Lines, Christopher

Background: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. Methods: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. Results: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom ( p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg ( p < .001) and nominally significant for 100 mg and 10 mg ( p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. Conclusions: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

Background: Endpoints used to evaluate the efficacy of acute anti-migraine drugs do not measure the tolerability. Sustained pain-free response with no adverse events has been recommended as a composite endpoint which measures the efficacy and tolerability attributes that patients desire. Methods: The aim of this study was to evaluate new composite efficacy-plus-tolerability endpoints based on a post-hoc analysis of patient-level data from a previous randomized, placebo-controlled trial of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, and zolmitriptan in the acute treatment of migraine. Endpoints were 2–24-hour sustained pain freedom and no adverse events from 0–24 hours (SPF24NAE), 2–24 hour sustained pain relief and no adverse events from 0–24 hours (SPR24NAE), pain freedom at 2 hours and no adverse events from 0–24 hours (PF2NAE), and pain relief at 2 hours and no adverse events from 0–24 hours (PR2NAE). Results: Compared with placebo, both telcagepant 300 mg and 150 mg achieved nominal superiority ( p values <.05) for SPF24NAE, SPR24NAE, PF2NAE and PR2NAE. Zolmitriptan 5 mg showed nominal superiority versus placebo for SPF24NAE, SPR24NAE and PF2NAE, but not PR2NAE. Telcagepant 300 mg showed nominal superiority versus zolmitriptan for SPF24NAE, SPR24NA and PR2NAE. Conclusion: Composite efficacy-plus-tolerability endpoints may be useful for facilitating comparisons between treatments.