Clinical trial NCT01779947: Study to Evaluate the Safety and Bioequivalence of Estradiol Vaginal Inserts, 10 mcg and Vagifem® 10 mcg and Compare to Placebo
Official title: An Investigator-Blind, Randomized, Parallel-Group, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Bioequivalence of Estradiol Vaginal Inserts, USP 10 mcg and Vagifem® (Estradiol Vaginal Tablets) 10 mcg and Compare Both Active Treatments to a Placebo Control in Female Subjects With Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy Associated With Menopause
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Atrophic Vaginitis Due to Menopause
Lead sponsor: Amneal Pharmaceuticals, LLC
Sponsor class: INDUSTRY
First posted: 2013-01-30
Enrollment: 519
Sex: FEMALE
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the safety and efficacy of generic Estradiol Vaginal Inserts, USP 10 mcg to the reference product Vagifem® 10 mcg and to determined whether the efficacy of each of the 2 active treatments is superior to that of the placebo.


Eligibility criteria: Inclusion Criteria:

* Willing and able to provide and understand written informed consent for the study.
* Healthy female subject aged 30 to 75 years, inclusive, who was postmenopausal, defined as having had 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels \> 40 mIU/mL, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
* At least 1 subject-assessed moderate to severe symptom of VVA among the following 4 symptoms that was identified by the subject as being most bothersome to her:
* Vaginal dryness
* Vaginal and/or vulvar irritation/itching
* Dysuria
* Vaginal pain associated with sexual activity OR
* The presence of vaginal bleeding associated with sexual activity
* Had ≤ 5% superficial cells on vaginal smear cytology at Visit 1.
* Vaginal pH \> 5.0 at Visit 1.
* Systolic blood pressure ≤ 150 mm Hg and diastolic blood pressure ≤ 90 mm Hg at Visit 1.
* If \> 40 years old, documentation of a negative mammogram (obtained at Visit 1 or within 9 months prior to Visit 1). A radiology report documenting a negative mammogram must have been available and must have been taken within 9 months of Visit 1 or obtained at Visit 1.
* Normal clinical breast examination at Visit 1.
* For women with intact uterus, vaginal ultrasonography confirmation at Visit 1 of an inactive endometrial lining, with an endometrial thickness \< 4 mm.
* Documented Pap smear conducted within the previous 12 months of Visit 1 with no findings that the investigator believed would contraindicate the use of topical vaginal estradiol.
* In general good health with no clinically significant disease other than symptoms of VVA that might have interfered with the study evaluations.
* Was willing and able to understand and comply with the requirements of the study, including applying the medication as instructed, returning for the required study visits, complying with therapy prohibitions, and able to complete the study.

Exclusion Criteria:

* Known hypersensitivity to estradiol vaginal tablet or any component of the study medication.
* A subject who had received any treatment listed below more recently than the indicated washout period prior to Visit 1/Screening/Baseline.
* Prohibited Medications - (Washout Period Prior to Visit 1/Screening/Baseline)
* Vaginal lubricants or moisturizers - (at least 48 hours (2 days))
* Vaginal hormonal products (rings, creams, gels) - (at least 1 week (7 days))
* Transdermal estrogen alone or estrogen/progestin products - (at least 4 weeks (28 days))
* Oral estrogen and/or progestin therapy - (at least 8 weeks (56 days))
* Intrauterine progestin therapy - (at least 8 weeks (56 days))
* Progestin implants and estrogen alone injectable drug therapy - (at least 3 months (90 days))
* Estrogen pellet therapy or progestin injectable drug therapy - (at least 6 months (180 days))
* Subject who had engaged in sexual intercourse within 48 hours (2 days) of Visit 1.
* Screening mammogram or clinical breast examination results indicating any suspicion of breast malignancy.
* History of undiagnosed vaginal bleeding.
* Known bleeding disorder.
* History of significant risk factors for endometrial cancer (i.e., tamoxifen use, prior pelvic radiation therapy, and endometrial hyperplasia).
* For women with an intact uterus, screening vaginal ultrasonography showing endometrial thickness of ≥ 4 mm.
* Known, suspected, or history of breast cancer or cervical cancer.
* Known or suspected estrogen-dependent neoplasia.
* History of uncontrolled hypertension.
* Active deep vein thrombosis, pulmonary embolism, or history of these conditions.
* Active arterial thromboembolic disease (e.g., stroke or myocardial infarction) or a history of these conditions.
* Known liver dysfunction or disease.
* Known anaphylactic reaction or angioedema to estradiol vaginal tablets.
* Known protein C, protein S, antithrombin deficient, or other known thrombophilic disorders. - Active vaginal herpes simplex infection or any known concurrent vaginal infections.
* Abnormal Pap smear within the previous 12 months of Visit 1 or obtained during Visit 1. Any evidence of malignancy or premalignant changes or atypical squamous cell of undetermined significance (ASCUS) Pap smear with positive high risk human papillomavirus (HPV).
* Any clinically significant condition or situation (including laboratory values) other than the condition being studied that, in the opinion of the investigator, would have interfered with the study evaluations or optimal participation in the study.
* Use of any investigational drugs or device within 30 days of signing the ICF.
* Current participation in any other clinical study involving an investigational drug or device.
* Consumed excessive amounts of alcohol, abused drugs, or had any condition that would have compromised compliance with this protocol.
* Previous participation in this study.
* Subjects who, in the opinion of the Investigator, would have been non-compliant with the requirements of the study protocol.

Primary outcomes:
measure: Responders
timeFrame: Day 15 (1 day after the administration of the 14th dose of study treatment)
Secondary outcomes:
measure: Treatment Success
timeFrame: Day 15
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Medical Affiliated Research center, Inc.
state: Alabama
city: Montgomery
country: United States
facility: Montogmery Women's Health Associates
state: Alabama
city: San Diego
country: United States
facility: Medical Center for Clinical Research
state: California
city: San Diego
country: United States
facility: Women's Health Care Research Corp.
state: California
city: Denver
country: United States
facility: Downtown Women's Health care
state: Colorado
city: Denver
country: United States
facility: Horizons Clinical Research Center
state: Colorado
city: Washington
country: United States
facility: James A. Simon, MD PC/ Women's Health and Research Consultants
state: District of Columbia
city: Boynton Beach
country: United States
facility: Visions Clinical Reserach
state: Florida
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Lake Worth
country: United States
facility: Altus Research
state: Florida
city: Miami
country: United States
facility: New Age Medical Reserach Group
state: Florida
city: West Palm Beach
country: United States
facility: Comprehensive Clinical Trials, LLC
state: Florida
city: Roswell
country: United States
facility: Atlanta North Gynecology
state: Georgia
city: Sandy Springs
country: United States
facility: Mount Vernon Clinical Research, LLC
state: Georgia
city: Wichita
country: United States
facility: Cypress Medical Research Center. LLC
state: Kansas
city: Neptune
country: United States
facility: Meridian Health Care
state: New Jersey
city: Plainsboro
country: United States
facility: Center for Women's Health and Wellness, LLC/ Women's Health Research Center
state: New Jersey
city: Poughkeepsie
country: United States
facility: Premier Medical Group of the Hudson Valley
state: New York
city: Raleigh
country: United States
facility: Lyndhurst Clinical Research
state: North Carolina
city: Raleigh
country: United States
facility: Wake Research Associates
state: North Carolina
city: Winstom-Salem
country: United States
facility: Hawthorne Medical Research, Inc.
state: North Carolina
city: Winston-Salem
country: United States
facility: Lyndhurst Clinical Research
state: North Carolina
city: Columbus
country: United States
facility: Columbus Center for Women;s Health Reserach
state: Ohio
city: Philadelphia
country: United States
facility: Clinical Research of Philadelphia, LLC
state: Pennsylvania
city: Seattle
country: United States
facility: Seatlle Womne's Health,Reserach, Gynecology
state: Washington
Study officials:
affiliation: Amneal Pharmaceuticals, LLC
name: W. Todd Kays, PhD
role: STUDY_CHAIR
References: