Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism

Study Overview
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Brief Summary
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The purpose of ZA-301 is to determine the effects of Androxal on morning testosterone and reproductive status in younger overweight men with acquired hypogonadotropic hypogonadism (confirmed morning T<300 ng/dL) and normal sperm concentration, compared to changes with placebo. Subjects must not have previously been treated with testosterone products within the last 6 months.

Detailed Description
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Protocol ZA-301 is a randomized, double-blind, placebo-controlled multi-center Phase 3 study to evaluate normalization of morning testosterone levels in overweight men with acquired hypogonadotropic hypogonadism and normal baseline sperm concentrations. The study requires 10 to 12 clinic visits (2 for eye exams), and is approximately 4 to 5½ months in duration. Subjects will be treated for 12-18 weeks. At Visit 3 (Week 6) subjects who do not achieve morning T values ≥300 ng/dL will be up-titrated to 25 mg. Placebo subjects may be sham titrated. Up-titrated subjects will receive an additional 6 weeks of treatment (18 weeks total). A schedule of procedures and assessments is displayed in Section 4. The study will enroll up to 152 male subjects, up to 114 randomized to treatment with Androxal and up to 38 randomized to placebo, in a 3:1 ratio. Subjects must not have used any prior testosterone treatments within the last 6 months. Eligible subjects must have 2 consecutive assessments of morning T below 300 ng/dL and LH below 9.4 mIU/mL. They will provide 2 sperm samples at baseline, at least 2 days apart, another 2 after 12 weeks of treatment, and up-titrated subjects will provide an additional 2 samples at the end of treatment. After 12 weeks of treatment (V5) all subjects will undergo serial T assessment for determination of the Cavg. Safety assessments will include collection of adverse events, eye examinations, physical examinations and clinical laboratory assessments.

Official Title
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A Randomized, Double Blind, Placebo Controlled Multi-Center Phase III Study to Evaluate Normalization of Morning Testosterone Levels in Overweight Men With Acquired Hypogonadotropic Hypogonadism and Normal Sperm Concentration

Conditions
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Secondary Hypogonadism

Intervention / Treatment
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* Drug: Androxal
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overweight (BMI 25 to 42 kg/m2 inclusive) males age 18 to 60 inclusive All clinical laboratory tests within normal ranges (any clinically significant deviation of laboratory results will require approval of sponsor) Previously or concurrently diagnosed as having secondary hypogonadism characterized as having 2 consecutive morning testosterone assessments < 300ng/dL, one of which must be confirmed at Baseline. LH < 9.4 mIU/mL (at Visit 1 only) Sperm count ≥ 15 million per milliliter (assessed twice at least 48 hours apart) Ability to complete the study in compliance with the protocol Ability to understand and provide written informed consent Agreement to provide a total of up to 6 semen sample in a sponsor-approved clinic on up to 6 separate occasions. Exclusion Criteria: Any prior use of testosterone treatments within the last 6 months Use of spironolactone, cimetidine, Clomid, 5α-reductase inhibitors, hCG, androgen, estrogen, anabolic steroid, DHEA, or herbal hormone products during the study Use of Clomid in the past year Uncontrolled hypertension or diabetes mellitus based on the Investigator's assessment at baseline. Subjects treated for Type II diabetes will be allowed into the study. Newly diagnosed diabetics need to be treated for at least 48 hours before being enrolled in the study. Clinically significant abnormal findings at Screening (Visit 1) or Baseline, based on the Investigator's assessment A hematocrit >54% or a hemoglobin >17 g/dL (sponsor may approve enrollment of subjects with hemoglobin up to 17.5 g/dL if the subject is at a location with a high elevation) Use of an investigational drug or product, or participation in a drug or medical device research study within 30 days prior to receiving study medication. Known hypersensitivity to Clomid Symptomatic cataracts (nuclear sclerosis cataract or cortical cataract grade > 2 based on 0-4 scale or any trace of posterior subcapsular cataract) Abnormal fundoscopy exam such as central retinal vein occlusion Any condition which in the opinion of the investigator would interfere with the participant's ability to provide informed consent, comply with study instructions, possibly confound interpretation of study results, or endanger the participant if he took part in the study Irreversibly infertile or compromised fertility (cryptorchism, Kallman Syndrome, primary hypogonadism, vasectomy, or tumors of the pituitary) Current or history of breast cancer Current or history of prostate cancer or a suspicion of prostate disease unless ruled out by prostate biopsy, or a PSA>3.6 Presence or history of known hyperprolactinemia with or without a tumor Chronic use of medications such as glucocorticoids History of drug abuse or chronic narcotic use including methadone A recent history of alcoholism or illegal substance or steroid abuse (<2 years) or presence of moderate alcohol use (>21 drinks per week) Subjects with known history of HIV and/or Hepatitis C Subjects with end stage renal disease History of liver disease (including malignancy) or a confirmed AST or ALT >3 times the upper limit of normal History of myocardial infarction, unstable angina, symptomatic heart failure, ventricular dysrhythmia or know history of QTc interval prolongation History of cerebrovascular disease History of venous thromboembolic disease (e.g. deep vein thrombosis or pulmonary embolism) History of erythrocytosis or polycythemia Subjects with cystic fibrosis (mutation of the CFTR gene) Subjects unable to provide a semen sample in a sponsor-approved clinic Enrollment in a previous Androxal study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Androxal 12.5 mg<br>Androxal (enclomiphene citrate), 12.5 mg oral capsules taken once daily | Drug: Androxal<br>* oral, capsules, taken one time daily, for 3 months<br>* Other names: Enclomiphene citrate;|
| Experimental: Androxal 25 mg<br>Androxal (enclomiphene citrate), 25 mg oral capsules taken once daily | Drug: Androxal<br>* oral, capsules, taken one time daily, for 3 months<br>* Other names: Enclomiphene citrate;|
| Placebo Comparator: Placebo<br>Placebo oral capsules taken one time daily | Drug: Placebo<br>* Oral capsule taken one time daily for 3 months<br>* Other names: Dummy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion (Percentage) of Androxal Treated Subjects With Testosterone in the Normal Range | Proportion of pooled Androxal subjects with average serum concentration (Cavg) for T in the normal range (300 - 1040 ng/dL) after 12 weeks of treatment. Cavg will be calculated as the numerical average of 24-hour serial testosterone assessments at 0, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours after dosing. If the lower limit of the 95% confidence interval for the Androxal treatment group at Week 12 is at least 67%, then the co-primary endpoint based on the Cavg for testosterone has been achieved. FDA specified primary endpoint did not include comparison to placebo, thus the proportion of placebo subjects with average serum concentration (Cavg) for T in the normal range (300 - 1040 ng/dL) after 12 weeks of treatment was not calculated. | 3 months | 
| Subjects With 50% or Greater Decrease in Sperm Concentration Comparison of Proportion of Subjects With 50% or Greater Decrease in Sperm | Proportion of subjects with a 50% or greater decrease in sperm concentration from baseline after 12 weeks of treatment in Androxal treated subjects to placebo. The difference between the proportions (placebo minus Androxal) and corresponding 95% confidence interval was determined and compared to the equivalence limit of -20%. If the lower limit of the 95% confidence interval was greater than -20%, then Androxal would be concluded to be non-inferior to placebo in causing a 50% reduction in sperm concentrations. | 3 months |