Trial Outcomes & Findings for DHEA Against Vaginal Atrophy - Safety Study of 12 Months (NCT NCT01256671)

NCT ID: NCT01256671

Last Updated: 2017-10-18

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 530 participants
• Primary outcome timeframe: Baseline and Week 52 (or discontinuation)
• Results posted on: 2017-10-18

Participant Flow

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.

Participant milestones

Measure	0.50% DHEA DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
Overall Study STARTED	530
Overall Study Safety Population	521
Overall Study COMPLETED	435
Overall Study NOT COMPLETED	95

Reasons for withdrawal

Measure	0.50% DHEA DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
Overall Study Adverse Event	29
Overall Study Lost to Follow-up	16
Overall Study Withdrawal by Subject	31
Overall Study Physician Decision	3
Overall Study Lack of Efficacy	4
Overall Study Non-compliance/Sponsor Decision/Other	12

Baseline Characteristics

DHEA Against Vaginal Atrophy - Safety Study of 12 Months

Baseline characteristics by cohort

Measure	0.50% DHEA n=521 Participants DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
Age, Continuous	57.95 years STANDARD_DEVIATION 5.65 • n=5 Participants
Sex/Gender, Customized Female	521 Participants n=5 Participants
Race/Ethnicity, Customized White Caucasian	478 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	31 Participants n=5 Participants
Race/Ethnicity, Customized Asian	3 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	3 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	2 Participants n=5 Participants
Race/Ethnicity, Customized Other	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	0.50% DHEA n=457 Participants DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
Long-term Safety of Intravaginal Prasterone (DHEA): Endometrium Endometrium: Atrophic/Inactive	421 Participants
Long-term Safety of Intravaginal Prasterone (DHEA): Endometrium Endometrium: No/Insufficient Tissue for Diagnosis	36 Participants

PRIMARY outcome

Timeframe: Baseline and Week 52

Population: Data are presented for subjects in the Safety Population who have steroid data at both 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.

Outcome measures

Measure	0.50% DHEA n=429 Participants DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels DHEA: Baseline	2071.61 pg/mL Standard Error 65.70
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels DHEA: Week 52	2997.25 pg/mL Standard Error 85.23
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels DHEA: Change from Baseline	925.65 pg/mL Standard Error 74.35
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels E2: Baseline	6.05 pg/mL Standard Error 1.11
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels E2: Week 52	4.46 pg/mL Standard Error 0.32
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels E2: Change from Baseline	-1.59 pg/mL Standard Error 1.13
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels TESTO: Baseline	161.28 pg/mL Standard Error 6.93
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels TESTO: Week 52	189.44 pg/mL Standard Error 4.79
Long-term Safety of Intravaginal Prasterone (DHEA): Serum Steroid Levels TESTO: Change from Baseline	28.17 pg/mL Standard Error 6.55

SECONDARY outcome

Timeframe: 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)).

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.

Outcome measures

Measure	0.50% DHEA n=476 Participants DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
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
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
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
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
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
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 outcome

Timeframe: 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)).

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.

Outcome measures

Measure	0.50% DHEA n=476 Participants DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
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
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
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
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
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
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 outcome

Timeframe: 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)).

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.

Outcome measures

Measure	0.50% DHEA n=476 Participants DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
Change From Baseline to Week 52 of Vaginal pH. Baseline: Subgroup ALL	6.23 pH Standard Error 0.04
Change From Baseline to Week 52 of Vaginal pH. Week 52: Subgroup ALL	5.09 pH Standard Error 0.04
Change From Baseline to Week 52 of Vaginal pH. Change from Baseline: Subgroup ALL	-1.14 pH Standard Error 0.04
Change From Baseline to Week 52 of Vaginal pH. Baseline: Subgroup VVA	6.40 pH Standard Error 0.04
Change From Baseline to Week 52 of Vaginal pH. Week 52: Subgroup VVA	5.13 pH Standard Error 0.05
Change From Baseline to Week 52 of Vaginal pH. Change from Baseline: Subgroup VVA	-1.27 pH Standard Error 0.05

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Measure	0.50% DHEA n=476 Participants DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
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
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
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
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
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
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 outcome

Timeframe: 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).

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.

Outcome measures

Measure	0.50% DHEA n=476 Participants DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
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
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
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
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
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
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 outcome

Timeframe: 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).

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.

Outcome measures

Measure	0.50% DHEA n=476 Participants DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
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
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
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
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
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
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

Adverse Events

0.50% DHEA

Serious events: 18 serious events

Other events: 177 other events

Deaths: 0 deaths

Serious adverse events

Measure	0.50% DHEA n=521 participants at risk DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
Gastrointestinal disorders Colitis ischaemic	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Gastrointestinal disorders Duodenal stenosis	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Gastrointestinal disorders Dyspepsia	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Gastrointestinal disorders Pancreatitis	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Infections and infestations Infectious peritonitis	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Infections and infestations Staphylococcal infection	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Injury, poisoning and procedural complications Femur fracture	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Injury, poisoning and procedural complications Laceration	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Injury, poisoning and procedural complications Muscle rupture	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Musculoskeletal and connective tissue disorders Arthralgia	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Musculoskeletal and connective tissue disorders Osteoarthritis	0.38% 2/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Musculoskeletal and connective tissue disorders Pain in extremity	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer stage III	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Psychiatric disorders Anxiety	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Reproductive system and breast disorders Uterine prolapse	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Skin and subcutaneous tissue disorders Angioedema	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Surgical and medical procedures Cystocele repair	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Surgical and medical procedures Hysterectomy	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Surgical and medical procedures Rectocele repair	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Vascular disorders Arteriovenous fistula	0.19% 1/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)

Other adverse events

Measure	0.50% DHEA n=521 participants at risk DHEA (prasterone): Vaginal suppository containing 0.50% (6.5 mg) DHEA; daily dosing with one suppository for 52 weeks.
General disorders Application site discharge	14.0% 73/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Infections and infestations Nasopharyngitis	9.8% 51/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)
Infections and infestations Urinary tract infection	10.2% 53/521 • From Baseline to Week 52 (+ 30-day follow-up period after last dose)

Additional Information

Director of Data Analysis

Endoceutics

Phone: 418-653-0033

Email: celine.martel@endoceutics.com

Results disclosure agreements

• Principal investigator is a sponsor employee Investigators shall provide to the SPONSOR 30 days prior to submission all documents for publication, presentation, etc that report any trial results. The SPONSOR shall have editorial rights on documents and the right to review/comment with regard to (1) proprietary information, (2) accuracy of the information, (3) correctness of the scientific evaluation/conclusions and (4) to ensure that the information is fairly balanced and in compliance with regulations.
• Publication restrictions are in place

Restriction type: OTHER