The experimental agent TX-004HR effectively improved the vaginal mucosa of postmenopausal women with vulvovaginal atrophy (VVA) and reduced moderate-to-severe dyspareunia and vaginal dryness compared to placebo, according to results of a trial published in Menopause. Approximately two-thirds of postmenopausal women have visual signs of VVA and half experience symptoms.
TX-004HR is a vaginal, muco-adhesive, soft-gel capsule containing 17β-estradiol that is administered by a woman without the need for an applicator; the capsule dissolves quickly in the vagina but does not leak out as other topical vaginal preparations may. The treatment was tested at three doses (4, 10, and 25 mcg) in REJOICE, a double-blind, randomized, placebo-controlled, phase 3 trial. The trial lasted 12 weeks and was conducted at 89 sites in the United States and Canada. Women were included in the trial if they were postmenopausal, aged 40 to 75, had ≤ 5% superficial cells on vaginal cytological smear, vaginal pH > 5.0, and moderate-to-severe dyspareunia with onset after menopause. They were also required to have a body mass index (BMI) of < 38 kg/m2 and to be sexually active with vaginal penetration. The women were instructed to insert one capsule into the vagina daily for 2 weeks and then twice a week for 10 weeks.
Over 2,000 women were screened for the trial and 764 were enrolled and randomized to the active intervention and placebo groups. The four groups were similar in terms of demographics and baseline qualities, and most of the women in the trial were white, had a mean age of 59 years, and a BMI of 27 kg/m2.
Visual assessment was performed by clinicians at baseline and weeks 2, 6, 8, and 12 of the trial. Assessors were instructed to grade the appearance of the vagina in terms of color, vaginal epithelia integrity, vaginal epithelial surface thickness, and vaginal secretions on a 4-point scale (0-none, 1-mild, 2-moderate, to 3-severe). The majority of women were found to have moderate-to-severe scores on all four parameters on visual inspection at baseline.
Study subjects were asked to report on dyspareunia, vaginal dryness, and vaginal itching and/or irritation symptoms on the same 4-point scale. All of the women reported moderate-to-severe dyspareunia and 93% reported moderate-to-severe vaginal dryness at baseline.
Primary and Secondary Results
The primary results of the trial indicated that TX-004HR at all three doses tested resulted in statistically significant improvements in vaginal color, vaginal epithelial integrity, epithelial surface thickness, and vaginal secretions compared to placebo among two-thirds of participants (P < 0.0001 for most parameters). Positive changes were noted as soon as 2 weeks after initiation of treatment, and improvements were sustained throughout the 12 weeks of the trial. In addition, the sum of the four individual visual assessment scores correlated with scores for dyspareunia (P < 0.0001) and vaginal dryness (P < 0.0001) as symptoms of VVA.
A secondary goal of the trial was to evaluate the utility of visual assessment of the vagina by healthcare providers to diagnose VVA and evaluate response to treatment. The trial showed that visual assessment was both sensitive and specific for detecting moderate-to-severe dyspareunia and dryness, and correlated with vaginal pH and cell assessments. Although visual assessment was not validated in a separate study, the researchers noted that utilization by the large number of sites in the REJOICE trial suggested it will be useful for both research studies and in clinical practice. Furthermore, they stated that because both clinicians and patients are often reluctant to broach the topic of VVA, visual assessment may allow for easy identification of women at risk for dyspareunia and vaginal dryness and offer an opportunity to discuss VVA and its treatment.