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HIV-1 InfectionPhase 2PRIDE-HTNCT02412436

PK Study of Rifampicin Interactions With DMPA and Efavirenz in TB

A Phase 2 study testing Depot medroxyprogesterone acetate in people with HIV-1 Infection and Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 5 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 to 46 years, women only
Conditions the study is for
HIV-1 Infection, Tuberculosis
What is being tested?
Depot medroxyprogesterone acetate
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
62 participants
Where
5 sitesin 4 countries
Study dates
3 Nov 2015to 15 Jun 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 46 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • HIV-1 infection.
  • Current tuberculosis infection, confirmed or probable diagnosis.
  • Currently stable on EFV-based cART for at least 28 days with no intention to change the regimen during the 12-week study period.
  • 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. [Does not exclude the use of ethambutol on study.]
  • Premenopausal female with presumed normal ovarian function based on normal menstrual history and absence of previous ovarian dysfunction diagnosis.
  • Last menstrual period (LMP) ≤35 days prior to study entry.
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  • 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.
  • All participants must agree not to participate in a conception process (e.g., 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
  • Laboratory values within 30 days prior to study entry:
  • Absolute neutrophil count ≥500 cells/mm^3
  • Platelet count ≥50,000 platelets/mm^3
  • 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
  • Ability and willingness to provide written informed consent.

Who cannot join

  • Receipt of DMPA or any other injectable contraceptive within 180 days prior to study entry.
  • Receipt of other hormonal contraceptives within 30 days prior to study entry.
  • 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 ethambutol does not induce or inhibit the CYP3A4 system, its use is consistent with the language in the protocol.]
  • ≤40 kg in weight.
  • Bilateral oophorectomy.
  • Less than 30 days postpartum at study entry.
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  • Hypersensitivity to DMPA, medroxyprogesterone acetate (MPA), or any of the other ingredients in DMPA.
  • Any previous breast cancer diagnosis.
  • Serious illness requiring systemic treatment and/or hospitalization within 21 days prior to study entry.
  • Karnofsky performance score <70 within 14 days prior to study entry.
  • Use of any immunosuppressant medication including systemic corticosteroids within 30 days prior to study entry.
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • History of deep venous thrombosis or pulmonary emboli.

Trial locations and contacts

5 sites in 4 countries.

5 sites in 4 countries

South Africa2 sites

  • Durban Adult HIV CRS (11201)

    Durban, 4013 SF

  • Univ. of Witwatersrand CRS (11101)

    Johannesburg

Other trials in South Africa

Botswana1 site

  • Gaborone Prevention/Treatment Trials CRS (12701)

    Gaborone

Other trials in Botswana

Kenya1 site

  • Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)

    Kisumu, 40100

Other trials in Kenya

Zimbabwe1 site

  • UZ-Parirenyatwa CRS (30313)

    Harare

Other trials in Zimbabwe

About this study

Official title: 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 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.

Read the 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.

Being tested
Depot medroxyprogesterone acetate
Medical subject headings
Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Depot medroxyprogesterone acetateDrug

    Also called DMPA

    Depot medroxyprogesterone acetate intramuscular injection

Study groups in NCT02412436
Study groupRoleWhat they receive
Arm A: Depot medroxyprogesterone acetateExperimentalAt 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).
Receives: Drug: Depot medroxyprogesterone acetate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Week 12

    The percent of participants with plasma DMPA concentrations below 0.1 ng/mL was calculated with an exact Clopper-Pearson 95% confidence interval. Suppression of ovulation generally occurs as long as the DMPA level is => 0.1 ng/mL.

    Measured: Week 12

  2. Percent of Participants With Progesterone Levels Above 1 ng/mL at Week 12

    The percent of participants with plasma progesterone levels above 1 ng/mL was calculated with an exact Clopper-Pearson 95% confidence interval. Ovulation generally occurs when the progesterone level is > 5 ng/mL. If there were participants with plasma progesterone levels > 1 ng/mL, then the percent of participants with plasma progesterone levels > 5 ng/mL would have been calculated by study week.

    Measured: Week 12

Secondary outcomes (9)

  1. Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10

    The percents of participants with plasma DMPA concentrations below 0.1 ng/mL at weeks 2, 4, 6, 8, and 10 were calculated with exact Clopper-Pearson 95% confidence intervals. Suppression of ovulation generally occurs as long as the DMPA level is => 0.1 ng/mL.

    Measured: Weeks 2, 4, 6, 8, and 10

  2. Cumulative Percentage of Participants With DMPA < 0.1 ng/mL

    The cumulative percentage of participants having a DMPA concentration less than 0.1 ng/mL at week 12 was calculated using a Kaplan-Meier estimator with an associated standard error. The confidence interval was calculated using a log-log transformation. Suppression of ovulation generally occurs as long as the DMPA level is => 0.1 ng/mL.

    Measured: Weeks 0, 2, 4, 6, 8, 10, and 12

  3. DMPA AUC

    Describe the DMPA plasma area under the curve (AUC) between 0 and 12 weeks, where AUC(0-12wks) was calculated using non-compartmental methods.The Week 0 time point was drawn prior to DMPA injection.

    Measured: Weeks 0, 2, 4, 6, 8, 10, and 12

  4. DMPA Cmin

    Describe the DMPA minimum observed concentration (Cmin) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection.

    Measured: Weeks 0, 2, 4, 6, 8, 10, and 12

  5. DMPA Cmax

    Describe the DMPA maximum observed concentration (Cmax) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection.

    Measured: Weeks 0, 2, 4, 6, 8, 10, and 12

  6. DMPA CL/F

    Describe the apparent DMPA clearance (CL/F) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection.

    Measured: Weeks 0, 2, 4, 6, 8, 10, and 12

  7. Percent of Participants Who Experienced a Grade 3 or Higher Sign/Symptom or Laboratory Abnormality

    The percent of participants who experienced a grade 3 (severe) or higher sign/symptom or laboratory abnormality were calculated with an exact Clopper-Pearson 95% confidence interval. Events were graded (1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death) according to the DAIDS AE Grading Table (V1.0).

    Measured: Weeks 2, 4, 6, 8, 10, and 12

  8. DMPA Half-life

    Describe the terminal elimination half-life of DMPA (t½) between 0 and 12 weeks, where t½ was calculated using nonlinear mixed-effects (NLME) modelling. The Week 0 time point was drawn prior to DMPA injection.

    Measured: Weeks 0, 2, 4, 6, 8, 10, and 12

  9. Time at Which Participant-specific Estimated Elimination Slopes for DMPA Level Cross the Threshold of 0.1 ng/mL

    Describe the time at which DMPA levels drop below the threshold of 0.1 ng/mL, based on participant-specific estimated elimination slopes from nonlinear mixed-effects (NLME) models. The Week 0 time point was drawn prior to DMPA injection.

    Measured: Weeks 0, 2, 4, 6, 8, 10, and 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Apr 2015 (estimated)
  2. Study start3 Nov 2015
  3. Primary completion15 Jun 2017
  4. Study completion15 Jun 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
62 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02412436
Sponsor's protocol ID
ACTG A5338
Other IDs
UM1AI068636
Acronym
PRIDE-HT
Status last verified
Jun 2019
First submitted
17 Mar 2015
Last updated
1 Jul 2019
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Haas DW, Mngqibisa R, Francis J, McIlleron H, Robinson JA, Kendall MA, Baker P, Mawlana S, Badal-Faesen S, Angira F, Omoz-Oarhe A, Samaneka WP, Denti P, Cohn SE; AIDS Clinical Trials Group A5338 Study Team. Pharmacogenetics of interaction between depot medroxyprogesterone acetate and efavirenz, rifampicin, and isoniazid during treatment of HIV and tuberculosis. Pharmacogenet Genomics. 2022 Jan 1;32(1):24-30. doi: 10.1097/FPC.0000000000000448.

    PubMed 34369424

  • Mngqibisa R, Kendall MA, Dooley K, Wu XS, Firnhaber C, Mcilleron H, Robinson J, Cramer Y, Rosenkranz SL, Roa J, Coughlin K, Mawlana S, Badal-Faesen S, Schnabel D, Omoz-Oarhe A, Samaneka W, Godfrey C, Cohn SE; A5338 Study Team. Pharmacokinetics and Pharmacodynamics of Depot Medroxyprogesterone Acetate in African Women Receiving Treatment for Human Immunodeficiency Virus and Tuberculosis: Potential Concern for Standard Dosing Frequency. Clin Infect Dis. 2020 Jul 27;71(3):517-524. doi: 10.1093/cid/ciz863.

    PubMed 31504342

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Depot medroxyprogesterone acetate in people with HIV-1 Infection and Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 5 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in South Africa, Botswana, Kenya, Zimbabwe. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Sep 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Week 12 (time frame: Week 12). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02412436, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jul 2019.

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