Study to Evaluate the Safety and Bioequivalence of Estradiol Vaginal Inserts, 10 mcg and Vagifem® 10 mcg and Compare to Placebo

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Atrophic Vaginitis Due to Menopause

Intervention / Treatment
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* Drug: Estradiol Vaginal Tablets 10 mcg
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Estradiol Vaginal Insert 10 mcg<br>Estradiol Vaginal Insert 10 mcg - Test Product | Drug: Estradiol Vaginal Tablets 10 mcg<br> <br> * Other names: Vagifem®;|
| Active Comparator: Vagifem Tablets 10 mcg<br>Vagifem® (Estradiol Vaginal Tablets) 10 mcg - Reference Listed Drug | Drug: Estradiol Vaginal Tablets 10 mcg<br> <br> * Other names: Vagifem®;|
| Placebo Comparator: Placebo<br>Placebo for the test product Estradiol Vaginal Tablets 10 mcg | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responders | A responder was defined as a subject with at least a 25% reduction from baseline in the sum of % basal/parabasal and % intermediate cells on vaginal cytology AND vaginal pH < 5.0 with a change from baseline vaginal pH of at least 0.5, where baseline values were collected at Visit 1 | Day 15 (1 day after the administration of the 14th dose of study treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Success | Treatment success was defined as a subject who achieved a score of 0 (none) or 1 (mild) at Visit 3 for the Most Bothersome Symptom (MBS) if her MBS was vaginal dryness, vaginal or vulvar irritation or itching, dysuria or vaginal pain associated with sexual activity, or a result of absence (0) at Visit 3 if her MBS was vaginal bleeding with sexual activity. | Day 15 |