Healthy
Conditions
Keywords
Androgen replacement in men
Brief summary
The investigators will conduct a three-month, randomized, placebo-controlled trial comparing the effects of increasing doses of androgen supplementation with Testosterone (T) gel on the prostate in healthy men who are treated with acyline to block gonadal androgen production.
Detailed description
The investigators overall goals are (i) to determine the relationship between serum and prostate tissue hormone concentrations in men in response to increasing doses of exogenous androgens; (ii) to determine the impact that alterations in serum and tissue testosterone concentrations have on prostate epithelial cell function and phenotype; and (iii) to determine the relationships between prostatic androgens and alterations in the tissue microenvironment. The investigators will perform a study in healthy, middle-aged men to address the following Specific Aims: Specific Aims: To compare the dose-response relationships between serum testosterone and intraprostatic androgens and androgen action, and serum testosterone and anabolic activity in healthy, middle-aged men. Hypothesis: The investigators hypothesize that very low levels of serum testosterone will lower concentrations of intraprostatic testosterone and dihydrotestosterone (DHT). However, when serum testosterone concentrations are within or even above the normal range there will be no significant increases in intraprostatic testosterone and dihydrotestosterone. In contrast, the investigators expect that anabolic activity will increase with increasing concentrations of circulating testosterone. Secondarily, the investigators hypothesize that increasing levels of serum testosterone beyond the low normal range will have little impact on androgen action within the prostate. Approach: The investigators will conduct a randomized, placebo-controlled trial in healthy men who are medically castrated and administered one of five different doses of testosterone gel (Androgel) for 12 weeks.
Interventions
OTHERplacebo acyline
Placebo acyline subcutaneous injection every 2 weeks
OTHERplacebo gel
daily placebo testosterone gel applied transdermally x 12 weeks
DRUGTestosterone 1% gel 1.25 g
testosterone 1% gel 1.25 g daily applied transdermally x 12 weeks
DRUGTestosterone 1% gel 2.5 g
Testosterone 1% gel 2.5 g daily applied transdermally x 12 weeks
DRUGTestosterone 1% gel 5.0 g
Testosterone 1% gel 5.0 g daily applied transdermally x 12 weeks
DRUGtestosterone 1% gel 10 g
Testosterone 1% gel 10 g daily applied transdermally x 12 weeks
DRUGtestosterone 1% gel 15 g
Testosterone 1% gel 15 g daily applied transdermally x 12 weeks
DRUGAcyline
300 ug/kg subcutaneous injection every 2 weeks
Sponsors
National Institutes of Health (NIH)
National Institute on Aging (NIA)
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
25 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
In good health, without severe systemic illness (i.e., renal, liver, cardiac or lung disease, cancer, insulin dependent diabetes) * Male between the ages of 25 and 55 years old * Able to understand and comply with protocol instructions and requirements * International Prostate Symptom Score (IPSS) \<11 * Agrees to not donate blood during the study * Normal serum total T, LH, FSH, urine analysis, COMP, CBC and sperm count
Exclusion criteria
* History of, or current breast cancer or prostate cancer * Clinically significant findings on digital rectal exam such as nodules, areas of induration or any other malignancy or abnormal prostate ultrasound * History of invasive therapy for BPH * Current or past treatment with a 5α-reductase inhibitor * History of drug or alcohol abuse within the past 12 months * History of a bleeding disorder or anticoagulation * Skin disease that might interfere with T-gel absorption * Participation in another drug study in the past 3 months * A first-degree relative (i.e. father, brother) with a history of prostate cancer * History of infertility or desire for fertility within 6 months, or current pregnant female partner * Weight \>320 pounds or BMI \> 40 * PSA Level \> 2.1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prostate Tissue DHT Concentrations After Treatment | 12 weeks | To measure intraprostatic dihydrotestosterone \[DHT\] levels |
| Prostate Tissue Testosterone Concentrations After Treatment | 12 weeks | To measure intraprostatic testosterone levels |
| Dihydrotestosterone (DHT) | 12 weeks | — |
| Serum Testosterone | 12 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Prostate Specific Antigen | 12 weeks | — |
| Prostate Volume | 12 weeks | — |
| International Prostate Symptom Score (IPSS) | 12 weeks | IPSS score: 0-7 mildly symptomatic, 8-19 moderately symptomatic, 20-35 severely symptomatic |
Other
| Measure | Time frame |
|---|---|
| Androstenedione | 12 weeks |
| DHEA | 12 weeks |
| Androsterone | 12 weeks |
| Progesterone | 12 weeks |
| Pregnenolone | 12 weeks |
| 17-OHPreg | 12 weeks |
| 17-OHP | 12 weeks |
Countries
United States
Participant flow
Recruitment details
Healthy males, 25-55 years old, were recruited via advertisement: flyers and newspaper ads at the University of Washington.
Pre-assignment details
98 screened. 28 screen fails (or did not finish screen). 8 subjects dropped out prior to drug start. 62 subjects started drug. 7 subjects dropped after drug start/pre-drug finish. 2 dropped after finishing study drug, but prior to prostate biopsy. 2 subjects dropped from analysis for non-compliance. 51 completed entire study, included in analysis.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 Placebo acyline every 2 weeks for two weeks + daily placebo gel x 12 weeks
placebo acyline: Placebo acyline subcutaneous injection every 2 weeks
placebo gel: daily placebo testosterone gel applied transdermally x 12 weeks | 8 |
| Arm 2 Acyline (300µg/kg every two weeks) + testosterone 1% gel 1.25 g daily x 12 weeks
Testosterone 1% gel 1.25 g: testosterone 1% gel 1.25 g daily applied transdermally x 12 weeks
Acyline: 300 ug/kg subcutaneous injection every 2 weeks | 9 |
| Arm 3 Acyline (300µg/kg every two weeks) + testosterone 1% gel 2.5 g daily x 12 weeks
Testosterone 1% gel 2.5 g: Testosterone 1% gel 2.5 g daily applied transdermally x 12 weeks
Acyline: 300 ug/kg subcutaneous injection every 2 weeks | 8 |
| Arm 4 Acyline (300µg/kg every two weeks) + testosterone 1% gel 5.0 g daily x 12 weeks
Testosterone 1% gel 5.0 g: Testosterone 1% gel 5.0 g daily applied transdermally x 12 weeks
Acyline: 300 ug/kg subcutaneous injection every 2 weeks | 9 |
| Arm 5 Acyline (300µg/kg every two weeks) + testosterone 1% gel 10 g daily x 12 weeks
testosterone 1% gel 10 g: Testosterone 1% gel 10 g daily applied transdermally x 12 weeks
Acyline: 300 ug/kg subcutaneous injection every 2 weeks | 8 |
| Arm 6 Acyline (300µg/kg every two weeks) + testosterone 1% gel 15 g daily x 12 weeks
testosterone 1% gel 15 g: Testosterone 1% gel 15 g daily applied transdermally x 12 weeks
Acyline: 300 ug/kg subcutaneous injection every 2 weeks | 9 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 1 | 0 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Arm 1 | Arm 2 | Arm 3 | Arm 4 | Arm 5 | Arm 6 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 44 years | 45 years | 45 years | 46 years | 34 years | 42 years | 51 years |
| Body Mass Index (BMI) | 26 kg^m2 | 28 kg^m2 | 28 kg^m2 | 26 kg^m2 | 25 kg^m2 | 25 kg^m2 | 26 kg^m2 |
| DHT Level | 40 ng/dL | 36 ng/dL | 37 ng/dL | 43 ng/dL | 39 ng/dL | 49 ng/dL | 36 ng/dL |
| FSH | 5 mIU/mL | 5.5 mIU/mL | 4 mIU/mL | 5 mIU/mL | 5 mIU/mL | 5.5 mIU/mL | 7 mIU/mL |
| Hematocrit | 43 % | 43 % | 43 % | 43 % | 44 % | 45 % | 43 % |
| International Prostate Symptom Score (IPSS) | 2 units on a scale | 2.5 units on a scale | 1 units on a scale | 2 units on a scale | 0 units on a scale | 1.5 units on a scale | 2 units on a scale |
| Lutenizing Hormone | 4 mIU/mL | 3.5 mIU/mL | 5 mIU/mL | 4 mIU/mL | 3 mIU/mL | 4 mIU/mL | 3 mIU/mL |
| Prostate Specific Antigen (PSA) | 0.75 ng/dL | 0.80 ng/dL | 0.71 ng/dL | 1.09 ng/dL | 0.74 ng/dL | 0.67 ng/dL | 0.69 ng/dL |
| Prostate volume | 18 cm^3 | 20 cm^3 | 19 cm^3 | 17 cm^3 | 17 cm^3 | 17 cm^3 | 19 cm^3 |
| Sex/Gender, Customized Male | 51 Participants | 8 Participants | 9 Participants | 8 Participants | 9 Participants | 8 Participants | 9 Participants |
| Testosterone Level | 459 ng/dL | 450 ng/dL | 448 ng/dL | 554 ng/dL | 419 ng/dL | 482 ng/dL | 452 ng/dL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 10 | 8 / 11 | 6 / 10 | 7 / 9 | 10 / 11 | 6 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 | 0 / 10 | 0 / 9 | 0 / 11 | 0 / 11 |
Outcome results
Primary
Dihydrotestosterone (DHT)
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Dihydrotestosterone (DHT) | 0.3 ng/mL |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Dihydrotestosterone (DHT) | 0.6 ng/mL |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Dihydrotestosterone (DHT) | 0.9 ng/mL |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Dihydrotestosterone (DHT) | 1.0 ng/mL |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Dihydrotestosterone (DHT) | 1.5 ng/mL |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Dihydrotestosterone (DHT) | 1.8 ng/mL |
Primary
Prostate Tissue DHT Concentrations After Treatment
To measure intraprostatic dihydrotestosterone \[DHT\] levels
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Prostate Tissue DHT Concentrations After Treatment | 4.05 ng/g |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Prostate Tissue DHT Concentrations After Treatment | 4.26 ng/g |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Prostate Tissue DHT Concentrations After Treatment | 2.99 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Prostate Tissue DHT Concentrations After Treatment | 3.88 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Prostate Tissue DHT Concentrations After Treatment | 4.12 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Prostate Tissue DHT Concentrations After Treatment | 5.11 ng/g |
Primary
Prostate Tissue Testosterone Concentrations After Treatment
To measure intraprostatic testosterone levels
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Prostate Tissue Testosterone Concentrations After Treatment | 0.3 ng/g |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Prostate Tissue Testosterone Concentrations After Treatment | 0.13 ng/g |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Prostate Tissue Testosterone Concentrations After Treatment | 0.125 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Prostate Tissue Testosterone Concentrations After Treatment | 0.18 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Prostate Tissue Testosterone Concentrations After Treatment | 0.195 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Prostate Tissue Testosterone Concentrations After Treatment | 0.3 ng/g |
Primary
Serum Testosterone
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Serum Testosterone | 4.6 ng/mL |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Serum Testosterone | 1.9 ng/mL |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Serum Testosterone | 3.4 ng/mL |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Serum Testosterone | 3.5 ng/mL |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Serum Testosterone | 6.1 ng/mL |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Serum Testosterone | 7.7 ng/mL |
Secondary
International Prostate Symptom Score (IPSS)
IPSS score: 0-7 mildly symptomatic, 8-19 moderately symptomatic, 20-35 severely symptomatic
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | International Prostate Symptom Score (IPSS) | 1 units on a scale |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | International Prostate Symptom Score (IPSS) | 2 units on a scale |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | International Prostate Symptom Score (IPSS) | 2.5 units on a scale |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | International Prostate Symptom Score (IPSS) | 0 units on a scale |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | International Prostate Symptom Score (IPSS) | 2.5 units on a scale |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | International Prostate Symptom Score (IPSS) | 4 units on a scale |
Secondary
Prostate Specific Antigen
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Prostate Specific Antigen | 0.82 ng/dL |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Prostate Specific Antigen | 0.48 ng/dL |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Prostate Specific Antigen | 0.61 ng/dL |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Prostate Specific Antigen | 0.58 ng/dL |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Prostate Specific Antigen | 0.52 ng/dL |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Prostate Specific Antigen | 0.76 ng/dL |
Secondary
Prostate Volume
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Prostate Volume | 19 cm^3 |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Prostate Volume | 18 cm^3 |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Prostate Volume | 19 cm^3 |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Prostate Volume | 15 cm^3 |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Prostate Volume | 16 cm^3 |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Prostate Volume | 20 cm^3 |
Other Pre-specified
17-OHP
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | 17-OHP | 0.05 ng/g |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | 17-OHP | 0.05 ng/g |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | 17-OHP | 0.05 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | 17-OHP | 0.05 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | 17-OHP | 0.05 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | 17-OHP | 0.05 ng/g |
Other Pre-specified
17-OHPreg
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | 17-OHPreg | 1.19 ng/g |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | 17-OHPreg | 1.25 ng/g |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | 17-OHPreg | 1.23 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | 17-OHPreg | 1.05 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | 17-OHPreg | 1.02 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | 17-OHPreg | 1.36 ng/g |
Other Pre-specified
Androstenedione
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Androstenedione | 0.16 ng/g |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Androstenedione | 0.11 ng/g |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Androstenedione | 0.12 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Androstenedione | 0.13 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Androstenedione | 0.18 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Androstenedione | 0.14 ng/g |
Other Pre-specified
Androsterone
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Androsterone | 0.17 ng/g |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Androsterone | 0.15 ng/g |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Androsterone | 0.12 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Androsterone | 0.17 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Androsterone | 0.17 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Androsterone | 0.21 ng/g |
Other Pre-specified
DHEA
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | DHEA | 29.3 ng/g |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | DHEA | 26.2 ng/g |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | DHEA | 22.1 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | DHEA | 26.8 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | DHEA | 24.4 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | DHEA | 18.6 ng/g |
Other Pre-specified
Pregnenolone
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Pregnenolone | 28.7 ng/g |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Pregnenolone | 29.5 ng/g |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Pregnenolone | 32.7 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Pregnenolone | 32.4 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Pregnenolone | 27.9 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Pregnenolone | 23.9 ng/g |
Other Pre-specified
Progesterone
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1/Placebo Acyline Inject & Placebo Testosterone Gel | Progesterone | 0.09 ng/g |
| Arm 2 Acyline Inject Every 2 Weeks & Daily T 1% Gel 1.25g | Progesterone | 0.08 ng/g |
| Arm 3 Acyline Inject Every 2 Weeks & Daily T 1% Gel 2.5 | Progesterone | 0.06 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 5g | Progesterone | 0.08 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 10g | Progesterone | 0.09 ng/g |
| Acyline Inject Every 2 Weeks & Daily T 1% Gel 15g | Progesterone | 0.07 ng/g |