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

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ClinicalTrials.gov Identifier: NCT01880086
Recruitment Status : Completed
First Posted : June 18, 2013
Results First Posted : June 5, 2017
Last Update Posted : July 17, 2018
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Tracking Information
First Submitted Date  ICMJE June 7, 2013
First Posted Date  ICMJE June 18, 2013
Results First Submitted Date  ICMJE January 25, 2017
Results First Posted Date  ICMJE June 5, 2017
Last Update Posted Date July 17, 2018
Study Start Date  ICMJE August 2013
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 2, 2017)
Serum Total Testosterone (Change From Baseline) [ Time Frame: 3 months post initial visit ]
Morning venipuncture of serum total testosterone.
Original Primary Outcome Measures  ICMJE
 (submitted: June 13, 2013)
Serum Total Testosterone (Change From Baseline) [ Time Frame: Baseline, 2 weeks, 1 month, 3 months ]
Morning venipuncture of serum total testosterone to assess change over time.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 2, 2017)
  • Other Hormonal Profile (Change From Baseline) [ Time Frame: 3 months post initial visit ]
    Luteinizing hormone (LH)
  • Androgen Deficiency in the Aging Male (ADAM) Questionnaire [ Time Frame: 3 months post initial visit ]
    Overall, study subjects will be assessed for possible change in hypogonadal, sexual function, and pain symptoms. Minimum score is 0 and maximum score is 10. 0 is most symptomatic, and 10 is least symptomatic.
  • Hematocrit (%) [ Time Frame: 3 months post initial visit ]
    Measure hematocrit from baseline.
  • Estradiol [ Time Frame: 3 months post initial visit ]
  • Sexual Health Inventory for Men (SHIM) Questionnaire [ Time Frame: 3 months post initial visit ]
    Overall, study subjects will be assessed for possible change in hypogonadal, sexual function, and pain symptoms. Minimum score is 1, maximum score is 25. The minimum value is most symptomatic and maximum value is least symptomatic.
  • Men's Sexual Health Questionnaire (MSHQ) Questionnaire [ Time Frame: 3 months post initial visit ]
    Overall, study subjects will be assessed for possible change in hypogonadal, sexual function, and pain symptoms. Minimum score is 1, maximum score is 20. Minimum score is considered most symptomatic, maximum score is considered least symptomatic.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 13, 2013)
  • Other hormonal profile (change from baseline) [ Time Frame: Baseline, 2 weeks, 1 month, 3 months ]
    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 ]
    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 ]
    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 ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
Official Title  ICMJE Clomiphene Citrate for the Treatment of Opioid-Induced Androgen Deficiency: Randomized Controlled Clinical Trial
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.

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Hypogonadism
  • Opioid-Related Disorders
  • Male Infertility
Intervention  ICMJE
  • Drug: Clomiphene citrate
    Other Names:
    • Clomid
    • Milophene
    • Serophene
  • Drug: Placebo
    Placebo pill that will have appearance identical to the treatment pill but will not contain active medication.
    Other Name: Sugar pill
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Clomiphene citrate
  • 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.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 2, 2017)
13
Original Estimated Enrollment  ICMJE
 (submitted: June 13, 2013)
134
Actual Study Completion Date  ICMJE November 2017
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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.

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01880086
Other Study ID Numbers  ICMJE Cornell-1301013472
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Weill Medical College of Cornell University
Study Sponsor  ICMJE Weill Medical College of Cornell University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Peter N Schlegel, MD Weill Medical College of Cornell University
PRS Account Weill Medical College of Cornell University
Verification Date June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP