Phase III Study to Evaluated Morning Testosterone Normalization in Overweight Men Less Than 60 Years of Age With Secondary Hypogonadism

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