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Clinical Trial
. 2024 Jun 5;19(6):e0304552.
doi: 10.1371/journal.pone.0304552. eCollection 2024.

Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings

Sharon L Achilles  1   2 , Clifton W Kelly  3 , Craig J Hoesley  4 , Diana L Blithe  5 , Jill Brown  5 , Barbra A Richardson  3   6 , Brid Devlin  7 , Craig W Hendrix  8 , Samuel M Poloyac  9 , Mark A Marzinke  8 , Holly Gundacker  3 , Devika Singh  2 , Jeanna M Piper  10 , Sherri Johnson  11 , John Steytler  7 , Beatrice A Chen  1   2 ; MTN-030/IPM 041 and MTN-044/IPM 053/CCN019 Protocol Teams for the Microbicide Trials Network and the Contraceptive Clinical Trials Network
Affiliations
Clinical Trial

Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings

Sharon L Achilles et al. PLoS One. .

Abstract

Background: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy.

Methods: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported.

Results: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12).

Conclusions: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.

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Conflict of interest statement

The following authors have read the journal’s policy and have competing interests: Sharon L. Achilles has received consulting fees from Mayne Pharma and Merck and has received research funding from The National Institutes of Health, the US Food and Drug Administration, the Pennsylvania Department of Health, Society of Family Planning Research Fund, Estetra SRL (an affiliate company of Mithra Pharmaceuticals), EvoFem, and Merck, all of which were managed by Magee-Womens Research Institute. Barbra A. Richardson has received payment from Gilead Sciences for DSMB membership. Brid Devlin and John Steytler were full-time salaried employees of the International Partnership for Microbicides (IPM), a non-profit company registered in the United States of America, at the time the work was performed. Craig W. Hendrix is an Inventor on patent relating to vaginal microbicides and the founder of a microbicide development company, both unrelated to this study product and both managed by Johns Hopkins University. Beatrice A. Chen has served on a Merck & Co. advisory board and has received research grants from Sebela, Mylan, and Medicines360, all of which were managed by Magee-Womens Research Institute. NIH employees (Diana L. Blithe, Jill Brown, and Jeanna M. Piper) contributed to the study design, manuscript development and the decision to publish as well as providing safety oversight during study conduct but had no role in data collection and analysis. All other authors have declared that no competing interests exist. This does not alter our adherence to PLOS One policies on sharing data and materials.

Figures

Fig 1
Fig 1
a. MTN-030/IPM 041 Study Flow Diagram. MTN-030/IPM 041 Study Flow Diagram. b. MTN-044/IPM 053/CCN019 Study Flow Diagram. MTN-044/IPM 053/CCN019 Study Flow Diagram.
Fig 2
Fig 2. Concentration-time profiles for DPV and LNG in plasma and cervicovaginal fluid.
Median Dapivirine (DPV) and Levonorgestrel (LNG) concentrations in (A) blood plasma (pg/ml) and (B) cervicovaginal fluid (ng/mg). MTN-030/IPM 041 study data are represented by pink squares and labeled as ‘14-day’ in the legend. MTN-044/IPM 053/CCN019 study data are represented by blue (DPV) and green (LNG) circles and labeled as ‘90-day continuous’ (solid circles with solid connecting lines) and ‘90-day cyclic’ (open circles with dashed connecting lines) in the legend. Given the sparse sampling protocol not designed to evaluate the pharmacokinetics of return to steady-state drug concentrations following reinsertion of rings in cyclic users after days 30 and 60, double slash symbols to represent line breaks were drawn on the connecting lines of the curves between sampling on days 30 and 44 in the cyclic group. Arrows depict timing of ring removals for each group.
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