A Phase 1/2a Study to Determine the Dose Response Pharmacokinetics of TSX-011 (Testosterone Undecanoate) in Hypogonadal Males

This will be a phase 1/2a, open-label, single-center study with 3 periods. The aims of the study are to:

1. evaluate the dose-response curve following ascending single doses of TSX-011;
2. confirm optimum dosing conditions;
3. evaluate the efficacy of single or multiple daily adaptive dosing; and
4. evaluate the safety and tolerability of TSX-011.

This will be a phase 1/2a, open-label, single-center study with 3 periods. The aims of the study are to: 1) evaluate the dose-response curve following ascending single doses of TSX-011; 2) confirm optimum dosing conditions; 3) evaluate the efficacy of single or multiple daily adaptive dosing; and 4) evaluate the safety and tolerability of TSX-011. Up to 24 hypogonadal men will be enrolled in this study to yield 16 evaluable subjects, and it is desired that the same 24 subjects participate in all 3 study periods.

Period 1 is an ascending single-dose study of TSX-011 at 3 doses, with the lowest dose administered under fed and fasted conditions: 190 mg TSX-011 in the fed state, 190 mg TSX-011 in the fasted state, 380 mg TSX-011 in the fed state, and 570 mg TSX-011 in the fed state. Before exposure to TSX-011, a 24 hour baseline measurement of testosterone and DHT will be performed for each subject. Samples for analysis of testosterone will be obtained at the following time points on Day -1: hour 0 (8 am ± 60 minutes) and 1.5, 3, 4.5, 6, 8, 12, 16, and 24 hours (± 15 minutes for each time point).

The day following the sampling for endogenous testosterone (Day 1) in Period 1, each subject will receive the first single dose of TSX-011 (190 mg) under fed conditions. Following administration of TSX-011, blood samples will be obtained over a 24-hour period for PK analysis. Subjects will undergo a minimum 3-day and up to 7-day washout period between each of the doses of TSX-011 in Period 1. After the 570 mg TSX 011 dose in Period 1, a minimum 3-day and up to 7-day washout period will occur before the start of Period 2.

Period 2 is a twice-daily dosing period, where fed subjects will be dosed with 380 mg TSX-011 twice daily for 15 days (Days 1 through 15). Pharmacokinetic assessments over 24 hours will occur on Days 1 and 15. The TSX-011 dose will be titrated up or down beginning with the Day 16 (Period 3) morning dose, based on established dosing rules.

Period 3 is a dose-adjusted adaptive design period that begins on Day 16, with the first adjusted TSX-011 dose administered in the fed state on a once-daily or twice-daily schedule. The 6-hour postdose (± 15 minutes) testosterone level on Day 19 will be used to perform the second and final TSX-011 dose adjustment, based on established criteria. As specified by the dose adjustment rules, Day 26 begins with either a once-daily, twice-daily, or thrice-daily fed dose schedule. The thrice-daily dose schedule will be administered only to non-responders. On Day 30, a 24 hour PK assessment will be performed, and the subject's participation in the study is completed the morning of Day 31.

Eligibility Criteria:
Inclusion Criteria:

* Testosterone level \<350 ng/dL, 10 am \[± 2 hour\] sample.
* Body mass index (BMI) \<35.0 kg/m2 and weight ≥50 kg

Exclusion Criteria:

* History of clinically significant renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease or any other condition.
* Significant gastrointestinal or malabsorption conditions.
* Any man in whom testosterone therapy is contraindicated including the following:

  1. Known or suspected carcinoma (or history of carcinoma) of the prostate, clinically significant symptoms of benign prostatic hyperplasia, and/or clinically significant symptoms of lower urinary obstruction and International Prostate Symptom Score (IPSS) ≥19. A clinically significant digital rectal examination of the prostate or clinically significant elevated serum PSA levels (\>4.0 ng/mL).
  2. Known or suspected carcinoma (or history of carcinoma) of the breast.
  3. Liver disease defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2 × upper limit of normal (ULN) or bilirubin \>2 × ULN.
  4. Active deep vein thrombosis or thromboembolic disorder, or a documented history of these conditions.
  5. Untreated sleep apnea.
  6. Hematocrit \>50%.
  7. Untreated moderate to severe depression.
* Current use of long-acting testosterone or any of the testosterone esters injectables.
* Topical, oral, or injectable testosterone replacement therapy.
* Clinically significant changes in any medications (including dosages) or medical conditions in the 28 days before screening.
* Suspected reversible hypogonadism (e.g., leuprolide injection).
* Taking concomitant medications that affect testosterone concentrations or metabolism
* Uncontrolled diabetes (screening glycated hemoglobin \[HbA1c\] ≥9%).
* Donated blood or blood products or experienced significant blood loss within 90 days before dosing.
* Donated bone marrow within 6 months before dosing.
* History of drug or alcohol abuse in the last 6 months.
* Ingested St John's wort within 30 days of screening.