A phase III double-blind placebo-controlled trial of methylnaltrexone (MNTX) for opioid-induced constipation (OIC) in advanced medical illness (AMI)

Abstract

LBA8003 Background: Constipation is a common and distressing side effect of opioid treatment. Patients with AMI commonly experience severe OIC unresponsive to laxatives which can significantly complicate pain management. MNTX is a quaternary derivative of the pure opioid antagonist naltrexone formed by the addition of a methyl group to the ring nitrogen. MNTX does not cross the blood-brain barrier; hence it has the potential to antagonize the peripheral effects of opioids while sparing centrally mediated analgesia. MNTX has been shown to reverse OIC in chronic methadone users and we have previously reported positive results of a phase II trial of MNTX for relief of OIC in hospice patients without evidence of withdrawal or worsened pain (Thomas, et al. ProcASCO, 2003). The present phase III study was initiated to confirm the findings of phase II and assess the safety and efficacy of MNTX in treating OIC in patients with AMI. Methods: This is a multi-center, double-blind, randomized, placebo-controlled study of subcutaneous MNTX for OIC in AMI patients in hospice or palliative care programs. Patients must have a life expectancy of 1 to 6 months, no laxation for 48 hours, on stable opioids for pain and stable laxatives. Patients are randomized to either placebo, MNTX 0.15 mg/kg, or MNTX 0.30 mg/kg. 24 hours after a single subcutaneous dose of study drug, patients may receive open label MNTX, as needed over the next 4 weeks, titrated to effect and tolerability. Total accrual will be approximately 150 patients (50 per group). The primary endpoint is the efficacy of single-dose MNTX (0.15 mg/kg or 0.30 mg/kg vs. placebo) to induce laxation within 4 hours of dosing. We will also measure laxation over 24 hours and adverse events, pain scores, and opioid withdrawal symptoms. The primary analysis will be intent-to-treat and include all randomized patients using a Cochran-Mantel-Haenszel test of placebo against each MNTX dose level. Results: 150 patients have been enrolled as of 12/2/04 and enrollment will be closed on 12/15/04. Analysis of the primary and secondary endpoints and a summary of the demographics will be presented for all patients. Conclusions: To be reached after data becomes available. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Progenics Progenics Progenics