Clinical trial NCT04669678: Evaluation of Pharmacokinetic Drug-drug Interactions Between Hormonal Contraceptives and Doravirine-containing ART Among Women Living With HIV in South Africa
Official title: An Observational Pharmacokinetic Study to Evaluate Drug-drug Interactions Between Doravirine-containing ART and Hormonal Contraceptives Among Women Living With HIV in South Africa.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Contraception
Drug-drug Interaction
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
name: Wits Reproductive Health and HIV Institute
name: University of Washington
First posted: 2020-12-17
Enrollment: 110
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Different groups receive different interventions at same time during study.
Primary purpose: TREATMENT

Brief summary: The study investigators are conducting an observational, parallel group pharmacokinetic (PK) study among women living with HIV (WLHIV) already on 1st line antiretroviral therapy (ART) and virally suppressed, 18-45 years old (inclusive), to evaluate any bidirectional drug-drug interactions (DDIs) between doravirine (DOR)-containing ART and hormonal contraceptive methods. This PK study will enroll women in five distinct groups, each with 21 participants (total of 105 participants), and follow them for approximately 18-30 weeks.

Detailed description: While DOR-containing ART has been evaluated in two large clinical trials, only 16-17% of the study participants were women and only 6-10% of them were African. In an epidemic, where the gendered majority affected by the disease are women of reproductive age living in Africa, it is imperative to conduct a study evaluating reproductive health outcomes among and specific to African women. Further underscoring the issue is a notable data gap for DOR regarding DDIs with the most common leading hormonal contraceptives.

Our intention is to study potential DDIs between DOR and the most common contraceptive methods used by WLHIV in an African context, which generally include short- (e.g., OCPs/COCs), intermediate (e.g., injectable) or long-acting (e.g., implants or IUDs) methods. Since the drug maker of DOR has already conducted the industry standard PK study with DOR and a COC product, containing ethinyl estradiol and levonorgestrel, which did not demonstrate any bidirectional DDI, the investigators have chosen to exclude this method from the current study. Thus, the current EPIC study focuses on intermediate- and long-acting contraceptive methods, which have different PK profiles than daily administrated oral drugs and may be more susceptible to potential DDIs with DOR.

Participants who are interested in self-selecting and initiating one of the study contraceptive methods listed will be recruited for screening and eligibility assessments. If eligible and enrolled, there will be a 6-week lead-in period with daily use of oral DOR-containing ART followed by contraceptive method initiation of their choice. Study follow-up will take place every 2-4 weeks, at a minimum, for an additional 12 or 24 weeks for a total of 18 or 30 weeks of follow-up depending on the contraceptive method chosen.

The investigators will also enroll a dolutegravir (DTG) + IM DMPA group, who will be followed for 12 weeks, as the comparator group for the DOR + IM DMPA group.

The comparator group for the DOR + etonogestrel (ETG) implant group will be a historical control group from a similar PK study called PARVI (PK study of ARVs and Implants in Kenya) that is currently being conducted by Dr. Patel and colleagues in Kenya.

The five study groups are summarized below in Table 1.

Table 1: Study groups by ART regimen and contraceptive method choice

Group number N ART regimen and contraceptive method Group 1 21 DOR-containing ART + initiating ETG implant Group 2 21 DOR-containing ART + initiating IM DMPA Group 3 21 DOR-containing ART + initiating SC MPA Group 4 21 DOR-containing ART + initiating non-hormonal IUD Group 5 21 DTG-containing ART + initiating IM DMPA

The co-primary objectives are to evaluate any associations between doravirine (DOR), a newer antiretroviral agent for the treatment of HIV, exposure and hormonal contraceptive use in the four groups of DOR + 1) etonogestrel implant (ETG), 2) intramuscular depomedroxyprogesterone acetate (IM DMPA), 3) subcutaneous medroxyprogesterone acetate (SC MPA), or 4) non-hormonal IUD users by generating mean hormone concentrations at 12 weeks for IM and SC DMPA or 24 weeks for ETG implants and IUD groups; also to evaluate any bi-directional associations between hormonal contraceptive exposure and DOR use by generating mean DOR concentration at 24 hours.

The first hypotheses are: the mean implant hormone concentrations for DOR + ETG implant at 24 weeks after implant placement will be similar (i.e. geometric mean ratio \[GMR\] within 0.80 and 1.25) to the mean implant hormone concentrations for DTG + ETG implant (historical controls from Dr. Patel's current PARVI study in a similar population in Kenya). The mean MPA concentrations for DOR + IM DMPA or SC MPA at 12 weeks after DMPA/MPA administration will be similar (i.e. GMR within 0.8 and 1.25) to the mean DMPA concentrations for DTG + DMPA (contemporaneous study group). Also, the mean C24 hours of DOR in the ETG implant and MPA groups will be similar to the non-hormonal contraceptive method (i.e. the non-hormonal IUD) group.

The secondary objectives are to measure DOR-containing ART's efficacy, via HIV viral load \<40 copies/mL, at 12-24 weeks after contraceptive initiation among women of reproductive age using hormonal and non-hormonal contraceptives.

The second hypothesis is that proportion of women suppressed (defined as HIV viral load \<40 copies/mL) at 16-30 weeks after DOR-containing ART initiation will be similar to a contemporaneous or historical comparison of the proportion of women suppressed with non-DOR containing ART from the same study population/sample.

The exploratory objectives are to qualitatively explore decision-making around ART and contraceptive options, study experiences of ART switch, and use of the contraceptive method, including self-administration of SC MPA, and to describe self-reported experiences of social harms and social benefits related to study participation. Also, safety including side effects, satisfaction, and continuation rates of both the hormonal contraceptive method and ART will be assessed.

The third hypothesis is that the safety, satisfaction, and continuation rates of the various contraceptive methods will be similar to each other at 12-24 weeks after contraceptive initiation. The investigators will gain interesting insights into women's decision-making around ART and contraceptive method options and are uniquely positioned to describe experiences of self-administration of SC MPA.

Eligibility criteria: Inclusion Criteria:

* HIV-positive
* Currently on 1st line ART (namely EFV- or DTG-containing ART),
* Have documented or confirmed viral suppression for HIV (defined as \<40 copies/mL) within 3 months prior to study screening and after the start of the current ART regimen
* Contraception use:

  a) Not currently on reliable contraception and intending to or willing to initiate use of study hormonal/non-hormonal contraceptive methods 6 weeks after DOR lead in period (and willing to continue use for subsequent 12 to 24 weeks),
* Able and willing to comply with all study procedural requirements,
* Able and willing to provide informed consent for study participation in either English or Zulu,
* Able and willing to provide adequate locator information, as defined in site SOPs,
* Negative pregnancy test at Screening and Enrollment, and
* At Screening and Enrollment, agrees not to participate in other research studies involving drugs, medical devices, vaginal products, or vaccines for the duration of study participation.

Exclusion Criteria:

* Currently on 2nd line, 3rd line, or salvage ART regimens,
* Currently pregnant or intending to become pregnant within the next 6 months,
* Currently breastfeeding or intending to breastfeed within the next 6 months,
* Use or anticipated use of drugs for the duration of the study period known to interact with hormonal implants, DMPA/MPA, or the respective ART regimen
* Current or planned concomitant use of other hormonal contraceptives,
* Currently obese (BMI≥30),
* Has any of the following laboratory abnormalities at Screening Visit:

  1. Haemoglobin abnormality Grade 2 or higher
  2. Calculated creatinine clearance less than 50 mL/min by the Schwartz Equation
* Per participant report at Screening and Enrollment, intends to do any of the following during her study participation period:

  1. relocate away from the study site
  2. travel away from the study site for a time period that would interfere with product resupply and study participation
* Per participant report and/or clinical evidence of any of the following:

  1. Known adverse reaction to any of the study products (ever),
  2. Participation in any other research study involving drugs, medical devices or vaccines within 60 days of enrollment,
  3. At Enrollment, as determined by the PI/designee, has any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder, metabolic bone disease or infectious disease,
* We will test for hepatitis B and if participant has the infection, they will be excluded from the study. We also will test for hepatitis B immunity and the participant is not immune, we will offer the vaccination against hepatitis B infection.
* Has any other condition that, in the opinion of the PI/designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Primary outcomes:
measure: Hormonal Contraceptive Concentrations
timeFrame: at 2,4,8,12 weeks for IM DMPA and SC MPA or 2,4,8,12,20,24 weeks for ETG implants and IUD groups after contraceptive method initiation
measure: DOR Concentrations
timeFrame: at 2,4,8,12 weeks for IM and SC DMPA or 2,4,8,12,20,24 weeks for ETG implants and IUD groups after contraceptive method initiation
Secondary outcomes:
measure: Number of Participants With HIV Viral Suppression (i.e. ART Efficacy)
timeFrame: at 12-24 weeks after contraceptive initiation
Other outcomes:
Locations:
city: Johannesburg
country: South Africa
facility: Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site
Study officials:
affiliation: University of Washington
name: Anna Wald, MD, MPH
role: STUDY_CHAIR
affiliation: Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site
name: Thesla Palanee-Phillips, MMed Sci PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Patel RC, Stalter R, Onono M, et al. Dolutegravir-containing ART does not reduce etonogestrel implant concentrations. Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Virtual (Boston).
citation: Orkin C, Squires KE, Molina JM, Sax PE, Wong WW, Sussmann O, Kaplan R, Lupinacci L, Rodgers A, Xu X, Lin G, Kumar S, Sklar P, Nguyen BY, Hanna GJ, Hwang C, Martin EA; DRIVE-AHEAD Study Group. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial. Clin Infect Dis. 2019 Feb 1;68(4):535-544. doi: 10.1093/cid/ciy540.
citation: Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, Lai MT, Xu X, Rodgers A, Lupinacci L, Kumar S, Sklar P, Nguyen BY, Hanna GJ, Hwang C; DRIVE-FORWARD Study Group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018 May;5(5):e211-e220. doi: 10.1016/S2352-3018(18)30021-3. Epub 2018 Mar 25.