Healthy Males
Conditions
Keywords
testosterone, acyline, ketoconazole, dutasteride, anastrazole, Intratesticular hormone concentration
Brief summary
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.
Detailed 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.
Interventions
DRUGAcyline
300 mcg/kg on Day 1
DRUGTestosterone gel
5 gm of 1% T Gel applied transdermally for 10 days
DRUGketoconazole 400
400 mg PO daily, Days 3-10
DRUGKetoconazole 800
800 mg PO daily, Day 3-10
DRUGDutasteride
2.5 mg PO daily, Day 3-10
DRUGAnastrozole
1 mg PO daily, Day 3-10
placebo to mimic ketoconazole
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Intratesticular Testosterone (IT-T) Level | 10 days |
| Intratesticular Dihydrotestosterone (DHT) Level | 10 days |
| Intratesticular Androstenedione (ADD) Level | 10 days |
Countries
United States
Participant flow
Recruitment details
Healthy men, aged 18-50 years were recruited for this study using newspaper and online advertisement, including flyers posted at the University of Washington, Seattle.
Pre-assignment details
Fifty-two men were screened for the study and 46 met all inclusion criteria. Six subjects withdrew from the study prior to any procedures and 40 were randomized (n=8/group. Exclusion criteria included liver disease or adrenal insufficiency, Body Mass Index \> 32, abnormal test results, skin conditions for gel, alcohol/drug abuse etc.
Participants by arm
| Arm | Count |
|---|---|
| Acyline & T Gel & Ketoconazole 400 Acyline 300 mcg/kg on Day 1 + 1% testosterone gel 5 gm daily Days 1-10, + ketoconazole 400mg PO 1x daily, Days 3-10 | 8 |
| Acyline & T Gel & Dutasteride 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 | 8 |
| Acyline & T Gel & Placebo Ketoconazole 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 | 8 |
| Acyline & T Gel & Ketoconazole 800 Acyline 300 mcg/kg on Day 1 + 1% testosterone gel 5 gm daily Day 1-10, + ketoconazole 800mg PO 1x daily, Days 3-10 | 8 |
| Group 5: Anastrazole 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 | 8 |
| Total | 40 |
Baseline characteristics
| Characteristic | Acyline & T Gel & Ketoconazole 400 | Acyline & T Gel & Dutasteride | Acyline & T Gel & Placebo Ketoconazole | Acyline & T Gel & Ketoconazole 800 | Group 5: Anastrazole | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 22.5 years | 21.5 years | 24 years | 22 years | 21.5 years | 22 years |
| Region of Enrollment United States | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 40 participants |
| Serum 17-OHP | 6 ng/mL | 6.1 ng/mL | 7.2 ng/mL | 4.8 ng/mL | 6 ng/mL | 6.1 ng/mL |
| Serum ADD | 0.7 ng/mL | 0.75 ng/mL | 0.76 ng/mL | 0.69 ng/mL | 0.65 ng/mL | 0.67 ng/mL |
| Serum DHEA | 3.9 ng/mL | 3.9 ng/mL | 4.2 ng/mL | 4.6 ng/mL | 3.8 ng/mL | 3.9 ng/mL |
| Serum DHT | 0.44 ng/mL | 0.5 ng/mL | 0.5 ng/mL | 0.44 ng/mL | 0.42 ng/mL | 0.46 ng/mL |
| Serum E2 | 39 pg/mL | 24 pg/mL | 28.3 pg/mL | 39 pg/mL | 39.4 pg/mL | 28.3 pg/mL |
| Serum FSH | 2.3 IU/L | 2.7 IU/L | 2.7 IU/L | 2.4 IU/L | 2.3 IU/L | 2.6 IU/L |
| Serum LH | 5 IU/L | 4.7 IU/L | 4.3 IU/L | 5.8 IU/L | 4.9 IU/L | 4.8 IU/L |
| Serum Testosterone | 5.5 ng/mL | 5.4 ng/mL | 5.2 ng/mL | 5.3 ng/mL | 5.2 ng/mL | 5.3 ng/mL |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 8 | 2 / 8 | 5 / 8 | 6 / 8 | 5 / 8 |
| serious Total, serious adverse events | 1 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Intratesticular Androstenedione (ADD) Level
Time frame: 10 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyline + Testosterone Gel + Placebo | Intratesticular Androstenedione (ADD) Level | .87 ng/mL |
| Acyline + Tgel + Ketoconazole 400mg | Intratesticular Androstenedione (ADD) Level | 0.5 ng/mL |
| Acyline + Tgel + Ketoconazole 800mg | Intratesticular Androstenedione (ADD) Level | 0.12 ng/mL |
| Acyline & TGel & Dutasteride 2.5mg | Intratesticular Androstenedione (ADD) Level | 1.7 ng/mL |
| Acyline & TGel & Anastrazole 1mg | Intratesticular Androstenedione (ADD) Level | 3.6 ng/mL |
p-value: <0.05Kruskal-Wallis
Primary
Intratesticular Dihydrotestosterone (DHT) Level
Time frame: 10 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyline + Testosterone Gel + Placebo | Intratesticular Dihydrotestosterone (DHT) Level | 3.17 ng/mL |
| Acyline + Tgel + Ketoconazole 400mg | Intratesticular Dihydrotestosterone (DHT) Level | 2.08 ng/mL |
| Acyline + Tgel + Ketoconazole 800mg | Intratesticular Dihydrotestosterone (DHT) Level | 1.46 ng/mL |
| Acyline & TGel & Dutasteride 2.5mg | Intratesticular Dihydrotestosterone (DHT) Level | 0.12 ng/mL |
| Acyline & TGel & Anastrazole 1mg | Intratesticular Dihydrotestosterone (DHT) Level | 3.63 ng/mL |
p-value: <0.05Kruskal-Wallis
Primary
Intratesticular Testosterone (IT-T) Level
Time frame: 10 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyline + Testosterone Gel + Placebo | Intratesticular Testosterone (IT-T) Level | 14 ng/mL |
| Acyline + Tgel + Ketoconazole 400mg | Intratesticular Testosterone (IT-T) Level | 3.7 ng/mL |
| Acyline + Tgel + Ketoconazole 800mg | Intratesticular Testosterone (IT-T) Level | 1.7 ng/mL |
| Acyline & TGel & Dutasteride 2.5mg | Intratesticular Testosterone (IT-T) Level | 18.4 ng/mL |
| Acyline & TGel & Anastrazole 1mg | Intratesticular Testosterone (IT-T) Level | 24.0 ng/mL |
p-value: <0.05Kruskal-Wallis