OA06.03
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Randomized, Placebo Controlled Phase I Trial of Safety, Pharmacokinetics, Pharmacodynamics and Acceptability of a Multipurpose Prevention Vaginal Ring Containing Tenofovir and Levonorgestrel

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BACKGROUND:

Multipurpose prevention technologies that provide protection against HIV acquisition and unintended pregnancy, are safe and acceptable, and support flexible use, are critically needed. We report results from a Phase I study evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and acceptability of CONRAD’s tenofovir/levonorgestrel (TFV/LNG) intravaginal ring (IVR) following 3 months of continuous or interrupted use in women.


METHODS:

CONRAD A15-138 was an outpatient, randomized, partially-blinded, placebo-controlled, parallel study conducted in Norfolk, VA and the Dominican Republic. Participants were healthy, 18-50 years old, had a body mass index <30 kg/m2 and reported no use of exogenous hormones and regular menses. Participants were randomized to 1 of 4 study arms: TFV/LNG or placebo IVR worn continuously for ~90 days or cyclically for 3 cycles of 28 days of use with 3 days removal then re-insertion.


RESULTS:

We screened 68 women; 47 were randomized onto study and 40 completed all visits. IVRs were safe with no significant changes in cervicovaginal epithelium, immune cell populations or soluble immune and inflammatory markers from baseline. Most TFV/LNG IVR users reported no change in their menstrual cycle or fewer/lighter bleeding days. Median vaginal fluid TFV concentrations were 546-3077 ng/mg throughout 90 days of use. Median TFV-DP tissue concentrations exceeded 1,000 fmol/mg within 72 hours of IVR insertion. At 1 and 3 months of use, vaginal fluid of women using TFV/LNG IVRs had significantly greater inhibitory activity against HIV growth in vitro compared to baseline and to placebo (p<0.01). TFV/LNG IVR users had mean serum LNG concentrations exceeding 200 pg/mL within 2 hours of IVR insertion. All placebo users ovulated each month, while only 39-71% of TFV/LNG users ovulated during months 1, 2 or 3, consistent with previously tested, effective contraceptive LNG IVRs. TFV/LNG IVR users had significantly lower cervical mucus (CM) Insler scores and a higher proportion of poor or abnormal in vitro CM sperm penetration (p<0.05).


CONCLUSIONS:

The TFV/LNG IVR was safe, acceptable and delivered high TFV concentrations locally correlating with local PD. The microdose of LNG caused changes in CM, sperm penetration and ovulation compatible with contraceptive efficacy, while inducing acceptable changes in menstrual bleeding patterns.