Pharmacokinetics of a Novel Vaginal Delivery System for Testosterone and Dehydroepiandrosterone (DHEA)

Study Overview
=================
Brief Summary
-----------------
This study was performed to determine the pharmacokinetic parameters of vaginal rings that contain DHEA, testosterone, or combinations of both androgens, in comparison to the oral administration of DHEA and the transdermal administration of testosterone.

Official Title
-----------------
Prospective, Randomized, Open-label and Comparative Study to Determine the Pharmacokinetic Parameters of Vaginal Rings That Contain DHEA, Testosterone, or the Combination of Both Androgens, in Comparison With Oral Administration of DHEA and Transdermal Administration of Testosterone, in Postmenopausal Women

Conditions
-----------------
Pharmacokinetics, Hormone Deficiency

Intervention / Treatment
-----------------
* Drug: Dehydroepiandrosterone 2.2 g
* Drug: Dehydroepiandrosterone 1.5 g/Testosterone 25 mg
* Drug: Testosterone
* Drug: Testosterone Topical Gel
* Drug: Dehydroepiandrosterone Oral Capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women between 40 to 60 years old. Postmenopausal with spontaneous amenorrhea of 1 year or more, regardless of follicle stimulating hormone (FSH) levels; or amenorrhea of 6 to 12 months, in which the postmenopausal state will be confirmed with a FSH level of 0.040 international units per milliliter or higher. Body Mass Index between 19 and 30. Intact uterus. Not having received hormone therapy in the month prior to selection. Adequate veins to conduct serial blood samplings. Recent Pap smear (not more than 12 months), with a result negative for malignant neoplastic cells, and that contains sufficient endocervical cells for analysis. If the Pap smear was performed more than 12 months ago or cannot be verified through clinical documentation, it must be repeated during the selection process. Normal mammogram, BI.RADS I or II (American College of Radiology), within the last year. If the mammogram was performed more than 12 months ago or cannot be verified through clinical documentation, it must be repeated during the selection process. That provide written informed consent. Exclusion Criteria: Use at randomization of phenytoin, barbiturates, primidone, carbamazepine, rifampin, griseofulvin, ketoconazole, lipid-lowering agents. History of diseases such as coronary heart disease, breast cancer, uterine cancer, and/or chronic hepatic disease. Unconscious volunteers, severely ill, or with mental disability. Allergy and hypersensitivity to DHEA and/or testosterone. Untreated or uncontrolled hypertension, with systolic pressure above 140 mm Hg or diastolic pressure above 90 mm Hg. Current participation in other research at the moment of the screening visit, or having concluded their participation in a previous research in less than 30 days since their last visit. Pregnant or lactating women; pregnancy must be confirmed with a urine positive human chorionic gonadotropin (HCG) test during screening. History of vein thrombosis (deep vein thrombosis, pulmonary embolism). History of arterial thrombosis (myocardial infarction) or prodromic conditions (e.g. transient ischemic attack, angina pectoris). History of stroke. History of migraine with focal neurological manifestations. History of hepatic tumor (benign or malignant). History of clinical atherosclerosis in first grade relatives (parents, siblings, sons [men less than 55 years old and women less than 65 years old]). Smoking (5 or more cigarettes a day). Diabetes mellitus that will be ruled out at screening if fasting glucose is less than 100 mg/dL or between 100 and 125 mg/dL, with Oral Glucose Tolerance Test that rules out diabetes. Diabetes will be confirmed with blood glucose equal to or above 200 mg/dL or 2 fasting glucose tests equal to or above 126 mg/dL. High density lipopolysaccharide (HDL)-cholesterol below 35 mg/dL.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a prospective, randomized, open-label comparative, single-site study with 5 treatment groups. Each participant receives a single Treatment for 72 hours. Allocation to Treatment is in a 1:1:1:1:1 order.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: AVD<br>Vaginal ring with 2.2 grams dehydroepiandrosterone (DHEA), wearing time 72 hours | Drug: Dehydroepiandrosterone 2.2 g<br>* Vaginal ring with 2.2 grams DHEA.<br>|
| Experimental: Group 2: AVT<br>Vaginal ring with 35 mg testosterone, wearing time 72 hours. | Drug: Testosterone<br>* Vaginal ring with 35 mg testosterone.<br>|
| Experimental: Group 3: AVD+T<br>Vaginal ring with 1.5 grams DHEA and 25 mg testosterone, wearing time 72 hours. | Drug: Dehydroepiandrosterone 1.5 g/Testosterone 25 mg<br>* Vaginal ring with DHEA 1.5 grams/Testosterone 25 mg.<br>|
| Active Comparator: Group 4: DHEA capsule<br>Capsules with 25 mg DHEA, oral administration every 8 hours for a 72-hour period. | Drug: Dehydroepiandrosterone Oral Capsule<br>* Capsule containing 25 mg DHEA<br>|
| Active Comparator: Group 5: Testosterone transdermal gel<br>Testosterone transdermal gel with dosing valve (pump): administration of 3 pump actuations (equivalent to 5 mg of testosterone each) per day (total daily dose 15 mg), on 3 consecutive days (72 hours). | Drug: Testosterone Topical Gel<br>* Gel containing 1% testosterone.<br>* Other names: ActiserPump®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Testosterone: Area under the serum concentration time curve (AUC0-72) | Serum testosterone was measured pre-dose and at 30 minutes, at 1 hour, 2, 4, 6, 8, 24, 48, and 72 hours after vaginal ring insertion, the transdermal application of the testosterone gel, or after taking DHEA capsules. The AUC0-72 was calculated. | Pre-dose and from 30 minutes after administration of the assigned treatment to 72 hours | 
| DHEA: Area under the serum concentration time curve (AUC0-72) | Serum DHEA were measured pre-dose and at 30 minutes, at 1 hour, 2, 4, 6, 8, 24, 48, and 72 hours after vaginal ring insertion, the transdermal application of the testosterone gel, or after taking DHEA capsules. The AUC0-72 was calculated. | Pre-dose and from 30 minutes after administration of the assigned treatment to 72 hours | 
| Testosterone: Average serum concentration 0-24 hours | Serum testosterone was measured pre-dose and at 30 minutes, at 1 hour, 2, 4, 6, 8, 24, 48, and 72 hours after vaginal ring insertion, the transdermal application of the testosterone gel, or after taking DHEA capsules. The average serum concentration achieved in the first 24 hours after administration of the assigned treatment was calculated. | Pre-dose and from 30 minutes after administration of the assigned treatment to 24 hours | 
| DHEA: Average serum concentration 0-24 hours | Serum DHEA was measured pre-dose and at 30 minutes, at 1 hour, 2, 4, 6, 8, 24, 48, and 72 hours after vaginal ring insertion, the transdermal application of the testosterone gel, or after taking DHEA capsules. The average serum concentration achieved in the first 24 hours after administration of the assigned treatment was calculated. | Pre-dose and from 30 minutes after administration of the assigned treatment to 24 hours | 
| Testosterone: Maximum serum concentration (Cmax) | Serum testosterone was measured pre-dose and at 30 minutes, at 1 hour, 2, 4, 6, 8, 24, 48, and 72 hours after vaginal ring insertion, the transdermal application of the testosterone gel, or after taking DHEA capsules. Cmax was calculated. | Pre-dose and from 30 minutes after administration of the assigned treatment to 72 hours | 
| DHEA: Maximum serum concentration (Cmax) | Serum DHEA was measured pre-dose and at 30 minutes, at 1 hour, 2, 4, 6, 8, 24, 48, and 72 hours after vaginal ring insertion, the transdermal application of the testosterone gel, or after taking DHEA capsules. Cmax was calculated. | Pre-dose and from 30 minutes after administration of the assigned treatment to 72 hours | 
| Testosterone: Time to achieve maximum serum concentration (tmax) | Serum testosterone was measured pre-dose and at 30 minutes, at 1 hour, 2, 4, 6, 8, 24, 48, and 72 hours after vaginal ring insertion, the transdermal application of the testosterone gel, or after taking DHEA capsules. Tmax was calculated. | pre-dose and from 30 minutes after administration of the assigned treatment to 72 hours | 
| DHEA: Time to achieve maximum serum concentration (tmax) | Serum DHEA was measured pre-dose and at 30 minutes, at 1 hour, 2, 4, 6, 8, 24, 48, and 72 hours after vaginal ring insertion, the transdermal application of the testosterone gel, or after taking DHEA capsules. Tmax was calculated. | pre-dose and from 30 minutes after administration of the assigned treatment to 72 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Gynaecology, Obstetrics