HypogonadismPhase 2NCT01880086
Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
A Phase 2 study testing Clomiphene citrate in people with Hypogonadism and Opioid-Related Disorders, run by Weill Medical College of Cornell University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years, men only
- Conditions the study is for
- Hypogonadism, Opioid-Related Disorders, Male Infertility
- What is being tested?
- Clomiphene citrate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 13 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2013to Nov 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 10Show fewer
- 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.
Who cannot join
- 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
Show all 11Show fewer
- 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).
Trial locations and contacts
1 site in 1 country.
United States1 site
Weill Cornell Medical College, Department of Urology
New York, New York, 10065
About this study
Official title: Clomiphene Citrate for the Treatment of Opioid-Induced Androgen Deficiency: Randomized Controlled Clinical Trial
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.
Read the 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.
- Conditions
- Hypogonadism, Opioid-Related Disorders, Male Infertility
- Being tested
- Clomiphene citrate, Placebo
- 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
- Medical subject headings
- Hypogonadism, Opioid-Related Disorders, Infertility, Male, Chronic Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Clomiphene citrateDrug
Also called Clomid, Milophene, Serophene
PlaceboDrug
Also called Sugar pill
Placebo pill that will have appearance identical to the treatment pill but will not contain active medication.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Serum Total Testosterone (Change From Baseline)
Morning venipuncture of serum total testosterone.
Measured: 3 months post initial visit
Secondary outcomes (6)
Other Hormonal Profile (Change From Baseline)
Luteinizing hormone (LH)
Measured: 3 months post initial visit
Androgen Deficiency in the Aging Male (ADAM) Questionnaire
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.
Measured: 3 months post initial visit
Hematocrit (%)
Measure hematocrit from baseline.
Measured: 3 months post initial visit
Estradiol
Measured: 3 months post initial visit
Sexual Health Inventory for Men (SHIM) Questionnaire
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.
Measured: 3 months post initial visit
Men's Sexual Health Questionnaire (MSHQ) Questionnaire
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.
Measured: 3 months post initial visit
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2013 (estimated)
- Study startAug 2013
- Primary completionMar 2016
- Study completionNov 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for HypogonadismStudies of the same condition, open and under way.
- More trials run by Weill Medical College of Cornell UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Weill Medical College of Cornell University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Peter N Schlegel, MD, Principal investigator, Weill Medical College of Cornell University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01880086
- Sponsor's protocol ID
- Cornell-1301013472
- Status last verified
- Jun 2018
- First submitted
- 7 Jun 2013
- Last updated
- 17 Jul 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 17 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clomiphene Citrate for the Treatment of Opioid-Induced Androgen Deficiency: Randomized Controlled Clinical Trial
- ClinicalTrials.gov ID
- NCT01880086
- Acronym / sponsor ID
- Cornell-1301013472
- Conditions
- Hypogonadism, Opioid-Related Disorders, Male Infertility
- Keywords
- Chronic pain, Low testosterone, Hypogonadism, Opioid analgesics, Narcotics, Opioid-induced androgen deficiency, OPIAD, Male infertility
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Weill Medical College of Cornell UniversityUniversity, hospital or other
- Study start
- Aug 2013
- Primary completion
- Mar 2016 (actual)
- Study completion
- Nov 2017 (actual)
- First posted
- 18 Jun 2013 (estimated)
- Results
- Posted 5 Jun 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Clomiphene citrate | Experimental | Drug: Clomiphene citrateThe 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. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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)
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Clomiphene citrateAlso: Clomid, Milophene, Serophene | Drug | Clomiphene citrate |
| PlaceboAlso: Sugar pillPlacebo pill that will have appearance identical to the treatment pill but will not contain active medication. | Drug | Placebo |
Primary outcome
Serum Total Testosterone (Change From Baseline)
Time frame: 3 months post initial visit
Morning venipuncture of serum total testosterone.
6 secondary outcomes
Other Hormonal Profile (Change From Baseline)
Time frame: 3 months post initial visit
Androgen Deficiency in the Aging Male (ADAM) Questionnaire
Time frame: 3 months post initial visit
Hematocrit (%)
Time frame: 3 months post initial visit
Estradiol
Time frame: 3 months post initial visit
Sexual Health Inventory for Men (SHIM) Questionnaire
Time frame: 3 months post initial visit
Men's Sexual Health Questionnaire (MSHQ) Questionnaire
Time frame: 3 months post initial visit
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jul 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Weill Cornell Medical College, Department of UrologyLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
Related trials for Hypogonadism
RecruitingObservational study
Anticipated Stigma, Illness Identity, and Quality of Life in Male Hypogonadism
Hypogonadism, Male, Endocrine Disease
Recruiting
Feasibility of a Digital Self-help Program for Functional Hypothalamic Amenorrhea (HEAL-FHA Pilot)
Functional Hypothalamic Amenorrhea
RecruitingPhase 3
52 Week Study + 24-Month Long-Term Extension of Safety, PK, & Efficacy of XYOSTED® for Testosterone Replacement in Male Adolescents With Hypogonadism
Hypogonadism, Male
RecruitingPhase 4
Testosterone Replacement Therapy in Hypogonadal Patients With Prostate Cancer Under Active Surveillance
Prostate Cancer, Hypogonadism, Male
RecruitingObservational study
Late Subclinical Cardiovascular Disease in Testicular Cancer Survivors
Testicular Cancer, Survivorship
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter N Schlegel, MD principal investigator
Weill Medical College of Cornell University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Clomiphene citrate in people with Hypogonadism and Opioid-Related Disorders, run by Weill Medical College of Cornell University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Serum Total Testosterone (Change From Baseline) (time frame: 3 months post initial visit). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jul 2018.