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

NCT04140266 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: MTN-04338591
• Study Type: interventional
• Target: 394
• Locations: 4 countries
• Sites: 4

Brief Summary

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.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (22)

• 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 Outcomes (4)

• The Number of Mothers Non-adherent to Study Product for Each Month of Product Use by Study Product

  Measured through Month 3

• Residual Drug Levels in Returned VRs

  Measured through Month 3.5

• Participant Willingness to Use Their Assigned Study Products During Breastfeeding in the Future (Y/N)

  Measured through Month 3.5

• Proportion of Participants Who Find Their Study Product to be at Least as Acceptable as Other HIV Prevention Methods

  Measured through Month 3.5

Study Arms (2)

Group A: Dapivirine (DPV) Vaginal Ring (VR)-004

EXPERIMENTAL

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

Group B: Truvada Tablet

EXPERIMENTAL

Mothers will take one Truvada oral tablet daily for approximately three months.

Drug: Truvada Tablet

Interventions

Dapivirine (DPV) Vaginal Ring (VR)-004 DRUG

Vaginal ring containing 25 mg of DPV

Group A: Dapivirine (DPV) Vaginal Ring (VR)-004

Truvada Tablet DRUG

Oral tablet containing 200 mg emtricitabine (FTC)/300 mg tenofovir disoproxil fumarate (TDF)

Also known as: Emtricitabine/Tenofovir Disoproxil Fumarate, FTC/TDF

Group B: Truvada Tablet

Eligibility Criteria

• Age: 6 Weeks+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (4)

Blantyre CRS (Johns Hopkins Research Project/College of Medicine)

Blantyre, Malawi

Location

Wits RHI Shandukani Research Centre CRS

Johannesburg, Gauteng, 2001, South Africa

Location

MU-JHU Research Collaboration (MUJHU CARE LTD) CRS

Kampala, Uganda

Location

Zengeza CRS

Chitungwiza, Mashonaland East Province, Zimbabwe

Location

Related Publications (1)

• Noguchi LM, Owor M, Mgodi NM, Gati Mirembe B, Dadabhai S, Horne E, Gundacker H, Richardson BA, Bunge K, Scheckter R, Song M, Marzinke MA, Anderson PL, Livant E, Jacobson C, Piper JM, Chakhtoura N, Hillier SL, Balkus JE; MTN-043 Study Team. Safety and drug quantification of the dapivirine vaginal ring and oral pre-exposure prophylaxis in breastfeeding mother-infant pairs (MTN-043): a phase 3B, open-label, randomised trial. Lancet HIV. 2025 Mar;12(3):e180-e190. doi: 10.1016/S2352-3018(24)00306-0. Epub 2025 Feb 12.

  PMID: 39954697 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Dapivirine; Contraceptive Devices, Female; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Contraceptive Devices; Equipment and Supplies; Tenofovir; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Jen Balkus
• Organization: Hans Rosling Center for Population Health

jbalkus@uw.edu

260 616 6614

Study Officials

• Maxensia Owor, MBChB, MMed, MPH

  MU-JHU CARE

  STUDY CHAIR

• Lisa Noguchi, PhD, CNM

  Johns Hopkins Bloomberg School of Public Health

  STUDY CHAIR

• Jen Balkus, PhD, MPH

  Hans Rosling Center for Population Health

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2019
• First Posted: October 25, 2019
• Study Start: September 24, 2020
• Primary Completion: November 4, 2021
• Study Completion: November 4, 2021
• Last Updated: August 4, 2023
• Results First Posted: August 4, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: within 8 weeks of request approval and to be available as long as needed.
• Access Criteria: MTN-043 study management team approval

Locations

ZI (1); UG (1); ZA (1); MA (1)