Safety and Drug Detection Study of Dapivirine Vaginal Ring and Oral TRUVADA® in Breastfeeding Mother-Infant Pairs

Phase 3B, Randomized, Open-Label, Safety, and Drug Detection Study of Dapivirine Vaginal Ring and Oral TRUVADA® in Breastfeeding Mother-Infant Pairs

The purpose of this study is to evaluate the safety and drug detection of the dapivirine vaginal ring and oral Truvada in breastfeeding mother-infant pairs.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Dapivirine (DPV) Vaginal Ring (VR)-004; Drug: Truvada Tablet

Detailed Description

This study will evaluate the safety and drug detection of the dapivirine (DPV) vaginal ring (VR) and oral Truvada in breastfeeding mother-infant pairs.

Mother-infant pairs will be randomly assigned to receive either the DPV VR or oral Truvada. Mothers randomized to the DPV VR will use the VR continuously for approximately one month (4 weeks), replacing the VR each month for approximately three months (12 weeks). Mothers using the Truvada tablet will take one tablet by mouth daily for approximately three months (12 weeks).

Study visits will occur at Day 0, Weeks 1 and 2, and Months 1, 2, 3, and 3.5. Study visits may include behavioral assessments; product acceptability assessments; infant feeding assessments; physical examinations; blood, urine, and breast milk collection; and pelvic examination and specimen collection.

• Study Type: Interventional
• Enrollment (Actual): 394
• Phase: Phase 3

Contacts and Locations

Study Locations

• Malawi
  • Blantyre, Malawi
    • Blantyre CRS (Johns Hopkins Research Project/College of Medicine)
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2001
      • Wits RHI Shandukani Research Centre CRS
• Uganda
  • Kampala, Uganda
    • MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
• Zimbabwe
  • Mashonaland East
    • Chitungwiza, Mashonaland East, Zimbabwe
      • Zengeza CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Inclusion Criteria - Mother

Participant mothers must meet all the following criteria to be eligible for inclusion in the study:

• Age 18 years or older at Screening, as verified per site Standard Operating Procedures (SOPs).
• At Enrollment, between 6 to 12 weeks postpartum (verified by birth records and/or similar supportive documentation and defined as between 42 - 84 days after delivery, inclusive).

• By participant report at Screening and Enrollment, currently exclusively breastfeeding one infant and willing and able to continue exclusively breastfeeding that infant for the duration of their participation in the study.

  • Note: Exclusive breastfeeding will be defined as infant nutrition solely from breast milk, as determined by 7-day recall breastfeeding history. For the purposes of MTN-043, "breastfeeding" refers to all human milk feeding situations when an infant is fed with participant's own human milk whether the milk is received directly from the breast or as expressed milk.
• Consistently using an effective method of contraception per participant report at Enrollment, and intending to continue use of an effective method for the duration of study participation. Effective methods include contraceptive implants, intrauterine device, injectable progestin, oral contraceptive pills, and surgical sterilization.
• Able and willing to comply with all study requirements and complete all study procedures.

• Able and willing to provide the following:

  • Written informed consent to be screened for and to take part in the study.
  • Written informed consent for the breastfed infant to be screened for and take part in the study.
• Intention to stay within study catchment area for study duration and willingness to give adequate locator information, as defined in site SOPs.
• At Screening and Enrollment, HIV-uninfected based on HIV testing performed by study staff (per algorithm in the study protocol).
• At Screening and Enrollment, willing to be randomized at time of enrollment to either of the study products, and to continue study product use for at least 12 weeks.

Inclusion Criteria - Infant

Each mother eligible for MTN-043 will be asked to provide written informed consent for herself and her infant to participate in the study if the infant meets the following criteria:

• At Screening and Enrollment, infant is exclusively breastfed.

  • Note: Exclusive breastfeeding will be defined as infant nutrition solely from breast milk, as determined by 7-day recall breastfeeding history. For the purposes of MTN-043, "breastfeeding" refers to all human milk feeding situations when an infant is fed with participant's own human milk whether the milk is received directly from the breast or as expressed milk.
• At Screening and Enrollment, the infant is generally healthy, according to the judgment of the investigator of record (IoR)/designee.
• At Enrollment, the infant is between the ages of 6 and 12 weeks postpartum (verified by birth records and/or similar supportive documentation with age defined as between 42 - 84 days after delivery, inclusive).

Exclusion Criteria:

Exclusion Criteria - Mother

Mothers who meet any of the following criteria will be excluded from the study:

• At Screening or Enrollment, breastfeeding infant ineligible for enrollment in the study.

• At Screening or Enrollment, participant reports any of the following:

  • Known adverse reaction to any of the study products (ever).
  • Known adverse reaction to latex and polyurethane (ever).
  • Post-exposure prophylaxis (PEP) for HIV exposure within 6 months prior to Enrollment.
  • Use of vaginal medications(s) or other vaginal products within five days prior to Enrollment.
  • Non-therapeutic injection drug use in the 12 months prior to Enrollment.
  • History of exposure to any investigational drug(s) during pregnancy, including participation in MTN-042.
• At Screening or Enrollment, has a positive HIV test.
• At Screening or Enrollment, Grade 2 or higher breast or genitourinary findings.
• At Screening or Enrollment, has a positive urinary pregnancy test.

• At Screening, has any of the following laboratory abnormalities:

  • Positive for hepatitis B surface antigen (HBsAg).
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥ Grade 2.
  • Creatinine ≥ Grade 1.
  • Estimated creatinine clearance ≥ Grade 2 (Cockcroft Gault formula).

• Diagnosed with urinary tract infection (UTI), pelvic inflammatory disease (PID), sexually transmitted infection (STI) or reproductive tract infection (RTI), requiring treatment per World Health Organization (WHO) Guidelines.

  • Note: Otherwise eligible participants diagnosed during Screening with a UTI, PID or STI/RTI requiring treatment per WHO Guidelines - other than asymptomatic bacterial vaginosis (BV) and asymptomatic vulvovaginal candidiasis - are offered treatment consistent with WHO recommendations and may be enrolled after completing treatment if all symptoms have resolved. If treatment is completed and symptoms have resolved prior to obtaining informed consent for Screening, the participant may be enrolled. Genital warts requiring treatment also must be treated prior to enrollment. Genital warts requiring treatment are defined as those that cause undue burden or discomfort to the participant, including bulky size, unacceptable appearance, or physical discomfort.
• As determined by the IoR/designee, any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease.
• Has any other 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.

• At Enrollment, participant reports any of the following:

  • Participation in any research study involving drugs, vaccines, or medical devices 30 days or less prior to enrollment.
  • Currently participating in other research studies involving drugs, vaccines, or medical devices.
  • Expected to participate in other research studies involving drugs, vaccines, or medical devices during study participation.

Exclusion Criteria - Infants

• Has any condition that, in the opinion of the IoR/designee, would preclude eligibility, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

  • Note: Examples of exclusionary infant conditions include clinical evidence of stunting or illness.

• At Enrollment, according to the report of the mother, any of the following apply for the infant:

  • Infants with birth weight less than 2000g.
  • Participation in any research study involving drugs, vaccines, or medical devices since birth.
  • Currently participating in other research studies involving drugs, vaccines, or medical devices.
  • Expected to participate in other research studies involving drugs, vaccines, or medical devices for the duration of study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Dapivirine (DPV) Vaginal Ring (VR)-004; Mothers will use one DPV VR continuously for approximately one month, replacing the DPV VR each month for approximately three months.	Drug: Dapivirine (DPV) Vaginal Ring (VR)-004; Vaginal ring containing 25 mg of DPV
Experimental: Group B: Truvada Tablet; Mothers will take one Truvada oral tablet daily for approximately three months.	Drug: Truvada Tablet; Oral tablet containing 200 mg emtricitabine (FTC)/300 mg tenofovir disoproxil fumarate (TDF); Other Names: FTC/TDF; Emtricitabine/Tenofovir Disoproxil Fumarate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Mother Participants With Serious Adverse Events (SAEs) Including Maternal Deaths in Both Study Arms	As defined by the Manual for Expedited Reporting of Adverse Events to the Division of AIDS (DAIDS) (Version 2.0, January 2010)	Measured through Month 3.5
Number of Mother Participants With Grade 3 or Higher Adverse Events (AEs) in Both Study Arms	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 Month 3.5
Number of Infant Participants With SAEs Including Infant Deaths in Both Study Arms	As defined by the Manual for Expedited Reporting of Adverse Events to DAIDS (Version 2.0, January 2010)	Measured through Month 3.5
Number of Infant Participants With Grade 3 or Higher AEs in Both Study Arms	As defined by the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017	Measured through Month 3.5
Number and Proportion of Mothers With Detectable Plasma Dapivirine (DPV) Concentrations	This endpoint is based on DPV concentration laboratory results from evaluable plasma specimens from mother participants. DPV concentrations above the lower limit of quantification (LLOQ) are considered detectable. For DPV concentration in plasma, the LLOQ is 20 pg/ml. The infant endpoint is included as a separate section below.	Measured through Month 3.5
Number and Proportion of Mothers With Detectable Emtricitabine Triphosphate (FTC-TP) Concentrations	This endpoint is based on FTC-TP concentration laboratory results from evaluable dried blood spot (DBS) specimens from mother participants. FTC-TP concentrations above the lower limit of quantification (LLOQ) are considered detectable. For FTC-TP concentration in DBS specimens, the LLOQ is 0.125 pmol/punch. The infant endpoint is included as a separate section below.	Measured through Month 3.5
Number and Proportion of Mothers With Detectable Tenofovir Diphosphate (TFV-DP) Concentrations	This endpoint is based on TFV-DP concentration laboratory results from evaluable dried blood spot (DBS) specimens from mother participants. TFV-DP concentrations above the lower limit of quantification (LLOQ) are considered detectable. For TFV-DP concentrations, the LLOQ is 31.3 fmol/punch. The infant endpoint is included as a separate section below.	Measured through Month 3.5
Number and Proportion of Mothers With Detectable Breastmilk DPV Concentrations	This endpoint is based on DPV concentration laboratory results from evaluable breastmilk specimens from mother participants. DPV concentrations above the lower limit of quantification (LLOQ) are considered detectable. For DPV concentration in breastmilk, the LLOQ is 10 pg/ml.	Measured through Month 3.5
Number and Proportion of Mothers With Detectable Breastmilk FTC Concentrations	This endpoint is based on FTC concentration laboratory results from evaluable breastmilk specimens from mother participants. FTC concentrations above the lower limit of quantification (LLOQ) are considered detectable. For FTC concentrations in breastmilk, the LLOQ is 5 mg/ml.	Measured through Month 3.5
Number and Proportion of Mothers With Detectable Breastmilk TFV Concentrations	This endpoint is based on TFV concentration laboratory results from evaluable breastmilk specimens from mother participants. TFV concentrations above the lower limit of quantification (LLOQ) are considered detectable. For TFV concentrations in breastmilk, the LLOQ is 1 ng/ml.	Measured through Month 3.5
Number and Proportion of Infants With Detectable Plasma DPV Concentrations	This endpoint is based on DPV concentration laboratory results from evaluable plasma specimens from infant participants. DPV concentrations above the lower limit of quantification (LLOQ) are considered detectable. For DPV concentration in plasma, the LLOQ is 20 pg/ml. The mother endpoints are included as separate sections above.	Measured through Month 3.5
Number and Proportion of Infants With Detectable FTC-TP Concentrations	This endpoint is based on FTC-TP concentration laboratory results from evaluable dried blood spot (DBS) specimens from infant participants. FTC-TP concentrations above the lower limit of quantification (LLOQ) are considered detectable. For FTC-TP concentrations from DBS specimens, the LLOQ is 0.125 pmol/punch. The mother endpoints are included as separate sections above.	Measured through Month 3.5
Number and Proportion of Infants With Detectable TFV-DP Concentrations	This endpoint is based on TFV-DP concentration laboratory results from evaluable dried blood spot (DBS) specimens from infant participants. TFV-DP concentrations above the lower limit of quantification (LLOQ) are considered detectable. For TFV-DP concentrations from DBS specimens, the LLOQ is 31.3 fmol/punch. The mother endpoints are included as separate sections above.	Measured through Month 3.5
Geometric Mean of Maternal DPV Concentrations From Plasma by Visit	This endpoint is based on DPV concentration laboratory results from evaluable plasma specimens from mother participants. The geometric mean is summarized by study visit and includes only mothers randomized to the DPV VR arm. A value of 1/2 of the LLOQ is used if the concentration falls below the LLOQ (20pg/ml). The infant endpoints for geometric mean concentrations are included as separate sections below.	Measured through Month 3.5
Geometric Mean of Maternal FTC-TP Concentrations by Visit	This endpoint is based on FTC-TP concentration laboratory results from evaluable dried blood spot (DBS) specimens from mother participants. The geometric mean is summarized by study visit and includes only mothers randomized to the Truvada arm. A value of 1/2 of the LLOQ is used if the concentration falls below the LLOQ (0.125 pmol/punch). The infant endpoints for geometric mean concentrations are included as separate sections below.	Measured through Month 3.5
Geometric Mean of Maternal TFV-DP Concentrations by Visit	This endpoint is based on TFV-DP concentration laboratory results from evaluable dried blood spot (DBS) specimens from mother participants. The geometric mean is summarized by study visit and includes only mothers randomized to the Truvada arm. A value of 1/2 of the LLOQ is used if the concentration falls below the LLOQ (31.3 fmol/punch). The infant endpoints for geometric mean concentrations are included as separate sections below.	Measured through Month 3.5
Geometric Mean of Maternal DPV Concentrations From Breastmilk by Visit	This endpoint is based on DPV concentration laboratory results from evaluable breastmilk specimens from mother participants. The geometric mean is summarized by study visit and includes only mothers randomized to the DPV VR arm. A value of 1/2 of the LLOQ is used if the concentration falls below the LLOQ (10pg/ml). The infant endpoints for geometric mean concentrations are included as separate sections below.	Measured through Month 3.5
Geometric Mean of Maternal FTC Concentrations From Breastmilk by Visit	This endpoint is based on FTC concentration laboratory results from evaluable breastmilk specimens from mother participants. The geometric mean is summarized by study visit and includes only mothers randomized to the Truvada arm. A value of 1/2 of the LLOQ is used if the concentration falls below the LLOQ (5 mg/ml). The infant endpoints for geometric mean concentrations are included as separate sections below.	Measured through Month 3.5
Geometric Mean of Maternal TFV Concentrations From Breastmilk by Visit	This endpoint is based on TFV concentration laboratory results from evaluable breastmilk specimens from mother participants. The geometric mean is summarized by study visit and includes only mothers randomized to the Truvada arm. A value of 1/2 of the LLOQ is used if the concentration falls below the LLOQ (1 ng/ml). The infant endpoints for geometric mean concentrations are included as separate sections below.	Measured through Month 3.5
Geometric Mean of Infant DPV Concentrations From Plasma by Visit	This endpoint is based on DPV concentration laboratory results from evaluable plasma specimens from infant participants. The geometric mean is summarized by study visit and includes only infants of mothers randomized to the DPV VR arm. A value of 1/2 of the LLOQ is used if the concentration falls below the LLOQ (20pg/ml). The mother endpoints for geometric mean concentrations are included as separate sections above.	Measured through Month 3.5
Geometric Mean of Infant FTC-TP Concentration by Visit	This endpoint is based on FTC-TP concentration laboratory results from evaluable dried blood spot (DBS) specimens from infant participants. The geometric mean is summarized by study visit and includes only infants of mothers randomized to the Truvada arm. A value of 1/2 of the LLOQ is used if the concentration falls below the LLOQ (0.125 pmol/punch). The mother endpoints for geometric mean concentrations are included as separate sections above.	Measured through Month 3.5
Geometric Mean of Infant TFV-DP Concentrations by Visit	This endpoint is based on TFV-DP concentration laboratory results from evaluable dried blood spot (DBS) specimens from infant participants. The geometric mean is summarized by study visit and includes only infants of mothers randomized to the Truvada arm. A value of 1/2 of the LLOQ is used if the concentration falls below the LLOQ (31.3 fmol/punch). The mother endpoints for geometric mean concentrations are included as separate sections above.	Measured through Month 3.5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Mothers Non-adherent to Study Product for Each Month of Product Use by Study Product	The number and proportion of mother's visits with drug concentration indicative of non-adherence (no use) are reported by study month. Non-adherence is measured by residual drug in returned VRs for mothers assigned the DPV VR arm and by TFV-DP concentrations in dried blood spot specimens for mothers assigned the Truvada tablet arm. For mothers on the DPV VR arm, no use is defined as residual DPV concentration in the returned VRs <= 0.9mg/month. For mothers on the Truvada arm, no use is defined as TFV-DP concentrations < 16.6 fmol/punch. Only mother participants are included in this endpoint since infants did not directly use study product in this study.	Measured through Month 3
Residual Drug Levels in Returned VRs	The residual DPV concentrations from the returned VRs are summarized.	Measured through Month 3.5
Participant Willingness to Use Their Assigned Study Products During Breastfeeding in the Future (Y/N)	Based on participant report to the question "Would you be willing to use the study product for HIV prevention while breastfeeding in the future?"	Measured through Month 3.5
Proportion of Participants Who Find Their Study Product to be at Least as Acceptable as Other HIV Prevention Methods	Based on participant report on the question "Overall, how much did you like using the study product?" on the Product End Use Visit Behavioral Assessment.	Measured through Month 3.5

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Lisa Noguchi, PhD, CNM, Johns Hopkins Bloomberg School of Public Health; Study Chair: Maxensia Owor, MBChB, MMed, MPH, MU-JHU CARE; Study Chair: Jen Balkus, PhD, MPH, Hans Rosling Center for Population Health

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2020
• Primary Completion (Actual): November 4, 2021
• Study Completion (Actual): November 4, 2021

Study Registration Dates

• First Submitted: October 24, 2019
• First Submitted That Met QC Criteria: October 24, 2019
• First Posted (Actual): October 25, 2019

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: July 14, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Emtricitabine; Dapivirine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: MTN-043; 38591 (Registry Identifier: DAIDS-ES Registry Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data will be made available to researchers upon request. The IPD to be shared will be negotiated with the researchers
• IPD Sharing Time Frame: within 8 weeks of request approval and to be available as long as needed.
• IPD Sharing Access Criteria: MTN-043 study management team approval
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No