A Study Comparing Estradiol Vaginal Cream to Estrace® Cream in Females With Atrophic Vaginitis

Sponsor
Alvogen Pine Brook LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT02995694
Collaborator
(none)
535
3
9

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the therapeutic equivalence of Alvogen's estradiol vaginal cream to Estrace® cream and superiority of both products to placebo. The protocol describes a randomized, double-blind, multi-dose, placebo-controlled, parallel study of a 7 day treatment.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

This randomized, double-blind, placebo-controlled, parallel group, multiple-site study was designed to evaluate the therapeutic efficacy and safety of a generic Estradiol Vaginal Cream USP, 0.01% (Alvogen Pine Brook LLC) compared to the FDA Reference Listed Drug (RLD), Estrace® (estradiol vaginal cream USP, 0.01%, Warner Chilcott) in patients with atrophic vaginitis. Additionally, both the Test and the RLD formulations were tested for superiority against a Placebo.

Following the 14-day screening period, patients who continued to meet the inclusion/exclusion criteria were randomized in a 2:2:1 ratio (Test: Reference: Placebo) for 7 days of treatment.

Five hundred and thirty-five (535) patients were randomized to one of the three study products as follows:

  • Test: Estradiol Vaginal Cream USP, 0.01% (Alvogen Pine Brook LLC)

  • Reference: Estrace® (estradiol vaginal cream USP, 0.01%) (Warner Chilcott)

  • Placebo: Test product vehicle cream (Alvogen Pine Brook LLC)

Patients completed up to three clinic visits as follows:
  • Visit 1 - Screening: Day -14 to Day -1

  • Visit 2 - Randomization: Day 1

  • Visit 3 - End of Study: Day 8, maximum Day 10

Study product was self-administered by the patient for 7 days according to the dosing instructions provided. Each patient was required to dose once daily at approximately the me of day for 7 consecutive days.

Study Design

Study Type:
Interventional
Actual Enrollment :
535 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Other
Official Title:
Clinical Endpoint Therapeutic Equivalence Multi-Site Study Comparing Estradiol Vaginal Cream (0.01%; Alvogen Pine Brook LLC.) to Estrace® Cream (0.01%; Warner Chilcott) in Postmenopausal Females With Atrophic Vaginitis
Actual Study Start Date :
Mar 1, 2016
Actual Primary Completion Date :
Dec 1, 2016
Actual Study Completion Date :
Dec 1, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Test

Estradiol Vaginal Cream

Drug: Estradiol
Estradiol Vaginal Cream
Other Names:
  • Estadiol Vaginal Cream
  • Active Comparator: Reference.

    Estrace Vaginal Cream

    Drug: Reference
    Estrace Vaginal Cream
    Other Names:
  • Topical Vaginal Cream
  • Placebo Comparator: Placebos

    Placebo with no active pharmaceutical ingredients. Topical vaginal cream

    Drug: Placebos
    Placebo with no active pharmaceutical ingredients. Topical vaginal cream
    Other Names:
  • Topical Vaginal Cream
  • Outcome Measures

    Primary Outcome Measures

    1. Vaginal Cytology [Day 8]

      Number of patients in PP population identified as responders at end of the study.

    Secondary Outcome Measures

    1. Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy [Day 8]

      Number of participants with the most bothersome vulvar and/or vaginal atrophy symptom treatment success at end of study. A "Treatment Success" was defined as a score of 0 or 1 at Day 8 (maximum Day 10) for the symptom identified at baseline as the most bothersome. This evaluation was based on patient self-assessed symptoms of VVA on a scale of 0 to 3 where 0 = none, 1 = mild, 2 = moderate, and 3 = severe.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    30 Years to 75 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Signed Informed Consent that meets all criteria of current FDA regulations

    2. Females age: 30-75 years old inclusive who are postmenopausal.

    3. Postmenopausal defined as at least 12 months of spontaneous amenorrhea or at least 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml or at least 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. Hysterectomy without oophorectomy if of age that investigator believes would have naturally reached 12 months of spontaneous amenorrhea.

    4. Baseline evaluation requirements:

    • ≤5% superficial cells on vaginal smear cytology

    • Vaginal pH > 5.0

    • At least one patient self-assessed moderate to severe symptom of vulvar and/or vaginal atrophy (VVA) from the following list that is identified by the subject:

    • Vaginal dryness

    • Vaginal and/or vulvar irritation/itching

    • Dysuria

    • Vaginal pain associated with sexual activity*

    • Vaginal bleeding associated with sexual activity (absence vs. presence)* *provided that patient is currently sexually active and plans to remain so throughout study.

    1. Normal breast exam at screening and mammogram completed within 9 months prior to screening in patients >40 years old.

    2. For women with an intact uterus, an endometrial thickness < 4 mm as determined by vaginal ultrasonography.

    3. Documented PAP smear conducted within previous 12 months with no findings that the Investigator believes would contraindicate the use of topical vaginal estradiol

    Exclusion Criteria:
    1. Females younger than 30 years of age or older than 75 years of age

    2. Patients with a serum FSH level of ≤ 40mIU/ml at screening.

    3. Greater than 5% superficial cells on vaginal cytology.

    4. Vaginal pH ≤ 5

    5. Significant history or current evidence of chronic infectious disease, system disorder, organ disorder (including significant liver/kidney impairment) or other medical condition that in the Investigator's opinion would place the study patient at undue risk by participation or could jeopardize the integrity of the study evaluations.

    6. Patients with an intact uterus should have vaginal ultrasonography results to confirm an inactive endometrial lining. Patients with an endometrial thickness equal to or greater than 4mm should be excluded.

    7. Patients with known, suspected or current history of carcinoma of the breast. All patients over the age of 40 must have had a mammogram performed within 9 months of the study start and all patients will have a physical breast exam performed at screening.

    8. Patients with baseline systolic blood pressure of > 150mm Hg and/or diastolic pressure

    90 mm Hg

    1. Any patient with undiagnosed vaginal bleeding or significant risk factors for endometrial cancer.

    2. Any history of estrogen-dependent neoplasia (e.g., endometrial cancer).

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Alvogen Pine Brook LLC

    Investigators

    • Study Chair: Meena Venugopal, Ph.D., Alvogen Pine Brook LLC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Alvogen Pine Brook LLC
    ClinicalTrials.gov Identifier:
    NCT02995694
    Other Study ID Numbers:
    • 71462901
    First Posted:
    Dec 16, 2016
    Last Update Posted:
    Dec 1, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Test Reference. Placebos
    Arm/Group Description Estradiol Vaginal Cream Estradiol: Estradiol Vaginal Cream Estrace Vaginal Cream Reference: Estrace Vaginal Cream Placebo with no active pharmaceutical ingredients. Topical vaginal cream Placebos: Placebo with no active pharmaceutical ingredients. Topical vaginal cream
    Period Title: Overall Study
    STARTED 215 211 109
    COMPLETED 181 183 94
    NOT COMPLETED 34 28 15

    Baseline Characteristics

    Arm/Group Title Estradiol Vaginal Cream Estrace Vaginal Cream Placebo Total
    Arm/Group Description Estradiol Vaginal Cream, 0.01%, administered once daily for 7 days. Estradiol Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days) Estrace Vaginal Cream, 0.01%, administered once daily for 7 days. Estrace Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days) Placebo Cream, administered once daily for 7 days. Placebo Cream, (1 x 2 g for 7 days) Total of all reporting groups
    Overall Participants 181 183 94 458
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    167
    92.3%
    172
    94%
    89
    94.7%
    428
    93.4%
    >=65 years
    14
    7.7%
    11
    6%
    5
    5.3%
    30
    6.6%
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    59.0
    59.4
    59.9
    59.4
    Sex: Female, Male (Count of Participants)
    Female
    181
    100%
    183
    100%
    94
    100%
    458
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    62
    34.3%
    67
    36.6%
    30
    31.9%
    159
    34.7%
    Not Hispanic or Latino
    119
    65.7%
    116
    63.4%
    64
    68.1%
    299
    65.3%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    2
    1.1%
    2
    1.1%
    1
    1.1%
    5
    1.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    14
    7.7%
    25
    13.7%
    7
    7.4%
    46
    10%
    White
    165
    91.2%
    155
    84.7%
    85
    90.4%
    405
    88.4%
    More than one race
    0
    0%
    0
    0%
    1
    1.1%
    1
    0.2%
    Unknown or Not Reported
    0
    0%
    1
    0.5%
    0
    0%
    1
    0.2%
    Region of Enrollment (Count of Participants)
    United States
    181
    100%
    183
    100%
    94
    100%
    458
    100%

    Outcome Measures

    1. Primary Outcome
    Title Vaginal Cytology
    Description Number of patients in PP population identified as responders at end of the study.
    Time Frame Day 8

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Test Reference. Placebos
    Arm/Group Description Estradiol Vaginal Cream Estradiol: Estradiol Vaginal Cream Estrace Vaginal Cream Reference: Estrace Vaginal Cream Placebo with no active pharmaceutical ingredients. Topical vaginal cream Placebos: Placebo with no active pharmaceutical ingredients. Topical vaginal cream
    Measure Participants 181 183 94
    Number [participants]
    29
    16%
    19
    10.4%
    0
    0%
    2. Secondary Outcome
    Title Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy
    Description Number of participants with the most bothersome vulvar and/or vaginal atrophy symptom treatment success at end of study. A "Treatment Success" was defined as a score of 0 or 1 at Day 8 (maximum Day 10) for the symptom identified at baseline as the most bothersome. This evaluation was based on patient self-assessed symptoms of VVA on a scale of 0 to 3 where 0 = none, 1 = mild, 2 = moderate, and 3 = severe.
    Time Frame Day 8

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Estradiol Vaginal Cream Reference Placebo
    Arm/Group Description Estradiol Vaginal Cream, 0.01%, administered once daily for 7 days. Estradiol Vaginal Cream, 0.01%: Estradiol Vaginal Cream, 0.01% (1 x 2 g for 7 days) Estrace Vaginal Cream Placebo arm
    Measure Participants 181 183 94
    Count of Participants [Participants]
    115
    63.5%
    114
    62.3%
    0
    0%

    Adverse Events

    Time Frame 9 months
    Adverse Event Reporting Description There was one SAE, a death, reported for a subject during screening who had not yet been randomized into the study.
    Arm/Group Title Test Reference. Placebos
    Arm/Group Description Estradiol Vaginal Cream Estradiol: Estradiol Vaginal Cream Estrace Vaginal Cream Reference: Estrace Vaginal Cream Placebo with no active pharmaceutical ingredients. Topical vaginal cream Placebos: Placebo with no active pharmaceutical ingredients. Topical vaginal cream
    All Cause Mortality
    Test Reference. Placebos
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/215 (0%) 0/211 (0%) 0/109 (0%)
    Serious Adverse Events
    Test Reference. Placebos
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/215 (0%) 0/211 (0%) 0/109 (0%)
    Other (Not Including Serious) Adverse Events
    Test Reference. Placebos
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 88/215 (40.9%) 85/211 (40.3%) 30/109 (27.5%)
    Gastrointestinal disorders
    Gastrointestinal 36/215 (16.7%) 36/211 (17.1%) 20/109 (18.3%)
    Nervous system disorders
    Nervous System Disorders 13/215 (6%) 19/211 (9%) 5/109 (4.6%)
    Psychiatric disorders
    Psychiatric disorders 3/215 (1.4%) 3/211 (1.4%) 0/109 (0%)
    Reproductive system and breast disorders
    Breast Tenderness 36/215 (16.7%) 37/211 (17.5%) 5/109 (4.6%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Meena Venugopal
    Organization Alvogen Pine Brook
    Phone 973-532-7824
    Email meena.venugopal@alvogen.com
    Responsible Party:
    Alvogen Pine Brook LLC
    ClinicalTrials.gov Identifier:
    NCT02995694
    Other Study ID Numbers:
    • 71462901
    First Posted:
    Dec 16, 2016
    Last Update Posted:
    Dec 1, 2021
    Last Verified:
    Nov 1, 2021