A randomized, double-blind, placebo-controlled phase 2 pilot trial evaluating a novel, vaginal softgel capsule containing solubilized estradiol

Menopause is marked by a decline in endogenous estrogen, which causes atrophic changes to occur in the genital tract. Over time, the tissue lining the vagina becomes thinner, drier, and less elastic, resulting in vulvar and vaginal atrophy(VVA; also known as genitourinary syndrome of menopause).1 VVA is generally accompanied by symptoms such as vaginal dryness, irritation, itching, dysuria, and vaginalpain or bleeding associated with sexual activity2,3; however, early, sustained treatment can preclude irreversible declines in vaginalhealth.4 Up to 32 million women in the United States currently are suffering from symptoms of VVA,5,6 and more than 85% of this population currently receives no prescription therapy for the condition.7 Effective treatments designed to help relieve the pain and discomfort associated with VVA symptoms will improve the quality of life for many women. The North American Menopause Society and the International Menopause Society recommend local vaginal estrogenswhen menopausal symptoms are limited to VVA.4,8,9 Despite the relative safety and efficacy of local vaginaltreatments, consumers remain dissatisfied with the currently available local treatment options.7 Vaginalcreams approved in the 1980s are antiquated. They require an applicator, can be unsanitary and inconvenient for women to apply, and dosing can be complicated and confusing.3 The creams can be messy and cause excessive discharge, leading some women to alternatively choose vaginaltablets or rings.3,10 Vaginaltablets currently on the market, however, can be difficult to use, may not fully dissolve for days, and may be inconvenient, in addition to concerns of overall treatment efficacy. Likewise, the vaginal ringmay be difficult to insert and remove,3 may change position or dislodge,9 and has been shown to release an initial burst of systemic estradiol (E2).11 A new softgel vaginalcapsule (VagiCap) that contains solubilized 17β-E2, known as TX-004HR (TherapeuticsMD, Inc, Boca Raton, FL), was designed to treat moderate-to-severe symptoms of VVA in postmenopausal women. Pharmacokinetic studies have demonstrated lower systemic estrogen exposure with TX-004HR as compared with equivalent dosesof the vaginalE2 tablet (Vagifem, Novo Nordisk, Plainsboro, NJ).12 This lower systemic exposure of E2 supports the call of the Working Group on Women's Health and Well-Being in Menopause to modify the boxed warningon labels and package insertsfor low-dose vaginal estrogen.13 The warning included in the black box on low-dose vaginal estrogensis based on extrapolations from trials of systemic estrogen or combination estrogen-progestin hormone preparations.13 The Working Group proposes to distinguish that the relevance of findings of risks associated with systemic estrogen administration is not applicable to low-dose vaginal estrogenpreparations.13 This clarity is likely to increase use and compliance, resulting in substantial vaginalhealth benefits to a broader population. If approved, TX-004HR, as a vaginalE2 softgelcapsule, would fill an unmet need for a more user-friendly, modern product, considering that most of the available products were approved more than 20 years ago. TX-004HR is expected to provide improved ease of vaginaladministration without the need of an applicator and minimize vaginal dischargeafter administration. TX-004HR may also provide a more effective dosage form with improved efficacy, early onsetof action, and patient compliance, as well as lower systemic estrogen levels than currently available products. The phase 3 REJOICE trial evaluated the safety and efficacy of TX-004HR vaginalE2 softgelcapsules at 4, 10, and 25 μg doses in the United States and Canada. The overall objective of this phase 2 pilot study was to evaluate the safety and efficacy of 10-μg TX-004HR vaginalE2 softgelcapsules, when compared with placebo, as a treatment for postmenopausal women suffering from moderate-to-severe symptoms of VVA.