Clinical trial NCT05617820: Study Comparing Estradiol Vaginal Inserts 4mcg To IMVEXXY ® (Estradiol Vaginal Inerts 4 mcg) In The Treatment Of Dyspareunia in Women With Vulvur and Vaginal Atrophy
Official title: A Randomized, Double-Blind, Placebo-Controlled, Parallel- Design, Multiple-Site Study to Evaluate the Therapeutic Equivalence of Estradiol Vaginal Inserts 4 mcg (Teva Pharmaceuticals, Inc.) With IMVEXXY® (Estradiol Vaginal Inserts) (TherapeuticsMD, Inc.) in the Treatment of Dyspareunia in Women With Vulvar and Vaginal Atrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Dyspareunia
Lead sponsor: Teva Pharmaceuticals USA
Sponsor class: INDUSTRY
First posted: 2022-11-16
Enrollment: 1050
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Randomized, double-blind, placebo-controlled, parallel-designed, multiple-site, bioequivalence study with clinical endpoints.


Eligibility criteria: Inclusion Criteria:

1. Signed, IRB approved informed consent that meets all criteria of current FDA and local regulations.
2. Females aged 40-75 years inclusive who are postmenopausal, with at least:

   1. 12 months of spontaneous amenorrhea (women \<55 year of age with history of hysterectomy without bilateral oophorectomy prior to natural menopause must have Serum follicle-stimulating hormone (FSH) level \> 40 mIU/mL); or
   2. 6 months of spontaneous amenorrhea with FSH levels \>40mIU/mL; or
   3. At least 6 weeks postsurgical bilateral oophorectomy
3. Have less than or equal to 5% superficial cells on vaginal cytological smear.
4. Vaginal pH \> 5.0.
5. Moderate to severe symptom of vaginal pain associated with sexual activity considered the most bothersome vaginal symptom (dyspareunia) of VVA by the patient at screening visit. (i.e., a VVA Symptom Self-Assessment Questionnaire score of 2 or 3) (Appendix B).
6. Women should be sexually active (for example, have sexual activity with vaginal penetration within approximately one month of screening visit).
7. Women should anticipate having sexual activity (with vaginal penetration) during the conduct of the study, and agree to at least one episode of sexual intercourse within study days 10-13.
8. Baseline systolic blood pressure should be no greater than 150 mm Hg and diastolic blood pressure no greater than 90 mm Hg.
9. Normal mammogram completed within 9 months before randomization and a normal clinical breast examination prior to randomization in the study.
10. Patients who have underwent complete Hysterectomy, or in the case of patients with an intact uterus (including patients who underwent a partial hysterectomy) the later must have:

    1. A documented papanicolaou (PAP) smear conducted within 12 months before randomization with no findings that the Investigator believes would contraindicate the use of topical vaginal estradiol.
    2. Documented vaginal ultrasonography results within 3 months before randomization to confirm an inactive endometrial lining, defined as endometrial thickness \<4mm.
11. In the opinion of the Investigator, the patient will comply with the protocol and has a high probability of completing the study.

Exclusion Criteria:

1. Premenopasual, perimenopausal, pregnant or lactating patient or planning a pregnancy.
2. Significant history or current evidence of chronic infectious disease, system disorder, organ disorder 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.
3. Any clinically significant laboratory finding that, in the Investigator's opinion would contraindicate the use of estradiol or compromise patients' safety.
4. Significant history of cholestatic jaundice, hypertension, coronary heart disease or other serious heart problems, uncontrolled diabetes, hypercholesterolemia, hypercalcemia, hypoparathyroidism, hypertriglyceridemia, systemic lupus erythematosus, renal impairment, residual endometriosis posthysterectomy, asthma, epilepsy, migraine, porphyria, hepatic hemangiomas 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.
5. History of Protein C, Protein S, or antithrombin deficiency, or other thrombophilic disorder.
6. Patients with known concurrent vaginal infections including but not limited to: Candida albicans, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhea or Gardnerella vaginalis.
7. Patients with active vaginal herpes simplex infection or have had an outbreak within 40 days before Screening
8. History of sexual abuse that in the opinion of the investigator may interfere with the patient's assessment of vaginal pain with sexual activity.
9. Past or current diagnosis of endometrial hyperplasia.
10. Patients with known, suspected or current history of carcinoma of the breast.
11. Any patients with past or current undiagnosed vaginal bleeding or significant risk factors for endometrial cancer.
12. History of estrogen-dependent neoplasia (e.g., endometrial cancer).
13. Any patients with hypersensitivity to estrogens.
14. Liver impairment or disease or kidney dysfunction or disorder (e.g., chronic renal failure or hepatitis C).
15. History of thrombophlebitis, thrombosis, or thromboembolic disorders.
16. History of cerebrovascular accident, stroke, or transient ischemic attack.
17. History of Myocardial infarction or ischemic heart disease.
18. History or active presence of endocrine disease (except for controlled hypo- or hyper-thyroidism or controlled non-insulin dependent diabetes mellitus). Patients who are on a stable thyroid medication prior to the study should have normal baseline thyroid function test results and expect not to have to change thyroid hormone regimen during the study.
19. Any clinically significant abnormalities on screening physical exam, assessments, ECG, or laboratory tests such as:

    1. Vulvar or vaginal inflammatory condition such as a contact or allergic dermatitis, lichen sclerosis, or other pathological findings.
    2. Presence of suspicious vulvar or vaginal lesions for dysplasia, malignancy, or other pathology other than atrophy.
    3. History of active or chronic pelvic pain.
    4. Painful genital warts or localized areas of ulceration.
    5. Interstitial cystitis.
    6. Unresolved findings suspicious for malignancy on the breast exam; incomplete mammogram result or unresolved findings suggestive of malignant changes or findings requiring follow-up on the pre-study mammogram.
    7. Patients with an intact uterus who have an endometrial thickness of 4mm or greater.
20. Any prescription treatment for vaginal dryness/irritation within 2 weeks before screening or any over the counter or natural remedies, vaginal lubricants or moisturizers within 1 week before screening.
21. Taking inducers of CYP3A4 such as St. John's wort, anticonvulsants, phenylbutazone, rifampin, rifabutin, nevirapine and efavirenz.
22. Taking inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, nelfinavir and grapefruit juice.
23. Fasting triglyceride levels \> 350 mg/dL.
24. History of radiation therapy or recent (within previous 6 weeks) surgical therapy to the vaginal or cervical areas.
25. Any known or suspected allergies that in the Investigator's opinion would compromise the safety of the patient.
26. Patients who have used vaginal hormonal products (i.e. rings, creams, gels) within the 4 weeks before Screening.
27. Patients who have used transdermal estrogen and/or progestin therapy within the 4 weeks before Screening.
28. Patients who have used oral estrogen, progestin, androgen or selective estrogen receptor modular (SERM) containing drug products within 8 weeks before Screening visit.
29. Intrauterine progestin therapy within 8 weeks before Screening.
30. Use of an intrauterine device within 12 weeks before screening visit.
31. Patients who have used estrogen pellet therapy or progestin implants/ injectable drug therapy within the 6 months before Screening.
32. Patients who have engaged in sexual intercourse or used vaginal douching within 24 hours of the screening visit.
33. Inability to understand the requirements of the study and the relative information or are unable or not willing to comply with the study protocol.
34. Patients who are unable or unwilling to give informed consent.
35. Current history of heavy smoking (more than 15 cigarettes per day) or use of e-cigarettes.
36. Current use of marijuana.
37. Recent history of known alcohol or drug abuse, within one year start of the study.
38. Employees of the Investigator or research center or their immediate family members.
39. Receipt of any drug as part of a research study within 60 days before Screening.
40. Previous participation in this study.

Primary outcomes:
measure: Responder
timeFrame: 15 days
measure: Change in Most Bothersome Symptom
timeFrame: 15 days
Secondary outcomes:
measure: Treatment Success in Most bothersome symptom
timeFrame: 15 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Site 10112
state: Alabama
city: Chandler
country: United States
facility: Site 10146
state: Arizona
city: Sacramento
country: United States
facility: Site 10103
state: California
city: Sacramento
country: United States
facility: Site 10124
state: California
city: San Diego
country: United States
facility: Site 10135
state: California
city: Milford
country: United States
facility: Site 10136
state: Connecticut
city: Edgewater
country: United States
facility: Site 10130
state: Florida
city: Hialeah
country: United States
facility: Site 10123
state: Florida
city: Lake Worth
country: United States
facility: Site 10139
state: Florida
city: Leesburg
country: United States
facility: Site 10115
state: Florida
city: Maitland
country: United States
facility: Site 10138
state: Florida
city: Miami Lakes
country: United States
facility: Site 10107
state: Florida
city: Miami Lakes
country: United States
facility: Site 10144
state: Florida
city: Miami Springs
country: United States
facility: Site 10101
state: Florida
city: New Port Richey
country: United States
facility: Site 10106
state: Florida
city: Oldsmar
country: United States
facility: Site 10143
state: Florida
city: Ormond Beach
country: United States
facility: Site 10129
state: Florida
city: Palm Harbor
country: United States
facility: Site 10116
state: Florida
city: Sarasota
country: United States
facility: Site 10117
state: Florida
city: Sunrise
country: United States
facility: Site 10121
state: Florida
city: Tampa
country: United States
facility: Site 10140
state: Florida
city: West Palm Beach
country: United States
facility: Site 10119
state: Florida
city: Norcross
country: United States
facility: Site 10113
state: Georgia
city: Wichita
country: United States
facility: Site 10104
state: Kansas
city: Marrero
country: United States
facility: Site 10128
state: Louisiana
city: Metairie
country: United States
facility: Site 10109
state: Louisiana
city: New Orleans
country: United States
facility: Site 10122
state: Louisiana
city: Saginaw
country: United States
facility: Site 10105
state: Michigan
city: Las Vegas
country: United States
facility: Site 10111
state: Nevada
city: North Las Vegas
country: United States
facility: Site 10147
state: Nevada
city: Lawrenceville
country: United States
facility: Site 10126
state: New Jersey
city: New Bern
country: United States
facility: Site 10137
state: North Carolina
city: New Bern
country: United States
facility: Site 10145
state: North Carolina
city: Philadelphia
country: United States
facility: Site 10134
state: Pennsylvania
city: Upper Saint Clair
country: United States
facility: Site 10102
state: Pennsylvania
city: North Charleston
country: United States
facility: Site 10110
state: South Carolina
city: Chattanooga
country: United States
facility: Site 10118
state: Tennessee
city: Beaumont
country: United States
facility: Site 10142
state: Texas
city: Fort Worth
country: United States
facility: Site 10120
state: Texas
city: Houston
country: United States
facility: Site 10141
state: Texas
city: Norfolk
country: United States
facility: Site 10108
state: Virginia
city: Seattle
country: United States
facility: Site 10154
state: Washington
city: Santa Tecla
country: El Salvador
facility: Site 10148
state: La Libertad
city: San Salvador
country: El Salvador
facility: Site 10149
city: San Pedro Sula
country: Honduras
facility: Site 10151
city: San Pedro Sula
country: Honduras
facility: Site 10153
city: San Pedro Sula
country: Honduras
facility: Site 10150
city: San Pedro Sula
country: Honduras
facility: Site 10152
Study officials:
affiliation: Teva Pharmaceuticals USA
name: C Dias
role: STUDY_DIRECTOR
References: