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Original Articles

Early onset of action with a 17β-estradiol, softgel, vaginal insert for treating vulvar and vaginal atrophy and moderate to severe dyspareunia

Constantine, Ginger MD1; Millheiser, Leah S. MD2; Kaunitz, Andrew M. MD3; Parish, Sharon J. MD4; Graham, Shelli PhD5; Bernick, Brian MD5; Mirkin, Sebastian MD5

Author Information
doi: 10.1097/GME.0000000000001394
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Abstract

Dyspareunia and vaginal dryness are reported as the most common symptoms of vulvar vaginal atrophy (VVA),1 a component of the genitourinary syndrome of menopause (GSM).2 VVA has a reported prevalence of 4% to 47% from early to late menopause3,4; and these symptoms can interfere with sleep, mood, enjoyment of sex, and quality of life.1,5 A first-line therapeutic option for symptomatic, moderate to severe VVA, that has not responded to nonhormone treatment options, includes locally acting, low-dose vaginal estrogens, which have been shown to provide genitourinary symptom relief with minimal systemic absorption.6-9

Although VVA is chronic and progresses without treatment, in the 2016 Women's EMPOWER survey, half of postmenopausal women had never treated their VVA symptoms and only 7% were currently using prescribed VVA therapies.10,11 In fact, US surveys reported that 38% to 56% of postmenopausal women never discussed VVA symptoms with their healthcare providers (HCPs), mainly because they were uncomfortable, believed it was something they had to live with as they aged, or did not know there were treatments available.5,10-12 Discussing VVA treatments with HCPs is important as treatments used by women have been observed to be similar to those recommended by their HCPs.10 In the Women's EMPOWER survey, the most common VVA treatments recommended by HCPs were vaginal lubricant/moisturizers (52%) with over-the-counter drugs (28%) and vaginal estrogen therapies (23%) recommended less often.10 Of the women who had previously used and discontinued prescribed VVA therapies, lack of drug effectiveness (eg, late onset of action), high drug cost, inconveniences of the methods (eg, messiness/applicator use), and concerns about long-term risks and side effects were cited for discontinuing treatment.5,10,13

TX-004HR 4- and 10-μg 17β-estradiol (E2) softgel vaginal inserts were approved by the US Food and Drug Administration (FDA; May 2018) as Imvexxy (TherapeuticsMD, Boca Raton, FL) for the treatment of moderate to severe dyspareunia associated with postmenopausal VVA. The softgel inserts were designed to deliver a quick onset of symptom relief, to be rapidly dissolving and mucoadhesive, and to be administered without the use of an applicator. In the phase 3 REJOICE trial, the E2 vaginal insert significantly improved percentages of vaginal superficial and parabasal cells, vaginal pH, and dyspareunia versus placebo over 12 weeks, and as early as 2 weeks in postmenopausal women with VVA and moderate to severe dyspareunia.14 The inserts were well tolerated, with no clinically meaningful differences in adverse events compared with placebo and no endometrial hyperplasia or malignancy reported with up to 12 weeks of use.14 In pharmacokinetic analyses, systemic absorption of E2 observed with the E2 vaginal inserts was negligible to very low, remaining within the postmenopausal range (<10 pg/mL).15 The primary objective of this analysis of the REJOICE trial was to determine responder rates of the E2 vaginal inserts at week 2 and how week-2 findings may predict week-12 responders.

METHODS

Study design

REJOICE (NCT02253173) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study comparing three doses of an E2 softgel vaginal insert versus placebo administered over 12 weeks in postmenopausal women with VVA and moderate to severe dyspareunia (as their self-reported most bothersome symptom). Study participants were randomized 1:1:1:1 using a computer-generated randomization scheme to receive the E2 vaginal insert at a dose of 4, 10, or 25 μg, or matching placebo. Women were instructed to self-administer one insert daily for 2 weeks and then one insert twice weekly (approximately 3-4 d apart) for 10 weeks. Packaging and appearance of the vaginal E2 insert and placebo were identical to maintain blinding of participants and investigators.

All study materials, including the protocol and informed consent forms, were approved by the central or local institutional review board. The study was conducted in compliance with the International Conference on Harmonization Guideline for Good Clinical Practice and the ethical principles of the Declaration of Helsinki.

Participants

All participants provided written informed consent before initiation of any study procedure. Inclusion and exclusion criteria have been previously described.14 Briefly, eligible participants were postmenopausal women aged 40 to 75 years with ≤5% of superficial cells in a vaginal cytological smear, vaginal pH >5.0, body mass index ≤38 kg/m2, and a self-reported most bothersome symptom of moderate to severe dyspareunia associated with menopause. All women were sexually active (as defined by vaginal penetration) in the month before study enrollment and were expected to remain so during the trial. Women with an intact uterus were required to have an acceptable result from a screening endometrial biopsy sample. Hormonal preparations, treatments for VVA, and any investigational drugs other than study drug were prohibited during the study.

Study endpoints and responder analysis

The primary objective of the REJOICE trial was to assess the safety and efficacy of the E2 vaginal insert (4, 10, and 25 μg) compared with placebo at 12 weeks on four coprimary endpoints: percentage of vaginal superficial cells, percentage of vaginal parabasal cells, vaginal pH, and moderate to severe dyspareunia due to VVA. Post hoc analyses were to determine responder rates at weeks 2 and 12 (preplanned endpoint at week 12), and whether week-2 findings may predict week-12 responses.

Responders were defined a priori as women with at least 2 out of 3 clinical endpoints: vaginal superficial cells >5%, vaginal pH <5.0, and improvement from baseline in dyspareunia of ≥1 category (eg, moderate to mild). Dyspareunia was graded on a scale of 0 to 3, where 0 = no symptoms and 3 = severe symptoms. The proportion of responders was calculated by dividing the number of positive responders by the number of women with available responder data at each dose and time point (weeks 2, 6, 8 and 12).

Statistical analysis

The modified intent-to-treat (MITT) population included all women who met the inclusion criteria, received their randomized treatment, had baseline values for all four coprimary endpoints, and had at least 1 postbaseline value for any of the coprimary endpoints. Responder analyses were performed in the efficacy evaluable (EE) population, which included women in the MITT population who completed the study through week 12, had ≥80% study drug compliance based on diary data, did not use prohibited medications, and had no major protocol violations.

Numerically continuous variables are presented as means ± SD, unless otherwise specified. The proportion of responders was compared between each E2 group and placebo using Fisher's exact test. Odds ratios (ORs) and 95% CIs are presented for comparisons of responder percentages. ORs were also calculated to determine the likelihood of a positive response at week 12 given a positive response at week 2.

RESULTS

Disposition and demographics

Out of 2,183 women screened for eligibility, 764 women were randomized to 4 μg (n = 191), 10 μg (n = 191), and 25 μg (n = 190) softgel vaginal E2 inserts, or placebo (n = 192). Of these, 747 women constituted the MITT population, and 695 women met criteria for inclusion in the EE population used for the responder analysis (Fig. 1).

FIG. 1
FIG. 1:
Participant disposition through the study. E2, 17β-estradiol; EE, efficacy evaluable; MITT, modified intent-to-treat.

Demographic characteristics were similar among treatment groups in the EE population (Table 1). Mean age was 59.1 years (range, 41-75 y); most women were white (87.1%), and mean BMI was 26.8 kg/m2. Baseline values for percentage of vaginal superficial cells, vaginal pH, and dyspareunia severity were comparable between treatment groups (Table 2).

TABLE 1
TABLE 1:
Baseline demographics in the efficacy evaluable population
TABLE 2
TABLE 2:
Components of responder endpoint analyses at each time point in the efficacy evaluable population

Responder analysis

Mean values for the individual components of the responder analysis are shown in Table 2. Differences between placebo and each of the three E2 groups for the VVA outcomes were observed beginning at week 2 and continued through weeks 6, 8, and 12. The proportion of responders was 74% to 82% in the three E2 vaginal insert groups versus 24% with placebo at week 2, and 72% to 80% versus 33% at week 12 (Fig. 2). Significantly more responders were observed with each dose of the E2 vaginal insert than with placebo at weeks 2 and 12 (all, P < 0.0001).

FIG. 2
FIG. 2:
Responders to the E2, vaginal insert at weeks 2 and 12. E2, 17β-estradiol. a P < 0.0001 for E2 vaginal insert versus placebo.

The likelihood of being a responder with the E2 vaginal insert was 9- to 14-fold higher than with placebo at week 2 and 5- to 8-fold higher at week 12 (Table 3). The ORs also indicated a dose-dependent response at all time points.

TABLE 3
TABLE 3:
Likelihood of a positive response with estradiol vaginal insert versus placebo at weeks 2, 6, 8, and 12 in the efficacy evaluable population

The overall positive responder rate for those who were randomized to E2 vaginal inserts was similar at week 2 (79.5%) and week 12 (78.4%). Of the women in the E2 insert groups who responded at week 2, 85% responded at week 12; of the nonresponders at week 2 (20.5%), 46% were responders at week 12. Being a responder at week 2 was highly predictive of having a positive response at week 12 in both the overall EE population (OR 13.1; 95% CI, 8.8-19.7) and in the E2 vaginal insert groups (OR 7.9; 95% CI, 4.7-13.2).

DISCUSSION

In the REJOICE trial, postmenopausal women with moderate to severe dyspareunia due to VVA treated with E2 softgel vaginal inserts had statistically significant improvements in vaginal superficial and parabasal cells, vaginal pH, and moderate to severe dyspareunia compared with placebo as early as 2 weeks of therapy.14 In this analysis, an early treatment response (at week 2) was supported by data showing that more women had a positive response at week 2 with the E2 inserts than with placebo and that women were 9 to 14 times more likely to have a positive response at week 2 with the E2 inserts than with placebo. Similar observations were found at week 12. Furthermore, a positive response to the E2 vaginal insert at week 2 was predictive of a sustained and positive response at week 12.

In the REJOICE trial, women reported subjective and objective improvements as early as week 2. This current early onset of action with subjective and objective improvements at week 2 is in contrast to pivotal studies with an E2 vaginal tablet (10 or 25 μg) that reported early physiologic improvements in the signs of VVA, but did not find significant improvements in vaginal symptoms at week 2.16,17 With the E2 vaginal tablet, significant reductions in vaginal symptoms versus placebo were not observed until week 7 or 8.16,17 Likewise, the oral SERM ospemifene (60 mg/d) was reported to demonstrate a slower onset of action for subjective parameters in postmenopausal women with dyspareunia due to VVA.18-20 Although improvements in vaginal cell percentages and pH with ospemifene were noted as early as week 4 with treatment versus placebo, improvements in the most bothersome symptom were not reported to be statistically significant until week 12 (moderate to severe dyspareunia; P = 0.0004),18 or in fact were not significant at week 12 (vaginal dryness; P = 0.08).19 Another study of ospemifene found significant improvements in the self-reported most bothersome symptoms of dyspareunia and vaginal dryness at week 12, but did not analyze data earlier than that time point.20

Responder analyses are useful as they provide clinically intuitive observations.21,22 Possible disadvantages of this type of analysis can include an arbitrary definition of response21,22; however, the definition of a responder was prespecified for the REJOICE study. In addition, a large magnitude of difference in treatment effect between all E2 doses versus placebo was noted, and treatment effects in the primary analysis of the MITT population14 were consistent with those of the EE population reported here.

The approved 4- and 10-μg softgel vaginal inserts are new treatment options for moderate to severe dyspareunia in a formulation that offers favorable characteristics. In addition, the 4-μg insert represents the lowest dose vaginal E2 formulation available. Vaginal creams have been less preferable than other forms of treatment because of their messiness,23 and women are significantly less likely to continue therapy with a cream formulation.23-25 Some other drawbacks cited by women and leading to poor compliance with other VVA products have included vaginal tablet applicator causing discomfort, abrasions,26 vaginal discharge,27 and not being environmentally friendly, as well as a preference for “natural” hormones similar to endogenous estrogen (ie, 17β-E2 rather than conjugated equine estrogens).28 Indeed, a survey associated with the phase 3 REJOICE study showed high patient satisfaction with this E2 vaginal insert.29

CONCLUSIONS

Given the negative impact of VVA symptoms on quality of life, the importance of early relief of symptoms and sustainability of treatment is clear. These data may be able to help inform clinicians counseling postmenopausal women with moderate to severe dyspareunia regarding the benefits and potential early therapeutic effect of the low-dose E2 softgel vaginal insert.

Acknowledgments

We thank the investigators of the REJOICE Study Group, the statistical analysis provided by Harvey Kushner, PhD, and the medical writing assistance provided by Dominique J. Verlaan, PhD and Laura J. Ninger, ELS of Precise Publications, LLC (Bedminster, NJ).

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Keywords:

Dyspareunia; Estradiol; Estrogen therapy; Menopause; Vulvar and vaginal atrophy

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.