A Crossover Acceptability Study Assessing a DPP Capsule for HIV and Pregnancy Prevention
Condition: HIV Infections; Contraception
MeSH terms: HIV Infections
Study type: Interventional

Summary: 
      The study design is a single-site, two-arm, randomized, open-label crossover trial in 30 AGYW
      aged 16-24 in Chitungwiza (Harare), Zimbabwe. The aim of the study is to assess the
      acceptability of, preference for, and adherence to a single DPP capsule containing one PrEP
      tablet and one COC tablet compared to two separate tablets (FTC/TDF and EE/LNG), each taken
      for three consecutive menstrual cycles for a total of 24 weeks among current COC users.
    

Detailed description: 
      We will conduct a randomized, open-label, parallel group, 2-way crossover study among
      approximately 30 girls and young women (AGYW) aged 16-24 years old to compare adherence,
      preference, acceptability and safety of a single dual prevention pill (DPP) containing
      Truvada and the generic COC, Zinnia F (Regimen A), versus Truvada and Zinnia F taken
      separately (Regimen B). All participants must already be using COCs for at least 3 months
      prior to screening and must plan to continue using them for at least one year. We are
      enrolling women who are already using COCs because we believe they are most likely to be
      interested in a daily oral MPT. Furthermore, we would like participants who are already
      accustomed to COCs so that they can have a clearer sense of how PrEP - whether taken
      separately or in the DPP - makes them feel.

      Prior to the commencement of the study, the Population Council procured and qualified all
      study drugs required for the crossover study, including: bulk pills (Truvada and Zinnia F)
      for encapsulation, COC pill packs, and bottles of Truvada. Under the guidance of the
      Council's clinical and regulatory groups, PCI Pharma (Rockford, IL, USA) over-encapsulated
      Truvada and Zinnia F according to Good Manufacturing Practices. The over-encapsulated pills
      were then blister packaged, pouched, and kitted for distribution to participants.

      The DPP regimen (A) consists of a kit containing 4 pouches with a 28-day supply of
      over-encapsulated pills; 21 pink and white capsules will contain Truvada over-encapsulated
      together with a COC; the other 7 capsules, corresponding to the 7 placebo days in a COC pill
      pack, will be white and will contain Truvada only. The provider counseling manual will
      emphasize the fact that unlike a COC pill pack where 7 pills are placebo, all of the pills in
      the regimen contain Truvada, so it will be important to take them for all 28 days. For
      Regimen B, participants will receive a 28-day blister pack of Zinnia F, as is currently
      marketed, with 21 active pills and 7 placebo pills. Truvada will be dispensed in bottles of
      30 pills, as is currently marketed. Participants will be instructed to take one Truvada
      tablet and one COC table daily for 28 days.

      After providing written informed consent (or assent, with parental consent, for
      non-emancipated 16-17-year-old girls), women will be screened for eligibility. Participants
      can be enrolled if they are sexually-active (defined as having had penile-vaginal sex with a
      male ≤3 months before screening), currently using a COC that was started ≥3 months before
      screening, HIV-negative (based on HIV rapid test at screening), not-pregnant (based on hCG
      urine test at screening), have no contraindications for PrEP or COCs, and are in good health
      based on medical history and vital signs. PrEP screening will follow the standard of care in
      Zimbabwe, which recommends testing for Hepatitis B, hepatitis C, complete blood count (CBC),
      blood creatinine levels, pregnancy, and STIs. Women who test positive for pregnancy or HIV
      will be referred per the local standard of care. Participants who test positive for a curable
      STI will be treated and enrolled. Participants who are eligible will be scheduled for an
      enrollment visit on Day 0 of their menstrual cycle.

      At enrollment, women will be randomly assigned to one of two sequences of the two regimens,
      with all women using both regimens by the end of the crossover study. The Population Council
      study biostatistician created the randomization scheme using Statistical Analysis Software
      (SAS/STAT) version 9.4 (SAS Institute Inc., Cary, North Carolina) with a 1:1 allocation using
      permutated block sizes. 15 participants will be assigned to Sequence 1: DPP capsules (Regimen
      A) in period 1, and two separate tablets (Regimen B) in period 2, and 15 participants will be
      assigned to Sequence 2: Regimen B in period 1 and Regimen A in period 2. Randomization will
      be in blocks of 10, with 5 participants assigned to each sequence in each of the 3 blocks.
      Participants will use each regimen for 3 28-day menstrual cycles and will then switch to the
      second regimen at their crossover visit.

      Participants will attend a total of up to 8 clinic visits including Screening, Enrollment and
      monthly follow up visits for up to 7 months. No wash-out period is required between regimens.
      At Visit 1, prior to initiating product use, participants will be asked to complete a
      baseline behavioral interview and will be asked which regimen they think they will prefer. At
      all other visits, participants will complete behavioral interviews (approximately 30 minutes)
      about adherence and acceptability. All behavioral interviews will be conducted using computer
      assisted self-interviewing (CASI), which has been shown to elicit more truthful reporting
      than face-to-face interviewing. At the end of the Crossover period, participants will
      complete their final CASI interview, in which they will be asked to 1) state their preference
      for the DPP or 2 separate pills; 2) to qualify the strength of their preference on a scale of
      1-10; All of the participants who complete the study and anyone who withdraws early will be
      asked to take part in an in-depth interview to explore qualitatively reasons for continuation
      and discontinuation, as well as the influence of partners, family, support structures, side
      effects, provider interactions and other factors on cMPT choice and adherence.

      At all follow up visits, women will be tested for HIV and pregnancy, report adverse events
      (AEs) and have a clinical exam, if necessary, and respond to a structured questionnaire via
      computer assisted self-interview (CASI) with questions about acceptability, preference, and
      adherence. At the end of the Crossover period, women will be asked to state which regimen
      they prefer. Accrual is estimated to take approximately 6 months from first participant
      enrolling to last participant completing the study. We will assess and compare PrEP
      acceptability and adherence by regimen and overall, and we will investigate if specific
      socio-ecological factors (e.g., individual-, partner-, family-, and clinic-level) are
      associated with adherence and acceptability. We will also explore facilitators and barriers
      to use by conducting in-depth interviews with a subset of willing participants who complete
      the study and any women who withdraws early. Furthermore, because we assume people are
      predisposed to judge a specific regimen or technology based on initial impressions, we will
      assess if pre-use preferences are associated with actual experiences and preferences after
      using each regimen.

      At each visit, women will be tested for pregnancy and HIV and will provide a blood sample for
      DBS to assess drug levels/adherence to PrEP. Adverse events will be recorded during the
      study, although no pharmacokinetic interactions are expected because there are no drug-drug
      interactions between the reverse transcriptase inhibitors tenofovir and emtricitabine, and
      the contraceptive hormones levonorgestrel and ethinyl estradiol. In addition, the side
      effects profiles of the two products are similar; the most commonly reported side-effects for
      both Truvada® and COCs are headache and nausea. Since we are recruiting women who are already
      using COCs, participants will already be accustomed to side-effects of COCs. Participants
      will be encouraged to contact or visit the clinic with questions or concerns between visits.

      Rapid HIV testing will be done at screening, in accordance with local guidelines. Pregnancy
      will be tested based on hCG levels in urine. DBS collected from enrolled participants will be
      sent to the University of Cape Town where tenofovir disoproxil fumarate (TDF) drug levels
      will be measured to evaluate adherence based on expected levels for daily use.

      Quantitative and qualitative behavioral collection instruments will adhere to our theoretical
      framework for assessing acceptability, with questions adapted from previous HIV-prevention
      studies, as relevant. In-depth interview guides will be developed from instruments used in
      previous PrEP introduction studies and tailored for this study.

      Quantitative data from the CASI behavioral interviews will be saved at the site in .csv
      (comma separated value) format and shared with Population Council weekly via encrypted zip
      files. Clinical data collected from participants, including background demographics; medical
      and pregnancy history; vital signs; concomitant medications; AEs; enrollment and termination
      dates; and records of returned unused pills will be entered into REDCap, an electronic data
      system. Data from CASI interviews, eCRFs and DBS analysis will be formatted into SAS data
      sets for analysis. Descriptive statistics (frequencies, mean, standard deviation, range) will
      be used to summarize data collected and to characterize differences in participants assigned
      to each Sequence. Modeling will be used to assess the impact of background characteristics on
      adherence, preference and acceptability.

      PC conducted site initiation and training for the crossover study in collaboration with
      UZ-CTRC, which has extensive experience implementing qualitative and quantitative HIV
      prevention research studies. The Population Council and site coordinator have weekly
      teleconferences and the full teams are meeting monthly during data collection to discuss and
      resolve any issues as they occur. The PC clinical research associate will make periodic
      monitoring trips during data collection to ensure the safety of participants and adherence to
      the protocol. The PC team will also review data collected on a weekly basis.
    

Intervention name(s): Dual Prevention Pill; PrEP and combined oral contraceptive (COC) as two separate tablets
Intervention type(s): Drug; Drug
Intervention description(s): a single over-encapsulated DPP containing a PrEP tablet and a COC; PrEP tablet and a COC as two separate tablets
Other intervention name(s): DPP; Truvada; Zinnia F
Intervention MeSH terms: Contraceptive Agents; Contraceptives, Oral; Contraceptives, Oral, Combined
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: A randomized, open-label, parallel group, 2-way crossover study A total of 24 weeks (6 28-day menstrual cycles); 3 cycles of DPP capsule (12 weeks); 3 cycles of 2 separate tablets (PrEP and COC tablets; 12 weeks)
Masking: None (Open Label)
Primary purpose: Prevention