Vaginal Atrophy
Conditions
Keywords
Vulvar/Vaginal Atrophy, Atrophic Vaginitis, Dehydroepiandrosterone, DHEA, Prasterone, Vaginorm, Menopause, Intrarosa
Brief summary
The purpose of this Phase III trial is to assess the long-term safety of intravaginal dehydroepiandrosterone (DHEA) in non-hysterectomized postmenopausal women with vaginal atrophy aged 40 to 75 years.
Interventions
DRUGDHEA
Vaginal suppository containing 0.5% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
Sponsors
EndoCeutics Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Postmenopausal women (non-hysterectomized) * Women between 40 and 75 years of age. * Willing to participate in the study and sign an informed consent. * Women who have self-identified symptom(s) of vaginal atrophy. * Willing to have endometrial biopsy at screening and end of study (Week 52). Main
Exclusion criteria
* Undiagnosed abnormal genital bleeding. * Hypertension equal to or above 140/90 mm Hg. * The administration of any investigational drug within 30 days of screening visit. * Endometrial hyperplasia, cancer or endometrial histology showing proliferative, secretory or menstrual type characteristics at histologic evaluation of endometrial biopsy performed at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Long-term Safety of Intravaginal Prasterone (DHEA): Endometrium | Baseline and Week 52 (or discontinuation) | The long-term safety of intravaginal prasterone has been evaluated on different parameters including the endometrium. For this purpose, endometrial biopsies were performed at screening and at the end of the study (52 weeks) or at discontinuation visit for women who were exposed to intravaginal DHEA (prasterone) for at least 12 weeks. At screening, the endometrium had to be atrophic/inactive for women to be enrolled in the study. Only the end-of-study data are presented. |
| Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | Baseline and Week 52 | The long-term safety of intravaginal prasterone has been evaluated on different parameters including the serum levels of DHEA and its metabolites. For this purpose, blood samples were collected at Baseline and different post-Baseline timepoints for the determination of serum steroid levels by a central laboratory using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. The serum levels of dehydroepiandrosterone (DHEA), estradiol (E2) and testosterone (TESTO) obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 52 of Vaginal pH. | Baseline and Week 52 | A pH strip fixed on an Ayre spatula (or equivalent) was applied directly to the lateral wall of the vagina. The change in color of the pH indicator strip was compared to the color chart for pH evaluation. The corresponding pH value (with one decimal) was recorded. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented. |
| Change From Baseline to Week 52 of Self-assessment of VVA Symptom Dyspareunia | Baseline and Week 52 | The severity of dyspareunia was evaluated by a questionnaire. The severity of dyspareunia recorded as none, mild, moderate or severe was analyzed using the score values of 0, 1, 2 or 3, respectively. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented. |
| Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Parabasal Cells). | Baseline and Week 52 | The percentage of parabasal cells was determined from the vaginal smears collected during the study. A 100-cell count was performed by a central laboratory to classify cells as parabasal (P) (including basal), intermediate (I), and superficial (S) squamous cell types. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented. |
| Change From Baseline to Week 52 of Self-assessment of VVA Symptom Irritation/Itching | Baseline and Week 52 | The severity of irritation/itching was evaluated by a questionnaire. The severity of irritation/itching recorded as none, mild, moderate or severe was analyzed using the score values of 0, 1, 2 or 3, respectively. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented. |
| Change From Baseline to Week 52 of Self-assessment of VVA Symptom Vaginal Dryness | Baseline and Week 52 | The severity of vaginal dryness was evaluated by a questionnaire. The severity of vaginal dryness recorded as none, mild, moderate or severe was analyzed using the score values of 0, 1, 2 or 3, respectively. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented. |
| Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Superficial Cells). | Baseline and Week 52 | The percentage of superficial cells was determined from the vaginal smears collected during the study. A 100-cell count was performed by a central laboratory to classify cells as parabasal (P) (including basal), intermediate (I), and superficial (S) squamous cell types. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented. |
Countries
Canada, United States
Participant flow
Recruitment details
A total of 798 subjects were screened at 41 medical/research sites located in the US (31 centers) and Canada (10 centers) and 530 subjects were randomized. The first subject first visit was on 30-NOV-2010 and the last subject last visit was on 16-JUL-2012.
Participants by arm
| Arm | Count |
|---|---|
| 0.50% DHEA DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks. | 521 |
| Total | 521 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 29 |
| Overall Study | Lack of Efficacy | 4 |
| Overall Study | Lost to Follow-up | 16 |
| Overall Study | Non-compliance/Sponsor Decision/Other | 12 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Withdrawal by Subject | 31 |
Baseline characteristics
| Characteristic | 0.50% DHEA |
|---|---|
| Age, Continuous | 57.95 years STANDARD_DEVIATION 5.65 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 31 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race/Ethnicity, Customized Other | 4 Participants |
| Race/Ethnicity, Customized White Caucasian | 478 Participants |
| Sex/Gender, Customized Female | 521 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 177 / 521 |
| serious Total, serious adverse events | 18 / 521 |
Outcome results
Primary
Long-term Safety of Intravaginal Prasterone (DHEA): Endometrium
The long-term safety of intravaginal prasterone has been evaluated on different parameters including the endometrium. For this purpose, endometrial biopsies were performed at screening and at the end of the study (52 weeks) or at discontinuation visit for women who were exposed to intravaginal DHEA (prasterone) for at least 12 weeks. At screening, the endometrium had to be atrophic/inactive for women to be enrolled in the study. Only the end-of-study data are presented.
Time frame: Baseline and Week 52 (or discontinuation)
Population: Only subjects in the Safety Population who had an end-of-study endometrial biopsy are included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Endometrium | Endometrium: Atrophic/Inactive | 421 Participants |
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Endometrium | Endometrium: No/Insufficient Tissue for Diagnosis | 36 Participants |
Primary
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels
The long-term safety of intravaginal prasterone has been evaluated on different parameters including the serum levels of DHEA and its metabolites. For this purpose, blood samples were collected at Baseline and different post-Baseline timepoints for the determination of serum steroid levels by a central laboratory using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. The serum levels of dehydroepiandrosterone (DHEA), estradiol (E2) and testosterone (TESTO) obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented.
Time frame: Baseline and Week 52
Population: Data are presented for subjects in the Safety Population who have steroid data at both baseline and Week 52.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | DHEA: Baseline | 2071.61 pg/mL | Standard Error 65.7 |
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | DHEA: Week 52 | 2997.25 pg/mL | Standard Error 85.23 |
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | E2: Baseline | 6.05 pg/mL | Standard Error 1.11 |
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | E2: Week 52 | 4.46 pg/mL | Standard Error 0.32 |
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | E2: Change from Baseline | -1.59 pg/mL | Standard Error 1.13 |
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | TESTO: Baseline | 161.28 pg/mL | Standard Error 6.93 |
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | TESTO: Week 52 | 189.44 pg/mL | Standard Error 4.79 |
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | TESTO: Change from Baseline | 28.17 pg/mL | Standard Error 6.55 |
| 0.50% DHEA | Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels | DHEA: Change from Baseline | 925.65 pg/mL | Standard Error 74.35 |
Secondary
Change From Baseline to Week 52 of Self-assessment of VVA Symptom Dyspareunia
The severity of dyspareunia was evaluated by a questionnaire. The severity of dyspareunia recorded as none, mild, moderate or severe was analyzed using the score values of 0, 1, 2 or 3, respectively. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented.
Time frame: Baseline and Week 52
Population: Overall, 476 subjects met vulvovaginal atrophy (VVA) criteria by having moderate/severe (MS) dyspareunia, dryness and/or irritation/itching. The analysis MS dyspareunia only includes subjects having MS dyspareunia (being or not most bothersome (MBS)) (n=240); the analysis MBS/MS only includes subjects with MS dyspareunia being MBS (n=183).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Dyspareunia | Baseline: Subgroup MS | 2.53 units on a scale | Standard Error 0.03 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Dyspareunia | Week 52: Subgroup MS | 0.85 units on a scale | Standard Error 0.06 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Dyspareunia | Change from Baseline: Subgroup MS | -1.68 units on a scale | Standard Error 0.06 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Dyspareunia | Baseline: Subgroup MBS/MS | 2.57 units on a scale | Standard Error 0.04 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Dyspareunia | Week 52: Subgroup MBS/MS | 0.87 units on a scale | Standard Error 0.07 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Dyspareunia | Change from Baseline: Subgroup MBS/MS | -1.69 units on a scale | Standard Error 0.07 |
Secondary
Change From Baseline to Week 52 of Self-assessment of VVA Symptom Irritation/Itching
The severity of irritation/itching was evaluated by a questionnaire. The severity of irritation/itching recorded as none, mild, moderate or severe was analyzed using the score values of 0, 1, 2 or 3, respectively. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented.
Time frame: Baseline and Week 52
Population: Overall, 476 subjects met vulvovaginal atrophy (VVA) criteria by having moderate/severe (MS) dyspareunia, dryness and/or irritation/itching. The analysis MS only includes subjects having MS irritation/itching (being or not most bothersome (MBS)) (n=86); the analysis MBS/MS only includes subjects with MS irritation/itching being MBS (n=23).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Irritation/Itching | Baseline: Subgroup MS | 2.10 units on a scale | Standard Error 0.03 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Irritation/Itching | Week 52: Subgroup MS | 0.60 units on a scale | Standard Error 0.08 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Irritation/Itching | Change from Baseline: Subgroup MS | -1.50 units on a scale | Standard Error 0.09 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Irritation/Itching | Baseline: Subgroup MBS/MS | 2.13 units on a scale | Standard Error 0.07 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Irritation/Itching | Week 52: Subgroup MBS/MS | 0.74 units on a scale | Standard Error 0.14 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Irritation/Itching | Change from Baseline: Subgroup MBS/MS | -1.39 units on a scale | Standard Error 0.16 |
Secondary
Change From Baseline to Week 52 of Self-assessment of VVA Symptom Vaginal Dryness
The severity of vaginal dryness was evaluated by a questionnaire. The severity of vaginal dryness recorded as none, mild, moderate or severe was analyzed using the score values of 0, 1, 2 or 3, respectively. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented.
Time frame: Baseline and Week 52
Population: Overall, 476 subjects met vulvovaginal atrophy (VVA) criteria by having moderate/severe (MS) dyspareunia, dryness and/or irritation/itching. The analysis MS only includes subjects having MS dryness (being or not most bothersome (MBS)) (n=251); the analysis MBS/MS only includes subjects with MS dryness being MBS (n=81).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Vaginal Dryness | Baseline: Subgroup MS | 2.22 units on a scale | Standard Error 0.03 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Vaginal Dryness | Week 52: Subgroup MS | 0.59 units on a scale | Standard Error 0.05 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Vaginal Dryness | Change from Baseline: Subgroup MS | -1.63 units on a scale | Standard Error 0.05 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Vaginal Dryness | Baseline: Subgroup MBS/MS | 2.19 units on a scale | Standard Error 0.04 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Vaginal Dryness | Week 52: Subgroup MBS/MS | 0.67 units on a scale | Standard Error 0.09 |
| 0.50% DHEA | Change From Baseline to Week 52 of Self-assessment of VVA Symptom Vaginal Dryness | Change from Baseline: Subgroup MBS/MS | -1.52 units on a scale | Standard Error 0.09 |
Secondary
Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Parabasal Cells).
The percentage of parabasal cells was determined from the vaginal smears collected during the study. A 100-cell count was performed by a central laboratory to classify cells as parabasal (P) (including basal), intermediate (I), and superficial (S) squamous cell types. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented.
Time frame: Baseline and Week 52
Population: Subgroups of the Safety Population were used for analysis. The subgroup identified ALL includes subjects meeting or not the vulvovaginal atrophy (VVA) criteria at Baseline while the subgroup VVA only includes subjects meeting VVA criteria (pH ˃5, superficial cells ≤ 5% and moderate/severe VVA symptom being most bothersome (MBS)).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Parabasal Cells). | Baseline: Subgroup ALL | 55.49 percentage of parabasal cells | Standard Error 2.03 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Parabasal Cells). | Week 52: Subgroup ALL | 12.81 percentage of parabasal cells | Standard Error 0.97 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Parabasal Cells). | Change from Baseline: Subgroup ALL | -42.67 percentage of parabasal cells | Standard Error 1.84 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Parabasal Cells). | Baseline: Subgroup VVA | 63.95 percentage of parabasal cells | Standard Error 2.41 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Parabasal Cells). | Week 52: Subgroup VVA | 14.80 percentage of parabasal cells | Standard Error 1.27 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Parabasal Cells). | Change from Baseline: Subgroup VVA | -49.14 percentage of parabasal cells | Standard Error 2.22 |
Secondary
Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Superficial Cells).
The percentage of superficial cells was determined from the vaginal smears collected during the study. A 100-cell count was performed by a central laboratory to classify cells as parabasal (P) (including basal), intermediate (I), and superficial (S) squamous cell types. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented.
Time frame: Baseline and Week 52
Population: Subgroups of the Safety Population were used for analysis. The subgroup identified ALL includes subjects meeting or not the vulvovaginal atrophy (VVA) criteria at Baseline while the subgroup VVA only includes subjects meeting VVA criteria (pH ˃5, superficial cells ≤ 5% and moderate/severe VVA symptom being most bothersome (MBS)).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Superficial Cells). | Baseline: Subgroup ALL | 2.02 percentage of superficial cells | Standard Error 0.19 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Superficial Cells). | Week 52: Subgroup ALL | 9.42 percentage of superficial cells | Standard Error 0.36 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Superficial Cells). | Change from Baseline: Subgroup ALL | 7.41 percentage of superficial cells | Standard Error 0.38 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Superficial Cells). | Baseline: Subgroup VVA | 0.96 percentage of superficial cells | Standard Error 0.08 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Superficial Cells). | Week 52: Subgroup VVA | 8.81 percentage of superficial cells | Standard Error 0.41 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal Cell Maturation (Percentage of Superficial Cells). | Change from Baseline: Subgroup VVA | 7.85 percentage of superficial cells | Standard Error 0.42 |
Secondary
Change From Baseline to Week 52 of Vaginal pH.
A pH strip fixed on an Ayre spatula (or equivalent) was applied directly to the lateral wall of the vagina. The change in color of the pH indicator strip was compared to the color chart for pH evaluation. The corresponding pH value (with one decimal) was recorded. Data obtained at Baseline and Week 52 as well as the change from Baseline to Week 52 are presented.
Time frame: Baseline and Week 52
Population: Subgroups of the Safety Population were used for analysis. The subgroup identified ALL includes subjects meeting or not the vulvovaginal atrophy (VVA) criteria at Baseline while the subgroup VVA only includes subjects meeting VVA criteria (pH ˃5, superficial cells ≤ 5% and moderate/severe VVA symptom being most bothersome (MBS)).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal pH. | Baseline: Subgroup ALL | 6.23 pH | Standard Error 0.04 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal pH. | Week 52: Subgroup ALL | 5.09 pH | Standard Error 0.04 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal pH. | Change from Baseline: Subgroup ALL | -1.14 pH | Standard Error 0.04 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal pH. | Baseline: Subgroup VVA | 6.40 pH | Standard Error 0.04 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal pH. | Week 52: Subgroup VVA | 5.13 pH | Standard Error 0.05 |
| 0.50% DHEA | Change From Baseline to Week 52 of Vaginal pH. | Change from Baseline: Subgroup VVA | -1.27 pH | Standard Error 0.05 |