Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism

• Change in total morning testosterone from baseline to 6 months (26 weeks) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Changes in values from baseline of total morning testosterone levels at Week 26 comparing Androxal to Axiron
• Changes in follicle stimulating hormone and luteinizing hormone from baseline to 6 months (26 weeks) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Changes in values from baseline in FSH and LH at each dosing visit comparing Androxal to Axiron
• Absolute values of morning testosterone, follicle stimulating hormone, and luteinizing hormone [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Changes in diabetic parameters from baseline to 6 months (26 weeks) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Changes in HbA1c, fasting plasma glucose, and HOMA-IR
• Change in subject weight from baseline to 6 months (26 weeks) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Safety Assessment at baseline versus 6 months (26 weeks) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  Safety will be assessed by physical and visual acuity examinations, slit lamp eye examinations, clinical laboratory tests and adverse event reporting

ZA-300 is meant to determine the safety profile of Androxal (enclomiphene citrate) in men with secondary hypogonadism.

This study is a phase III, open label safety study with a six month active dosing period. All subjects will be started at 12.5 mg Androxal and titrated to 25 mg if needed. Safety will be assessed by physical and visual acuity exams, slit lamp eye exams, clinical laboratory tests and adverse event reporting.

• Secondary Hypogonadism
• Low Testosterone

• Drug: enclomiphene citrate
  oral, 12.5 mg capsule, taken once daily. Dose may be increased from 12.5 mg to 25 mg if indicated
  Other Name: Androxal
• Drug: Testosterone
  topical testosterone product applied once daily per manufacturer's instructions. Dose may be increased per manufacturer's instructions if indicated.
  Other Name: Axiron

• Experimental: Androxal
  Intervention: Drug: enclomiphene citrate
• Experimental: Axiron
  Intervention: Drug: Testosterone

Inclusion Criteria:

1. Secondary hypogonadal males between the ages of 18 and 65
2. Men currently using topical testosterone products should wash-out for at least 7 days before Visit 1.
3. All clinical laboratory tests within normal ranges (any clinically significant deviation of laboratory results will require approval of sponsor)
4. Previously or concurrently diagnosed as having secondary hypogonadism and confirmed with morning testosterone level < 350 ng/dL for men age < 55 and < 300ng/dl for men age 55-65
5. LH < 15mIU/mL (at Visit 1 only)
6. Ability to complete the study in compliance with the protocol
7. Ability to understand and provide written informed consent.

Exclusion Criteria:

1. Use of an injectable pelleted testosterone within 6 months prior to study (men currently on topical testosterone products may be enrolled in the study after a 7-day washout period).
2. Use testosterone injection, 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 based on the Investigator's assessment at baseline. Subjects treated for Type II diabetes will be allowed into the study.
5. A hematocrit ≥ 51% or a hemoglobin ≥ 17 g/dL
6. Clinically significant abnormal findings on screening examination, based on the Investigator's assessment.
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. 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
11. Irreversibly infertile or compromised fertility (cryptorchism, Kallman Syndrome, primary hypogonadism, or tumors of the pituitary)
12. Current or history of breast cancer
13. Current or history of prostate cancer or a suspicion of prostate disease unless ruled out by prostate biopsy, or a PSA > 3.6
14. Presence or history of known hyperprolactinemia with or without a tumor
15. Chronic use of medications use such as glucocorticoids
16. Chronic use of narcotics
17. Subjects know to be positive for HIV
18. End stage renal disease
19. Subjects with cystic fibrosis (mutation of the CFTR gene)
20. Enrollment in a previous Androxal study