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

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

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.

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.

Inclusion Criteria:

1. Overweight (BMI 25 to 42 kg/m2 inclusive) males age 18 to 60 inclusive
2. All clinical laboratory tests within normal ranges (any clinically significant deviation of laboratory results will require approval of sponsor)
3. 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.
4. LH < 9.4 mIU/mL (at Visit 1 only)
5. Sperm count ≥ 15 million per milliliter (assessed twice at least 48 hours apart)
6. Ability to complete the study in compliance with the protocol
7. Ability to understand and provide written informed consent
8. Agreement to provide a total of up to 6 semen sample in a sponsor-approved clinic on up to 6 separate occasions.

Exclusion Criteria:

1. Any prior use of testosterone treatments within the last 6 months
2. Use of spironolactone, cimetidine, Clomid, 5α-reductase inhibitors, hCG, androgen, estrogen, anabolic steroid, DHEA, or herbal hormone products during the study
3. Use of Clomid in the past year
4. 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.
5. Clinically significant abnormal findings at Screening (Visit 1) or Baseline, based on the Investigator's assessment
6. 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)
7. 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.
8. Known hypersensitivity to Clomid
9. Symptomatic cataracts (nuclear sclerosis cataract or cortical cataract grade > 2 based on 0-4 scale or any trace of posterior subcapsular cataract)
10. Abnormal fundoscopy exam such as central retinal vein occlusion
11. 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
12. Irreversibly infertile or compromised fertility (cryptorchism, Kallman Syndrome, primary hypogonadism, vasectomy, or tumors of the pituitary)
13. Current or history of breast cancer
14. Current or history of prostate cancer or a suspicion of prostate disease unless ruled out by prostate biopsy, or a PSA>3.6
15. Presence or history of known hyperprolactinemia with or without a tumor
16. Chronic use of medications such as glucocorticoids
17. History of drug abuse or chronic narcotic use including methadone
18. A recent history of alcoholism or illegal substance or steroid abuse (<2 years) or presence of moderate alcohol use (>21 drinks per week)
19. Subjects with known history of HIV and/or Hepatitis C
20. Subjects with end stage renal disease
21. History of liver disease (including malignancy) or a confirmed AST or ALT >3 times the upper limit of normal
22. History of myocardial infarction, unstable angina, symptomatic heart failure, ventricular dysrhythmia or know history of QTc interval prolongation
23. History of cerebrovascular disease
24. History of venous thromboembolic disease (e.g. deep vein thrombosis or pulmonary embolism)
25. History of erythrocytosis or polycythemia
26. Subjects with cystic fibrosis (mutation of the CFTR gene)
27. Subjects unable to provide a semen sample in a sponsor-approved clinic
28. Enrollment in a previous Androxal study