A phase 1/2, open-label, parallel group study to evaluate the safety and pharmacokinetics of DARE-HRT1 (80 μg estradiol/4 mg progesterone and 160 μg estradiol/8 mg progesterone intravaginal rings) over 12 weeks in healthy postmenopausal women

Abstract

Objectives Primary objectives were to evaluate the safety and systemic pharmacokinetics (PK) of DARE-HRT1, an intravaginal ring (IVR), which releases 17β2-Estradiol (E2) with progesterone (P4) for 28 days in healthy postmenopausal women. Methods This was a randomized, open-label, 2-arm, parallel group study in 21 healthy postmenopausal women with an intact uterus. Women were randomized (1:1) to either DARE-HRT1 IVR1 (E2 80 μg/d with P4 4 mg/d) or DARE-HRT1 IVR2 (E2 160 μg/d with P4 8 mg/d). They used the IVR for three 28-day cycles, inserting a new IVR monthly. Safety was measured by treatment emergent adverse events and changes in systemic laboratories and the endometrial bilayer width. Baseline adjusted plasma PK of E2, P4, and estrone (E1) was described. Results Both DARE-HRT1 IVR were safe. All treatment emergent adverse events were mild or moderate and were distributed similarly among IVR1 versus IVR2 users. Month 3 median maximum plasma (C max) P4 concentrations were 2.81 and 3.51 ng/mL and C max E2 was 42.95 and 77.27 pg/mL for IVR1 and IVR2 groups, respectively. Month 3 median steady state (C ss) plasma P4 concentrations were 1.19 and 1.89 ng/mL, and C ss E2 was 20.73 and 38.16 pg/mL for IVR1 and IVR2 users, respectively. Conclusions Both DARE-HRT1 IVRs were safe and released E2 in systemic concentrations, which were in the low, normal premenopausal range. Systemic P4 concentrations predict endometrial protection. Data from this study support further development of DARE-HRT1 for the treatment of menopausal symptoms.

A phase 1/2, open-label, parallel group study to evaluate the preliminary efficacy and usability DARE-HRT1 (80 μg estradiol/4 mg progesterone and 160 μg estradiol/8 mg progesterone intravaginal RinGSM) over 12 weeks in healthy postmenopausal women

“…The study was approved by the ethics boards at each study site (Central Adelaide Local Health Network Human Research Ethics Committee 2021HRE00421) and registered at ClinicalTrials.gov (NCT05367973). The primary objectives of the study were to describe the safety and PK of the two doses of DARE-HRT1 over 12 weeks in healthy postmenopausal women, reported in a separate article 14 . The exploratory objectives, reported here, were to describe the preliminary efficacy and usability/acceptability of DARE-HRT1.…”

“…The primary objectives of the study were to describe the safety and PK of the two doses of DARE-HRT1 over 12 weeks in healthy postmenopausal women, reported in a separate article. 14 The exploratory objectives, reported here, were to describe the preliminary efficacy and usability/acceptability of DARE-HRT1. Participants provided written informed consent before the performance of any study procedures.…”

“…open-label, and the primary end points were to measure safety and PK. 14 Because of the open-label, non-placebo-controlled design, interpretation of preliminary efficacy for VMS and GMS must be interpreted with caution. We used a Fisher's exact test to compare the frequency of the severity scores of the VMS domain of MENQOL (Table 3), which is not impacted by sample size.…”

“…The results of the primary objectives are described in a separate article. 14 Exploratory objectives of this study, reported herein, included assessing the usability and acceptability of the DARE-HRT1 IVR and conducting a preliminary evaluation of the effect of the DARE-HRT1 IVR on systemic (VMS) and local (GSM) signs and symptoms of menopausal hypoestrogenism.…”

“…The primary objectives of the DARE-HRT1-002 study were to evaluate the safety and systemic serum pharmacokinetics (PK) of DARE-HRT1 in two doses: DARE-HRT1-IVR1, which delivers E 2 80 μg/d with P 4 4 mg/d versus DARE-HRT1-IVR2, which delivers E 2 160 μg/d with P 4 8 mg/d. The results of the primary objectives are described in a separate article 14 . Exploratory objectives of this study, reported herein, included assessing the usability and acceptability of the DARE-HRT1 IVR and conducting a preliminary evaluation of the effect of the DARE-HRT1 IVR on systemic (VMS) and local (GSM) signs and symptoms of menopausal hypoestrogenism.…”