Vulvar and Vaginal Atrophy
Conditions
Keywords
Vaginal Dryness, Vaginal and/or Vulvar Irritation/Itching, Dysuria, Vaginal Pain and Bleeding
Brief summary
The objectives of this study are to evaluate the therapeutic equivalence of the Test formulation, Estradiol Vaginal Cream 0.01% (Prasco, LLC) to the marketed product, Estrace® Cream (estradiol vaginal cream, 0.01%) in patients with vulvar and vaginal atrophy, and compare the safety of Test, Reference and Placebo treatments in patients with vulvar and vaginal atrophy.
Interventions
DRUGEstrace® Cream
Estrace® Cream
Estradiol Vaginal Cream
DRUGVehicle Cream
Vehicle Cream
Sponsors
Prasco LLC
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
1. Signed IRB-approved informed consent form that meets all criteria of current FDA regulations. 2. Postmenopausal females aged 30-75 years inclusive. Postmenopausal is defined as follows: 1. At least 6 months of spontaneous amenorrhea. 2. At least 6 weeks post-surgical bilateral oophorectomy, with or without hysterectomy. 3. Hysterectomy without oophorectomy if of age that the Investigator believes would have naturally reached 12 months of spontaneous amenorrhea if uterus had remained intact. 3. Patients with a serum Follicle Stimulating Hormone (FSH) level of ≥ 40 mIU/mL at Screening. 4. Have ≤ 5% superficial cells on vaginal smear cytology. 5. Have a vaginal pH \> 5.0. 6. At least one of the following patient self-assessed moderate to severe symptoms of VVA from the following list that is identified by the patient as being the most bothersome to her: * Vaginal Dryness * Vaginal and/or Vulvar Irritation/Itching * Dysuria * Vaginal Pain associated with sexual activity * Vaginal Bleeding associated with sexual activity (presence or absence) * Provided that patient is currently sexually active and plans to remain so throughout the study. 7. Have Normal Screening mammogram completed within 9 months before Screening in all patients \> 40 years old, with no findings that, in the opinion of the Investigator, would indicate any suspicion of breast malignancy. 8. Normal clinical breast examination at Screening. 9. Patients with an intact uterus (including patients who underwent a partial hysterectomy) must have a 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. 10. Patients with an intact uterus should have vaginal ultrasonography results within 3 months before Screening to confirm an inactive endometrial lining, defined as endometrial thickness \< 4 mm.
Exclusion criteria
1. 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. 2. Any clinically significant laboratory finding that, in the Investigator's opinion would contraindicate the use of estradiol or compromise patient safety. 3. Patients with known concurrent vaginal infections including but not limited to: Candida albicans, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhea or Gardnerella vaginalis. 4. Patients with active vaginal herpes simplex infection or have had an outbreak within 30 days before the Screening. 5. Patients with known, suspected or current history of carcinoma of the breast. 6. Patients with baseline systolic blood pressure of \> 150 mmHg and/or diastolic pressure \> 90 mmHg. 7. Any patient with past or current undiagnosed vaginal bleeding or significant risk factors for endometrial cancer. 8. Any history of estrogen-dependent neoplasia (e.g., endometrial cancer). 9. Patients with known, suspected or current history of hormone dependent tumor. 10. History of acute thrombophlebitis or thromboembolic disorder. 11. Any prescription treatment for vaginal dryness/irritation within 14 days before Screening or any over-the-counter or natural remedies within 7 days before Screening. 12. Any prescription treatment for bacterial or yeast infections within 30 days before Screening. 13. Fasting triglyceride levels \> 350 mg/dL. 14. History of radiation therapy or recent (within previous 6 weeks) surgical therapy to the vaginal or cervical areas. 15. Any known or suspected allergies that, in the Investigator's opinion, would compromise the safety of the patient. 16. Patients who have used vaginal hormonal products (rings, creams, gels) within the 7 days before Screening. 17. Patients who have used transdermal estrogen and/or progestin therapy within the 28 days before Screening. 18. Patients who have used oral estrogen and/or progestin therapy or intrauterine progestin therapy within the 56 days before Screening. 19. Patients who have used progestin implants or estrogen alone injectable drug therapy within the 3 month before Screening. 20. Patients who have used estrogen pellet therapy or progestin injectable drug therapy within 6 months before Screening. 21. History of significant alcohol abuse within 1 year prior to Screening or regular use of alcohol within 6 months before Screening (more than 14 units of alcohol per week \[1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol\]). 22. History of significant drug abuse within 1 year prior to Screening, use of soft drugs (such as marijuana) within 3 months before Screening, or hard drugs (such as cocaine, phencyclidine \[PCP\], crack, opioid derivatives including heroin, and amphetamine derivatives) within 1 year before Screening. 23. Use within 30 days of Screening with known strong CYP3A4 inducers or inhibitors that, in the opinion of the Investigator, may affect estrogen metabolism. Examples of strong CYP3A4 inhibitors are macrolide antibiotics such as clarithromycin and telithromycin; azole antifungals such as itraconazole and ketoconazole; antidepressants such as nefazodone; and foods such as grapefruit or grapefruit juice. Examples of strong CYP3A4 inducers are anticonvulsants such as carbamazepine and phenytoin; bactericidals such as rifampin and rifabutin; and natural health products such as St. John's wort. 24. Inability to understand the requirements of the study and the relative information or are unable or not willing to comply with the study protocol. 25. Receipt of any drug as part of a research study within 30 days before Screening. 26. Employees of the Investigator or research center or their immediate family members. 27. Patients who have participated in this study previously.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Efficacy Endpoint | Study Day 8 or Study Day 9 | The primary efficacy endpoint is the number of participants in each treatment group that were identified as Responders at the end of the treatment period evaluated on Day 8 or Day 9. A Responder was defined as a participant with at least a 25% reduction from baseline in the sum of % basal/parabasal + % 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Secondary Efficacy Endpoint | Study Day 8 or Study Day 9 | The secondary efficacy endpoint is the number of participants in each treatment group that are considered a Treatment Success at the end of the treatment period evaluated on Day 8 or Day 9. A Treatment Success is defined as a score of 0 or 1 on Day 8 or Day 9 for the symptom identified at baseline as the most bothersome. This evaluation will be based on (one) participant self-assessed symptom of VVA (vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, or vaginal pain associated with sexual activity) on a scale of 0 to 3 where 0 = none and 3 = severe. Evaluation of vaginal bleeding during sexual activity will be based on a score of 1 (presence) if it is identified by the participant as the most bothersome symptom at baseline and a score of 0 (absent) on Day 8 or Day 9. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Duration of Post-menopausal Status (Years) | Visit 1 (Day - 28 to Day -1) | Baseline Characteristic for Participants who reported Natural Cause for Menopause (Total n = 373 patients) with mean and standard deviation (SD) evaluated per Arm/Group at Visit 1 (Day -28 to Day -1) during Medical History and Demographics Screening |
Countries
United States
Participant flow
Recruitment details
A total of 540 participants were randomized at 26 investigative sites (medical clinic/research) located in the US. 215 participants were assigned to the test drug arm, 216 participants were assigned to the reference drug arm, and 109 participants were assigned to the placebo arm. The first subject was enrolled on 26-OCT-2017 and the last subject visit was 15-MAR-2018. The study duration was approximately 5 months.
Pre-assignment details
Following the 28-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 test Estradiol Vaginal Cream USP, 0.01%; Estrace Vaginal Cream USP, 0.01%; or Placebo test vehicle vaginal cream.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) Estradiol Vaginal Cream, USP, 0.01%, administered once daily for 7 days.
Intervention: Drug: Estradiol Vaginal Cream, USP, 0.01%
Estradiol Vaginal Cream: Estradiol Vaginal Cream | 215 |
| Active Comparator: Estrace® Cream Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01%), administered once daily for 7 days.
Intervention: Drug: Estrace® Cream (Estradiol Vaginal Cream, USP, 0.01%)
Estrace® Cream: Estrace® Cream | 216 |
| Placebo Comparator: Placebo (Test Vehicle Cream) Vaginal Cream Placebo (Test vehicle cream) Vaginal Cream, administered once daily for 7 days.
Intervention: Drug: Placebo (Test vehicle cream) Vaginal Cream
Vehicle Cream: Vehicle Cream | 109 |
| Total | 540 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Participant developed concurrent vaginal infection/illness | 4 | 1 | 0 |
| Overall Study | Participant did not administer 75-125% of intended dose | 0 | 3 | 0 |
| Overall Study | Participant did not complete Study Visit 3 within Day 8 - Day 9 window | 10 | 10 | 3 |
| Overall Study | Participant did not dose | 1 | 2 | 0 |
| Overall Study | Participant did not have at least one post-randomization evaluation | 0 | 1 | 0 |
| Overall Study | Participant did not meet all inclusion/exclusion criteria | 4 | 2 | 2 |
| Overall Study | Participant had a significant protocol deviation | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Active Comparator: Estrace® Cream | Total | Experimental: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) | Placebo Comparator: Placebo (Test Vehicle Cream) Vaginal Cream |
|---|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 6.2 | 61.0 years STANDARD_DEVIATION 5.9 | 61.2 years STANDARD_DEVIATION 5.5 | 61.2 years STANDARD_DEVIATION 6.1 |
| Dysuria Mild | 29 Participants | 80 Participants | 30 Participants | 21 Participants |
| Dysuria Moderate | 12 Participants | 31 Participants | 10 Participants | 9 Participants |
| Dysuria None | 174 Participants | 424 Participants | 173 Participants | 77 Participants |
| Dysuria Severe | 1 Participants | 5 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 34 Participants | 91 Participants | 34 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 182 Participants | 449 Participants | 181 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Most Bothersome Sign or Symptom Dysuria | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Most Bothersome Sign or Symptom Vaginal Bleeding during or after Sexual Activity | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Most Bothersome Sign or Symptom Vaginal Dryness | 131 Participants | 324 Participants | 130 Participants | 63 Participants |
| Most Bothersome Sign or Symptom Vaginal Pain during Sexual Activity | 70 Participants | 178 Participants | 71 Participants | 37 Participants |
| Most Bothersome Sign or Symptom Vaginal/Vulvar Irritation/Itching | 14 Participants | 36 Participants | 13 Participants | 9 Participants |
| Natural or Surgical Menopause Natural Menopause | 141 Participants | 373 Participants | 154 Participants | 78 Participants |
| Natural or Surgical Menopause Surgical Menopause | 75 Participants | 167 Participants | 61 Participants | 31 Participants |
| % of Basal/Parabasal Cells | 36.0 percent STANDARD_DEVIATION 36.9 | 38.9 percent STANDARD_DEVIATION 36.4 | 41.6 percent STANDARD_DEVIATION 36.1 | 39.3 percent STANDARD_DEVIATION 36 |
| % of Intermediate Cells | 62.8 percent STANDARD_DEVIATION 36.3 | 62.7 percent STANDARD_DEVIATION 34.8 | 57.4 percent STANDARD_DEVIATION 35.5 | 59.5 percent STANDARD_DEVIATION 35.4 |
| % of Superficial Cells | 1.1 percent STANDARD_DEVIATION 1.6 | 1.1 percent STANDARD_DEVIATION 1.5 | 1.1 percent STANDARD_DEVIATION 1.5 | 1.2 percent STANDARD_DEVIATION 1.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 7 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 28 Participants | 62 Participants | 25 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 182 Participants | 466 Participants | 185 Participants | 99 Participants |
| Region of Enrollment United States | 216 participants | 540 participants | 215 participants | 109 participants |
| Sex: Female, Male Female | 216 Participants | 540 Participants | 215 Participants | 109 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Vaginal Bleeding During or After Sexual Activity Absent | 136 Participants | 334 Participants | 131 Participants | 67 Participants |
| Vaginal Bleeding During or After Sexual Activity Not Reported | 49 Participants | 124 Participants | 52 Participants | 23 Participants |
| Vaginal Bleeding During or After Sexual Activity Present | 31 Participants | 82 Participants | 32 Participants | 19 Participants |
| Vaginal Dryness Mild | 6 Participants | 16 Participants | 7 Participants | 3 Participants |
| Vaginal Dryness Moderate | 114 Participants | 294 Participants | 127 Participants | 53 Participants |
| Vaginal Dryness None | 3 Participants | 4 Participants | 0 Participants | 1 Participants |
| Vaginal Dryness Severe | 93 Participants | 226 Participants | 81 Participants | 52 Participants |
| Vaginal Pain During Sexual Activity Mild | 6 Participants | 28 Participants | 11 Participants | 11 Participants |
| Vaginal Pain During Sexual Activity Moderate | 69 Participants | 150 Participants | 59 Participants | 22 Participants |
| Vaginal Pain During Sexual Activity None | 9 Participants | 25 Participants | 12 Participants | 4 Participants |
| Vaginal Pain During Sexual Activity Not Reported | 49 Participants | 124 Participants | 52 Participants | 23 Participants |
| Vaginal Pain During Sexual Activity Severe | 83 Participants | 213 Participants | 81 Participants | 49 Participants |
| Vaginal pH | 6.2 pH STANDARD_DEVIATION 0.7 | 6.2 pH STANDARD_DEVIATION 0.62 | 6.2 pH STANDARD_DEVIATION 0.7 | 6.2 pH STANDARD_DEVIATION 0.7 |
| Vaginal/Vulvar Irritation/Itching Mild | 49 Participants | 129 Participants | 53 Participants | 27 Participants |
| Vaginal/Vulvar Irritation/Itching Moderate | 54 Participants | 127 Participants | 45 Participants | 28 Participants |
| Vaginal/Vulvar Irritation/Itching None | 104 Participants | 259 Participants | 107 Participants | 48 Participants |
| Vaginal/Vulvar Irritation/Itching Severe | 9 Participants | 25 Participants | 10 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 215 | 0 / 216 | 0 / 109 |
| other Total, other adverse events | 66 / 215 | 59 / 216 | 23 / 109 |
| serious Total, serious adverse events | 0 / 215 | 1 / 216 | 0 / 109 |
Outcome results
Primary
The Primary Efficacy Endpoint
The primary efficacy endpoint is the number of participants in each treatment group that were identified as Responders at the end of the treatment period evaluated on Day 8 or Day 9. A Responder was defined as a participant with at least a 25% reduction from baseline in the sum of % basal/parabasal + % 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: Study Day 8 or Study Day 9
Population: Therapeutic Equivalence Between Experimental and Active Comparator Arms: Per Protocol (PP) Population Superiority over Placebo: Modified Intent-to-treat population (mITT, all randomized study participants who administered at least one dose of randomized study product and had a post-randomization evaluation)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) | The Primary Efficacy Endpoint | Equivalence: PP Population | 49 participants |
| Experimental: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) | The Primary Efficacy Endpoint | Superiority: mITT Population | 52 participants |
| Active Comparator: Estrace® Cream | The Primary Efficacy Endpoint | Equivalence: PP Population | 59 participants |
| Active Comparator: Estrace® Cream | The Primary Efficacy Endpoint | Superiority: mITT Population | 63 participants |
| Placebo Comparator: Placebo (Test Vehicle Cream) Vaginal Cream | The Primary Efficacy Endpoint | Superiority: mITT Population | 1 participants |
Comparison: Therapeutic equivalence was evaluated for both primary and secondary endpoints in the per-protocol (PP) population.90% CI: [-13, 2.8]
Comparison: Superiority of the Test and Reference products against the Placebo product for the primary endpoint was evaluated in the modified Intent-to-Treat (mITT) population using last observation carried forward (LOCF).p-value: <0.0001Cochran-Mantel-Haenszel
Comparison: Superiority of the Test and Reference products against the Placebo product for the primary endpoint was evaluated in the modified Intent-to-Treat (mITT) population using last observation carried forward (LOCF).p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
The Secondary Efficacy Endpoint
The secondary efficacy endpoint is the number of participants in each treatment group that are considered a Treatment Success at the end of the treatment period evaluated on Day 8 or Day 9. A Treatment Success is defined as a score of 0 or 1 on Day 8 or Day 9 for the symptom identified at baseline as the most bothersome. This evaluation will be based on (one) participant self-assessed symptom of VVA (vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, or vaginal pain associated with sexual activity) on a scale of 0 to 3 where 0 = none and 3 = severe. Evaluation of vaginal bleeding during sexual activity will be based on a score of 1 (presence) if it is identified by the participant as the most bothersome symptom at baseline and a score of 0 (absent) on Day 8 or Day 9.
Time frame: Study Day 8 or Study Day 9
Population: Therapeutic Equivalence Between Experimental and Active Comparator Arms: Per Protocol (PP) Population Superiority over Placebo: Modified Intent-to-treat population (mITT, all randomized study participants who administered at least one dose of randomized study product and had a post-randomization evaluation)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) | The Secondary Efficacy Endpoint | Equivalence: PP Population | 112 participants |
| Experimental: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) | The Secondary Efficacy Endpoint | Superiority: mITT Population | 122 participants |
| Active Comparator: Estrace® Cream | The Secondary Efficacy Endpoint | Equivalence: PP Population | 116 participants |
| Active Comparator: Estrace® Cream | The Secondary Efficacy Endpoint | Superiority: mITT Population | 127 participants |
| Placebo Comparator: Placebo (Test Vehicle Cream) Vaginal Cream | The Secondary Efficacy Endpoint | Superiority: mITT Population | 63 participants |
Comparison: Therapeutic equivalence was evaluated for both primary and secondary endpoints in the per-protocol (PP) population.90% CI: [-10.7, 6.7]
Comparison: Superiority of the Test and Reference products against the Placebo product for the secondary endpoint was evaluated in the modified Intent-to-Treat (mITT) population using last observation carried forward (LOCF).p-value: 0.8068Cochran-Mantel-Haenszel
Comparison: Superiority of the Test and Reference products against the Placebo product for the secondary endpoint was evaluated in the modified Intent-to-Treat (mITT) population using last observation carried forward (LOCF).p-value: 0.8003Cochran-Mantel-Haenszel
Other Pre-specified
Duration of Post-menopausal Status (Years)
Baseline Characteristic for Participants who reported Natural Cause for Menopause (Total n = 373 patients) with mean and standard deviation (SD) evaluated per Arm/Group at Visit 1 (Day -28 to Day -1) during Medical History and Demographics Screening
Time frame: Visit 1 (Day - 28 to Day -1)
Population: Participants who reported Natural Cause for Menopause during Medical History and Demographics Screening
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Estradiol Vaginal Cream, USP, 0.01% (Prasco LLC) | Duration of Post-menopausal Status (Years) | 11.1 years | Standard Deviation 6.4 |
| Active Comparator: Estrace® Cream | Duration of Post-menopausal Status (Years) | 11.4 years | Standard Deviation 6.5 |
| Placebo Comparator: Placebo (Test Vehicle Cream) Vaginal Cream | Duration of Post-menopausal Status (Years) | 12.3 years | Standard Deviation 7.6 |