Atrophic Vaginitis
Conditions
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.
Interventions
DRUGGeneric Estradiol Vaginal Cream USP, 0.01%
Vaginal cream, generic formulation of the brand product.
DRUGEstrace® Vaginal Cream USP, 0.01%
Vaginal cream, brand product.
DRUGVehicle Vaginal Cream
Vaginal cream, placebo. Has no active ingredient
Sponsors
Teva Pharmaceuticals USA
Actavis Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
30 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups | Up to Day 9 | Treatment comparison of the number of participants in the PP population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder. |
| 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 | Up to Day 9 | Treatment comparison of the number of participants in the mITT population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups | Up to Day 9 | The number of participants in the PP population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation was based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder. |
| 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 | Up to 9 months | The number of participants in the mITT Population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation is to be based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding. |
Countries
United States
Participant flow
Recruitment details
The populations for this study included the Safety Population, the modified Intent-to-Treat (mITT) population, and the Per-Protocol (PP) Population.
Pre-assignment details
Following the 14-day screening period, participants who continued to meet the inclusion/exclusion (I/E) criteria were randomly assigned to treatment on a 2:2:1 ratio of generic Estradiol Vaginal Cream United States Pharmacopoeia (USP), 0.01%; Estrace Vaginal Cream USP, 0.01%; or vehicle vaginal cream.
Participants by arm
| Arm | Count |
|---|---|
| Generic Estradiol Vaginal Cream USP, 0.01% Participants were to self-administer 2 g of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days. | 267 |
| Estrace Vaginal Cream USP, 0.01% Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days. | 262 |
| Vehicle Vaginal Cream Participants were to self-administer 2 g of vehicle vaginal cream once daily at approximately the same time of the day for 7 consecutive days. | 132 |
| Total | 661 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Outside of Visit Window | 4 | 4 | 1 |
Baseline characteristics
| Characteristic | Generic Estradiol Vaginal Cream USP, 0.01% | Estrace Vaginal Cream USP, 0.01% | Vehicle Vaginal Cream | Total |
|---|---|---|---|---|
| Age, Continuous | 59.5 Years STANDARD_DEVIATION 6.4 | 59.5 Years STANDARD_DEVIATION 6.5 | 60.8 Years STANDARD_DEVIATION 5.6 | 59.9 Years STANDARD_DEVIATION 6.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 79 Participants | 88 Participants | 42 Participants | 209 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 188 Participants | 174 Participants | 90 Participants | 452 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Percent of Basal/Parabasal Cells | 34.4 percent of cells STANDARD_DEVIATION 35.1 | 31.5 percent of cells STANDARD_DEVIATION 34.8 | 36.3 percent of cells STANDARD_DEVIATION 34.3 | 34.1 percent of cells STANDARD_DEVIATION 34.7 |
| Percent of Intermediate Cells | 64.7 percent of cells STANDARD_DEVIATION 34.5 | 67.5 percent of cells STANDARD_DEVIATION 34.3 | 62.8 percent of cells STANDARD_DEVIATION 33.9 | 65 percent of cells STANDARD_DEVIATION 34.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 3 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 25 Participants | 24 Participants | 10 Participants | 59 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 235 Participants | 232 Participants | 121 Participants | 588 Participants |
| Sex: Female, Male Female | 267 Participants | 262 Participants | 132 Participants | 661 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Vaginal pH | 6.2 pH STANDARD_DEVIATION 0.8 | 6.2 pH STANDARD_DEVIATION 0.8 | 6.1 pH STANDARD_DEVIATION 0.7 | 6.2 pH STANDARD_DEVIATION 0.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 267 | 0 / 262 | 0 / 132 |
| other Total, other adverse events | 63 / 267 | 74 / 262 | 25 / 132 |
| serious Total, serious adverse events | 0 / 267 | 1 / 262 | 0 / 132 |
Outcome results
Primary
Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups
Treatment comparison of the number of participants in the PP population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.
Time frame: Up to Day 9
Population: Participants who met I/E criteria, didn't develop a concurrent vaginal infection, completed Day 8 visit, and took 6-8 doses and didn't miss \>1 dose of study drug (PP Population). As pre-specified in the protocol, only the active groups (Generic Estradiol Vaginal Cream USP, 0.01% and Estrace Vaginal Cream USP, 0.01%) were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Generic Estradiol Vaginal Cream USP, 0.01% | Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups | 49 Participants |
| Estrace Vaginal Cream USP, 0.01% | Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups | 44 Participants |
Comparison: Therapeutic equivalence of the generic estradiol vaginal cream group to the Estrace Vaginal Cream group based on the primary endpoint was evaluated in the PP population.90% CI: [-5.8, 7.2]
Primary
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
Treatment comparison of the number of participants in the mITT population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5.
Time frame: Up to Day 9
Population: Participants in the PP population, administered at least 1 dose of study drug, and had a post-randomization evaluation (mITT Population). Participants who discontinued early for reasons other than efficacy were included in the mITT population using Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Generic Estradiol Vaginal Cream USP, 0.01% | 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 | 53 Participants |
| Estrace Vaginal Cream USP, 0.01% | 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 | 53 Participants |
| Vehicle Vaginal Cream | 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 | 0 Participants |
Comparison: Superiority of the generic estradiol vaginal cream group and the Estrace Vaginal Cream group to the vehicle vaginal cream group based on the primary endpoint was evaluated in the mITT population.p-value: <0.0001Cochran-Mantel-Haenszel
Comparison: Superiority of the generic estradiol vaginal cream group and the Estrace Vaginal Cream group to the vehicle vaginal cream group based on the primary endpoint was evaluated in the mITT population.p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups
The number of participants in the PP population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation was based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.
Time frame: Up to Day 9
Population: Participants who met I/E criteria, didn't develop a concurrent vaginal infection, completed Day 8 visit, and took 6-8 doses and didn't miss \>1 dose of study drug (PP Population). As pre-specified in the protocol, only the active groups (Generic Estradiol Vaginal Cream USP, 0.01% and Estrace Vaginal Cream USP, 0.01%) were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Generic Estradiol Vaginal Cream USP, 0.01% | Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups | 161 Participants |
| Estrace Vaginal Cream USP, 0.01% | Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups | 153 Participants |
Comparison: Therapeutic equivalence of the generic estradiol vaginal cream group to the Estrace Vaginal Cream group based on the secondary endpoint was evaluated in the PP population.90% CI: [-9, 6.2]
Secondary
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
The number of participants in the mITT Population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation is to be based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding.
Time frame: Up to 9 months
Population: Participants in the PP population, administered at least 1 dose of study drug, and had a post-randomization evaluation (mITT Population). Participants who discontinued early for reasons other than efficacy were included in the mITT population using LOCF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Generic Estradiol Vaginal Cream USP, 0.01% | 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 | 175 Participants |
| Estrace Vaginal Cream USP, 0.01% | 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 | 169 Participants |
| Vehicle Vaginal Cream | 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 | 80 Participants |
Comparison: Superiority of the generic estradiol vaginal cream group and the Estrace Vaginal Cream group to the vehicle vaginal cream group based on the secondary endpoint was evaluated in the mITT population.p-value: 0.2897Cochran-Mantel-Haenszel
Comparison: Superiority of the generic estradiol vaginal cream group and the Estrace Vaginal Cream group to the vehicle vaginal cream group based on the primary endpoint was evaluated in the mITT population.p-value: 0.4949Cochran-Mantel-Haenszel