Methylnaltrexone for Opioid-induced Constipation in Cancer Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of methylnaltrexone in relieving opioid-induced constipation in cancer patients at various stages of disease.

Detailed Description
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Pain is one of the most common and important symptoms of cancer, often requiring opioid analgesics for control. However constipation is one of the most frequent and debilitating side effects of opioids, occurring in 40%-70% of patients being treated for chronic pain. Although laxatives are commonly used to manage opioid-induced constipation, these agents are not always effective or satisfactory. Methylnaltrexone bromide is a peripherally acting antagonist of the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood-brain barrier is limited. This allows methylnaltrexone to function as a peripherally-acting antagonist in the gastrointestinal tract without impacting opioid-mediated analgesic effects in the central nervous system. The efficacy and safety of methylnaltrexone in treating opioid-induced constipation in patients with advanced disease receiving palliative care has been demonstrated. However the efficacy of this agent has not been evaluated in more active patients who are earlier in their disease course. The present study will evaluate the efficacy and safety of methylnaltrexone for the relief of severe opioid-induced constipation in this population and will attempt to identify factors predictive of methylnaltrexone response.

Official Title
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Phase II Trial of Subcutaneous Methylnaltrexone in the Treatment of Severe Opioid-induced Constipation in Cancer Patients

Conditions
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Neoplasms, Constipation, Opioid-Related Disorders

Intervention / Treatment
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* Drug: Methylnaltrexone bromide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed neoplasm 18 years of age or older Have received opioids for analgesia for at least 2 weeks and been on a stable regimen of opioids and laxatives for 3 or more days before study entry Fewer than three laxation during the preceding week and no laxation within 24 hours before study entry, or no laxation within 48 hours before study entry Life expectancy of at least 6 months World Health Organization Performance Status 0-3 Women of childbearing potential must have a negative pregnancy test Breastfeeding should be discontinued prior to study entry Ability to understand and the willingness to sign a written informed consent document. Laboratory values within a week of study entry: Absolute neutrophil count > 1,500/microliter Hemoglobin > 7 g/dL Platelet count > 100,000/microliter Calculated calcium < 10.5 mg/dL Calculated creatinine clearance > 30 mg.min Alanine aminotransferase < 3 x upper limit of normal (ULN) Aspartate aminotransferase < 3 x ULN Alkaline phosphatase < 2.5 x ULN Bilirubin < 1.5 x ULN Exclusion Criteria: Constipation not primarily caused by opioids, such as mechanical gastrointestinal obstruction or ongoing vinca alkaloid administration Indwelling peritoneal catheter Clinically active diverticular disease Fecal impaction Acute surgical abdomen Fecal ostomy Peritoneal carcinomatosis Known hypersensitivity to methylnaltrexone, naltrexone, or naloxone Administration of any investigational drug or experimental product within the previous 30 days Initiation of a new bowel regimen or prokinetic agents within a week of study entry

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylnaltrexone bromide<br>A single dose of methylnaltrexone will be administered subcutaneously to eligible subjects based on weight at the study entry. Since we will include subjects at all stages of cancer management, administering this study drug is considered experimental. We will use the dose approved by FDA, i.e., 0.15 mg/kg (round dose up to nearest 0.1 mL of volume) for weight less than 38 kg or greater than 114 kg; 8 mg (0.4 mL) for weight 38 kg to less than 62 kg; and 12 mg (0.6 mL) for weight 62 kg to 114 kg. | Drug: Methylnaltrexone bromide<br>* Methylnaltrexone bromide, dosage based on weight (0.15 mg/kg (round dose up to nearest 0.1 mL of volume) for weight less than 38 kg or greater than 114 kg; 8 mg (0.4 mL) for weight 38 kg to less than 62 kg; and 12 mg (0.6 mL) for weight 62 kg to 114 kg), single dose<br>* Other names: Relistor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rescue-free Laxation After Administration of Subcutaneous Methylnaltrexone |  | 4 hours after the dose of subcutaneous methylnaltrexone | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Laxation After Administration of Subcutaneous Methylnaltrexone |  | 24 and 48 hours after the dose of subcutaneous methylnaltrexone | 
| Time to Laxation After Administration of Subcutaneous Methylnaltrexone |  | 48 hours after the dose of subcutaneous methylnaltrexone | 
| Overall Pain Scores (0-10; 0=no Pain, 10=Worst Pain) After Administration of Subcutaneous Methylnaltrexone |  | 48 hours after the dose of subcutaneous methylnaltrexone | 
| Symptoms of Opioid Withdrawal (Modified Himmelsbach Withdrawal Scales (Ranging 7-28 in Total; 1=None - 4=Severe for 7 Items)) After Administration of Subcutaneous Methylnaltrexone |  | 48 hours after the dose of subcutaneous methylnaltrexone | 
| Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone |  | 48 hours after the dose of subcutaneous methylnaltrexone | 
| Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone |  | 48 hours after the dose of subcutaneous methylnaltrexone | 
| Patient Satisfaction With the Study Medication After Administration of Subcutaneous Methylnaltrexone |  | 48 hours after the dose of subcutaneous methylnaltrexone | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methylnaltrexone, Constipation, Narcotic Antagonists, Analgesics, Opioid, Neoplasms