Clinical trial NCT03294538: Study to Evaluate Equivalence of Estradiol Vaginal Cream 0.01% to Estrace® Cream 0.01% in Atrophic Vaginitis
Official title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the Therapeutic Equivalence of Estradiol Vaginal Cream USP, 0.01% (Teva Pharmaceuticals, USA) to Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Atrophic Vaginitis
Lead sponsor: Actavis Inc.
Sponsor class: INDUSTRY
Collaborators: name: Teva Pharmaceuticals USA
First posted: 2017-09-27
Enrollment: 663
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 objectives of this study were to evaluate the therapeutic equivalence of the Test formulation, generic Estradiol Vaginal Cream United States Pharmacopoeia (USP), 0.01% (Teva Pharmaceuticals, United States of America) to the marketed product, Estrace® Cream estradiol vaginal cream USP, 0.01% (Warner Chilcott) in participants with atrophic vaginitis; to demonstrate the superiority of the Test and Reference (active) treatments over Placebo (vehicle) cream in participants with atrophic vaginitis; and to compare the safety of Test, Reference, and Placebo treatments in participants with atrophic vaginitis.

Detailed description: Systemic (oral or transdermal patch administration) estrogen therapies have been shown to effectively treat symptoms of atrophic vaginitis but bear undesirable side effects including increased risk of heart attacks, stroke, endometrial cancer, and breast cancer. Topical therapies (creams and transvaginal delivery systems) provide low doses of estrogen to the vaginal mucosa to provide local relief for the symptoms of atrophic vaginitis, while reducing the unwanted side effects associated with systemic delivery systems. Low dose, topical estrogen therapy is considered most appropriate and convenient for the treatment of vaginal symptoms associated with menopause, particularly when other symptoms including bone loss or vasomotor dysfunction do not need to be targeted.

Eligibility criteria: Inclusion Criteria:

* Signed Informed Consent Form (ICF) that meets all criteria of current Food and Drug Administration (FDA) regulations.
* Females aged 30-75 years inclusive who are postmenopausal, defined as follows:
* At least 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) level of \>40 milli-international units per milliliter (mIU/mL); at least 6 weeks post-surgical bilateral oophorectomy, with or without hysterectomy; or hysterectomy without oophorectomy if of age that the Investigator believes would have been naturally reached 12 months of spontaneous amenorrhea.
* Vaginal pH \>5.0.
* At least 1 of the following participant self-assessed moderate to severe symptoms of vulvar and vaginal atrophy (VVA) from the following list that is identified by the participant as being most bothersome to her:

  1. Vaginal Dryness
  2. Vaginal and/or vulvar irritation/itching
  3. Dysuria
  4. Vaginal pain or bleeding associated with sexual activity, provided that participant is currently sexually active and plans to remain so throughout study.
* "Normal" Screening mammogram completed within 9 months prior to Screening in all participants \>40 years old.
* Normal clinical breast examination at the Screening Visit.
* Documented papanicolaou (PAP) smear conducted within the previous 12 months with no findings that the Investigator believes would contraindicate the use of topical vaginal estradiol.
* Participants with an intact uterus should have vaginal ultrasonography results to confirm an inactive endometrial lining, defined as endometrial thickness less than 4 millimeters (mm).

Exclusion Criteria:

1. Females younger than 30 years of age or older than 75 years of age.
2. Participants with a Serum follicle-stimulating hormone (FSH) level of ≤40 mIU/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 participant at undue risk by participation or could jeopardize the integrity of the study evaluations.
6. Participants with an intact uterus should have vaginal ultrasonography results to confirm an inactive endometrial lining. Participants with an endometrial thickness equal to or greater than 4 mm.
7. Documented PAP smear conducted within the previous 12 months with findings that the Investigator believes would contraindicate the use of topical vaginal estradiol.
8. Participants with known concurrent vaginal infections including but not limited to:

   Candida albicans, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhea, or Gardnerella vaginalis.
9. Participants with active vaginal herpes simplex infection or have had an outbreak within 30 days of the first dosing day.
10. Participants with known, suspected, or current history of carcinoma of the breast. All participants over the age of 40 must have had a mammogram performed within 9 months of the study start and all participants will have a physical breast exam performed at Screening.
11. Participants with known, suspected or current history of hormone dependent tumor.
12. Participants with baseline systolic blood pressure of \>150 millimetres of mercury (mmHg) and/or diastolic pressure \>90 mmHg.
13. Any participant with undiagnosed vaginal bleeding or significant risk factors for endometrial cancer.
14. Any history of estrogen-dependent neoplasia (for example, endometrial cancer).
15. History of acute thrombophlebitis or thromboembolic disorder.
16. Any current or recent (within the previous 6 months) genital bleeding of unknown etiology.
17. Any prescription treatment or over-the-counter (OTC) or natural remedies for vaginal dryness/irritation within 28 days of Screening. Products used for lubrication during sexual intercourse within 7 days of Screening.
18. Participants whose fasting triglyceride levels are greater than 350 mg/dL.
19. Any participant with a history of radiation therapy or recent (within previous 6 weeks) surgical therapy to the vaginal or cervical areas.
20. Any known or suspected allergies that in the Investigator's opinion would compromise the safety of the participant.
21. Participants who have used vaginal hormonal products (rings, creams, gels) within the 28 days prior to Screening.
22. Any participant who has used transdermal estrogen and/or progestin therapy within the 28 days prior to Screening.
23. Participants who have used oral estrogen and/ or progestin therapy or intrauterine progestin therapy within the 56 days prior to Screening.
24. Participants who have used progestin implants or estrogen alone injectable drug therapy within the 3 months before Screening.
25. Participants who have used estrogen pellet therapy or progestin injectable drug therapy within the 6 months before Screening.
26. Participants who, in the opinion of the Investigator, would be non-compliant with the requirements of the study protocol.
27. Participants who are unable or unwilling to give informed consent.
28. Receipt of any drug as part of a research study within 30 days prior to Screening.
29. Participants who have participated in this study previously.

Primary outcomes:
measure: Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups
timeFrame: Up to Day 9
measure: Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups
timeFrame: Up to Day 9
Secondary outcomes:
measure: Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups
timeFrame: Up to Day 9
measure: Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups
timeFrame: Up to 9 months
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Site Number 44
state: Arizona
city: Tucson
country: United States
facility: Site Number 17
state: Arizona
city: La Mesa
country: United States
facility: Site Number 31
state: California
city: Sacramento
country: United States
facility: Site Number 11
state: California
city: San Diego
country: United States
facility: Site Number 05
state: California
city: San Diego
country: United States
facility: Site Number 15
state: California
city: Colorado Springs
country: United States
facility: Site Number 25
state: Colorado
city: Denver
country: United States
facility: Site Number 01
state: Colorado
city: Denver
country: United States
facility: Site Number 14
state: Colorado
city: New London
country: United States
facility: Site Number 18
state: Connecticut
city: Jupiter
country: United States
facility: Site Number 06
state: Florida
city: Lake Worth
country: United States
facility: Site Number 13
state: Florida
city: Miami Lakes
country: United States
facility: Site Number 30
state: Florida
city: Miami
country: United States
facility: Site Number 27
state: Florida
city: Miami
country: United States
facility: Site Number 40
state: Florida
city: Miami
country: United States
facility: Site Number 20
state: Florida
city: Miami
country: United States
facility: Site Number 39
state: Florida
city: Miami
country: United States
facility: Site Number 38
state: Florida
city: New Port Richey
country: United States
facility: Site Number 08
state: Florida
city: Ormond Beach
country: United States
facility: Site Number 03
state: Florida
city: Port Saint Lucie
country: United States
facility: Site Number 45
state: Florida
city: Saint Petersburg
country: United States
facility: Site Number 19
state: Florida
city: Sarasota
country: United States
facility: Site Number 10
state: Florida
city: West Palm Beach
country: United States
facility: Site Number 02
state: Florida
city: Roswell
country: United States
facility: Site Number 29
state: Georgia
city: Savannah
country: United States
facility: Site Number 22
state: Georgia
city: Wichita
country: United States
facility: Site Number 21
state: Kansas
city: Metairie
country: United States
facility: Site Number 33
state: Louisiana
city: Kalamazoo
country: United States
facility: Site Number 16
state: Michigan
city: Saginaw
country: United States
facility: Site Number 34
state: Michigan
city: Lincoln
country: United States
facility: Site Number 35
state: Nebraska
city: Lawrenceville
country: United States
facility: Site Number 12
state: New Jersey
city: Plainsboro
country: United States
facility: Site Number 26
state: New Jersey
city: Raleigh
country: United States
facility: Site Number 36
state: North Carolina
city: Winston-Salem
country: United States
facility: Site Number 04
state: North Carolina
city: Winston-Salem
country: United States
facility: Site Number 37
state: North Carolina
city: Columbus
country: United States
facility: Site Number 07
state: Ohio
city: Englewood
country: United States
facility: Site Number 24
state: Ohio
city: West Chester
country: United States
facility: Site Number 28
state: Ohio
city: Bluffton
country: United States
facility: Site Number 23
state: South Carolina
city: Mount Pleasant
country: United States
facility: Site Number 41
state: South Carolina
city: Myrtle Beach
country: United States
facility: Site Number 43
state: South Carolina
city: Dallas
country: United States
facility: Site Number 32
state: Texas
city: Seattle
country: United States
facility: Site Number 09
state: Washington
Study officials:
affiliation: Teva Pharmaceuticals USA
name: Study Director
role: STUDY_DIRECTOR
References: