Safety and Efficacy Trial of Oral Testosterone Undecanoate (TU) in Hypogonadal Men

Phase 3, Active-Controlled, Safety and Efficacy Trial of Oral Testosterone Undecanoate (TU) in Hypogonadal Men

The purpose of this study is to determine the safety and efficacy of an oral testosterone undecanoate formulation for use as testosterone-replacement therapy in men with low testosterone.

This was a randomized, open-label, 2-arm, active controlled, 12-month study of Oral TU that planned to enroll ≈ 300 hypogonadal men (≈ 150/group) at multiple study sites. Incorporated in the design was dose titration based on serum T concentration assessed 4-6 hrs post AM dose. Following a 2-visit screening period during which a serum T concentration was measured, eligible subjects were randomized to either Oral TU (Group A) or transdermal T-gel (Group B) for dosing during Treatment Period 1 (Days 0 to 42). Group A was initially dosed with 400 mg T daily (two 100 mg capsules, orally, twice a day [BID]), and Group B was initially dosed with 5 g of transdermal 1% T-gel. Serum T sampling was done on Day 30, 4-6 hours after the morning dose and these T concentration results were used to determine the need for dose titration. Dose titration occurred on Day 42 for Treatment Period 2, until Day 90. Subjects whose dose was titrated on Day 42 were re-evaluated on Day 60 , with dose adjustments made as necessary on Day 74. Serum T sampling was performed on Day 90, for Oral TU subjects who had dose titration on Day 74, on Day 105. If the serum T level was > 1800 ng/dL, the sample was repeated; subjects were discontinued if the second assayed T concentration was > 1800 ng/dL. An additional dose titration was done for subjects whose Day 180 occurred after a protocol amendment. Subjects taking 150 mg T BID with serum T over 1500 ng/dL on two separate draws were discontinued. Safety measures included physical examination, vital signs, fasting laboratory analysis (hematology, chemistry, urinalysis), CV biomarker monitoring [hs-CRP, Lp-PLA2, Lp(a), and ApoA1], measurement of sex hormone binding globulin (SHBG); luteinizing hormone (LH), follicle-stimulating hormone (FSH); prostate specific antigen (PSA), and the American Urological Association/International Prostate Symptom Score (AUA/I-PSS).

Treatment Period 1: 100 mg capsules, BID, with food Treatment Period 2: One of the following dosages: 100 mg BID 150 mg BID 100 mg BID 100 mg and 150 mg BID 150 mg capsules BID Safety Follow-up Phase: Initial dose: ~84 doses Maintenance dose-Titrated dose: ~96 doses Safety follow-up at maintenance dose: ~540 doses

Treatment Period 1: 5 g of 1% transdermal T-gel applied QD Treatment Period 2: 2.5 g of 1% transdermal T-gel applied QD 5 g of 1% transdermal T-gel applied QD 7.5 g of 1% transdermal T-gel applied QD 10 g of 1% transdermal T-gel applied QD Safety Follow-up Phase: Initial dose: ~42 doses Maintenance dose-Titrated dose: ~48 doses Safety follow-up at maintenance dose: ~270 doses

Starting dose: 200 mg T (as TU) BID. Doses may be titrated up to a maximum dose of 300 mg T (as TU) BID or down to a minimum dose of 100 mg T (as TU) BID based on serum T values collected at 4-6 hours post AM dose on Days 30 and 60.

Starting dose: 5 g T applied once daily. Doses may be titrated up to a maximum dose of 10 g daily or down to a minimum dose of 2.5 g daily based on serum T values collected at 4-6 hours post AM dose on Days 30 and 60.

Percentage of Treated Patients With Average Serum Testosterone (T) Concentrations (Cavg) Between 300 and 1000 ng/dL

The percentages of treated subjects that had 24-hour serum testosterone (T) average concentrations (Cavg) between 300 and 1000 ng/dL

% of Oral TU Subjects With 24-hour Maximum Serum T Concentrations (Cmax) Greater Than 1500 ng/dL on Day 90

Percentage of Oral TU treated patients who reached study day 90 and had a maximum serum T concentrations (Cmax) values greater than 1500 ng/dL(objective to meet <15%).

Inclusion Criteria: Serum testosterone of less than or equal to 300 ng/dL on two occasions within one week (may wash out from previous oral, topical or buccal testosterone therapy) Exclusion Criteria: Significant intercurrent disease of any type, in particular liver, kidney, uncontrolled or poorly controlled heart disease, or psychiatric illness Recent history of stroke, not including transient ischemic attack Untreated, sever obstructive sleep apnea. Hematocrit <35% or >48 Serum transaminases >2 times upper limit of normal, serum bilirubin > 2.0 mg/dL and serum creatinine > 2.0 mgk/dL BMI > or equal to 36 Stable doses of lipid-lowering medication for less than 3 months Stable doses of oral medication for diabetes for less than 2 months Abnormal prostate DRE [palpable nodule(s)], elevated PSA (>4 ng/mL), IPSS score > or equal to 19 points. History of breast cancer Use of dietary supplement saw palmetto or phytoestrogens and use of any dietary supplements that may increase serum testosterone within previous 4 weeks Known malabsorption syndrome and/or current treatment with oral lipase inhibitors History of abuse of alcohol or any drug substance within the previous 2 years Current use of antiandrogens, estrogens, oral CYP3A4 inducers or inhibitors, or long-acting opioid analgesics Receipt of any drug as part of a research study within 30 days of initial dose administration in this study. Blood donation within the 12 week period before the initial study dose.