Efficacy of Intravaginal Dehydroepiandrosterone (DHEA) on Moderate to Severe Dyspareunia and Vaginal Dryness, Symptoms of Vulvovaginal Atrophy, and of the Genitourinary Syndrome of Menopause

Fernand Labrie, MD, PhD; David F. Archer, MD; William Koltun, MD; Andrée Vachon, MD; Douglas Young, MD; Louise Frenette, MD; David Portman, MD; Marlene Montesino, MD; Isabelle Côté, BSc; Julie Parent, PhD; Lyne Lavoie, MSc; Adam Beauregard, BSc, MBA; Céline Martel, PhD; Mario Vaillancourt, BSc, MBA; John Balser, PhD; Érick Moyneur, BSc, MA; the members of the VVA Prasterone Research Group

Disclosures

Menopause. 2016;23(3):243-256. 

In This Article

Methods

This was a phase III, placebo-controlled, double-blind, prospective, and randomized study (ERC-238; NCT02013544, ClinicalTrials.gov) to confirm the efficacy of daily intravaginal administration of 0.50% DHEA ovules (suppositories) for 12 weeks on moderate to severe pain at sexual activity as the MBS of VVA. Women were randomized in a 2:1 ratio between the 0.50% DHEA and placebo ovules.

Independent Ethics Committee or Institutional Review Board

The protocol was approved by the Institutional Review Board (IRB) Services (Central IRB) for all investigational sites, except for the Eastern Virginia Medical School, Department of Obstetrics and Gynecology, and Clinical Research Center, where a local IRB gave approval before the start of the study.

Informed Consent

A written informed consent was obtained from all participants before the performance of any study-related procedure.

Inclusion Criteria

The inclusion criteria were as follows:
(1) Postmenopausal women (non-hysterectomized or hysterectomized) must satisfy either of the following:
(a) No menses for at least 1 year for non-hysterectomized women, or
(b) Follicle-stimulating hormone (FSH) levels above 40 IU/L or above the postmenopausal value of the laboratory where the FSH assay is performed (a woman with previously measured elevated serum FSH meets the inclusion criteria) in women with no menses for more than 6 months, but less than 12 months, or in hysterectomized women who were premenopausal at the time of hysterectomy, or
(c) Six months or more of day 1 visit after bilateral oophorectomy with or without hysterectomy.
(2) Women between 40 and 80 years of age.
(3) Women who have self-identified at screening and baseline (day 1) pain at sexual activity as moderate to severe and as the most bothersome VVA symptom.
(4) Women having 5% or less of superficial cells on vaginal smear at screening and baseline (day 1).
(5) Women having a vaginal pH above 5 at screening and baseline (day 1).
(6) Women who currently have intercourse or other sexual activity (masturbation, etc) at least once a month (with or without a partner), or who had intercourse or other sexual activity at least once a month in the past, but later decreased sexual activity due to excessive pain or vaginal dryness.
(7) Normal mammogram (American College of Radiology Breast Imaging-Reporting and Data System [BI-RADS] category 1 or 2) within 9 months of study initiation (day 1).
(8) Normal breast examination.
(9) A normal Pap smear (which includes inflammatory changes) within the past 12 months (of day 1) for both non-hysterectomized and hysterectomized women after specimen collection (see "exclusion criteria no. 14").
(10) Willing to participate in the study and sign an informed consent.
(11) No former or present narcotic addiction or alcoholism.
(12) For non-hysterectomized women, willing to have an endometrial biopsy during the screening period to exclude endometrial pathology.

Exclusion Criteria

The exclusion criteria were as follows:
(1) Previous enrollment in EndoCeutics studies performed with intravaginal DHEA (ERC-210, ERC-213, ERC-230, ERC-231, or ERC-234).
(2) Previous diagnosis of cancer, except skin cancer (nonmelanoma).
(3) Active or history of thromboembolic disease (thromboembolic event after an accident, a surgery, or immobilization is not an exclusion criterion).
(4) Clinically significant metabolic or endocrine disease (including diabetes mellitus) not controlled by medication.
(5) Use of estrogen alone injectable drug therapy or progestin implant within 6 months before study entry (screening visit).
(6) Use of estrogen pellet or progestin injectable drug within 6 months before study entry (screening visit).
(7) Oral estrogen, progestin, or DHEA exposure or intrauterine progestin therapy in the 8 weeks before baseline assessments (screening visit).
(8) Vaginal hormonal products (rings, creams, gels, or tablets) or transdermal estrogen alone or estrogen/progestin products in the 8 weeks before baseline assessments (screening visit).
(9) Previous treatment with androgens or anabolic steroids within 6 months before screening visit.
(10) Natural oral estrogenic products in the 4 weeks before baseline assessments (screening visit), whether intended or not, for the relief of symptoms of VVA and/or hot flushes.

Regarding exclusion criteria 5 to 10, participants can washout as indicated below, but the questionnaire on VVA, as well as the evaluation of cell maturation and pH, must be answered or evaluated after the required washout period.

  • At least an 8-week washout period for prior oral estrogen, DHEA, and/or progestin therapy.

  • At least an 8-week washout period for prior transdermal hormone therapy (HT).

  • At least an 8-week washout period for locally delivered hormone replacement therapy for vaginal dryness (rings, creams, gels, or tablets).

  • Eight weeks or longer for prior intrauterine progestin therapy.

  • At least 6 months for prior estrogen pellet therapy or progestin injectable drug therapy.

  • Six months or longer for prior progestin implants and estrogen alone injectable drug therapy.

  • Six months or longer for previous treatment with androgens or anabolic steroids.

  • Four weeks or longer for prior natural oral "estrogenic" products.

(11) Confirmed clinically significant depression (not controlled by standard therapy) or confirmed history of severe psychiatric disturbance.
(12) The administration of any investigational drug within 30 days of screening visit.
(13) Clinically significant abnormal serum biochemistry, urinalysis, or hematology.
(14) Baseline cervical cytology showing atypia of squamous cells of undetermined significance (ASC-US) or worse. Since ASC-US can be due to atrophy, a woman with ASC-US without history of abnormal Pap within the past 2 years and a negative human papillomavirus (HPV) test can be enrolled.
(15) Palpable fibroids, or grade 2 uterine prolapse (when the cervix reaches labia minora) by gynecologic examination.
(16) Endometrial hyperplasia (simple or complex hyperplasia with or without atypia), cancer, or endometrial histology showing proliferative, secretory, or menstrual-type characteristics at histologic evaluation of endometrial biopsy performed at screening.
(17) Women who suffer from vulvar lichen sclerosis.
(18) Endometrial polyps.
(19) Women who had endometrial ablation.

Randomization

Randomization was done centrally by Veristat Inc. A randomization with permuted blocks of three women at a 2:1 ratio of DHEA (group B) and DHEA-placebo (group A), respectively, was performed to ensure a balanced allocation to the two treatments by investigational site. A list of randomization provided the association between each randomization number and a specific medication container. Each container contained 0.50% DHEA or DHEA placebo ovules.

Dosing

Participants randomized into groups A and B were instructed to insert one vaginal ovule (suppository) daily before bedtime (usually in the evening) for 12 weeks. Before first administration of the study treatment, proper instructions were given to the participants on how to apply the vaginal ovule using the single-use applicator provided.

Compliance and Drug Accountability

Study drug containers were collected and verified at all visits by designated site personnel. Participants were questioned regarding study drug application technique, and use of any additional topical or systemic products. The time of drug application was to be recorded on a daily basis in the diary card provided by the Sponsor.

The person from the clinical trials team who was responsible for treatment dispense and return had to keep an accurate count of the number of investigational units received, dispensed to the participants, returned to the Investigator by the women, and the number of units returned to EndoCeutics during and at the completion of the study. Any discrepancy in the study drug accountability was to be reconciliated and documented.

Vaginal Cell Maturation

Vaginal smears were collected at screening, baseline (day 1), week 6 and week 12 (or at discontinuation visit, if applicable). Vaginal smears were obtained by gently scraping the middle (second third) of the side wall of the vagina using wooden or plastic spatula gently applied to a glass slide and immediately fixed with Cytospray or its equivalent. Vaginal smears were not collected if the participant had sexual intercourse within the preceding 24 hours and/or has used vaginal products (lubricant, cream, vaginal douching, etc) within 48 hours before sampling. Vaginal smears were sent to the central laboratory (Centre Hospitalier Universitaire de Québec) for determination of the MI.

All samples were examined by an experienced cytopathologist blinded to the treatment regimens. A 100-cell count was performed to classify cells as parabasal (P) (including the basal), intermediate (I), and superficial (S) squamous cell types (a number greater than 100 cells is usually counted, and the numbers obtained for each of the three cell populations are divided to be reported as a total of 100).

Vaginal pH

The vaginal pH was determined at screening, baseline (day 1), week 6 and week 12 (or at discontinuation visit, if applicable). A pH strip fixed on an Ayre spatula (or equivalent) was applied directly to the lateral wall of the vagina opposite to the side scraped to obtain the vaginal smear.

Vaginal Atrophy Symptoms Questionnaire

Self-assessment of symptoms of vulvovaginal atrophy associated with menopause were evaluated at screening, baseline (day 1), week 6, and week 12 (or at discontinuation visit, if applicable) by a questionnaire.[29] The self-reported symptom score takes the following values: none, mild, moderate, or severe, and was analyzed using values of 0, 1, 2, or 3, respectively.

Observations at Vaginal Examination

The aspect of the mucosa and tolerance to treatment were verified by gynecological examinations performed at screening, day 1, and weeks 6 and 12 (or at discontinuation visit, if applicable)[29] as follows:
(1) Vaginal secretions:
(a) No atrophy: normal clear secretions noted on vaginal walls.
(b) Mild: superficial coating of secretions, difficulty with speculum insertion.
(c) Moderate: scant and covering entire vaginal vault, may need lubrication with speculum insertion to prevent pain.
(d) Severe: none, inflamed, ulceration noted, need lubrication with speculum insertion to prevent pain.
(2) Vaginal epithelial integrity:
(a) No atrophy: normal.
(b) Mild: vaginal surface bleeds with scraping.
(c) Moderate: vaginal surface bleeds with light contact.
(d) Severe: vaginal surface has petechiae before contact and bleeds with light contact.
(3) Vaginal epithelial surface thickness:
(a) No atrophy: rugation and elasticity of vault.
(b) Mild: poor rugation with some elasticity noted of vaginal vault.
(c) Moderate: smooth, some elasticity of vaginal vault.
(d) Severe: smooth, no elasticity, constricts in upper 1/3 of vagina or loss of vaginal tone (cystocele and rectocele).
(4) Vaginal color:
(a) No atrophy: pink.
(b) Mild: lighter in color.
(c) Moderate: pale in color.
(d) Severe: transparent—either no color or inflamed.

The above-indicated parameters (secondary endpoints), evaluated as no atrophy, mild, moderate, and severe, were analyzed using values of 1, 2, 3, and 4, respectively.

Safety

Physical examination, gynecological examination (for inspection of vaginal mucosa at day 1, wk 6, and wk 12) and clinical laboratory tests were performed. Adverse events (AEs) were recorded for safety evaluation and then coded into system organ class and preferred terms using the Medical Dictionary for Regulatory Authorities (MedDRA version 16.1). The potential influence of DHEA on participant's male partner was investigated as secondary objective. Clinical laboratory measurements were done at a central laboratory (URMC Laboratories, Rochester, NY). Serum steroids (namely DHEA, DHEA sulfate [DHEA-S], testosterone [Testo], dihydrotestosterone [DHT], androstenedione [4-dione], androst-5-ene-3β,17β-diol [5-diol], estrone [E1], 17β-estradiol [E2], estrone sulfate [E1-S], androsterone glucuronide [ADT-G], and androstane-3α,17β-diol-17 glucuronide [3α-diol-17G]) were measured at the Central Laboratory of EndoCeutics Bioanalytical Unit by validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methodology.[30,31,32,33]

Statistical Analysis

Statistical analyses were performed at the two-sided significance level of 0.05. The primary analyses in this study were based on the comparison of DHEA to placebo, and statistical significance of this comparison permits to demonstrate the superiority of DHEA to placebo in the treatment of VVA.

The coprimary endpoints for the analysis consist of the following:
(1) Pain at sexual activity (dyspareunia)
(2) Percentage of parabasal cells
(3) Percentage of superficial cells
(4) Vaginal pH

No P value adjustment was used for the analysis of these four coprimary endpoints for the primary statistical comparisons of DHEA to placebo, since statistical significance of all four is required to reach a conclusion of superiority of the DHEA over placebo. The four endpoints were analyzed as continuous measurements.

The symptom score parameters of the other two symptoms of vaginal atrophy, namely vaginal dryness and vulvovaginal irritation/itching, were tested statistically as second-order and third-order endpoints. Therefore, the primary symptom score parameter of dyspareunia must be statistically significant before the test for vaginal dryness, which in turn must be significant before the test for significance of vulvovaginal irritation/itching. This procedure controls the type 1 error rate for these secondary and tertiary comparisons.

The analysis of primary and secondary endpoints was performed using analysis of covariance (ANCOVA), with the treatment group as the main factor and the baseline value as the covariate. Two separate ANCOVAs were used for the 6 and 12-week data. The P value for the baseline adjusted least square mean (LSM) difference between groups was presented (specifically, P values for 0.50% DHEA vs placebo).

Analysis Populations

Efficacy. The intent-to-treat (ITT) population consists of all women who have received at least one dose of the study drug (based on diary card) with a baseline (day 1) evaluation meeting the study entry criteria. This analysis population was considered as the primary analysis population for efficacy parameters. Women in this population who had missing observations had the last value carried forward for efficacy analyses. In particular, women must have met all the following inclusion criteria both at screening and at day 1: 5% or less of superficial cells on vaginal smear, a vaginal pH above 5, and who have selfidentified moderate to severe vaginal pain at sexual activity (dyspareunia) as their MBS; the observations at day 1 before treatment were used for the change from baseline analysis. If some data of efficacy parameters were missing at day 1, the screening value was used for baseline.

Safety. The safety population consists of all women who received an administration of any amount of test article (DHEA or placebo) (based on diary card and/or drug accountability), and who had any post-baseline safety information available. This analysis population was considered the primary analysis population for safety parameters.

Data Processing. Electronic forms (including diaries and questionnaires) were filled out by clinical site personnel. For parameters described herein, verification of the data entry with the source was performed 100% by clinical research associates for all case report form pages completed by the clinical site personnel. The verified-source data were captured in the electronic data capture (EDC) system.

The web-based BioClinica Express EDC system provided and hosted by BioClinica was used for this study. The MI results were captured by EndoCeutics' personnel in the EDC system and were 100% verified by a second person, whereas the Clinical laboratory results provided by the University of Rochester Medical Center (URMC) central laboratory were uploaded in the EDC system using the software import functionalities. Data from participant source records were captured in the EDC system by designated clinical site personnel.

A database quality assurance audit was performed at the end of the study. To generate study data after locking of the database, a parallel programming process was used to minimize potential errors related to SAS programming and/or interpretation of the statistical analysis plan. In this process, two programmers independently executed all planned analyses of the statistical analysis plan, starting from the xml export of the clinical database and SAS datasets (for steroid data) approved in SOLABS (Montreal, Canada). Sets of tables and listings obtained from both programmers were matched; after all discrepancies had been resolved, the complete set of tables/listings was assigned a "QC passed" or "final" mark.

Disposition of Participants

Please refer to Figure 1 for disposition of participants. For 23 women in the randomized placebo group and 49 women in the DHEA group, all the study entry criteria (including VVA criteria) were met at screening, but one or more required study entry criteria (including VVA criteria) was not present at baseline (day 1), thus automatically excluding these participants from the ITT population. These women were kept on study treatment (placebo or DHEA as randomized) to obtain additional exposure and safety data, but they were not part of the efficacy analysis due to their lack of compliance with the study entry criteria on day 1.

Figure 1.

Participant disposition. DHEA, dehydroepiandrosterone.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....