The REJOICE trial: a phase 3 randomized, controlled trial evaluating the safety and efficacy of a novel vaginal estradiol soft-gel capsule for symptomatic vulvar and vaginal atrophy

Ginger D Constantine, James A Simon, James H Pickar, David F Archer, Harvey Kushner, Brian Bernick, Gina Gasper, Shelli Graham, Sebastian Mirkin, REJOICE Study Group, Ginger D Constantine, James A Simon, James H Pickar, David F Archer, Harvey Kushner, Brian Bernick, Gina Gasper, Shelli Graham, Sebastian Mirkin, REJOICE Study Group

Abstract

Objective: To evaluate the safety and efficacy of TX-004HR vaginal estradiol soft-gel capsules for moderate-to-severe dyspareunia associated with postmenopausal vulvar and vaginal atrophy.

Methods: In this randomized, double-blind, placebo-controlled, phase 3 study, postmenopausal women with a self-identified most bothersome symptom of dyspareunia received 4, 10, or 25 μg TX-004HR or placebo for 12 weeks. Four co-primary efficacy endpoints were change from baseline to week 12 in percentages of superficial and parabasal cells, vaginal pH, and severity of dyspareunia. Secondary endpoints included severity of vaginal dryness and vulvar and/or vaginal itching or irritation. Endometrial histology and adverse events (AEs) were included in the safety endpoints.

Results: In all, 764 women were randomized (modified intent-to-treat population, n = 747; mean age 59 y). Compared with placebo, all three doses of TX-004HR significantly improved the four co-primary endpoints (P < 0.0001 for all, except dyspareunia with 4 μg, P = 0.0149). Changes in cytology, pH, and dyspareunia were also significant at weeks 2, 6, and 8. Vaginal dryness and vaginal itching/irritation improved. Sex hormone binding globulin concentrations did not change with treatment. TX-004HR was well-tolerated, with no clinically meaningful differences in treatment-emergent AEs versus placebo, and no treatment-related serious AEs or deaths.

Conclusions: TX-004HR (4, 10, and 25 μg) was safe, well-tolerated, and effective for treating moderate-to-severe dyspareunia within 2 weeks with minimal systemic estrogen exposure. This novel product may be a potential new treatment option for women experiencing postmenopausal vulvar and vaginal atrophy.

Figures

FIG. 1
FIG. 1
Participant disposition through the study. MITT, modified intent-to-treat.
FIG. 2
FIG. 2
Co-primary endpoints: change from baseline to week 12 in (A) percentage of superficial cells; (B) percentage of parabasal cells; (C) vaginal pH units, and (D) dyspareunia severity scores with three doses of TX-004HR compared with placebo. ∗P < 0.05; †P < 0.0001 versus placebo (MITT population, n = 747). LS, least square; MITT, modified intent-to-treat.
FIG. 3
FIG. 3
Effect of each of three doses of TX-004HR at 12 weeks compared with placebo on the secondary endpoints of (A) severity of vaginal dryness and (B) severity of vulvar and/or vaginal itching or irritation (MITT population, n = 747). ∗P < 0.05; †P < 0.01; ‡P < 0.0001 versus placebo. LS, least square; MITT, modified intent-to-treat.

References

    1. Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal atrophy. Mayo Clin Proc 2010; 85:87–94.
    1. Gass ML, Cochrane BB, Larson JC, et al. Patterns and predictors of sexual activity among women in the hormone therapy trials of the Women's Health Initiative. Menopause 2011; 18:1160–1171.
    1. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med 2009; 6:2133–2142.
    1. Simon JA, Kokot-Kierepa M, Goldstein J, Nappi RE. Vaginal health in the United States: results from the Vaginal Health: Insights, Views & Attitudes survey. Menopause 2013; 20:1043–1048.
    1. Portman DJ, Gass ML. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause 2014; 21:1063–1068.
    1. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000; 96:351–358.
    1. Nappi RE, Kokot-Kierepa M. Women's voices in the menopause: results from an international survey on vaginal atrophy. Maturitas 2010; 67:233–238.
    1. Kingsberg SA, Wysocki S, Magnus L, Krychman ML. Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (Real Women's Views of Treatment Options for Menopausal Vaginal Changes) survey. J Sex Med 2013; 10:1790–1799.
    1. US Census Bureau. Age and sex composition: 2010 Census Briefs. Issued May 2011. Available at: Accessed April 14, 2015.
    1. North American Menopause Society. Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013; 20:888–902.
    1. De Villiers TJ, Pines A, Panay N, et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric 2013; 16:316–337.
    1. Manson JE, Goldstein SR, Kagan R, et al. Why the product labeling for low-dose vaginal estrogen should be changed. Menopause 2014; 21:911–916.
    1. Freedman MA. Perceptions of dyspareunia in postmenopausal women with vulvar and vaginal atrophy: findings from the REVIVE survey. Womens Health (Lond Engl) 2014; 10:445–454.
    1. Minkin MJ, Maamari R, Reiter S. Postmenopausal vaginal atrophy: evaluation of treatment with local estrogen therapy. Int J Womens Health 2014; 6:281–288.
    1. Vagifem (estradiol vaginal tablets). Prescribing Information. Bagsvaerd, Denmark: Novo Nordisk Pharmaceuticals Inc; 2012.
    1. Wysocki S, Kingsberg S, Krychman M. Management of vaginal atrophy: implications from the REVIVE study. Clin Med Insights Reprod Health 2014; 8:23–30.
    1. Portman D, Shulman L, Yeaw J, et al. One-year treatment persistence with local estrogen therapy in postmenopausal women diagnosed as having vaginal atrophy. Menopause 2015; 22:1197–1203.
    1. Fishman JR, Flatt MA, Settersten RA., Jr Bioidentical hormones, menopausal women, and the lure of the “natural” in U.S. anti-aging medicine. Soc Sci Med 2015; 132:79–87.
    1. Pickar JH, Amadio JM, Hill JM, Bernick BA, Mirkin S. A randomized, double-blind, placebo-controlled phase 2 pilot trial evaluating a novel, vaginal softgel capsule containing solubilized estradiol. Menopause 2016; 23:506–510.
    1. Archer DF, Constantine G, Kushner H, et al. TX-004HR Vaginal estradiol effectively treats vulvar and vaginal atrophy (VVA) with negligible to low systemic absorption of estradiol. Poster presented at: the Endocrine Society's 98th Annual Meeting & Expo, Boston, MA, 2016.
    1. Simon J, Nachtigall L, Gut R, Lang E, Archer DF, Utian W. Effective treatment of vaginal atrophy with an ultra-low-dose estradiol vaginal tablet. Obstet Gynecol 2008; 112:1053–1060.
    1. Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M. Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet Gynecol 2008; 111:67–76.
    1. Portman DJ, Bachmann GA, Simon JA. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause 2013; 20:623–630.
    1. Premarin (conjugated estrogens tablets, USP). Prescribing Information. Philadelphia, PA: Wyeth Pharmaceuticals Inc; 2010.
    1. Shionogi, Inc, Osphena (ospemifene) tablets, for oral use. Prescribing Information. 2013.
    1. Portman D, Palacios S, Nappi RE, Mueck AO. Ospemifene, a non-oestrogen selective oestrogen receptor modulator for the treatment of vaginal dryness associated with postmenopausal vulvar and vaginal atrophy: a randomised, placebo-controlled, phase III trial. Maturitas 2014; 78:91–98.
    1. Eriksen PS, Rasmussen H. Low-dose 17 beta-estradiol vaginal tablets in the treatment of atrophic vaginitis: a double-blind placebo controlled study. Eur J Obstet Gynecol Reprod Biol 1992; 44:137–144.
    1. Ulrich LS, Naessen T, Elia D, Goldstein JA, Eugster-Hausmann M. Endometrial safety of ultra-low-dose Vagifem 10 microg in postmenopausal women with vaginal atrophy. Climacteric 2010; 13:228–237.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel