Atrophic Vaginitis
Conditions
Keywords
vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain and bleeding associated with sexual activity, vaginal atrophy
Brief summary
The purpose of this study is to determine the therapeutic equivalence of Mylan'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.
Interventions
DRUGEstradiol Vaginal Cream, 0.01%
Estradiol Vaginal Cream, 0.01% (1 x 2g for 7 days)
DRUGEstrace® 0.01% cream
Estrace® 0.01% vaginal cream ( 1 x 2g for 7 days)
Placebo Vaginal Cream ( 1 x 2 g for 7 days)
Sponsors
Mylan Pharmaceuticals Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
1. Capable of providing informed consent. 2. Age: 40-70 years old. 3. Sex: Female 4. 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. 5. Weight: At least 48 kg with all subjects having a Body Mass Index less than or equal to 38 kg/m2 but greater than or equal to 19 kg/m2. 6. 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) 7. All subjects should be judged to be eligible for participation in this study by the principal or sub-investigator physician during a pre-study medical evaluation performed within 28 days of the initial dose of study medication which will include: 1. a normal or non-clinically significant physical examination, including vital signs 2. a normal or non-clinically significant pelvic examination that was consistent with hypoestrogenemia 3. a normal or non-clinically significant breast exam and mammogram 4. a normal or non-clinically significant ASCUS Papanicolaou (Pap) smear that is negative for HPV for subjects with an intact uterus and cervix 5. within normal limits or non-clinically significant laboratory evaluation results (unless otherwise noted in the
Exclusion criteria
) for the following tests: * Serum Chemistry * Hematology * Coagulogram * Urinalysis 6. normal or non-clinically significant 12- Lead ECG. 7. negative urine drug screen including amphetamine, barbiturates, benzodiazepines, cannabinoid, cocaine, opiates, methadone and phencyclidine with the following exceptions: positive tests for amphetamines, barbiturates, benzodiazepines, or opiates may be allowed provided the subject has a valid prescription and is on a stable regimen that complies with
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Endpoint (Vaginal Cytology + Vaginal pH) Equivalence | Study Day 8 | Treatment comparison of the proportion of patients in the Per Protocol (PP) population who received either Estradiol Vaginal Cream or Estrace® that were identified as responders at the end of the treatment period on Study Day 8. A responder was defined as a patient 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. |
| Primary Endpoint (Vaginal Cytology + Vaginal pH) Comparison of Active Treatments to Placebo | Study Day 8 | Treatment comparison of the proportion of patients in the Per Protocol (PP) population who received either Estradiol Vaginal Cream, Estrace®, or Placebo that were identified as responders at the end of the treatment period on Study Day 8. A responder was defined as a patient 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Equivalence | Day 8 | Evaluation and comparison between Estradiol Vaginal Cream and Estrace® treatment groups of the change from baseline in the most bothersome vulvar and/or vaginal atrophy symptom including vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, or vaginal bleeding associated with sexual activity as identified by each subject. A score ≤ 1 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment success. A score ≥ 2 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment failure. |
| Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Comparison to Placebo | Day 8 | Evaluation and comparison between Estradiol Vaginal Cream, Estrace®, and Placebo treatment groups of the change from baseline in the most bothersome vulvar and/or vaginal atrophy symptom including vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, or vaginal bleeding associated with sexual activity as identified by each subject. A score ≤ 1 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment success. A score ≥ 2 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment failure. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Estradiol Vaginal Cream 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) | 146 |
| Estrace® 0.01% Cream Estrace® 0.01% vaginal cream, administered once daily for 7 days.
Estrace® 0.01% cream: Estrace® 0.01% vaginal cream (1 x 2 g for 7 days) | 147 |
| Placebo Vaginal Cream Placebo Vaginal Cream, administered once daily for 7 days.
Placebo Vaginal Cream: Placebo Vaginal Cream (1 x 2 g for 7 days) | 73 |
| Total | 366 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 0 |
| Overall Study | Family Emergency | 0 | 0 | 1 |
| Overall Study | Non-compliance | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | Estradiol Vaginal Cream | Estrace® 0.01% Cream | Placebo Vaginal Cream | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 23 Participants | 12 Participants | 53 Participants |
| Age, Categorical Between 18 and 65 years | 128 Participants | 124 Participants | 61 Participants | 313 Participants |
| Age, Continuous | 59.2 years STANDARD_DEVIATION 5.25 | 59.6 years STANDARD_DEVIATION 5.88 | 59.4 years STANDARD_DEVIATION 5.82 | 59.4 years STANDARD_DEVIATION 5.61 |
| BMI | 26.6 kg/m^2 STANDARD_DEVIATION 4.41 | 26.6 kg/m^2 STANDARD_DEVIATION 4.56 | 25.6 kg/m^2 STANDARD_DEVIATION 4.11 | 26.4 kg/m^2 STANDARD_DEVIATION 4.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 30 Participants | 23 Participants | 13 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 116 Participants | 124 Participants | 60 Participants | 300 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 162.1 cm STANDARD_DEVIATION 6.43 | 161.5 cm STANDARD_DEVIATION 6.18 | 162.6 cm STANDARD_DEVIATION 6.55 | 161.9 cm STANDARD_DEVIATION 6.35 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 18 Participants | 11 Participants | 44 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 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 | 130 Participants | 125 Participants | 61 Participants | 316 Participants |
| Region of Enrollment United States | 146 participants | 147 participants | 73 participants | 366 participants |
| Sex: Female, Male Female | 146 Participants | 147 Participants | 73 Participants | 366 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Weight | 69.77 kg STANDARD_DEVIATION 12.74 | 69.39 kg STANDARD_DEVIATION 12.67 | 67.61 kg STANDARD_DEVIATION 11.37 | 69.19 kg STANDARD_DEVIATION 12.44 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 146 | 0 / 144 | 0 / 72 |
| other Total, other adverse events | 31 / 146 | 27 / 144 | 8 / 72 |
| serious Total, serious adverse events | 1 / 146 | 0 / 144 | 0 / 72 |
Outcome results
Primary
Primary Endpoint (Vaginal Cytology + Vaginal pH) Comparison of Active Treatments to Placebo
Treatment comparison of the proportion of patients in the Per Protocol (PP) population who received either Estradiol Vaginal Cream, Estrace®, or Placebo that were identified as responders at the end of the treatment period on Study Day 8. A responder was defined as a patient 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.
Time frame: Study Day 8
Population: The Intent-to-treat (ITT) population was used for the comparison of active treatments versus placebo analysis which consisted of all randomized subjects that used at least one dose of Test, Reference or Placebo and returned for at least one post-baseline visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Estradiol Vaginal Cream | Primary Endpoint (Vaginal Cytology + Vaginal pH) Comparison of Active Treatments to Placebo | 49 Participants |
| Estrace® 0.01% Cream | Primary Endpoint (Vaginal Cytology + Vaginal pH) Comparison of Active Treatments to Placebo | 51 Participants |
| Placebo Vaginal Cream | Primary Endpoint (Vaginal Cytology + Vaginal pH) Comparison of Active Treatments to Placebo | 1 Participants |
Comparison: Both the test and reference products should both be statistically superior to placebo (p\<0.05, two-sided) using the Chi squared test with Yate's correction for the primary endpoint responder rate, using the ITT study population and last observation carried forward. The compound hypothesis to test was: H0: PT - PP ≤ 0 versus HA: PT - PP \> 0; Where PT = cure rate of test treatment, and PP = cure rate of placebo.p-value: <0.000195% CI: [0.2743, 0.479]Chi-squared
Comparison: Both the test and reference products should both be statistically superior to placebo (p\<0.05, two-sided) using the Chi squared test with Yate's correction for the primary endpoint responder rate, using the ITT study population and last observation carried forward. The compound hypothesis to test was: H0: PT - PP ≤ 0 versus HA: PT - PP \> 0; Where PT = cure rate of test treatment, and PP = cure rate of placebo.p-value: <0.000195% CI: [0.257, 0.4514]Chi-squared
Primary
Primary Endpoint (Vaginal Cytology + Vaginal pH) Equivalence
Treatment comparison of the proportion of patients in the Per Protocol (PP) population who received either Estradiol Vaginal Cream or Estrace® that were identified as responders at the end of the treatment period on Study Day 8. A responder was defined as a patient 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.
Time frame: Study Day 8
Population: The Per Protocol population was used for the primary endpoint equivalence comparison which consisted of all randomized subjects that were dosed with 75%-125% of scheduled applications of Test or Reference and completed primary endpoint evaluation on Study Day 8 +/- 2 days with no protocol violations that would affect treatment evaluation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Estradiol Vaginal Cream | Primary Endpoint (Vaginal Cytology + Vaginal pH) Equivalence | 42 Participants |
| Estrace® 0.01% Cream | Primary Endpoint (Vaginal Cytology + Vaginal pH) Equivalence | 45 Participants |
Comparison: The compound hypothesis to test was: H0: PT -PR \< -.20 or PT -PR \> .20 versus HA : -.20 ≤ PT -PR ≤ .20 Where PT = cure rate of test treatment, and PR = cure rate of reference treatment.90% CI: [-0.1209, 0.1084]
Secondary
Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Comparison to Placebo
Evaluation and comparison between Estradiol Vaginal Cream, Estrace®, and Placebo treatment groups of the change from baseline in the most bothersome vulvar and/or vaginal atrophy symptom including vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, or vaginal bleeding associated with sexual activity as identified by each subject. A score ≤ 1 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment success. A score ≥ 2 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment failure.
Time frame: Day 8
Population: The Intent-to-treat (ITT) population was used for the Superiority Analysis which consisted of all randomized subjects that used at least one dose of Estradiol Vaginal Cream, Estrace®, or Placebo and returned for at least one post-baseline visit
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Estradiol Vaginal Cream | Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Comparison to Placebo | 82 Participants |
| Estrace® 0.01% Cream | Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Comparison to Placebo | 77 Participants |
| Placebo Vaginal Cream | Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Comparison to Placebo | 33 Participants |
Comparison: Both the test and reference products should both be statistically superior to placebo (p\<0.05, two-sided) using the Chi squared test with Yate's correction for the secondary endpoint responder rate, using the ITT study population and last observation carried forward. The compound hypothesis to test was: H0: PT - PP ≤ 0 versus HA: PT - PP \> 0; Where PT = cure rate of test treatment, and PP = cure rate of placebo.p-value: 0.109295% CI: [-0.028, 0.3054]Chi-squared
Comparison: Both the test and reference products should both be statistically superior to placebo (p\<0.05, two-sided) using the Chi squared test with Yate's correction for the secondary endpoint responder rate, using the ITT study population and last observation carried forward. The compound hypothesis to test was: H0: PT - PP ≤ 0 versus HA: PT - PP \> 0; Where PT = cure rate of test treatment, and PP = cure rate of placebo.p-value: 0.180595% CI: [-0.0491, 0.2883]Chi-squared
Secondary
Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Equivalence
Evaluation and comparison between Estradiol Vaginal Cream and Estrace® treatment groups of the change from baseline in the most bothersome vulvar and/or vaginal atrophy symptom including vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, or vaginal bleeding associated with sexual activity as identified by each subject. A score ≤ 1 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment success. A score ≥ 2 on Study Day 8 for the most bothersome symptom as identified by the subject at baseline (Study Day -1) was considered a treatment failure.
Time frame: Day 8
Population: The Per Protocol population was used for the secondary endpoint equivalence comparison which consisted of all randomized subjects that were dosed with 75%-125% of scheduled applications of Test or Reference and completed secondary endpoint evaluation on Study Day 8 +/- 2 days with no protocol violations that would affect treatment evaluation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Estradiol Vaginal Cream | Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Equivalence | 72 Participants |
| Estrace® 0.01% Cream | Comparison of the Number of Participants With Treatment Success for the Patient Self-assessment of the Symptoms of Vulvar and Vaginal Atrophy - Equivalence | 63 Participants |
90% CI: [-0.0687, 0.1686]