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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Weill Medical College of Cornell University
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT01880086
First received: June 7, 2013
Last updated: September 5, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Hypogonadism
Opioid-Related Disorders
Male Infertility
Drug: Clomiphene citrate
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Clomiphene Citrate for the Treatment of Opioid-Induced Androgen Deficiency: Randomized Controlled Clinical Trial

Resource links provided by NLM:


Further study details as provided by Weill Medical College of Cornell University:

Primary Outcome Measures:
  • Serum total testosterone (change from baseline) [ Time Frame: Baseline, 2 weeks, 1 month, 3 months ] [ Designated as safety issue: No ]
    Morning venipuncture of serum total testosterone to assess change over time.


Secondary Outcome Measures:
  • Other hormonal profile (change from baseline) [ Time Frame: Baseline, 2 weeks, 1 month, 3 months ] [ Designated as safety issue: No ]
    Serum free testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle stimulating hormone (FSH), dihydrotestosterone (DHT), estradiol, prolactin, adrenocorticotropic hormone (ACTH), cortisol, insulin like growth factor 1 (IGF-1), complete blood count (CBC), cholesterol, B-endorphin, met-enkephalin. Each lab test is intended to assess change over time.

  • Urine studies (change from baseline) [ Time Frame: Baseline, 2 weeks, 1 month, 3 months ] [ Designated as safety issue: No ]
    24 hour urine aldosterone/cortisol to assess change over time.

  • Semen analysis (sperm count, concentration, motility, morphology: change from baseline) [ Time Frame: Baseline, 2 weeks, 1 month, 3 months ] [ Designated as safety issue: No ]
    This portion of the study will be completed with patient consent and may be omitted if desired by the patient.

  • Questionnaires- self-administered [ Time Frame: Baseline, 2 weeks, 1 month, 3 months ] [ Designated as safety issue: No ]
    The following validated questionnaires will be used: Androgen Deficiency in the Aging Male (ADAM) questionnaire (with 10 yes/no questions assessing low testosterone symptoms), IIEF-5 (International Index of Erectile Function 5 question survey each with 1 to 5 answers, summed: score of 22-25 demonstrates no erectile dysfunction, score of 5-7 demonstrates severe erectile dysfunction), and Visual Analog Scale (VAS, scored 0=no pain to 10=worst possible pain). Overall, study subjects will be assessed for possible change in hypogonadal, sexual function, and pain symptoms.


Estimated Enrollment: 134
Study Start Date: August 2013
Estimated Study Completion Date: June 2014
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Clomiphene citrate
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
Other Names:
  • Clomid
  • Milophene
  • Serophene
Placebo Comparator: Placebo
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
Placebo pill that will have appearance identical to the treatment pill but will not contain active medication.
Other Name: Sugar pill

Detailed Description:

Chronic nonmalignant pain is a widespread issue affecting 15-30% of the population. Many patients with chronic pain are responsive to first-line combination of physical modalities and non-opioid analgesics. Up to 20% of these patients, however, require opioid therapy for adequate pain relief. The use of long-acting opioids, including morphine sulfate, oxycodone, fentanyl, and methadone, although effective for pain control, carries risks of addiction, tolerance, and systemic side effects including nausea, itching, constipation, and hypogonadotropic hypogonadism with consequent testosterone depletion (in up to 86% of patients taking chronic pain medication) leading to the multiple adverse effects. Opioid-induced androgen deficiency (OPIAD), occurs with high frequency and persistence, and commonly remains undiagnosed in the pain clinic. Low testosterone may be treated using exogenous testosterone (topical or gel) or other medications such as selective estrogen receptor modulators (i.e. clomiphene citrate). While both medication types increase serum testosterone levels, clomiphene citrate is known to benefit sperm parameters in hypogonadal men while exogenous testosterone is known to inhibit sperm production. Few studies have examined the hormonal changes caused by long-term opioid usage in men, and no studies have formally studied clomiphene citrate for this patient population.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male
  • 18 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 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.

Exclusion Criteria:

  • 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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01880086

Contacts
Contact: Matthew Wosnitzer, MD 212-746-5470 maw7011@med.cornell.edu

Locations
United States, New York
Weill Cornell Medical College, Department of Urology Recruiting
New York, New York, United States, 10065
Contact: Matthew Wosnitzer, MD    212-746-5470      
Principal Investigator: Peter N Schlegel, MD         
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
Principal Investigator: Peter N Schlegel, MD Weill Medical College of Cornell University
  More Information

Additional Information:
No publications provided

Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT01880086     History of Changes
Other Study ID Numbers: Cornell-1301013472
Study First Received: June 7, 2013
Last Updated: September 5, 2013
Health Authority: United States: Institutional Review Board
United States: Data and Safety Monitoring Board

Keywords provided by Weill Medical College of Cornell University:
Narcotics
Chronic pain
Low testosterone
Hypogonadism
Opioid analgesics
Opioid-induced androgen deficiency
OPIAD
Male infertility
Clomiphene citrate
Selective Estrogen Receptor Modulators
Testosterone replacement therapy

Additional relevant MeSH terms:
Hypogonadism
Infertility
Infertility, Male
Opioid-Related Disorders
Gonadal Disorders
Endocrine System Diseases
Genital Diseases, Male
Genital Diseases, Female
Substance-Related Disorders
Mental Disorders
Testosterone
Testosterone enanthate
Testosterone undecanoate
Testosterone 17 beta-cypionate
Androgens
Methyltestosterone
Clomiphene
Citric Acid
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Analgesics, Opioid
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Anabolic Agents
Anticoagulants

ClinicalTrials.gov processed this record on July 28, 2014