In postmenopausal women with vulvar and vaginal atrophy, ospemifene showed higher responder rates than placebo in two phase 3 randomized trials and offered relief from symptoms, according to data presented at the 25th annual meeting of The North American Menopause Society.

Responder rates

Rates were better with 60 mg daily than 30 mg daily, and the effect ofospemifene (Osphena, Shionogi Inc.) could be attributed to improvement in vaginal physiology, including maturation value and pH, according to Risa Kagan, MD, of Sutter East Bay Medical Foundation, Berkeley, Calif.

Risa Kagan

“Oral ospemifene 60 mg per day demonstrated significantly higher responder rates than placebo in both trials, as did oral ospemifene 30 mg per day, which was only studied in one,” Kagan said.

The analysis was based on two double blind, placebo-controlled trials evaluating the efficacy and safety of ospemifene, approved by the FDA in 2013 for the treatment of dyspareunia in postmenopausal women.

In both studies, women aged 40 to 80 years were diagnosed with vulvar and vaginal atrophy (VVA) based on vaginal pH, maturation index in the vaginal smear and VVA symptoms reported at baseline.

In study A, 826 women were randomly assigned 1:1:1 to ospemifene 30 mg per day, 60 mg per day or placebo and followed for 12 weeks based on most bothersome symptom (MBS). In study B, 919 participants were stratified into two categories by MBS — moderate to severe dyspareunia or vaginal dryness — reported at baseline, then randomly assigned, respectively, 1:1 to ospemifene 60 mg daily or placebo for 12 weeks. Lubricants could be used by all women in both trials.

Kagan and considered objective measures, including the percentage of parabasal cells and vaginal pH, along with subjective measures, including self-reported VVA symptoms, as parameters to assess efficacy.

A responder was defined by: more than 10-unit increase from baseline in maturation value; vaginal pH decrease of at least 0.5 from baseline; and decrease in severity of MBS by at least one point from baseline.

“The criteria of a responder for this specific trial was chosen by the sponsor when designing the phase 3 trials and was agreed to by the US FDA,” Kagan said.

Responder percentage, either at week 12 or last observation carried forward (LOCF), was compared between groups. The researchers used Cochran-Mantel-Haenszel (CMH) general association test, controlling for study center and uterine status, in study A, and CMH row mean score test, controlling for stratum, in study B.

In study A, the responder percentage at week 12/LOCF was 20.6% (58/282) with ospemifene 30 mg and 33.7% (93/276) with 60 mg vs. 3.4% (9/268) with placebo. Both ospemifene groups showed higher responder rates than placebo, with 60 mg better than 30 mg (P<.001 for both).

The researchers conducted an exploratory analysis to assess the percentage of women who met individual criteria in the responder definition; 20.9% in the placebo, 48.9% in the ospemifene 30-mg and 54% in 60-mg groups were maturation value responders, and 32.1% in the placebo, 56.7% in the ospemifene 30-mg and 70.7% in 60-mg groups were vaginal pH responders (P<.001 vs. placebo, for both).

In study B, the responder percentage at week 12/LOCF was significantly higher with ospemifene 60 mg (39.7%, 184/463) than placebo (5.5%, 25/456; P<.0001). The percentage of maturation value responders was 65.7% with ospemifene 60 mg vs. 23% with placebo, and the percentage of pH responders was 70.4% with ospemifene vs. 34.9% with placebo (P<.0001, for both).

“Interpretation of the most bothersome symptom results may be confounded by the use of lubricant in these two trials,” Kagan said.

Subjective symptoms

Besides its effects on objective measures of vaginal epithelium physiology, ospemifene 60 mg daily alleviated subjective VVA symptoms, whether they were reported as MBS, according to Ginger D. Constantine, MD, of EndoRheum consultants, Malvern, Pa.

Ginger D. Constantine

“Oral ospemifene 60 mg per day demonstrated improvements in the severity of the most bothersome symptom of dyspareunia and vaginal dryness,” Constantine said. “In one trial, both symptoms were significantly improved, and in the second trial only dyspareunia was significantly improved.”

Based on the same phase 3 trials, Constantine and colleagues compared women treated with ospemifene 60 mg daily (n=276) vs. placebo (n=278) in study A and study B (n=463 and n=456, respectively) to evaluate subjective endpoints of VVA, looking at both patient-reported MBS and all moderate to severe VVA symptoms.

The trials assessed: vaginal dryness, dyspareunia, vulvar and/or vaginal irritation/itching, difficult and/or painful urination and vaginal bleeding associated with sexual activity. Symptoms were self-reported at baseline, week 4 and week 12; those reported at baseline as moderate to severe were included in the analysis. The researchers used CMH row mean scores test to analyze change in the severity of VVA symptoms from baseline to week 4 or 12.

In study A, ospemifene demonstrated superiority over placebo at week 12 for all endpoints, including mean change in severity of MBS of dyspareunia (–1.19 vs. –0.89; P=.023) or MBS of vaginal dryness (–1.26 vs. –0.84; P=.021). At week 4, the change in severity of MBS dyspareunia or MBS vaginal dryness was numerically but not statistically improved with treatment vs. placebo.

Ospemifene showed superiority compared with placebo in VVA symptoms, regardless of being reported as MBS, including vaginal dryness at week 4 (P<.05) and week 12 (P<.001) and dyspareunia at week 12 (P<.05). Difficult/painful urination was numerically improved with treatment vs. placebo at week 12 (P=.052).

In study B strata, the mean changes in MBS of dyspareunia (n=605) were significantly different between groups at week 12 (P=.0001) and numerically different at week 4 (P=.1698); the mean change in MBS of vaginal dryness was not significant at week 12 (P=.0803) or week 4 (P=.1886).

Ospemifene was better than placebo in reducing the severity of dryness at both weeks 4 and 12 (P<.0001) for VVA symptoms reported as moderate or severe at baseline, regardless of being reported as MBS.

Severity of dyspareunia and vulvar and/or vaginal irritation/itching were significantly reduced with ospemifene (P=.0003) vs. placebo (P=.0421) at week 12. Numerical improvements were seen in severity of dyspareunia at week 4 (P=.2614) and vaginal bleeding associated with sexual activity at week 12 (P=.0691).

“The severity of VVA symptoms, when most bothersome symptom was not a construct, that were reported as moderate to severe at baseline was improved with regard to dyspareunia, vaginal dryness and itching and irritation.” – by Allegra Tiver