ITT4 Intratesticular Hormonal Milieu in Man (ITT4)

University of Washington

Status and phase: Completed; Phase 2; Phase 1

Conditions: Healthy Males

Treatments: Drug: Dutasteride; Drug: Acyline; Drug: Ketoconazole 800; Drug: Testosterone gel; Drug: Placebo ketoconazole; Drug: ketoconazole 400; Drug: Anastrozole

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01215292

U54HD012629 (U.S. NIH Grant/Contract)

38692-K

Details and patient eligibility

About

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:

1. to determine if ketoconazole plus acyline will suppress intratesticular testosterone(ITT) to a greater degree than acyline alone.
2. to determine if dutasteride plus acyline will suppress intratesticular dihydrotestosterone (IT-DHT) to a greater degree than acyline alone.
3. to determine if anastrazole plus acyline will suppress intratesticular estradiol(IT-E2) to a greater degree than acyline alone.

Full description

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.

Enrollment: 46 patients

Sex: Male

Ages: 18 to 50 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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46 participants in 5 patient groups, including a placebo group

Acyline & T Gel & Placebo Ketoconazole

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo ketoconazole

Drug: Testosterone gel

Drug: Acyline

Acyline & T Gel & Ketoconazole 400

Experimental group

Description:

Acyline 300 mcg/kg on Day 1 + 1% testosterone gel 5 gm daily Days 1-10, + ketoconazole 400mg PO 1x daily, Days 3-10

Treatment:

Drug: ketoconazole 400

Drug: Testosterone gel

Drug: Acyline

Acyline & T gel & Ketoconazole 800

Experimental group

Description:

Acyline 300 mcg/kg on Day 1 + 1% testosterone gel 5 gm daily Day 1-10, + ketoconazole 800mg PO 1x daily, Days 3-10

Treatment:

Drug: Testosterone gel

Drug: Ketoconazole 800

Drug: Acyline

Acyline & T gel & Dutasteride

Experimental group

Description:

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

Treatment:

Drug: Testosterone gel

Drug: Acyline

Drug: Dutasteride

Group 5: anastrazole

Experimental group

Description:

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

Treatment:

Drug: Anastrozole

Drug: Testosterone gel

Drug: Acyline