Disclosures: William D. Chey, MD: Redhill (Products/Services: Yes) (Consultant/Advisory Board)

Objective: To characterize the predictability of onset of response within 48hrs following the first dose of naloxegol.

Design: Pooled analysis.Setting : Two randomized, double-blind, placebo-controlled, Phase 3 trials (NCT01309841/NCT01323790).Participants : Patients treated with opioids for chronic non-cancer pain who had Opioid Induced Constipation (OIC).

Interventions: Naloxegol and placebo.

Main Outcome Measures: Time to first post-dose spontaneous bowel movement (SBM) without use of laxatives was analyzed via the Cox proportional hazard model; treatment effect was analyzed via the hazard ratio (HR). The median time to first post-dose SBM was derived via the Kaplan-Meier method (KM). A step-wise testing of superiority vs placebo was conducted for the overall pooled dataset, followed by testing superiority of individual naloxegol doses (12.5 and 25mg) vs placebo. Statistical significance required p < 0.05 for pairwise treatment group comparisons. Onset of action was measured by the proportion of patients with SBM starting at 4hrs through 48hrs post-first dose, which reflects a clinically relevant timeframe.

Results: In the pooled analysis (Intent-to-Treat), the time to first SBM was significantly shorter for the 12.5 and 25mg naloxegol groups (p < 0.001) vs placebo. The corresponding HRs favored naloxegol vs placebo (HR 1.58 for 12.5mg and HR 1.84 for 25mg; both p < 0.001). Overall, there was approximately a two to five fold reduction in the median time to first SBM for naloxegol vs placebo [7.8hrs (25 mg), 19.9hrs (12.5mg), and 36.4hrs (placebo), respectively]. The KM curve showed clear separation of naloxegol treatments from placebo. Higher proportions of patients achieved a SBM by ≤4hr, ≤6hr, ≤8hr, ≤12hr, ≤24hr, and ≤48hr for the naloxegol groups compared to placebo.Conclusions: This analysis demonstrated that treatment with naloxegol (12.5/25mg) was associated with rapid onset of action that was dose-dependent and predictable. Given the bothersome OIC symptoms experienced by patients, early symptom relief is an important therapeutic consideration.

Level of Evidence: Level I

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PM&R Meeting Abstracts - https://pmrjabstracts.org/abstract/rapid-onset-of-time-to-first-spontaneous-bowel-movement-and-predictable-efficacy-of-oral-once-daily-naloxegol-in-opioid-induced-constipation-pooled-analysis-of-two-global-randomized-controlled-trials/