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

Study Overview
=================
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.

Official Title
-----------------
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral TRUVADA® Use in Pregnancy

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Drug: Dapivirine (DPV) Vaginal Ring (VR)
* Drug: Truvada Tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Dapivirine (DPV) Vaginal Ring (VR)<br>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. | Drug: Dapivirine (DPV) Vaginal Ring (VR)<br>* Vaginal ring containing 25 mg of DPV<br>|
| Experimental: Cohort 1: Truvada Tablet<br>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. | Drug: Truvada Tablet<br>* Tablet taken orally<br>* Other names: FTC/TDF;|
| Experimental: Cohort 2: Dapivirine (DPV) Vaginal Ring (VR)<br>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. | Drug: Dapivirine (DPV) Vaginal Ring (VR)<br>* Vaginal ring containing 25 mg of DPV<br>|
| Experimental: Cohort 2: Truvada Tablet<br>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. | Drug: Truvada Tablet<br>* Tablet taken orally<br>* Other names: FTC/TDF;|
| Experimental: Cohort 3: Dapivirine (DPV) Vaginal Ring (VR)<br>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. | Drug: Dapivirine (DPV) Vaginal Ring (VR)<br>* Vaginal ring containing 25 mg of DPV<br>|
| Experimental: Cohort 3: Truvada Tablet<br>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. | Drug: Truvada Tablet<br>* Tablet taken orally<br>* Other names: FTC/TDF;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of all serious maternal adverse events, including maternal deaths | As defined by the Manual for Expedited Reporting of Adverse Events to Division of AIDS (DAIDS) (Version 2.0, January 2010) | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of all Grade 3 or higher maternal adverse events (AEs) | As defined by the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and/or Addendum 1 (Female Genital Grading Table for Use in Microbicide Studies [Dated November 2007]) | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of all serious infant adverse events, including infant deaths and congenital anomalies | As defined by the Manual for Expedited Reporting of Adverse Events to DAIDS (Version 2.0, January 2010) | Measured through Week 52 | 
| Frequency of all Grade 3 or higher infant AEs | As defined by the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 | Measured through Week 52 | 
| Frequency of full term live births (greater than or equal to 37 0/7 weeks) |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of premature live births (less than 37 0/7 weeks) |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of pregnancy loss (greater than or equal to 20 0/7 weeks) |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of pregnancy loss (less than 20 0/7 weeks) |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of hypertensive disorders of pregnancy |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of chorioamnionitis |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of puerperal sepsis |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of endometritis |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of peripartum hemorrhage |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of postpartum hemorrhage |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of preterm premature rupture of membranes (PROM) |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Frequency of fever of unclear etiology |  | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Infant blood tenofovir diphosphate (TFV-DP) concentrations | Based on laboratory evaluations | Measured at the 2-week post pregnancy outcome (PPO) visit | 
| Infant blood emtricitabine triphosphate (FTC-TP) concentrations | Based on laboratory evaluations | measured at the 2-week post pregnancy outcome (PPO) visit | 
| Infant plasma DPV concentrations | Based on laboratory evaluations | measured at the 2-week post pregnancy outcome (PPO) visit | 
| Maternal blood TFV-DP concentrations | Based on laboratory evaluations | Measured through participant's 2-week PPO visit, at approximately Week 8-32, depending on participant's cohort | 
| Maternal blood FTC-TP concentrations | Based on laboratory evaluations | Measured through participant's 2-week PPO visit, at approximately Week 8-32, depending on participant's cohort | 
| Maternal plasma DPV concentrations | Based on laboratory evaluations | Measured through participant's 2-week PPO visit, at approximately Week 8-32, depending on participant's cohort | 
| Frequency of study product use | Based on participant report, as defined by missed doses for oral Truvada and VR removal/expulsions [voluntary and involuntary] and duration without VR in vagina | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Residual drug levels in returned VRs | Based on laboratory evaluations | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Participant willingness to use study products during pregnancy (Y/N) | Based on participant report | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort | 
| Proportion of participants who find the study products to be at least as acceptable as other HIV prevention methods | Based on participant report | Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort |