a phase 1/2a study to determine the dose response pharmacokinetics of tsx-011 (testosterone undecanoate) in hypogonadal males

Conditions: Hypogonadism; Hypogonadism, Male; Gonadal Disorders; Endocrine System Diseases; Testosterone Deficiency

Summary: 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.

Keywords: hypogonadism testosterone testosterone undecanoate