vaginal atrophy

Vaginal estradiol softgel capsule viable option for atrophy symptoms

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In postmenopausal women with moderate to severe vulvar and vaginal atrophy, a vaginal softgel suppository containing estradiol was a safe and effective treatment option and yielded lower systemic estrogen absorption compared with currently available intravaginal treatments, study results show.

James H. Pickar, MD, an adjunct associate professor of obstetrics and gynecology at Columbia University Medical Center, and colleagues evaluated 50 postmenopausal women aged 40 to 75 years with at least one moderate to severe vulvar and vaginal atrophy symptom randomly assigned to 10 µg vaginal estradiol softgel capsules (TX-004HR, TherapeuticsMD Inc.; n = 24) or placebo (n = 26) administered intravaginally once daily for 14 days.

James Pickar

James H. Pickar

From baseline to day 15, prevalence of superficial cells increased more in the treatment group (35.2 percentage points) compared with the placebo group (8.75 percentage points; P = .0002), and percentage of intermediate cells increased more in the treatment group (18.7 percentage points) compared with placebo (–3.54 percentage points; P = .0017). Parabasal cell prevalence decreased more in the treatment group (–54.4 percentage points) compared with the placebo group (–4.8; P < .0001); similarly, vaginal pH decreased more in the treatment group (–0.974) compared with the placebo group (–0.339; P = .0002).

No significant differences were found between the groups for severity of the most bothersome vulvar and vaginal atrophy symptoms. The treatment group yielded greater mean decreases in vaginal epithelial integrity (treatment group, –0.342 vs. placebo, 0.176; P = .0001) and vaginal secretions (–0.643 vs. –0.274; P = .0401).

Overall, 28% of participants experienced adverse events, but no serious adverse events were reported.

“Vaginal estradiol softgels provide practitioners a new option for local treatment of postmenopausal women with moderate-to-severe vulvar and vaginal atrophy with lower systemic estrogen absorption than other current local estrogen products,” Pickar told Endocrine Today. “There appears to be a good local response with estrogen at very low levels and a better patient user experience, providing physicians and their patients an alternative therapy, if approved for local treamtnet.” – by Amber Cox

Novel bioidentical estradiol vaginal capsule shows promise in pilot study

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A novel estradiol vaginal gel cap containing low doses of solubilized bioidentical estradiol improved vaginal cytology and pH in healthy postmenopausal women, according to a presentation at the 25th annual meeting of The North American Menopause Society.

About a half-inch in size, TX-004HR (TherapeuticsMD) capsules of 10 mcg and 25 mcg were safe and well tolerated, with less systemic exposure than with equivalent doses of an existing vaginal estradiol tablet, suggesting another local option for treating menopause-related vulvovaginal atrophy, the researchers said.

“The idea is for the vaginal estrogen to work locally, you really don’t want to get systemic absorption,” James H. Pickar, MD, of Columbia University Medical Center, New York, told Endocrine Today. “That’s exactly what happened. We saw blood levels that were roughly half to a third of those seen with the FDA-approved product at similar doses.”

Pickar and colleagues initially conducted two randomized, single-dose, two-way crossover pharmacokinetic trials comparing the bioavailability of TX-004HR with that of an existing vaginal estradiol tablet (Reference).

Each trial involved 36 healthy postmenopausal women (BMI, 19-30 kg/m2) aged 40 to 65 years. Single vaginal doses of TX-004HR or Reference were administered, followed by single vaginal doses of the alternate therapy after a 14-day washout; one trial used 10-mcg doses and the other 15 mcg.

The scientists sampled blood pre- and post-insertion at set intervals for 24 hours and analyzed for concentration-time curve (AUC0-24), peak concentration (Cmax) and time to peak concentration (tmax) for estradiol and estrone.

Safety and efficacy of TX-004HR was then tested in a pilot study that included 50 healthy postmenopausal women (BMI ≤34 kg/m2) aged 40 to 75 years with at least one moderate to severe vulvovaginal atrophy symptom, superficial cells ≤5% and a vaginal pH >5. The women were randomly assigned to a single vaginal gel cap containing 10 mcg of solubilized 17beta-estradiol or placebo for 14 days.

AUC0-24 values were 63% (10 mcg) and 69% (25 mcg) less for estradiol and 50% (10 mcg) and 70% (25 mcg) less for estrone with TX-004HR vs. Reference, after baseline adjustments. Similar decreases were seen in Cmax values at 29% (10 mcg) and 46% (25 mcg) less for estradiol and 26% (10 mcg) and 55% (25 mcg) less for estrone with TX-004HR vs. Reference. Systemic exposure was significantly reduced with both doses of TX-004HR compared with equivalent doses of Reference. No adverse events were seen in either trial.

At the end of the 2-week pilot, women had higher mean increases from baseline with TX-004HR compared with placebo for superficial cells (35% vs. 4%; P=.0002) and intermediate cells (13% vs. 4%; P=.0002). The mean decrease from baseline in parabasal cells was greater with TX-004HR than placebo (54% vs. 5%; P=.0001), as was the mean decrease in vaginal pH (0.97 vs. 0.34; P=.0002).

“The next thing you would hope to see over time would be relief from symptoms including pain during intercourse, bleeding with intercourse, vaginal itching and burning — the standard symptoms you would see with vaginal atrophy,” Pickar said.

Women treated with TX-004HR also achieved greater improvements in vaginal epithelial integrity and secretions than with placebo. Improvement in vaginal symptoms was similar between groups, which the researchers attribute to small size and short duration.

In 14 of 50 women (28%), 17 treatment-emergent adverse events were observed, although not all were treatment-related. Eye contusion, nephrolithiasis, blood pressure increase, vaginal discharge, dysplasia or pruritus, vulvovaginal pain or burning, hot flush and cervical dysplasia occurred with TX-004HR. Paresthesia, vaginal hemorrhage or vulvovaginal discomfort occurred with placebo. Most events were mild and none were serious, the researchers said.

TherapeuticsMD is running a phase 3 Rejoice Trial for the investigational therapy in doses of 4 mcg, 10 mcg and 25 mcg.

“Our trial includes 700 women with vulvovaginal atrophy and dyspareunia,” Sebastian Mirkin, MD, chief medical officer of TherapeuticsMD, told Endocrine Today. “We are evaluating the effect of this compound over 12 weeks, fulfilling the regulatory guidelines for this particular indication. We expect to have it completed in late 2015.” – by Allegra Tiver

Ospemifene benefited postmenopausal women with vulvar, vaginal atrophy

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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

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 Constantine

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