinear mixed effects modelling is described in this section. 
10.1 
Pharmacology Objectives 
Using nonlinear mixed‐effects (NLME) modeling, the population PK of MPA will be described in the 
population in order: 
10.1.1  To describe the structural PK model for MPA given in the DMPA formulation. 
10.1.2  To identify and quantify the effects of covariates influences on PK (eg, weight [including 
total, fat and lean components], age, time on TB treatment, time on ART, adherence to 
ART and TB treatments, CYP2B6 genotype, etc.). 
10.1.3  To characterize between subject and random unexplained components of the PK 
variability. 
10.1.4  To predict the time at which the proportion of women with MPA <0.1 ng/L matches that 
at 12 weeks from historical data. 
10.2 
Pharmacology Study Design 
Doses of all ARV and TB medications taken for 48 hours prior to PK will be collected on the CRF at weeks 
2, 4, 6, 8, 10, and 12. The participant should be contacted one week prior to the scheduled visit to 
reinforce the importance of 100% adherence to RIF and EFV and of her upcoming appointment. A 
participant who misses 2 or more doses of RIF and EFV within one week prior to the scheduled PK 
sampling at weeks 2, 4, 6, 8, 10, and 12 will have the visit rescheduled to one week later. For the week 
10 and week 12 visits, the rescheduled PK sampling should be strictly within the original visit window for 
that visit. The schedule for the remaining visit weeks should not be changed. The rules for replacing 
participants who do not complete the PK are described in sections 8.1 and 9.5.  
A single 4 mL blood sample for PK will be collected just prior to DMPA injection at week 0 and at the 
scheduled visits at weeks 2, 4, 6, 8, 10, and 12. The blood sample will be centrifuged within 1 hour of 
collection to separate the plasma which will be stored at ‐70°C or colder until assay for MPA and 
progesterone. 
The ACTG Pharmacology Specialty Laboratory at the University of Cape Town will use liquid 
chromatography‐tandem mass spectrometry (LC MS/MS) to measure MPA and progesterone in the 
plasma. The assay methods will be validated and submitted to Clinical Pharmacology Quality Assurance 
(CPQA) for review.  


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10.3 
Primary and Secondary Data, Modeling, and Data Analysis 
The concentration vs. time data for DMPA will be analyzed using NLME modelling using the software 
NONMEM (Version 7.2) [see protocol for reference].  
The modelling approach will follow a stepwise procedure to first identify the structural model best 
describing the data, and then incorporate the effect of the study covariates such as weight, age, and 
effect of concomitant anti‐retroviral and anti‐tuberculosis treatment. 
Various structural pharmacokinetic models will be evaluated, focusing on correctly characterizing the 
absorption after intra‐muscular injection. The tested models will include one, two, and three 
compartments disposition with first‐order elimination and zero‐, first‐order, or saturable absorption.  
Statistically significant variability and correlation estimates for the PK parameters will be included and 
the covariates of interest will be evaluated with respect to their impact on the PK parameters and their 
variability. 
Allometric scaling [see protocol for reference] will be used to account for the effect of body size on the 
PK parameters, using total body weight or fat‐free mass. Other covariate effects will be evaluated and 
included if they significantly improve the ability of the model to describe the data. The effect of 
adherence to and time on ART and TB regimens, and CYP2B6 genotype (if available), will be investigated 
on clearance.  
Concentrations below the limit of quantification will be included in the analysis and handled with 
established methods [see protocol for reference]. 
The tools used for model development and graphical and statistical diagnostics will include Xpose, and 
Perl Speaks NONMEM, and Pirana [see protocol for reference ].  
The PK profiles will be analyzed using post‐hoc Bayesian methods to extract information such as peak 
concentration, overall exposure (AUC), and time above target concentration. Simulations will be 
employed to explore the pharmacokinetic profiles, their variability in a population, and how they are 
affected by weight, concomitant anti‐retroviral or anti‐tuberculosis treatment, other covariates found 
significant, and possibly under different dosing scenarios, and to predict the time at which the 
proportion of women with MPA <0.1 ng/L matches that at 12 weeks from historical data. 
10.4 
Anticipated Outcomes 
The anticipated outcomes are described in the section above. They are the model outputs: firstly the 
population PK of MPA will be described using the primary model parameters and secondary measure 
estimates. Covariate effects on the model parameters will be identified and quantified. The model will 
ascribe variability (due to fixed effects, inter individual and random unexplained variability) with 
accuracy. Secondly, simulations will predict the optimal dosing frequency to achieve a target trough 
concentration of >0.1 ng/mL in the target proportion of women. 
10.5 
Pharmacogenomics – Host Genetic Analysis 
Inter‐individual differences in host genes (eg, those that encode drug‐metabolizing and transporter 
proteins) have been associated with inter‐individual differences in plasma PK of EFV [see protocol for 
references] and RIF [see protocol for reference]. The study will therefore evaluate human genetic 
polymorphisms that are known to affect steady‐state plasma PK of EFV and RIF. Among study 


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participants that receive EFV and RIF, analyses of PK data will take into consideration such 
polymorphisms. If additional polymorphisms are reported to affect sex hormones, these may also be 
studied. 
 
 


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7 
References 
LeBel M, Masson E, Guilbert E, et al. Effects of Rifabutin and Rifampicin on the Pharmacokinetics of 
Ethinylestradiol and Norethindrone. Journal of Clinical Pharmacology. 1998;38:1042‐1050. 
 
Mishell DR. Pharmacokinetics of depot medroxyprogesterone acetate contraception. Journal of 
Reproductive Medicine. 1996;41(5 suppl):381‐90. 
 
Smit J, Botha J, McFadyen L, Beksinska M. Serum medroxyprogesterone acetate levels in new and repeat 
users of depot medroxyprogesterone acetate at the end of the dosing interval. Contraception. 2004 
Jan;69(1):3‐7. 
 
Trussell J (2011). "Contraceptive efficacy".  In Hatcher RA.; Trussell J; Nelson AL.; Cates W Jr.; Kowal D; 
Policar MS (eds.). Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 779–863. 
ISBN 978‐1‐59708‐004‐0. ISSN 0091‐9721. OCLC 781956734. (Tables 26–1 = Table 3–2 Percentage of 
women experiencing an unintended pregnancy during the first year of typical use and the first year of 
perfect use of contraception, and the percentage continuing use at the end of the first year.)