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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03965923
Recruitment Status : Recruiting
First Posted : May 29, 2019
Last Update Posted : January 22, 2020
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: Dapivirine (DPV) Vaginal Ring (VR) Drug: Truvada Tablet Phase 3

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 four 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: 20 0/7 weeks - 29 6/7 weeks
  • Cohort 4: 12 0/7 weeks - 19 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 4. Infants born to study participants will be followed for approximately 52 weeks.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 750 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral TRUVADA® Use in Pregnancy
Actual Study Start Date : January 9, 2020
Estimated Primary Completion Date : April 30, 2023
Estimated Study Completion Date : April 30, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
Drug Information available for: Truvada

Arm Intervention/treatment
Experimental: Cohort 1: 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.
Drug: Dapivirine (DPV) Vaginal Ring (VR)
Vaginal ring containing 25 mg of DPV

Experimental: Cohort 1: 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.
Drug: Truvada Tablet
Tablet taken orally
Other Names:
  • Emtricitabine/Tenofovir Disoproxil Fumarate
  • FTC/TDF

Experimental: Cohort 2: 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.
Drug: Dapivirine (DPV) Vaginal Ring (VR)
Vaginal ring containing 25 mg of DPV

Experimental: Cohort 2: 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.
Drug: Truvada Tablet
Tablet taken orally
Other Names:
  • Emtricitabine/Tenofovir Disoproxil Fumarate
  • FTC/TDF

Experimental: Cohort 3: Dapivirine (DPV) Vaginal Ring (VR)
Participants in Cohort 3 (20 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)
Vaginal ring containing 25 mg of DPV

Experimental: Cohort 3: Truvada Tablet
Participants in Cohort 3 (20 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
Tablet taken orally
Other Names:
  • Emtricitabine/Tenofovir Disoproxil Fumarate
  • FTC/TDF

Experimental: Cohort 4: Dapivirine (DPV) Vaginal Ring (VR)
Participants in Cohort 4 (12 0/7 weeks - 19 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)
Vaginal ring containing 25 mg of DPV

Experimental: Cohort 4: Truvada Tablet
Participants in Cohort 4 (12 0/7 weeks - 19 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
Tablet taken orally
Other Names:
  • Emtricitabine/Tenofovir Disoproxil Fumarate
  • FTC/TDF




Primary Outcome Measures :
  1. Frequency of all serious maternal adverse events, including maternal deaths [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
    As defined by the Manual for Expedited Reporting of Adverse Events to Division of AIDS (DAIDS) (Version 2.0, January 2010)

  2. Frequency of all Grade 3 or higher maternal adverse events (AEs) [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
    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])

  3. Frequency of all serious infant adverse events, including infant deaths and congenital anomalies [ Time Frame: Measured through Week 52 ]
    As defined by the Manual for Expedited Reporting of Adverse Events to DAIDS (Version 2.0, January 2010)

  4. Frequency of all Grade 3 or higher infant AEs [ Time Frame: Measured through Week 52 ]
    As defined by the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017

  5. Frequency of full term live births (greater than or equal to 37 0/7 weeks) [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  6. Frequency of premature live births (less than 37 0/7 weeks) [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  7. Frequency of pregnancy loss (greater than or equal to 20 0/7 weeks) [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  8. Frequency of pregnancy loss (less than 20 0/7 weeks) [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]

Secondary Outcome Measures :
  1. Frequency of hypertensive disorders of pregnancy [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  2. Frequency of chorioamnionitis [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  3. Frequency of puerperal sepsis [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  4. Frequency of endometritis [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  5. Frequency of peripartum hemorrhage [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  6. Frequency of postpartum hemorrhage [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  7. Frequency of preterm premature rupture of membranes (PROM) [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  8. Frequency of fever of unclear etiology [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
  9. Infant blood tenofovir diphosphate (TFV-DP) concentrations [ Time Frame: Measured through Week 52 ]
    Based on laboratory evaluations

  10. Infant blood emtricitabine triphosphate (FTC-TP) concentrations [ Time Frame: Measured through Week 52 ]
    Based on laboratory evaluations

  11. Infant plasma DPV concentrations [ Time Frame: Measured through Week 52 ]
    Based on laboratory evaluations

  12. Maternal blood TFV-DP concentrations [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
    Based on laboratory evaluations

  13. Maternal blood FTC-TP concentrations [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
    Based on laboratory evaluations

  14. Maternal plasma DPV concentrations [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
    Based on laboratory evaluations

  15. Frequency of study product use [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
    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

  16. Residual drug levels in returned VRs [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
    Based on laboratory evaluations

  17. Participant willingness to use study products during pregnancy (Y/N) [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
    Based on participant report

  18. Proportion of participants who find the study products to be at least as acceptable as other HIV prevention methods [ Time Frame: Measured through participant's last study visit, at approximately Week 12 to 36, depending on participant's cohort ]
    Based on participant report



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03965923


Locations
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South Africa
Wits RHI Shandukani Research Centre CRS Recruiting
Johannesburg, Gauteng, South Africa, 2001
Contact: Hermien Gous, Pharm.D.    27-11-3585500 ext 5502    hgous@wrhi.ac.za   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Study Chair: Katherine Bunge, MD, MPH University of Pittsburgh
Study Chair: Bonus Makanani, MBBS, FCOG(SA) Johns Hopkins University Research Project

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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03965923    
Other Study ID Numbers: MTN-042
38544 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: May 29, 2019    Key Record Dates
Last Update Posted: January 22, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Tenofovir
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Dapivirine
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents