Hypogonadism, Hypogonadism, Male, Hypogonadotropic Hypogonadism
Conditions
Brief summary
Testosterone is the principal androgen produced by the male testes. Male Hypogonadism is the result of inadequate production of testosterone by the Leydig cells of the testes and is reflected by total serum concentrations of testosterone of \< 300 nanograms (ng)/deciliters (dL), with no discernible diurnal pattern. The etiology of hypogonadism may be primary or secondary. The treatment of males with primary, and in some cases, secondary hypogonadism includes administration of testosterone. Testim® and Fortesta® are topical gels that when applied daily help to increase the total testosterone levels in the blood through skin absorption. Aveed® is an injectable form of testosterone treatment and participants randomized to this treatment arm will receive 3 injections over the course of 16 weeks. This study is designed to evaluate the effect on blood pressure of approved testosterone products (Testim®, Fortesta®, and Aveed®) after 16 weeks of therapy using 24-hour ambulatory blood pressure to reveal shifts in blood pressure levels.
Interventions
DRUGAveed Injectable Product
Testosterone undecanoate administered by intramuscular injections.
DRUGFortesta
Testosterone gel administered topically. The daily dose of the study drug will be titrated for each participant, according to approved dosage and administration instructions, until the circulating testosterone concentrations of the participant reaches normal concentrations (300-1000 ng/dL).
DRUGTestim
Testosterone gel administered topically. The daily dose of the study drug will be titrated for each participant, according to approved dosage and administration instructions, until the circulating testosterone concentrations of the participant reaches normal concentrations (300-1000 ng/dL).
Sponsors
Endo Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have a diagnosis of primary hypogonadism or hypogonadotropic hypogonadism. 2. Have a total serum testosterone at screening \< 300 ng/dL based on 2 blood samples obtained at 10 am (+/-2 hours) on 2 separate occasions at least 48 hours apart 3. Be naïve to androgen replacement or washout of 12 weeks following intramuscular androgen injections; 4 weeks following topical or buccal, nasal, or oral androgens. 4. Have a screening blood pressure at rest of less than 140 millimeters of mercury (mm Hg) for systolic blood pressure and less than 90 mm Hg for diastolic blood pressure. 5. Be judged to be in good health. 6. Participants enrolled in the Testim or Fortesta treatment arms: participants agree to take necessary precautions to avoid skin-to-skin contact and potential transfer and if male use effective contraception. 7. Be willing and able to cooperate with the requirements of the study.
Exclusion criteria
1. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) Title 45, Part 46, Section 46.111(b) and other local and national regulations, including but not limited to, employees (temporary, part-time, full time, etc) or a family member of the research staff conducting the study, or of the sponsor, or of the contract research organization, or of the Institutional Review Board/Independent Ethics Committee (IRB/IEC). 2. Has a history of significant sensitivity or allergy to the study drugs, including androgens, or product excipients. 3. Has a history of or medical examination findings renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric conditions, cardiovascular disease/dysrhythmia) or any other condition(s) that restricts study participation. 4. Has clinically significant changes in any medications (including dosages) or medical conditions in the 28 days prior to screening 5. Is not on a stable medication regimen for at least 3 months for the treatment of a chronic condition. 6. Has had a cardiovascular and/or cerebrovascular event within the last 6 months. 7. Needs blood pressure cuff size larger than 50 centimeters. 8. Works a night shift or performs heavy manual labor. 9. Has any known contraindication(s) to active study treatment including, but not limited to: known or suspected carcinoma of the prostate or breast, previous history of cancer (except basal cell carcinoma of the skin) liver disease, active deep vein thrombosis, atrial fibrillation, untreated sleep apnea, or is immune compromised. 10. Uses known inhibitors (for example, ketoconazole) or inducers of cytochrome P450 3A (for example, dexamethasone, phenytoin, rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 days prior to study drug administration and through the end of the study. 1. Uses any of the above listed drugs within 5 half lives of the last dose in the past 6 months prior to study drug administration. 2. Has received any of the above listed drugs by injection within 30 days or 10 half lives (whichever is longer) prior to study drug administration. 3. Uses nutraceuticals or homeopathic compounds which have a known effect on blood pressure. 11. Has a history of drug or alcohol abuse within 6 months prior to study drug administration. 12. Has untreated moderate to severe depression. 13. Has any skin lesions/cuts/injury at the application site that prohibits topical application and/or intramuscular injection of study drug. 14. Has suspected reversible hypogonadism. 15. Donated blood or blood products or experienced significant blood loss within 90 days prior to study drug administration. 16. Intends to conceive at any time during the study. 17. Donated bone marrow within 6 months prior to study drug administration. 18. Has participated in a previous investigational study or received treatment with an investigational product within 30 days of screening. 19. Has a diagnosis of, is undergoing therapy for, or has received therapy for a hematologic malignancy in the 5 years prior to screening. 20. Has a history of substance abuse or is taking any substance of abuse (Note: participants on a stable dose of any medications that have been prescribed by a healthcare practitioner for a properly documented medical condition are exempt). 21. Abnormal electrocardiogram (ECG) (QT prolongation with QTc ≥450 milliseconds). 22. Has evidence of abnormalities on physical examination, vital signs, ECG, or clinical lab values, unless judged to be clinically insignificant by the investigator 23. Has any other condition that, in the investigator's opinion, might indicate the participant to be unsuitable for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-Hour Average Systolic Ambulatory Blood Pressure to End of Study (EOS) | Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms | The mean change from Baseline to EOS in 24-hour average systolic ambulatory blood pressure, for each treatment group was analyzed using an analysis of covariance (ANCOVA) model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour average systolic ambulatory blood pressure as covariate. EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-Hour Average Diastolic Ambulatory Blood Pressure to EOS | Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms | The mean change from Baseline to EOS in 24-hour average diastolic ambulatory blood pressure, for each treatment group was analyzed using an ANCOVA model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour average diastolic ambulatory blood pressure as covariate. EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114. |
| Change From Baseline in 24-Hour Average Heart Rate to EOS | Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms | The mean change from Baseline to EOS in 24-hour average heart rate, for each treatment group was analyzed using an ANCOVA model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour average heart rate as covariate. EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114. |
| Change From Baseline in 24-Hour Average Mean Arterial Pressure (MAP) to EOS | Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms | The mean change from Baseline to EOS in 24-hour MAP, for each treatment group was analyzed using an ANCOVA model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour MAP as covariate.EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114. |
| Percentage of Participants Taking New Antihypertensive Medications | EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms | A new antihypertensive medication was any antihypertensive medication taken on or after the screening Visit through the EOS visit and not taken prior to the screening visit. |
| Percentage of Participants With Dose Increase From Baseline in Antihypertensive Medications | EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms | A new antihypertensive medication was any antihypertensive medication taken on or after the screening Visit through the EOS visit and not taken prior to the screening visit. |
| Change From Baseline in 24-Hour Average Pulse Pressure (PP) to EOS | Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms | The mean change from Baseline to EOS in 24-hour average PP for each treatment group was analyzed using an ANCOVA model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour average PP as covariate. EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AVEED® (Testosterone Undecanoate Injection) Participants received 750 mg/3 mL of injection administered by intramuscular route on Days 2, 30 and 100. | 222 |
| FORTESTA® (Testosterone Gel) Participants received 40 mg once daily topical gel application starting from Day 2. Participants were followed up on Day 16, Day 37, Day 67, and Day 97. | 223 |
| TESTIM® (Testosterone Gel) Participants received 50 mg once daily topical gel application starting from Day 2. Participants were followed up on Day 16, Day 37, Day 67, and Day 97. | 225 |
| Total | 670 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 2 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 5 | 6 |
| Overall Study | Other than specified | 0 | 1 | 4 |
| Overall Study | Randomized, not treated | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 14 | 21 | 21 |
Baseline characteristics
| Characteristic | AVEED® (Testosterone Undecanoate Injection) | Total | TESTIM® (Testosterone Gel) | FORTESTA® (Testosterone Gel) |
|---|---|---|---|---|
| 24-Hour Average Systolic Ambulatory Blood Pressure | 124.90 mmHg STANDARD_DEVIATION 12.178 | 124.43 mmHg STANDARD_DEVIATION 12.058 | 124.45 mmHg STANDARD_DEVIATION 12.505 | 123.95 mmHg STANDARD_DEVIATION 11.499 |
| Age, Continuous | 59.9 years STANDARD_DEVIATION 10.1 | 58.2 years STANDARD_DEVIATION 10.46 | 58.4 years STANDARD_DEVIATION 10.22 | 56.3 years STANDARD_DEVIATION 10.78 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 71 Participants | 242 Participants | 79 Participants | 92 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 151 Participants | 428 Participants | 146 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 19 Participants | 10 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 37 Participants | 121 Participants | 43 Participants | 41 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 174 Participants | 521 Participants | 168 Participants | 179 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 222 Participants | 670 Participants | 225 Participants | 223 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 224 | 0 / 224 | 0 / 225 |
| other Total, other adverse events | 8 / 222 | 9 / 223 | 13 / 225 |
| serious Total, serious adverse events | 3 / 222 | 1 / 223 | 2 / 225 |
Outcome results
Primary
Change From Baseline in 24-Hour Average Systolic Ambulatory Blood Pressure to End of Study (EOS)
The mean change from Baseline to EOS in 24-hour average systolic ambulatory blood pressure, for each treatment group was analyzed using an analysis of covariance (ANCOVA) model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour average systolic ambulatory blood pressure as covariate. EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114.
Time frame: Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms
Population: Full analysis set included all ITT participants with valid Baseline and EOS ABPM assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AVEED® (Testosterone Undecanoate Injection) | Change From Baseline in 24-Hour Average Systolic Ambulatory Blood Pressure to End of Study (EOS) | 2.77 millimeters of mercury (mmHg) |
| FORTESTA® (Testosterone Gel) | Change From Baseline in 24-Hour Average Systolic Ambulatory Blood Pressure to End of Study (EOS) | 2.78 millimeters of mercury (mmHg) |
| TESTIM® (Testosterone Gel) | Change From Baseline in 24-Hour Average Systolic Ambulatory Blood Pressure to End of Study (EOS) | 2.15 millimeters of mercury (mmHg) |
Secondary
Change From Baseline in 24-Hour Average Diastolic Ambulatory Blood Pressure to EOS
The mean change from Baseline to EOS in 24-hour average diastolic ambulatory blood pressure, for each treatment group was analyzed using an ANCOVA model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour average diastolic ambulatory blood pressure as covariate. EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114.
Time frame: Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms
Population: Full analysis set included all ITT participants with valid Baseline and EOS ABPM assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AVEED® (Testosterone Undecanoate Injection) | Change From Baseline in 24-Hour Average Diastolic Ambulatory Blood Pressure to EOS | 1.85 mmHg |
| FORTESTA® (Testosterone Gel) | Change From Baseline in 24-Hour Average Diastolic Ambulatory Blood Pressure to EOS | 1.22 mmHg |
| TESTIM® (Testosterone Gel) | Change From Baseline in 24-Hour Average Diastolic Ambulatory Blood Pressure to EOS | 0.81 mmHg |
Secondary
Change From Baseline in 24-Hour Average Heart Rate to EOS
The mean change from Baseline to EOS in 24-hour average heart rate, for each treatment group was analyzed using an ANCOVA model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour average heart rate as covariate. EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114.
Time frame: Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms
Population: Full analysis set included all ITT participants with valid Baseline and EOS ABPM assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AVEED® (Testosterone Undecanoate Injection) | Change From Baseline in 24-Hour Average Heart Rate to EOS | 2.89 beats per minute |
| FORTESTA® (Testosterone Gel) | Change From Baseline in 24-Hour Average Heart Rate to EOS | 1.56 beats per minute |
| TESTIM® (Testosterone Gel) | Change From Baseline in 24-Hour Average Heart Rate to EOS | 1.84 beats per minute |
Secondary
Change From Baseline in 24-Hour Average Mean Arterial Pressure (MAP) to EOS
The mean change from Baseline to EOS in 24-hour MAP, for each treatment group was analyzed using an ANCOVA model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour MAP as covariate.EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114.
Time frame: Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms
Population: Full analysis set included all ITT participants with valid Baseline and EOS ABPM assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AVEED® (Testosterone Undecanoate Injection) | Change From Baseline in 24-Hour Average Mean Arterial Pressure (MAP) to EOS | 2.13 mmHg |
| FORTESTA® (Testosterone Gel) | Change From Baseline in 24-Hour Average Mean Arterial Pressure (MAP) to EOS | 1.78 mmHg |
| TESTIM® (Testosterone Gel) | Change From Baseline in 24-Hour Average Mean Arterial Pressure (MAP) to EOS | 1.21 mmHg |
Secondary
Change From Baseline in 24-Hour Average Pulse Pressure (PP) to EOS
The mean change from Baseline to EOS in 24-hour average PP for each treatment group was analyzed using an ANCOVA model with treatment and study center (pooled centers) as fixed effects, Baseline 24-hour average PP as covariate. EOS for the Aveed arm was Day 107 and EOS for Fortesta and Testim, was Day 114.
Time frame: Baseline (Day 1), EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms
Population: Full analysis set included all ITT participants with valid Baseline and EOS ABPM assessments.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AVEED® (Testosterone Undecanoate Injection) | Change From Baseline in 24-Hour Average Pulse Pressure (PP) to EOS | 0.80 mmHg |
| FORTESTA® (Testosterone Gel) | Change From Baseline in 24-Hour Average Pulse Pressure (PP) to EOS | 1.49 mmHg |
| TESTIM® (Testosterone Gel) | Change From Baseline in 24-Hour Average Pulse Pressure (PP) to EOS | 1.40 mmHg |
Secondary
Percentage of Participants Taking New Antihypertensive Medications
A new antihypertensive medication was any antihypertensive medication taken on or after the screening Visit through the EOS visit and not taken prior to the screening visit.
Time frame: EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms
Population: Full analysis set included all ITT participants with valid Baseline and EOS ABPM assessments.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AVEED® (Testosterone Undecanoate Injection) | Percentage of Participants Taking New Antihypertensive Medications | 1.4 Percentage of participants |
| FORTESTA® (Testosterone Gel) | Percentage of Participants Taking New Antihypertensive Medications | 1.5 Percentage of participants |
| TESTIM® (Testosterone Gel) | Percentage of Participants Taking New Antihypertensive Medications | 2.2 Percentage of participants |
Secondary
Percentage of Participants With Dose Increase From Baseline in Antihypertensive Medications
A new antihypertensive medication was any antihypertensive medication taken on or after the screening Visit through the EOS visit and not taken prior to the screening visit.
Time frame: EOS Visit: up to Day 107 for the Aveed Arm, and up to Day 114 for Fortesta and Testim Arms
Population: Full analysis set included all ITT participants with valid Baseline and EOS ABPM assessments.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AVEED® (Testosterone Undecanoate Injection) | Percentage of Participants With Dose Increase From Baseline in Antihypertensive Medications | 0 Percentage of participants |
| FORTESTA® (Testosterone Gel) | Percentage of Participants With Dose Increase From Baseline in Antihypertensive Medications | 0 Percentage of participants |
| TESTIM® (Testosterone Gel) | Percentage of Participants With Dose Increase From Baseline in Antihypertensive Medications | 0 Percentage of participants |