Hypogonadism
Conditions
Brief summary
The main purpose of this study is to evaluate if testosterone solution can raise testosterone hormone levels into the normal range, and also improve levels of sexual arousal, interest and drive and/or energy level, in men with low testosterone and decreased sexual arousal, interest and drive and/or decreased energy. The study will last about 16 weeks, followed by an optional 24 week open label treatment phase to investigate the long term safety of testosterone solution.
Interventions
DRUGTestosterone Solution
Administered topically to axillae.
DRUGPlacebo Solution
Administered topically to axillae.
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Total testosterone level \<300 nanogram per deciliter (ng/dL) \[10.4 nanomole per Liter (nmol/L)\] at each of 2 screening visits * At least 1 symptom of testosterone deficiency, which must include decreased energy or decreased sexual drive * Prostate Specific Antigen (PSA) \<4 nanogram per milliliter (ng/ml) at screening
Exclusion criteria
* Sexual partner who is or becomes pregnant at any time during the study * Use of long-acting intramuscular (IM) testosterone undecanoate or testosterone pellets in the 6-month period prior to screening * Body Mass Index (BMI) \>37 kilogram per square meter (kg/m\^2) at screening * Severe lower urinary tract symptoms and/or significant prostate enlargement * Prolactin lab test result of \>30 ng/mL at screening * Hemoglobin A1c (HbA1c) \>11% at screening * Hematocrit ≥50% (\>54% at elevated altitude) at screening * Current use of any medications, herbal, and/or nutritional supplements that can interfere with testosterone * Dermatologic condition in underarm area that might interfere with testosterone absorption (for example, eczema) or be exacerbated by topical testosterone replacement therapy * Currently receiving treatment with cancer chemotherapy or antiandrogens * Chronic use of systemic glucocorticoids (use for \>14 days within the 3 months prior to screening); use of non-testosterone anabolic steroids within 12 months prior to screening * Competitive athletes involved in a sport in which they may be screened for anabolic steroids * History of use of estrogenizing agents within 12 months prior to screening * History of luteinizing hormone-releasing hormone antagonist or agonist treatment in the last 6 months prior to screening * History of clomiphene or other anti-estrogen treatment in the 3 months prior to screening * Use of finasteride within 3 months prior to screening, or use of dutasteride within 6 months prior to screening * Current use of warfarin or phenprocoumon * History of frequent opioid use: \>1 time/week during any week within 30 days prior to screening * Current use of dopamine receptor agonists (cabergoline, pergolide, bromocriptine) * Have a history of significant central nervous system injuries or disease (including stroke, spinal cord injury, or multiple sclerosis) within 6 months prior to screening * Systolic blood pressure \>170 or \<90 millimeter of mercury (mm Hg) or diastolic blood pressure \>100 or \<50 mm Hg at screening or a history of malignant hypertension * History of unstable angina as defined by Braunwald Classification of Unstable Angina or angina occurring during sexual intercourse in the last 6 months * History of any of the following coronary conditions within 90 days of screening: myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention (angioplasty or stent placement) * Have any supraventricular arrhythmia with an uncontrolled ventricular response \[mean heart rate \>100 beats per minute (bpm)\] at rest, or have any history of spontaneous or induced sustained ventricular tachycardia (heart rate \>100 bpm for ≥30 seconds), or use of an automatic internal cardioverter-defibrillator * Have a history of sudden cardiac arrest * Exhibit any evidence of congestive heart failure \[New York Heart Association (NYHA) Class 2 or above\], within 6 months prior to screening * Have had a new, significant cardiac conduction defect within 90 days prior to screening * Clinical suspicion (or history) of prostate cancer during digital rectal examination at screening * Known or suspected breast cancer (or history of breast cancer) or other active cancer (with the exception of nonmelanotic skin cancer) * Exhibit evidence of severe renal impairment \[creatinine clearance \<30 milliliter per minute (mL/min) as determined by the Cockcroft-Gault formula\] at screening * Exhibit a history of severe liver disease or clinical evidence of hepatic impairment at screening * Have a history of human immunodeficiency virus (HIV) infection * Severe sleep apnea * Untreated hypothyroidism, hypercortisolism or other significant endocrinopathy (other than hypogonadism) that contributes to symptoms of low energy or fatigue
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Total Serum Testosterone Concentration Within Normal Range at Week 12 | Week 12 | Normal range for total serum testosterone was defined as 300 to 1050 nanograms per deciliter (ng/dL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Sexual Arousal, Interest, and Drive (SAID) Scale Scores | Baseline, Week 12 | The SAID Scale is a self-administered instrument used to assess sexual arousal, interest, and sex drive in men with symptomatic hypogonadism. The SAID consists of 5 questions that were scored on a scale from 1 to 5, with 5 corresponding to greater levels of sexual arousal, interest, or drive. The SAID Scale total score was computed by summing the item scores and linearly transforming the sum to a 0 to 100 scale, with higher scores corresponding to greater sexual arousal, interest, and drive. Least squares (LS) mean change from baseline was calculated using an analysis of covariance (ANCOVA) with treatment group and the baseline value as covariates. |
| Change From Baseline to Week 12 in Hypogonadism Energy Diary (HED) Scores | Baseline, Week 12 | The HED is a self-administered instrument used to assess real-time energy levels in men with symptomatic hypogonadism. It consists of 2 questions that were scored on a scale from 0 to 10, with 10 corresponding to Full of Energy or Not Tired at All (The Tiredness scale was reverse-mapped, as it was collected with 10 corresponding to Extreme Tiredness). The questionnaire was completed 3 times daily (forming 6 unique items) for 7 consecutive days. Item scores were computed by averaging the values for each item across 7 days. If more than 2 days were missing for an item, the item score was missing. The total score was computed by summing the item scores and linearly transforming the sum to a 0 to 100 scale, with higher scores corresponding to greater energy. If any item score was missing, the total score was missing. LS mean change from baseline was calculated using ANCOVA with treatment group and the baseline value as covariates. |
| Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL) | Double Blind Baseline, Week 12, Open Label Baseline, Week 36 | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total International Prostate Symptom Score (IPSS) | Baseline, Week 12, Week 36 | The IPSS is a self-administered instrument used to assess for the severity of lower urinary tract symptoms. The IPSS consists of 7 questions that were scored on a scale from 0 (none/no symptoms) to 5 (frequent symptoms), for a total score range of 0 to 35. Higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. LS mean change from baseline was calculated using ANCOVA with treatment group and the baseline value as covariates. |
Countries
Argentina, Canada, Germany, Italy, Puerto Rico, South Korea, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Solution Placebo solution applied topically to axillae once daily for 12 week double-blind treatment period. In optional open label extension (OLE) period, 60 milligram (mg) testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 24 weeks. | 357 |
| Testosterone Solution Sixty mg testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 12 week double-blind treatment period. Optional OLE period starting at 60 mg/day with possible down/up titration (30 - 120 mg/day) for 24 weeks. | 358 |
| Total | 715 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Phase | Adverse Event | 11 | 8 |
| Double Blind Phase | Entry Criteria Not Met | 0 | 2 |
| Double Blind Phase | Lost to Follow-up | 3 | 5 |
| Double Blind Phase | Physician Decision | 2 | 2 |
| Double Blind Phase | Protocol Violation | 17 | 11 |
| Double Blind Phase | Sponsor Decision | 8 | 8 |
| Double Blind Phase | Withdrawal by Subject | 22 | 20 |
| OLE Phase | Adverse Event | 17 | 15 |
| OLE Phase | Death | 1 | 0 |
| OLE Phase | Entry Criteria Not Met | 3 | 5 |
| OLE Phase | Lack of Efficacy | 3 | 7 |
| OLE Phase | Lost to Follow-up | 5 | 5 |
| OLE Phase | Physician Decision | 3 | 1 |
| OLE Phase | Protocol Violation | 4 | 4 |
| OLE Phase | Sponsor Decision | 7 | 9 |
| OLE Phase | Withdrawal by Subject | 10 | 10 |
Baseline characteristics
| Characteristic | Placebo Solution | Total | Testosterone Solution |
|---|---|---|---|
| Age, Continuous | 55.9 years STANDARD_DEVIATION 11.35 | 55.3 years STANDARD_DEVIATION 10.98 | 54.7 years STANDARD_DEVIATION 10.58 |
| Body Mass Index (BMI) | 30.9 kilogram per square meter (kg/m²) STANDARD_DEVIATION 4.21 | 30.6 kilogram per square meter (kg/m²) STANDARD_DEVIATION 4.14 | 30.3 kilogram per square meter (kg/m²) STANDARD_DEVIATION 4.06 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 51 Participants | 108 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 280 Participants | 559 Participants | 279 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 26 Participants | 48 Participants | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 38 Participants | 83 Participants | 45 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants | 50 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 282 Participants | 563 Participants | 281 Participants |
| Region of Enrollment East Asia | 34 participants | 74 participants | 40 participants |
| Region of Enrollment Europe | 63 participants | 120 participants | 57 participants |
| Region of Enrollment North America | 232 participants | 463 participants | 231 participants |
| Region of Enrollment South America | 28 participants | 58 participants | 30 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 357 Participants | 715 Participants | 358 Participants |
| Symptoms of Hypogonadism Both Symptoms Present | 269 participants | 540 participants | 271 participants |
| Symptoms of Hypogonadism Only Decreased Sexual Drive | 39 participants | 79 participants | 40 participants |
| Symptoms of Hypogonadism Only Low Energy | 49 participants | 96 participants | 47 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 143 / 356 | 148 / 354 | 252 / 558 |
| serious Total, serious adverse events | 8 / 356 | 4 / 354 | 24 / 558 |
Outcome results
Primary
Number of Participants With Total Serum Testosterone Concentration Within Normal Range at Week 12
Normal range for total serum testosterone was defined as 300 to 1050 nanograms per deciliter (ng/dL).
Time frame: Week 12
Population: All randomized participants who completed 12 weeks of treatment and had non-missing testosterone concentration at week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Solution | Number of Participants With Total Serum Testosterone Concentration Within Normal Range at Week 12 | 43 participants |
| Testosterone Solution | Number of Participants With Total Serum Testosterone Concentration Within Normal Range at Week 12 | 217 participants |
p-value: <0.001Chi-squared
Secondary
Change From Baseline to Week 12 in Hypogonadism Energy Diary (HED) Scores
The HED is a self-administered instrument used to assess real-time energy levels in men with symptomatic hypogonadism. It consists of 2 questions that were scored on a scale from 0 to 10, with 10 corresponding to Full of Energy or Not Tired at All (The Tiredness scale was reverse-mapped, as it was collected with 10 corresponding to Extreme Tiredness). The questionnaire was completed 3 times daily (forming 6 unique items) for 7 consecutive days. Item scores were computed by averaging the values for each item across 7 days. If more than 2 days were missing for an item, the item score was missing. The total score was computed by summing the item scores and linearly transforming the sum to a 0 to 100 scale, with higher scores corresponding to greater energy. If any item score was missing, the total score was missing. LS mean change from baseline was calculated using ANCOVA with treatment group and the baseline value as covariates.
Time frame: Baseline, Week 12
Population: Randomized participants who reported low energy at baseline with non-missing HED questionnaire at baseline and at least one post baseline visit. Missing data endpoints were imputed using LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Solution | Change From Baseline to Week 12 in Hypogonadism Energy Diary (HED) Scores | 7.5 units on a scale | Standard Error 0.87 |
| Testosterone Solution | Change From Baseline to Week 12 in Hypogonadism Energy Diary (HED) Scores | 10.5 units on a scale | Standard Error 0.89 |
p-value: 0.01999.5% CI: [-0.59, 6.45]ANCOVA
Secondary
Change From Baseline to Week 12 in Sexual Arousal, Interest, and Drive (SAID) Scale Scores
The SAID Scale is a self-administered instrument used to assess sexual arousal, interest, and sex drive in men with symptomatic hypogonadism. The SAID consists of 5 questions that were scored on a scale from 1 to 5, with 5 corresponding to greater levels of sexual arousal, interest, or drive. The SAID Scale total score was computed by summing the item scores and linearly transforming the sum to a 0 to 100 scale, with higher scores corresponding to greater sexual arousal, interest, and drive. Least squares (LS) mean change from baseline was calculated using an analysis of covariance (ANCOVA) with treatment group and the baseline value as covariates.
Time frame: Baseline, Week 12
Population: Randomized participants who reported low sex drive at baseline with non-missing SAID Scale data at baseline and at least one post baseline visit. Missing data endpoints were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Solution | Change From Baseline to Week 12 in Sexual Arousal, Interest, and Drive (SAID) Scale Scores | 6.3 units on a scale | Standard Error 0.99 |
| Testosterone Solution | Change From Baseline to Week 12 in Sexual Arousal, Interest, and Drive (SAID) Scale Scores | 11.4 units on a scale | Standard Error 1.02 |
p-value: <0.00199.5% CI: [1.05, 9.07]ANCOVA
Secondary
Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL)
Time frame: Double Blind Baseline, Week 12, Open Label Baseline, Week 36
Population: All participants with non-missing PSA result at the specified time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Solution | Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL) | Double-Blind Baseline (n=350, 347) | 1 participants |
| Placebo Solution | Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL) | Week 12 (n=289, 299) | 3 participants |
| Placebo Solution | Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL) | Open Label Baseline (n=269, 278) | 0 participants |
| Placebo Solution | Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL) | Week 36 (n=219, 223) | 4 participants |
| Testosterone Solution | Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL) | Week 36 (n=219, 223) | 4 participants |
| Testosterone Solution | Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL) | Double-Blind Baseline (n=350, 347) | 0 participants |
| Testosterone Solution | Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL) | Open Label Baseline (n=269, 278) | 0 participants |
| Testosterone Solution | Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL) | Week 12 (n=289, 299) | 4 participants |
Other Pre-specified
Change From Baseline in Total International Prostate Symptom Score (IPSS)
The IPSS is a self-administered instrument used to assess for the severity of lower urinary tract symptoms. The IPSS consists of 7 questions that were scored on a scale from 0 (none/no symptoms) to 5 (frequent symptoms), for a total score range of 0 to 35. Higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. LS mean change from baseline was calculated using ANCOVA with treatment group and the baseline value as covariates.
Time frame: Baseline, Week 12, Week 36
Population: All randomized participants with non-missing baseline IPSS measurement and at least one non-missing post baseline IPSS measurement. Missing data endpoints were imputed using LOCF.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Solution | Change From Baseline in Total International Prostate Symptom Score (IPSS) | Change from Baseline to Week 12 | -0.7 units on a scale | Standard Error 0.24 |
| Placebo Solution | Change From Baseline in Total International Prostate Symptom Score (IPSS) | Change from Baseline to Week 36 (n=247, 255) | -0.7 units on a scale | Standard Error 0.28 |
| Testosterone Solution | Change From Baseline in Total International Prostate Symptom Score (IPSS) | Change from Baseline to Week 12 | -0.9 units on a scale | Standard Error 0.24 |
| Testosterone Solution | Change From Baseline in Total International Prostate Symptom Score (IPSS) | Change from Baseline to Week 36 (n=247, 255) | -0.7 units on a scale | Standard Error 0.27 |
Comparison: Change from Baseline to Week 12p-value: 0.44295% CI: [-0.94, 0.41]ANCOVA
Comparison: Change from Baseline to Week 36p-value: 0.90595% CI: [-0.82, 0.72]ANCOVA