Hypogonadism
Conditions
Brief summary
A Phase 3, Randomized, Active-controlled, Open-label Study of the Safety and Efficacy of Oral Testosterone Undecanoate (TU) in Hypogonadal Men
Detailed description
This is a multicenter, Phase 3, randomized, open-label, active-comparator group, efficacy (based on Cavg of T), and safety study in adult hypogonadal male subjects. Enrollment is based on criteria designed to select the general population of hypogonadal men. Study drug doses will be titrated using a dose-titration algorithm based on total T Cavg. Subjects may be androgen treatment-naïve or washed out of prior androgen replacement therapies. Subjects must have 2 total T levels \< 300 ng/dL based on 2 blood samples obtained in the morning (AM) on 2 separate days approximately 7 days apart. Approximately 180 subjects will be randomly assigned to receive open-label treatment in a 3:1 ratio of oral TU to Axiron (ie, approximately 135 subjects will be randomly assigned to oral TU and approximately 45 subjects will be randomly assigned to Axiron topical solution). Subjects who complete the study will receive approximately 105 days of treatment. Dose titrations will be based on the T Cavg from serial PK sampling obtained on day 21 and 56 of treatment. Primary efficacy will be based on percentage of subjects within eugonadal range at Visit 7. A subset of approximately 30 subjects will participate in a cosyntropin stimulation test on Day 1 (before administration of study drug) and Day 106 after the last 24-hour PK sample has been drawn.
Interventions
Subjects assigned to oral TU treatment will begin at 237 mg TU twice daily. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg \< 350 ng/dL, decreased if \> 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.
DRUGAxiron Testosterone Topical Solution
Subjects assigned to Axiron treatment will begin at 60 mg Axiron every morning. Axiron is applied to the axilla only. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg \< 350 ng/dL, decreased if \> 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL.
Sponsors
Syneos Health
Clarus Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Man 18 to 65 years of age, inclusive, with hypogonadism as defined by 2 AM total T values of \<300 ng/dL drawn on 2 separate days (\[approximately 7 days apart\]). 2. Adequate venous access 3. Must be naïve to androgen-replacement therapy or washed out of prior androgen replacement therapies; willing to cease current T treatment or currently not be taking T treatment. Subjects must remain off all forms of T, except for dispensed study drug, throughout the entire study. 4. Subjects on replacement therapy for hypopituitarism or multiple endocrine deficiencies must be on stable doses of thyroid hormone and adrenal replacement hormones for at least 14 days before Screen 1. 5. Voluntarily given written informed consent to participate in this study.
Exclusion criteria
1. Received oral topical, intranasal, or buccal T therapy within the previous 2 weeks, intramuscular T injection of short-acting duration within the previous 4 weeks, intramuscular T injection of long-acting duration within the previous 20 weeks, or T implantable pellets within the previous 6 months. 2. Received oral TU in a previous Clarus-sponsored investigational study. 3. Significant intercurrent disease of any type; in particular, liver, kidney, uncontrolled or poorly controlled heart disease, including hypertension, congestive heart failure or coronary heart disease, or psychiatric-illness, including severe depression. 4. Recent (within 2 years) history of stroke, transient ischemic attack, or acute coronary event. 5. A mean of the triplicate assessment of systolic blood pressure (sBP) \> 150 mm Hg and/or diastolic blood pressure (dBP) \> 90 mm Hg at screening. 6. Recent (within 2 years) history of angina or stent (coronary or carotid) placement. 7. Untreated, severe obstructive sleep apnea. 8. Clinically significant abnormal laboratory values (serum transaminases \> 2 × ULN, serum bilirubin \> 1.5 × ULN and serum creatinine \> 1.5 × ULN). 9. Hematocrit (HCT) value of \< 35% or \> 48%. 10. Has a history of polycythemia, either idiopathic or associated with testosterone replacement therapy (TRT). 11. Glycosylated hemoglobin (A1C) \> 8.5%. 12. BMI ≥ 38 kg/m2. 13. If receiving the following medications: * Has been on stable doses of lipid-lowering medication for \< 3 months; * Has been on stable doses of oral medication for diabetes for \< 2 months; or * Has been on stable doses of antihypertensive medication for \< 3 months. 14. Abnormal prostate digital rectal examination (palpable nodules), elevated Prostate Specific Antigen (serum PSA \> 4.0 ng/mL), International Prostate Symptom Score (I-PSS) \> 19 points at screening, and/or history of, or current or suspected, prostate cancer. 15. History of, or current or suspected, breast cancer. 16. History of abnormal bleeding tendencies or thrombophlebitis unrelated to venipuncture or intravenous cannulation within the previous 2 years. 17. Use of dietary supplements such as saw palmetto or phytoestrogens and any dietary supplements that may increase total T, such as androstenedione or dehydroepiandrosterone within the previous 4 weeks. 18. Known malabsorption syndrome and/or current treatment with oral lipase inhibitors and bile acid-binding resins. 19. Inability to refrain from smoking during the confinement periods as required by the individual study center. 20. History of alcohol abuse or any drug substance within the previous 2 years. 21. Poor compliance or unlikely to keep clinic appointments. 22. Has received any drug as part of another research study within 30 days of initial dose administration in this study. 23. Donated blood (≥ 500 mL) within the 12-week period before the initial study dose. 24. Currently uses antiandrogens, 5-alpha-reductase inhibitors, estrogens, potent oral CYP3A4 inducers, potent CYP3A4 inhibitors, or long acting opioid analgesics. 25. Unwilling or unable to follow the dietary guidelines for this study, related to taking oral TU with meals that contain approximately 20 to 40 g of fat
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Oral TU Treated Subjects Who Have a Total T Cavg in the Eugonadal Range of 252 to 907 ng/dL at Visit 7 | Day 105 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Post-stimulation Cortisol Level of >18 ug/dL at Visit 8 | Approximately 4.5 months | Compare the Oral TU-treated subjects and the Topical Axiron®-treated subjects with respect to number of subjects in the cosyntropin stimulation test substudy with a normal maximum post-stimulation (cosyntropin stimulation) cortisol level at Visit 8. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oral Testosterone Undecanoate Approximately 135 subjects will receive oral TU treatment during the study for approximately 3.5 months. Subjects randomly assigned to the oral TU treatment group will begin treatment at a dose of 237 mg TU twice daily (BID).
Oral Testosterone Undecanoate: Subjects assigned to oral TU treatment will begin at 237 mg TU twice daily. Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg \< 350 ng/dL, decreased if \> 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL. | 166 |
| Axiron Testosterone Topical Solution Subjects randomly assigned to the Axiron treatment group will begin treatment at a dose of 60 mg every morning.
Axiron Testosterone Topical Solution: Subjects assigned to Axiron treatment will begin at 60 mg Axiron every morning. Axiron is applied to the axilla only.
Serial PK samples over 24 hours will be obtained after 21 days and 56 days of treatment. Dose adjustments may be made on Day 35 and Day 70, based on the T Cavg results obtained at Day 21 and Day 56, respectively. Dose will be increased if Cavg \< 350 ng/dL, decreased if \> 800 ng/dL and maintained if Cavg = 350 ng/dL to 800 ng/dL. | 56 |
| Total | 222 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | High PSA pre-study/ not eligible | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Site closure not study related | 0 | 1 |
| Overall Study | Subject declined after tx assignment | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Oral Testosterone Undecanoate | Axiron Testosterone Topical Solution | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 2 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 160 Participants | 54 Participants | 214 Participants |
| Age, Continuous | 51.6 years STANDARD_DEVIATION 9.08 | 53.4 years STANDARD_DEVIATION 7.86 | 52 years STANDARD_DEVIATION 8.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 15 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 141 Participants | 41 Participants | 182 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants | 11 Participants | 40 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 133 Participants | 42 Participants | 175 Participants |
| Region of Enrollment United States | 166 Participants | 56 Participants | 222 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 166 Participants | 56 Participants | 222 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 166 | 0 / 56 |
| other Total, other adverse events | 31 / 166 | 8 / 55 |
| serious Total, serious adverse events | 2 / 166 | 0 / 55 |
Outcome results
Primary
Number of Oral TU Treated Subjects Who Have a Total T Cavg in the Eugonadal Range of 252 to 907 ng/dL at Visit 7
Time frame: Day 105
Population: Intent-to-treat study population All subjects randomized to either Oral TU or Axiron
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Testosterone Undecanoate | Number of Oral TU Treated Subjects Who Have a Total T Cavg in the Eugonadal Range of 252 to 907 ng/dL at Visit 7 | 145 Participants |
| Axiron Testosterone Topical Solution | Number of Oral TU Treated Subjects Who Have a Total T Cavg in the Eugonadal Range of 252 to 907 ng/dL at Visit 7 | 48 Participants |
Other Pre-specified
Number of Participants With Post-stimulation Cortisol Level of >18 ug/dL at Visit 8
Compare the Oral TU-treated subjects and the Topical Axiron®-treated subjects with respect to number of subjects in the cosyntropin stimulation test substudy with a normal maximum post-stimulation (cosyntropin stimulation) cortisol level at Visit 8.
Time frame: Approximately 4.5 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Testosterone Undecanoate | Number of Participants With Post-stimulation Cortisol Level of >18 ug/dL at Visit 8 | 19 Participants |
| Axiron Testosterone Topical Solution | Number of Participants With Post-stimulation Cortisol Level of >18 ug/dL at Visit 8 | 8 Participants |