Consistency of Effect with a Low-Dose, Estradiol Vaginal Capsule (TX-004HR): Evaluating Improvement in Vaginal Physiology and Moderate-to-Severe Dyspareunia in Subgroups of Postmenopausal Women

Abstract

Background: The 12-week, randomized, double-blind, placebo-controlled, multicenter, phase 3 REJOICE trial demonstrated that TX-004HR, an investigational, applicator-free, low-dose vaginal softgel capsule containing solubilized 17β-estradiol, effectively and rapidly treats symptoms of vulvar and vaginal atrophy (VVA) with negligible to very low systemic absorption. The aim of this analysis was to assess whether the efficacy of TX-004HR varies with age, body mass index (BMI), uterine status, pregnancy status, and vaginal delivery.Methods: The REJOICE trial evaluated the efficacy of 4-, 10-, and 25-μg doses of TX-004HR in postmenopausal women (40–75 years) with VVA and a self-identified most bothersome symptom of moderate-to-severe dyspareunia. Prespecified subgroup analyses of the four co-primary endpoints (percentages of superficial cells and parabasal cells, vaginal pH, and severity of dyspareunia) were analyzed with respect to age, BMI, uterine status, pregnancy status, and vaginal births. Each dose was compared with placebo for change from baseline to week 2 through week 12, respectively.Results: TX-004HR significantly improved superficial cells, parabasal cells, and vaginal pH from baseline to weeks 2 and 12 in most subgroups. All TX-004HR doses numerically reduced the severity of dyspareunia by 2 weeks and maintained efficacy over 12 weeks, with many of the subgroups having statistically significant improvement relative to placebo.Conclusions: TX-004HR was efficacious for treating symptomatic VVA, and it demonstrated a consistency of effect when women's age, BMI, uterine status, pregnancy status, and vaginal births were evaluated. Clinical Trial Identifier: NCT02253173.

TX-004HR clinically improves symptoms of vulvar and vaginal atrophy in postmenopausal women

“…While the magnitudes of improvement for vaginal dryness severity were similar among most subgroups, showing a consistency of effect with TX-004HR, statistical significance was not observed for all subgroups. These results are similar to what was observed with dyspareunia subgroup analyses 12 . The REJOICE trial was sufficiently powered to compare differences between treatment groups in the entire study population, but the power was insufficient to detect differences among smaller subgroups.…”

“…Baseline characteristics showed significant differences in the percentages of parabasal cells and vaginal pH by age as well as BMI, as previously reported 12 . Although not powered to evaluate efficacy in subgroups, treatment with 4, 10, and 25 mg of the E2 vaginal insert reduced vaginal dryness from baseline to week 12 in the majority of subgroups for age, BMI, uterine status, prior pregnancy, and number of vaginal births.…”

Estradiol softgel inserts for the treatment of VVA symptoms: an expert opinion

“…At baseline, the percentage of parabasal cells and vaginal pH were positively correlated with age and inversely correlated with BMI (all, p ≤ 0.002). Overall, treatment effects observed with the E2 inserts compared with placebo occurred regardless of age, BMI, uterine status, pregnancy history, and previous vaginal births, with most subgroup comparisons being statistically significant at weeks 2 and 12 [19,20].…”

“…Subgroup analyses (secondary endpoints) were performed to determine if age (≤ 56, 57-61, and ≥ 62 years), BMI (≤ 24, 25-28, and ≥ 29 kg/m 2 ), uterine status (intact uterus or no intact uterus), pregnancy history (0 or ≥ 1), or number of vaginal births (0 or ≥ 1) had any effects on treatment outcomes (percentages of superficial and parabasal cells, vaginal pH, and severity of dyspareunia or vaginal dryness [19]) [20]. Descriptive analyses…”

“…were used because the REJOICE study was not powered to evaluate these secondary endpoints [19,20]. At baseline, the percentage of parabasal cells and vaginal pH were positively correlated with age and inversely correlated with BMI (all, p ≤ 0.002).…”