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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01739595
Recruitment Status : Completed
First Posted : December 3, 2012
Results First Posted : May 27, 2015
Last Update Posted : May 27, 2015
Information provided by (Responsible Party):
Repros Therapeutics Inc.

Brief Summary:
The purpose of ZA-302 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.

Condition or disease Intervention/treatment Phase
Secondary Hypogonadism Drug: enclomiphene citrate Drug: Placebo Phase 3

Detailed Description:

Protocol ZA-302 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 181 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : November 2012
Actual Primary Completion Date : September 2013
Actual Study Completion Date : September 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Androxal 12.5 mg
Androxal (enclomiphene citrate), 12.5 mg oral capsules taken once daily
Drug: enclomiphene citrate
oral, capsules, taken one time daily, for 3 months
Other Name: Androxal

Experimental: Androxal 25 mg
Androxal (enclomiphene citrate), 25 mg oral capsules taken once daily
Drug: enclomiphene citrate
oral, capsules, taken one time daily, for 3 months
Other Name: Androxal

Placebo Comparator: Placebo
Placebo oral capsules taken one time daily
Drug: Placebo
Oral capsule taken one time daily for 3 months
Other Name: Dummy

Primary Outcome Measures :
  1. Subjects With Testosterone in Normal Range After Treatment [ Time Frame: 3 months ]

    Proportion (percent) of subjects with average serum concentration (Cavg) for T in the normal range (300 - 1040 ng/dL) after 12 weeks of treatment. Cavg was 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 coprimary endpoint based on the Cavg for testosterone would have 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.

  2. Change in Sperm Concentration [ Time Frame: 3 months ]

    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01739595

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United States, Alabama
Coastal Clinical Research
Mobile, Alabama, United States, 36608
United States, Arkansas
Baptist Health Center for Clinical Research
Little Rock, Arkansas, United States, 72205
United States, California
Rancho Cucamonga Clinical Trials
Rancho Cucamonga, California, United States, 91730
United States, Florida
Meridien Research
Bradenton, Florida, United States, 34208
All Medical Research
Cooper City, Florida, United States, 33024
Clinical Research of South Florida
Coral Gables, Florida, United States, 33134
Phase One Solutions
Miami Gardens, Florida, United States, 33169
United States, Kentucky
Central Kentucky Research Associates
Lexington, Kentucky, United States, 40509
United States, New York
Rochester Clinical Research
Rochester, New York, United States, 14609
United States, South Carolina
Coastal Carolina Research Center
Mount Pleasant, South Carolina, United States, 29464
United States, Texas
New Orleans Center for Clinical Research
Knoxville, Texas, United States, 37920
United States, Utah
Lone Peak Family Medicine
Draper, Utah, United States, 84020
Granger Medical Clinic
Riverton, Utah, United States, 84065
Sponsors and Collaborators
Repros Therapeutics Inc.
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Study Chair: Joseph S Podolski Repros Therapeutics Inc.
Additional Information:
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Responsible Party: Repros Therapeutics Inc. Identifier: NCT01739595    
Other Study ID Numbers: ZA-302
First Posted: December 3, 2012    Key Record Dates
Results First Posted: May 27, 2015
Last Update Posted: May 27, 2015
Last Verified: May 2015
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplastic Processes
Pathologic Processes
Body Weight
Gonadal Disorders
Endocrine System Diseases
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators