Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral TRUVADA® Use in Pregnancy

Phase 3

Completed

Conditions: HIV Infections

Interventions: Drug: Dapivirine (DPV) Vaginal Ring (VR)
Drug: Truvada Tablet

Registration Number: NCT03965923

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: The purpose of this study is to evaluate the maternal and infant safety of the dapivirine (DPV) vaginal ring (VR) and daily oral Truvada in HIV-uninfected pregnant women and their infants.

Detailed Description: The purpose of this study is to evaluate the maternal and infant safety of the dapivirine (DPV) vaginal ring (VR) and daily oral Truvada in HIV-uninfected pregnant women and their infants.

Participants will be assigned to one of three cohorts based on gestational age:

* Cohort 1: 36 0/7 weeks - 37 6/7 weeks

* Cohort 2: 30 0/7 weeks - 35 6/7 weeks

* Cohort 3: 12 0/7 weeks - 29 6/7 weeks

Within each cohort, participants will be randomized to receive either DPV VR or oral Truvada. Participants randomized to the DPV VR will use the VR continuously for approximately one month, replacing the VR each month. Participants taking the Truvada tablet will take one tablet orally per day. Participants will use their assigned study product until their pregnancy outcome, but no later than 41 6/7 weeks of gestation.

Participants will attend several study visits throughout the study and study staff will also contact participants by phone at different timepoints throughout the study.

The total duration of study participation will vary depending on gestational age at time of enrollment and length of pregnancy prior to pregnancy outcome and will range from approximately 12 weeks or less for Cohort 1 to approximately 36 weeks or less for Cohort 3. Infants born to study participants will be followed for approximately 52 weeks.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 1104

Inclusion Criteria

Age 18 through 40 years (inclusive) at Enrollment, verified per site standard operating procedures (SOPs).
At Enrollment, evidence of a viable, intrauterine, singleton pregnancy with sonographic confirmation, including for gestational age assessment.
- Note: If adequate (per judgment of Investigator of Record [IoR]/designee) sonographic results are not available from medical records at Screening, an ultrasound must be performed and results be available for review at Enrollment for all Cohorts. The ultrasound should be performed no later than the 36th week of gestation for Cohort 1 or the 28th week of gestation for Cohort 2.
At Enrollment, pregnancy within gestational age limits of the currently enrolling cohort (per the study protocol).
HIV-uninfected based on testing performed at Screening and Enrollment (per protocol algorithm in the study protocol).
At Screening and Enrollment, intending to continue her pregnancy until delivery.
At Screening and Enrollment, intending to deliver at a health center or hospital where adequate records may be obtained, as defined in site SOPs.
- Note: Plans to deliver at a health center or hospital where adequate records may be obtained is inclusionary due to logistical challenges related to collection of vaginal rings (VRs), specimens and delivery outcome data outside of those settings.
At Screening and Enrollment, willing to be randomized at time of enrollment to either of the two study arms, and to continue study product use until delivery.
Able and willing to comply with all study requirements and complete all study procedures.
Able and willing to provide the following:
- Informed consent for her and her infant to be screened for and to enroll in MTN-042, as defined in site SOPs.
- Adequate locator information, as defined in site SOPs.
- Adequate documentation of registration for antenatal care, as defined in site SOPs.
- Permission to contact participant's antenatal and postpartum care provider(s) and to obtain copies of antenatal and postpartum care records.
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, unless approved by the Protocol Safety Review Team (PSRT).

Exclusion Criteria

Per participant report at Screening and/or Enrollment, intends to do any of the following during the study participation period:
- Use oral pre-exposure prophylaxis (PrEP) outside the context of study participation.
- Relocate away from the study site.
- Travel away from the study site for a time period that would interfere with study participation.
At Screening or Enrollment, has a positive HIV test.
At Screening or Enrollment, diagnosed with urinary tract infection (UTI), cervicitis, sexually transmitted infection (STI) or reproductive tract infection (RTI) requiring treatment per World Health Organization (WHO) guidelines.
- Note: Detection of bacterial vaginosis (BV) or candida in the absence of symptoms is not exclusionary. Otherwise eligible participants diagnosed during screening with a UTI, cervicitis, or STI/RTI requiring treatment per WHO guidelines are offered treatment consistent with WHO recommendations. If treatment is completed and symptoms have resolved within 35 days of obtaining informed consent for screening, the participant may be enrolled.
At Enrollment, has a clinically apparent Grade 2 or higher pelvic exam finding.*
- Note: Cervical friability bleeding associated with speculum insertion and/or specimen collection judged to be within the range of normal according to the clinical judgment of the Investigator of Record (IoR)/designee is considered expected bleeding and is not exclusionary.
Participant report, clinical evidence and/or antenatal/medical care record of any of the following:
- Currently breastfeeding at Enrollment.
- Known adverse reaction to any of the study products (ever).
- Known adverse reaction to latex and polyurethane (ever).
- Symptoms suggestive of acute HIV infection at Screening or Enrollment.
- Non-therapeutic injection drug use in the 12 months prior to Enrollment.
- Use of HIV post-exposure prophylaxis (PEP) and/or PrEP during the current pregnancy.
- Participation in any other research study involving drugs, medical devices, vaginal products, or vaccines during the current pregnancy.
- At Screening or Enrollment, known to have any of the following during the current pregnancy:
  - Multiple gestation
  - Placenta previa
  - Cervical cerclage
  - Abnormal fetal anatomy (in the opinion of the IoR or designee)
  - Intrauterine growth restriction
  - Pre-existing or gestational diabetes
  - Hypertensive disorder of pregnancy
  - Severe malaria
  - Treatment for preterm labor
  - Abnormal quantity of amniotic fluid (oligohydramnios or polyhydramnios)
- At Screening, known to have had any of the following in a previous pregnancy:
  - Intrauterine growth restriction
  - Gestational diabetes
  - Hypertensive disorder of pregnancy
  - Intrauterine fetal demise (estimated gestational age greater than or equal to 20 weeks)
  - Delivery prior to 37 0/7 weeks
- At Enrollment, as determined by the IoR/designee, has any significant obstetrical complication (e.g., premature rupture of membranes, any abnormal placentation) or uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease that would make study participation unsafe.
At Screening, has any of the following laboratory abnormalities:
- Positive for hepatitis B surface antigen (HBsAg).
- Aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than or equal to Grade 1.**
- Hemoglobin greater than or equal to Grade 2.**
- Platelet count greater than or equal to Grade 1.**
- Creatinine greater than or equal to Grade 1.**
- Estimated creatinine clearance greater than or equal to Grade 2 (Cockcroft Gault formula).**
- Glycosuria greater than or equal to Grade 2.**
- Proteinuria greater than or equal to Grade 2.**
- Note: Otherwise eligible participants with an exclusionary test (other than HBsAg) may be re-tested during the screening process; re-testing procedure details can be found in the MTN-042 Study Specific Procedures (SSP) Manual. If improvement to a non-exclusionary grade or resolution is documented within 35 days of providing informed consent for screening, the participant may be enrolled.
Has any condition that, in the opinion of the IoR/designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.
*Female Genital Grading Table for Use in Microbicide Studies Addendum 1 (Dated November 2007) to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017.
**DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1, July 2017.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1 Mothers: Dapivirine (DPV) Vaginal Ring (VR)	Dapivirine (DPV) Vaginal Ring (VR)	Participants in Cohort 1 (36 0/7 weeks - 37 6/7 weeks) will use one DPV VR continuously for approximately one month, replacing the DPV VR each month. Participants will use the DPV VR until their pregnancy outcome but no later than 41 6/7 weeks of gestation.
Cohort 1 Mothers: Truvada Tablet	Truvada Tablet	Participants in Cohort 1 (36 0/7 weeks - 37 6/7 weeks) will take one Truvada oral tablet daily. Participants will take Truvada until their pregnancy outcome but no later than 41 6/7 weeks of gestation.
Cohort 2 Mothers: Dapivirine (DPV) Vaginal Ring (VR)	Dapivirine (DPV) Vaginal Ring (VR)	Participants in Cohort 2 (30 0/7 weeks - 35 6/7 weeks) will use one DPV VR continuously for approximately one month, replacing the DPV VR each month. Participants will use the DPV VR until their pregnancy outcome but no later than 41 6/7 weeks of gestation.
Cohort 2 Mothers: Truvada Tablet	Truvada Tablet	Participants in Cohort 2 (30 0/7 weeks - 35 6/7 weeks) will take one Truvada oral tablet daily. Participants will take Truvada until their pregnancy outcome but no later than 41 6/7 weeks of gestation.
Cohort 3 Mothers: Dapivirine (DPV) Vaginal Ring (VR)	Dapivirine (DPV) Vaginal Ring (VR)	Participants in Cohort 3 (12 0/7 weeks - 29 6/7 weeks) will use one DPV VR continuously for approximately one month, replacing the DPV VR each month. Participants will use the DPV VR until their pregnancy outcome but no later than 41 6/7 weeks of gestation.
Cohort 3 Mothers: Truvada Tablet	Truvada Tablet	Participants in Cohort 3 (12 0/7 weeks - 29 6/7 weeks) will take one Truvada oral tablet daily. Participants will take Truvada until their pregnancy outcome but no later than 41 6/7 weeks of gestation.
Cohort 1 Infants: Dapivirine (DPV) Vaginal Ring (VR)	Dapivirine (DPV) Vaginal Ring (VR)	Infants born to maternal participants in the Cohort 1 (36 0/7 weeks - 37 6/7 weeks) DPV VR arm.
Cohort 1 Infants: Truvada Tablet	Truvada Tablet	Infants born to maternal participants in the Cohort 1 (36 0/7 weeks - 37 6/7 weeks) Truvada oral tablet daily arm.
Cohort 2 Infants: Dapivirine (DPV) Vaginal Ring (VR)	Dapivirine (DPV) Vaginal Ring (VR)	Infants born to maternal participants in the Cohort 2 (30 0/7 weeks - 35 6/7 weeks) DPV VR arm.
Cohort 2 Infants: Truvada Tablet	Truvada Tablet	Infants born to maternal participants in the Cohort 2 (30 0/7 weeks - 35 6/7 weeks) Truvada oral tablet daily arm.
Cohort 3 Infants: Dapivirine (DPV) Vaginal Ring (VR)	Dapivirine (DPV) Vaginal Ring (VR)	Infants born to maternal participants in the Cohort 3 (12 0/7 weeks - 29 6/7 weeks) DPV VR arm.
Cohort 3 Infants: Truvada Tablet	Truvada Tablet	Infants born to maternal participants in the Cohort 3 (12 0/7 weeks - 29 6/7 weeks) Truvada oral tablet daily arm.

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Composite Safety Endpoint Adverse Event (AE)	Measured through participant's last study visit. For mothers, this occurred at approximately Week 12 to 36, depending on participant's cohort, and for infants at approximately Week 52.	All AEs were reported as per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Composite safety endpoint AEs were AEs that were either categorized as serious adverse events (SAEs) or were Grade 3 or higher. This measure is the number of participants with at least one composite AE.
Pregnancy Outcomes	Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort	Frequency of different types of pregnancy outcomes among mothers.

Secondary Outcome Measures

Name	Time	Method
Adherence: Maternal Blood FTC-TP Concentrations	Measured through participant's 2-week PPO visit, at approximately Week 8-32, depending on participant's cohort	Maternal blood FTC-TP was collected at the 2-week, bi-weekly (starting at 4-weeks), and PPO visits for participants randomized to receive Truvada Tablet. In Cohort 1 this was done for a randomly selected subset of those participants.
Adherence: Maternal Plasma DPV Concentrations	Measured through participant's 2-week PPO visit, at approximately Week 8-32, depending on participant's cohort	Maternal plasma DPV was collected at the 2-week, bi-weekly (starting at 4-weeks), and PPO visits for a randomly selected subset of participants (approximately 50%) randomized to receive the VR. Participants are categorized as ever being exposed if they had at least one measure that was greater than the LLOQ (i.e., greater than or equal to 20 pg/mL). They are categorized as never being exposed if they had at least one analyzable sample and none met the criteria.
Acceptability: Participant Willingness to Use Study Products During Pregnancy in the Future	Measured at Week 4 and 6-Week PPO/SEV visits.	Based on participant report of whether they would be willing to use the study product they were randomized to receive when pregnant in the future. Only asked of participants in Cohorts 2 and 3.
Acceptability: Participants Who Are Satisfied With the Study Products for Preventing HIV	Measured at Week 4 visits.	Based on participant report of how satisfied they have been with the the study product they were randomized to receive for HIV prevention. Only asked of participants in Cohorts 2 and 3.
Pregnancy Complications: Frequency of Pregnancy Complications	Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort	Frequency of different types of pregnancy complications among mothers. The categories of pregnancy complications were pre-defined on the case report form, and after the completion of Cohort 1 follow-up there were some changes made to the pregnancy complication categories. In Cohort 1 the category "peripartum hemorrhage" was collected, but in Cohort 2 and 3 this category was removed from the list of pre-defined complications. Two other categories, "antepartum hemorrhage" and "intrapartum hemorrhage", were added to the list for Cohort 2 and Cohort 3. As a result, participants in Cohort 1 were not evaluated for antepartum or intrapartum hemorrhage, while participants in Cohorts 2 and 3 were not evaluated for peripartum hemorrhage. All other complications were collected for all three cohorts, and participants in all three cohorts were evaluated for each complication.
Infant Drug Levels: Number of Infants With Detectable Blood Emtricitabine Triphosphate (FTC-TP)	measured at the 2-week post pregnancy outcome (PPO) visit	Infant blood FTC-TP was measured at infants' PPO visit. The outcome is defined as having detectable drug level, with detectable drug levels defined as a FTC-TP concentration above the lower limit of quantification (LLOQ) for the assay.
Adherence: Maternal Blood TFV-DP Concentrations	Measured through participant's 2-week PPO visit, at approximately Week 8-32, depending on participant's cohort	Maternal blood TFV-DP was collected at the 2-week, bi-weekly (starting at 4-weeks), and PPO visits for participants randomized to receive Truvada Tablet. In Cohort 1 this was done for a randomly selected subset of those participants. Participants are categorized as ever being exposed if they had at least one measure that was \>= 200 fmol/punch (if the sample was collected more than 6 weeks after randomization) or \>= 150 fmol/punch (if the sample was collected within 6 weeks of randomization). They are categorized as never being exposed if they had at least one analyzable sample and none met the criteria.
Adherence: Number of Participants With Product Exposure (Measured in Residual Drug Levels in Returned VRs)	Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort	Residual drug levels were collected from returned VRs, which were expected to be returned at monthly visits throughout study follow-up. Drug release rate was calculated by subtracting the residual level from the amount of residual drug in the manufacturer lot, divided by the number of days the participant was expected to use that ring, times 28 days. For each individual ring, a ring was considered to show evidence of use if the residual drug level was greater than or equal to 0.9mg/28 days of use. Participants are categorized as either ever being exposed or never being exposed to product over the course of study follow-up. They are categorized as ever being exposed to product if they had at least one ring with evidence of use (i.e., greater than or equal to 0.9 mg/28 days of release). They are categorized as never being exposed if they had at least one analyzable returned ring and none of these rings had evidence of use.
Infant Drug Levels: Number of Infants With Detectable Infant Blood Tenofovir Diphosphate (TFV-DP)	Measured at the 2-week post pregnancy outcome (PPO) visit	Infant blood TFV-DP was measured at infants' post pregnancy outcome (PPO) visit (up to 14 days after pregnancy outcome). The outcome is defined as having detectable drug level, with detectable drug levels defined as a TFV-DP concentration above the lower limit of quantification (LLOQ) for the assay.
Adherence: Frequency of Missing Taking the Pills	Measured at Week 4 and PPO visits	Based on participant report, as defined by self-reported missed doses for oral Truvada. This was only reported by participants in Cohorts 2 and 3.
Adherence: Frequency of Ring Removal/Expulsion	Measured at Week 4 visit and Post-Pregnancy Outcome (PPO) (occurring within 2 weeks of pregnancy outcome) visit	Based on participant report, as defined by self-reported occurrences of the ring being out of the vagina for more than 12 hours, being out for any time. This was only reported by participants in Cohorts 2 and 3.
Infant Drug Levels: Number of Infants With Detectable Plasma DPV	measured at the 2-week post pregnancy outcome (PPO) visit	Infant plasma DPV concentration was measured at infants' post pregnancy outcome (PPO) visit (up to 14 days after pregnancy outcome). The outcome is defined as having detectable drug level, with detectable drug levels defined as a DPV concentration above the lower limit of quantification (LLOQ) for the assay.
Acceptability: Participants Who Find the Study Products to be at Least as Acceptable as Other HIV Prevention Methods	Measured at Week 4 visits.	Based on participant report of how much they liked or disliked the study product they were randomized to receive for HIV prevention, and of how much they liked or disliked male condoms for HIV prevention. Only asked of participants in Cohorts 2 and 3.

Trial Locations

Locations (4): Blantyre CRS (Johns Hopkins Research Project/College of Medicine)
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Blantyre, Malawi
Wits RHI Shandukani Research Centre CRS
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Johannesburg, Gauteng, South Africa
MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
🇺🇬
Kampala, Uganda
Zengeza CRS
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Chitungwiza, Mashonaland East, Zimbabwe
Blantyre CRS (Johns Hopkins Research Project/College of Medicine)
🇲🇼Blantyre, Malawi