Efficacy and Safety of Oral Testosterone Undecanoate in Hypogonadal Men

This will be a randomized, multicenter, open-label, active-controlled, efficacy, and safety study in adult hypogonadal men. The study duration is 12 months (365 days), including a 90-day, open-label efficacy period and a 9-month (275-day) safety evaluation period.

MRS-TU-2019 was a 12-month study designed to determine the efficacy of oral SOV2012-F1 as measured by the percentage of male hypogonadal subjects with average total testosterone (T Cavg) in plasma within the normal range after 90 days of treatment. This study included an AndroGel™ arm as a safety comparator; after the 90-day efficacy period, dosing continued for 9 additional months in both arms to gather safety data. This study also examined the percentage of SOV2012-F1-treated subjects with maximum total testosterone (Cmax) in plasma values after 90 days of treatment: a. ≤1.5 X upper limit of normal (ULN); b. 1.8 X ULN to 2.5 X ULN' and c. \>2.5 X ULN. The study also included an adrenal cortical function substudy conducted in 30 SOV2012-F1 subjects and 15 AndroGel subjects. Four patient-reported outcome measures were also used during the study: IPSS, PDQ, SF-36 and IIEF.

Eligibility Criteria:
Inclusion Criteria:

1. Male aged 18 to 65 years, inclusive, at the time of providing informed consent to participate in the study.
2. Hypogonadism defined as having 2 consecutive serum total T levels≤ 281 ng/dL based on a blood sample, drawn at least 3 days apart, between 7 a.m. and 10 a.m.
3. At least 1 clinical feature consistent with male hypogonadism. If a subject is receiving commercial TRT prior to Screening Visit 1, he must have a history of at least 1 clinical feature consistent with male hypogonadism.
4. Must be naïve to androgen replacement therapy or washed out adequately of prior androgen replacement therapies; willing to cease current T treatment; or currently not taking any T treatment. Subjects must remain off all forms of T, except for dispensed study drug, throughout the entire study.
5. No unstable ongoing concomitant medical conditions. Treated and well-controlled conditions such as type 2 diabetes, hypertension, or dyslipidemia are acceptable with stable medication in place for at least 3 months prior to study entry:

   1. Hemoglobin A1c ≤ 8.0%
   2. BP \< 150/90 mm Hg
   3. Low-density lipoprotein cholesterol \< 190 mg/dL.
6. Subjects with an endocrine disorder requiring treatment other than hypogonadism must be on a stable dose of replacement medication for at least 3 months prior to study entry.
7. Adequate venous access to allow collection of a number of blood samples via a venous cannula.
8. Written informed consent to participate in the study and ability to comply with all study requirements.

Exclusion Criteria:

1. Serum PSA \> 2.5 ng/ml and/or abnormal prostate gland on palpation, eg, palpable nodes, at Screening Visit 2.
2. 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.
3. Use of any drug that could interfere with measurement or assessment of serum androgen levels, including 5 alpha-reductase inhibitors, anabolic steroids, and drugs with antiandrogenic properties (eg, spironolactone, cimetidine, flutamide, bicalutamide, and ketoconazole). These drugs must be stopped for at least 1 month prior to study entry (6 months in the case of dutasteride). Patients taking potent, long-acting opiate therapy on a daily basis are not eligible for the study. Conversely, ad hoc use of potent, short-acting opiates for a period of less than 7 days may be permitted after discussion with the Marius Pharmaceuticals medical monitor.
4. Use of over-the-counter products, including natural health products (eg, food supplements and herbal supplements such as saw palmetto or phytoestrogens) that may affect total T levels, within 7 days prior to study entry.
5. History of drug or alcohol abuse within the past 2 years that in the opinion of the investigator could interfere with study participation and/or influence study efficacy and safety endpoints assessments.
6. Unstable or chronic disease that could interfere with participation in the study or patient safety, including psychiatric disorders.
7. Myocardial infarction, coronary artery surgery, heart failure, stroke, unstable angina, or other unstable cardiovascular disease within the past 6 months.
8. Abnormal ECG considered clinically significant by investigator at Screening.
9. Diagnosis of any cancer within the previous 5 years other than basal or squamous cell skin cancer with clear margins.
10. Any surgical or medical condition that might alter administration of the study drug or comparator, including history of gastric surgery, cholecystectomy, vagotomy, bowel resection, or any surgical procedure that might interfere with gastrointestinal motility, pH, or absorption of TU.
11. Duodenal or gastric ulcers, or gastrointestinal/rectal bleeding during the 3 months prior to screening.
12. Chronic skin conditions on the chest or upper arms that would prevent administration of AndroGel in a manner designed to ensure reliable and consistent absorption thereof.
13. Human immunodeficiency virus (HIV) infection.
14. Chronic hepatitis B virus and/or hepatitis C virus (HCV) infection (as determined by positive testing for hepatitis B virus surface antigen or HCV antibody with confirmatory testing, ie, detectable serum HCV ribonucleic acid \[RNA\]).
15. Clinically significant abnormal laboratory values at screening including but not limited to:

    1. Elevated liver enzymes (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\] \> 2x upper limit of normal)
    2. Estimated glomerular filtration rate \< 60 ml/min/1.73m2 as calculated by the Modification of Diet in Renal Disease formula
    3. Hemoglobin \< 11.0 g/dL or \> 16.0 g/dL. For a subject previously on testosterone replacement therapy with less than 30 days washout prior to screening Visit 2, hemoglobin \< 11.0 g/dL or \> 17.0 g/dL.
16. Severe and untreated obstructive sleep apnea syndrome.
17. Severe lower urinary tract symptoms (American Urological Association/ IPSS ≥ 19).
18. History of any clinically significant illness, infection, or surgical procedure within 1 month prior to study entry.
19. Past, current, or suspected prostate or breast cancer.
20. History of long QT syndrome or unexplained sudden death in a first-degree relative (parent, sibling, or child).
21. Concurrent treatment with medications that may impact the absorption, distribution, metabolism, or excretion of TU or place the subject at risk for treatment with T.
22. Subject has a partner who is currently pregnant or planning pregnancy during the course of the study.
23. Treatment with any other investigational drug within 30 days of study entry or \> 5 half-lives (whichever is longer) and at any time during the study.
24. History of noncompliance to medical regimens or potential unreliability in the opinion of the investigator.
25. Unwilling or unable to comply to the dietary requirements for this study.
26. History of polycythemia, either idiopathic or associated with TRT.
27. Donated blood (≥ 500 mL) within the 12-week period prior to study entry.
28. History of an abnormal bleeding tendency or thrombophlebitis within the previous 2 years that is not linked to venipuncture or intravenous cannulation.
29. Onset of gynecomastia within the previous 6 months.
30. For adrenocorticotropic hormone (ACTH) stimulation substudy only: Primary or secondary adrenal insufficiency.
31. For Bioanalytical Sample Stability Substudy only: subjects with a hemoglobin less than 13 g/dL at most recent assessment\* \[should be excluded\].