MTN-038

Primary Objectives 

• To characterize the local and systemic pharmacokinetics (PK) of one tenofovir (TFV) intravaginal ring (IVR) used continuously for 91 days
• To evaluate the safety of one TFV IVR used continuously for 91 days

Study Summary
MTN-038 was a Phase 1, two-arm, multi-site, randomized (2:1), placebo-controlled trial. The study evaluated the safety and PK of a 90-day TFV IVR. The study enrolled 49 healthy, HIV-uninfected women ages 18 to 45. Participants were randomized (2:1) to TFV IVR or placebo and used the assigned IVR for approximately 90 days. MTN-038 evaluated TFV and TFV-DP levels in plasma, cervicovaginal fluid (CVF), rectal fluid, and cervical tissue during approximately 91 days of continuous use of a single ring containing 1.4 g TFV. PK data would help determine the concentration-time profile using pooled data across all participants. The study design included frequent collection of corresponding blood, rectal and CVF samples following the insertion of a TFV IVR to allow for the detection of drug release from the ring. PK parameters of TFV were calculated for blood plasma, CVF, rectal fluid, and cervical tissue. It is hypothesized that plasma, CVF, and rectal fluid TFV levels and cervical tissue TFV and TFV-DP levels would be measurable in all participants, and that continuous exposure to TFV due to sustained release from the 1.4 g TFV IVR for 91 days would be safe.

The study completed follow-up on September 25, 2019. The primary results were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) held virtually on February 12-16, 2022. Two papers have been published from this study. Primary and secondary manuscripts are in development.

Primary Result
Participant Mean age was 29.4 (range 18-43) years; 22% were Black, 53% white, 10% Asian, and 14% mixed/other race. Retention was 98% through day 91, and 84% reported being fully adherent. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs in the TFV vs. placebo arms (p=0.41); no grade ≥3 AEs were reported. For the Geometric mean of TFV concentrations and PK parameters, tmax was 34 days for CVF and rectal fluid, with mean TFV concentrations declining at day 91. Geometric mean TFV-DP tissue concentrations exceeded the 1,000fmol/mg target through day 56, but fell to 456 fmol/mg by day 91. Mean and median residual TFV concentrations in used rings were 0.29 and 0.15 g respectively (IQR 0.00-0.58 g). Among 32 returned rings, 13 had no or low (<0.1 g) residual TFV. Participants with no/low residual TFV had lower geometric mean TFV concentrations in CVF (11 vs. 2471 ng/mg) and lower cervical tissue concentrations of TFV (0.1 vs. 72 ng/mg) and TFV-DP (12 vs. 3296 fmol/mg) at day 91 vs. those with higher residual TFV (all p<0.001), however concentrations at earlier time points were not significantly different between groups. Residual TFV in returned rings did not differ by sociodemographics, sexual activity, or baseline Nugent Score. A majority of participants reported liking the ring (median (IQR): 8(7-9) on 10-point Likert scale) and reported high likelihood of using the ring in the future, if effective (median (IQR): 9 (7-10)).