ITT4 Intratesticular Hormonal Milieu in Man (ITT4)

Study Overview
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Brief Summary
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The purpose of this research study is to determine how much male hormone, testosterone, is necessary to maintain sperm production in the testis. This knowledge will be used to help in the development of a safe male hormonal contraception. Specific Aims: to determine if ketoconazole plus acyline will suppress intratesticular testosterone(ITT) to a greater degree than acyline alone. to determine if dutasteride plus acyline will suppress intratesticular dihydrotestosterone (IT-DHT) to a greater degree than acyline alone. to determine if anastrazole plus acyline will suppress intratesticular estradiol(IT-E2) to a greater degree than acyline alone.

Detailed Description
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Five drugs will be used in this study: acyline, testosterone gel, ketoconazole, dutasteride, and anastrazole. Acyline suppresses luteinizing hormone (LH) and follicle stimulating hormone (FSH), which are hormones made by the pituitary gland in the brain, thus blocking the signal from the brain that causes the testes to make testosterone. Therefore, acyline blocks testosterone production. Men may experience some side effects from the low levels of testosterone caused by acyline. Acyline is an experimental drug. Over 125 men have received acyline from our lab. Acyline will be given by injection, and injections are formulated by subject's weight and may be given in multiple injections. Testosterone gel is given to replace testosterone level back to the normal range. Testosterone gel is approved for use in men with low testosterone levels. Ketoconazole suppresses testosterone production as well. Ketoconazole works in the adrenal glands to prevent testosterone production. It is approved by the U.S. FDA for treatment of fungal infections but for this study the use is considered investigational. Dutasteride blocks metabolism of testosterone into dihydrotestosterone (DHT). It is approved by the FDA for treatment of benign enlargement of the prostate gland, but the use is considered investigational in this study. Also, the dose is 5 times higher than the FDA approved dose. Anastrazole blocks metabolism of testosterone into estradiol. It is approved by the FDA for treatment of breast cancer but its use is considered investigational in this study. Participation will last approximately 2 months. The study involves a minimum of 7 visits. Clinic visits at Screening, Day 3 and Day 10 will take about 1-1.5 hours each. On Day 3 & 10 a fine needle aspiration of one testis will be performed. The Day 1 visit will take approximately 45 minutes. The Day 7 visit will take about 15 minutes. The Day 17 and Day 40 visits will take approximately 30 minutes each. Over the course of the study, which includes 7 separate blood draws, approximately 12 ounces (one and a half cups) of blood will be drawn. The acyline will be given by injection. The testosterone or placebo gel is applied to the skin on the chest, upper arms, and upper back. The ketoconazole, dutasteride, anastrazole, or placebo medication will be taken by mouth. Subjects randomly assigned to Group 3 will have a Cosyntropin Stimulation Test performed at the day 10 visit to evaluate the function of adrenal glands. This is NOT a trial of a male contraceptive, and the study medications will not prevent pregnancy. Subjects must use an acceptable form of birth control.

Official Title
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Mechanisms of Control of the Intratesticular Hormonal Milieu in Man

Conditions
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Healthy Males

Intervention / Treatment
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* Drug: Acyline
* Drug: Testosterone gel
* Drug: ketoconazole 400
* Drug: Ketoconazole 800
* Drug: Dutasteride
* Drug: Anastrozole
* Drug: Placebo ketoconazole


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Males age 18-50 Normal serum testosterone, LH and FSH prostate-specific antigen (PSA) < 4.0 Agrees not to donate blood or participate in another research study during the study Informed consent Able to understand and comply with protocol requirements, instructions and protocol-stated restrictions In general good health based on normal screening evaluation (consisting of a medical history, physical exam, normal serum chemistry and hematology) Must be willing to use a reliable form of contraception during the study EXCLUSION CRITERIA: Poor general health, with clinically significant abnormal blood results Participation in a long-term male contraceptive study within the past three months Participation in long-term contraceptive or drug study within the past 3 months History of or current liver disease Current use of terfenadine, astemizole, cisapride, budesonide, felodipine, fluticasone, lovastatin, midazolam, sildenafil, or vardenafil History of testicular, prostate, or scrotal surgery/trauma or genital abnormal exam BMI > 32 History of sleep apnea and/or major psychiatric problems Chronic pain syndrome History of testosterone or anabolic steroid abuse currently or in the past Known bleeding disorder or current use of anticoagulation History of or current skin disorder that will interfere with testosterone gel Unwilling to adhere to protocol-stated restrictions while in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Acyline & T Gel & Placebo Ketoconazole<br>Acyline 300 mcg/kg on Day 1 + 1% testosterone gel (T gel) 5 gm daily Days 1-10, + placebo tab PO 1x daily, Day 3-10 | Drug: Acyline<br>* 300 mcg/kg on Day 1<br>* Other names: Acyline GnRH antagonist;Drug: Testosterone gel<br>* 5 gm of 1% T Gel applied transdermally for 10 days<br>* Other names: Androgel;Drug: Placebo ketoconazole<br>* placebo to mimic ketoconazole<br>|
| Experimental: Acyline & T Gel & Ketoconazole 400<br>Acyline 300 mcg/kg on Day 1 + 1% testosterone gel 5 gm daily Days 1-10, + ketoconazole 400mg PO 1x daily, Days 3-10 | Drug: Acyline<br>* 300 mcg/kg on Day 1<br>* Other names: Acyline GnRH antagonist;Drug: Testosterone gel<br>* 5 gm of 1% T Gel applied transdermally for 10 days<br>* Other names: Androgel;Drug: ketoconazole 400<br>* 400 mg PO daily, Days 3-10<br>* Other names: Teva;|
| Experimental: Acyline & T gel & Ketoconazole 800<br>Acyline 300 mcg/kg on Day 1 + 1% testosterone gel 5 gm daily Day 1-10, + ketoconazole 800mg PO 1x daily, Days 3-10 | Drug: Acyline<br>* 300 mcg/kg on Day 1<br>* Other names: Acyline GnRH antagonist;Drug: Testosterone gel<br>* 5 gm of 1% T Gel applied transdermally for 10 days<br>* Other names: Androgel;Drug: Ketoconazole 800<br>* 800 mg PO daily, Day 3-10<br>* Other names: Teva;|
| Experimental: Acyline & T gel & Dutasteride<br>Acyline 300 mcg/kg on Day 1 + 1% testosterone gel 5 gm daily Day 1-10, + dutasteride 2.5 mg PO 1x daily, Days 3-10 | Drug: Acyline<br>* 300 mcg/kg on Day 1<br>* Other names: Acyline GnRH antagonist;Drug: Testosterone gel<br>* 5 gm of 1% T Gel applied transdermally for 10 days<br>* Other names: Androgel;Drug: Dutasteride<br>* 2.5 mg PO daily, Day 3-10<br>* Other names: Avodart;|
| Experimental: Group 5: anastrazole<br>Acyline 300 mcg/kg on Day 1 + 1% testosterone gel 5 gm daily Day 1-10, + anastrazole 1 mg PO 1x daily, Days 3-10 | Drug: Acyline<br>* 300 mcg/kg on Day 1<br>* Other names: Acyline GnRH antagonist;Drug: Testosterone gel<br>* 5 gm of 1% T Gel applied transdermally for 10 days<br>* Other names: Androgel;Drug: Anastrozole<br>* 1 mg PO daily, Day 3-10<br>* Other names: Arimidex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intratesticular Testosterone (IT-T) Level |  | 10 days | 
| Intratesticular Dihydrotestosterone (DHT) Level |  | 10 days | 
| Intratesticular Androstenedione (ADD) Level |  | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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testosterone, acyline, ketoconazole, dutasteride, anastrazole, Intratesticular hormone concentration