A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene

Study Overview
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Brief Summary
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The purpose of this study is to compare the effects of 12 months of treatment with enclomiphene 12.5 mg, 25 mg, or placebo capsules on body composition and metabolic parameters in overweight men with acquired hypogonadotropic hypogonadism [confirmed morning testosterone (T) ≤300 ng/dL] following a 6 month diet and 15 month exercise program.

Detailed Description
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To compare the effects of 12 months of treatment with enclomiphene 12.5 mg, 25 mg, or placebo capsules on body composition and metabolic parameters in overweight men with acquired hypogonadotropic hypogonadism (confirmed morning T≤300 ng/dL) following a 6 month diet and 15 month exercise program. Participants must not have been treated with testosterone products in the 6 months prior to the study and must not ever have used testosterone products for a year or longer.

Official Title
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A Randomized, Double Blind, Placebo-Controlled, Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene

Conditions
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Acquired Hypogonadotropic Hypogonadism, Obesity

Intervention / Treatment
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* Drug: Placebo
* Drug: Enclomiphene


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overweight (Body Mass Index (BMI) 30 to 42 (kg/m^2) inclusive) males age 18 to 60 inclusive. Waist circumference ≥ 40 inches (101.6 cm). Previously or concurrently diagnosed as having secondary hypogonadism. Must have 2 morning testosterone assessments at Visit 1, collected before 10 AM, 2-4 days apart, and both of which must be ≤ 300 (ng/dL). Luteinizing hormone (LH) >1.4 and < 9.4 milli International units per milliliter (mIU/mL) (at Visit 1 only). Glycated hemoglobin A1c (HbA1c) ≤7.5. Stable weight for last 3 months (+/- 10 pounds). Participant lives or works within 10 miles of the gym that will be used for the study. Must be fit enough to participate in the fitness program. Ability to complete the study in compliance with the protocol requirements. Ability to understand and provide written informed consent. Exclusion Criteria: Any use of testosterone products (injectable, pelleted, transdermal or sublingual) in the 6 months prior to the study or any prior use of testosterone products for 12 months or longer at any time. Use of testosterone, Clomid, 5α-reductase inhibitors, human chorionic gonadotropin (hCG), androgen, estrogen, anabolic steroid, dehydroepiandrosterone (DHEA), or herbal hormone products during the study. Use of Clomid in the past year. Known hypersensitivity to Clomid. Allergy to soy, peanuts or latex. Chronic use of glucocorticoids (chronic use of inhaled or topical glucocorticoids is acceptable). 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). 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. A hematocrit >54%. Presence or known history of hyperprolactinemia with or without a tumor (prolactin >20 ng/mL). Current or history of prostate cancer or a suspicion of prostate disease unless ruled out by prostate biopsy, or a prostate specific antigen (PSA)>3.6. Current or history of breast cancer. Uncontrolled hypertension based on the Investigator's assessment at screening. History of bulimia nervosa or binge eating. Participant has (had) a lap band or undergone gastric bypass surgery. Participant has celiac disease or gluten intolerance. Participant has Type I diabetes. Participant has 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. Enrolled and randomized (if applicable) in a previous enclomiphene study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enclomiphene 12.5 mg<br>Enclomiphene 12.5 milligram (mg) capsule daily in the morning with approximately 8 ounces of water for up to 12 months. Participant followed a commercial diet plan and exercised with a personal trainer at least 3 times a week. | Drug: Enclomiphene<br>* Enclomiphene capsule daily in the morning with approximately 8 ounces of water for up to 12 months.<br>|
| Experimental: Enclomiphene 25 mg<br>Enclomiphene 25 mg capsule daily in the morning with approximately 8 ounces of water for up to 12 months. Participant followed a commercial diet plan and exercised with a personal trainer at least 3 times a week. | Drug: Enclomiphene<br>* Enclomiphene capsule daily in the morning with approximately 8 ounces of water for up to 12 months.<br>|
| Placebo Comparator: Placebo<br>One matching placebo capsule daily in the morning with approximately 8 ounces of water for up to 12 months. Participant followed a commercial diet plan and exercised with a personal trainer at least 3 times a week. | Drug: Placebo<br>* One matching placebo capsule daily in the morning with approximately 8 ounces of water for up to 12 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Lean Body Mass (LBM) at Week 48 | LBM was assessed using dual-energy X-ray absorptiometry (DXA). A positive change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Body Strength (Chest Press Weight) at Week 48 | Body strength was assessed from maximum chest and leg press weight achieved, using an inclined plane leg press and vertical chest press. A positive change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Body Strength (Leg Press Weight) at Week 48 | Body strength was assessed from maximum chest and leg press weight achieved, using an inclined plane leg press and vertical chest press. A positive change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood Luteinizing Hormone (LH) Level at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the hormone parameter LH measured in milli-International Units per milliliter (mIU/mL). A positive change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood Testosterone (T) Level at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the hormone parameter T. A positive change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood Dihydrotestosterone (DHT) Level at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the hormone parameter DHT. A positive change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood Estradiol (E2) Level at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the hormone parameter E2. A positive change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Ratio of Testosterone: Estradiol (T:E2) at Week 48 | The T:E2 ratio was calculated as the value of T/value of E2 using the same units. A positive change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Ratio of Dihydrotestosterone: Testosterone (DHT:T) at Week 48 | The DHT:T ratio was calculated as the value of DHT/value of T using the same units. A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Glycated Hemoglobin A1c (HbA1c) at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the metabolic parameter HbA1c. A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood Glucose Level at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the metabolic parameter Glucose. A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood C-reactive Protein (CRP) Level at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the metabolic parameter CRP. A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood Interleukin-6 (IL-6) Level at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the metabolic parameter IL-6. A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood Tumor Necrosis Factor Alpha (TNF-α) Level at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the metabolic parameter TNF-α . A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood Leptin Level at Week 48 | A blood sample was collected at Baseline and Week 48 for the assessment of the metabolic parameter leptin. A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Homeostatic Model of Assessment - Insulin Resistance (HOMA-IR) at Week 48 | The HOMA-IR is the product of the blood Glucose and Insulin levels, divided by a constant. HOMA-IR is expressed as the following: HOMA-IR = fasting serum insulin (μU/mL) × fasting plasma glucose (mmol/L)/22.5. A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Blood Quantose-Insulin Resistance (IR) Score at Week 48 | Quantose-IR is a laboratory-developed test that assesses insulin resistance. Quantose-IR score is based on a linear regression algorithm utilizing the quantitative measures (natural log transformed) of alpha-hydroxybutyrate, oleate, linoleoylglycerophosphocholine and insulin and was designed to estimate the natural log of insulin-induced glucose infusion rate normalized by whole body mass. The algorithm score is converted to the Quantose-IR score within a range of 1-120 by an arithmetic calculation where higher scores denote greater insulin resistance. A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Body Mass Index (BMI) at Week 48 | BMI is calculated as weight (kg)/height(cm^2). A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Waist Circumference at Week 48 | A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 | 
| Change From Baseline in Weight at Week 48 | A negative change from Baseline indicates improvement. | Baseline (Day 0) to Week 48 |