Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration

NCT01880086 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: Cornell-1301013472
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this randomized controlled clinical trial is to evaluate the effects of clomiphene citrate compared to placebo (substance without active medication) in men who are taking pain medication (opioids) for chronic pain conditions and who have low blood testosterone levels. The condition of men having low testosterone with long-term pain medication (opioid) usage is called opioid-induced androgen deficiency (OPIAD). Low testosterone can be caused by pain medication effects on part of the brain (hypothalamic-pituitary axis) which ultimately result in decreased testosterone production by the testes. Typical symptoms of low testosterone (hypogonadism) may include decreased muscle mass, increased fat, osteoporosis, anemia, erectile dysfunction, delayed ejaculation. In addition, men with low testosterone may experience decreased attention, and decreased libido, fatigue, and depressed mood. Few studies have looked at hormonal changes caused by long-term opioid usage in men. Clomiphene citrate, a selective estrogen receptor modulator (SERM) oral medication which inhibits estrogen effects (feedback) on the brain, has been identified by prior studies to raise testosterone in men with low testosterone (due to reasons other than chronic pain medication). Clomiphene citrate is also known to lead to increased sperm production in men with low testosterone unlike testosterone topical or injection medications. Although clomiphene citrate has been studied in hypogonadal men with beneficial outcomes and minimal side effects, no group has previously studied clomiphene citrate as treatment in patients with OPIAD.

Conditions

Hypogonadism; Opioid-Related Disorders; Male Infertility

Keywords

Chronic pain; Low testosterone; Hypogonadism; Opioid analgesics; Narcotics; Opioid-induced androgen deficiency; OPIAD; Male infertility; Clomiphene citrate; Selective Estrogen Receptor Modulators; Testosterone replacement therapy

Outcome Measures

Primary Outcomes (1)

• Serum Total Testosterone (Change From Baseline)

  Morning venipuncture of serum total testosterone.

  3 months post initial visit

Secondary Outcomes (6)

• Other Hormonal Profile (Change From Baseline)

  3 months post initial visit

• Androgen Deficiency in the Aging Male (ADAM) Questionnaire

  3 months post initial visit

• Hematocrit (%)

  3 months post initial visit

• Estradiol

  3 months post initial visit

• Sexual Health Inventory for Men (SHIM) Questionnaire

  3 months post initial visit

Study Arms (2)

Clomiphene citrate

EXPERIMENTAL

The initial dose of clomiphene citrate will be 25 mg (po, pill by mouth) every other day. This will be started at visit 2, week 0 of the study following diagnosis of low baseline testosterone (serum total testosterone \<350 ng/dl in men \<55 years, \<300 ng/dl in men 55-65 years). Clomiphene citrate dose will be titrated up to a maximum of 50 mg daily according to serum total testosterone levels measured at follow-up visits during the 3 month duration of the study.

Drug: Clomiphene citrate

Placebo

PLACEBO COMPARATOR

Placebo pill will be administered (po, pill by mouth) every other day starting at week 0 of the study in men diagnosed with low testosterone. Treatment will be delayed in these men until the 3 month completion of the study, at which time this group may also receive testosterone replacement therapy.

Drug: Placebo

Interventions

Clomiphene citrate DRUG

Also known as: Clomid, Milophene, Serophene

Clomiphene citrate

Placebo DRUG

Placebo pill that will have appearance identical to the treatment pill but will not contain active medication.

Also known as: Sugar pill

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male
• years to 65 years
• Low testosterone as defined by criteria (serum total testosterone \<350 ng/dl in men \<55 years, \<300 ng/dl in men 55-65 years)
• EITHER taking opioid pain medication (see A below) OR planning to start new pain medication regimen (see B below)
• A) EITHER continuous opioid treatment for chronic nonmalignant pain for \>=6 months receiving one of several specified opioid regimens for the past 1 month (including \>=20 mg/day of oral methadone, \>=30 mg/day of oral sustained release oxycodone, \>=30 mg/day of oral morphine sulfate, \>=6 mg/day of oral dilaudid or \>= 8 mg/day of dilaudid ER, or \>=25 mcg/hr of transdermal fentanyl or buprenorphine, or intrathecal morphine pump)
• B) OR the pain management physician is planning to start pain medication (opioid or non-opioid pain therapy) but you have not received it yet. If this is the case, your testosterone will be checked before starting and during 1 month of pain therapy to determine if you have low testosterone to qualify to begin medication (clomiphene or placebo) treatment in this study.
• BMI (20-35 kg/m2)
• Presence of clear secondary hypogonadism with hypogonadal symptoms and low total testosterone level (confirmed with morning testosterone level \<= 350 ng/dL for men age \>= 55 and \<= 300ng/dl for men age 55-65) or total testosterone \<=200 ng/dl (regardless of symptoms). Additionally luteinizing hormone (LH) should be \<15 mIU (milli-International unit )/mL (at baseline only). Symptoms of hypogonadism include fatigue, decreased energy level/endurance, depressed mood, decreased libido, erectile dysfunction.
• Chronic nonmalignant pain etiology includes rheumatoid arthritis, osteoarthritis, spinal stenosis, polymyalgia, complex region pain syndrome I and II, neurinoma, phantom limb pain, neuropathic pain of other origin, scoliosis, neck pain, failed back surgery, or chronic pancreatitis.
• All patients must have ability to complete the study in compliance with the protocol, and the ability to understand and provide written informed consent.

You may not qualify if:

• Chronic pain of malignant etiology (cancer-related)
• Preexisting testosterone deficiency
• Concomitant use of medication that could interfere with testosterone levels including antidepressant medication, spironolactone, cimetidine, clomiphene (use in the past 1 year), human chorionic gonadotropin (hCG), androgen, estrogen, anabolic steroid, 5-alpha-reductase inhibitors such as finasteride, dehydroepiandrosterone (DHEA), testosterone therapy (topical testosterone within 7 days of study, injectable testosterone within 6 months of study),
• Uncontrolled hypertension
• Clinically significant abnormal findings on screening examination based on the Investigator's assessment
• Known hypersensitivity to clomiphene
• Symptomatic cataracts
• Presence or history of known hyperprolactinemia with or without a tumor
• End-stage renal disease
• Any contraindication to testosterone supplementation therapy
• Absolute contraindications to hormone supplementation therapy which include active prostate cancer (or suspicion of prostate disease unless ruled out by biopsy), prostatic specific antigen (PSA)\>=3.6, breast cancer, hematocrit\>=51% (hemoglobin\>=17 g/dL), uncontrolled congestive heart failure (CHF), myocardial infarction, acute coronary event, unstable angina, coronary revascularization procedure in the preceding 6 months, untreated obstructive sleep apnea, high risk of prostate cancer (ethnicity or family history), or severe lower urinary tract symptoms (AUA symptom score\>19).

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead

Study Sites (1)

Weill Cornell Medical College, Department of Urology

New York, New York, 10065, United States

Location

Related Links

• Weill Cornell Medical College, Department of Urology

MeSH Terms

Conditions

Hypogonadism; Opioid-Related Disorders; Infertility, Male; Chronic Pain

Interventions

Clomiphene; Sugars

Condition Hierarchy (Ancestors)

Gonadal Disorders; Endocrine System Diseases; Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Infertility; Male Urogenital Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Carbohydrates

Results Point of Contact

• Title: Dr. Peter N. Schlegel
• Organization: Weill Cornell Medical College

pnschleg@med.cornell.edu

2127465491

Study Officials

• Peter N Schlegel, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2013
• First Posted: June 18, 2013
• Study Start: August 1, 2013
• Primary Completion: March 1, 2016
• Study Completion: November 1, 2017
• Last Updated: July 17, 2018
• Results First Posted: June 5, 2017

Record last verified: 2018-06

Locations

US (1)