Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
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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. |
ClinicalTrials.gov Identifier: NCT01739595 |
Recruitment Status :
Completed
First Posted : December 3, 2012
Results First Posted : May 27, 2015
Last Update Posted : May 27, 2015
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Condition or disease | Intervention/treatment | Phase |
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Secondary Hypogonadism | Drug: enclomiphene citrate Drug: Placebo | Phase 3 |
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.
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 |

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 |
- 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.
- 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.

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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:
- 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

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 ClinicalTrials.gov identifier (NCT number): NCT01739595
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 |
Study Chair: | Joseph S Podolski | Repros Therapeutics Inc. |
Responsible Party: | Repros Therapeutics Inc. |
ClinicalTrials.gov 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 |
Neoplasm Metastasis Hypogonadism Overweight Neoplastic Processes Neoplasms Pathologic Processes Body Weight Gonadal Disorders Endocrine System Diseases Enclomiphene Clomiphene |
Zuclomiphene 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 |