Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine.
OBJECTIVE
To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine.


METHODS
Randomized, double-blind, parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 (25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief (reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses.


RESULTS
Per the adaptive study design, the four lowest MK-0974 groups (25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg (n = 38) 68.1%, 400 mg (n = 45) 48.2%, 600 mg (n = 40) 67.5%, rizatriptan 10 mg (n = 34) 69.5%, and placebo (n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant (P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose.


CONCLUSIONS
The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.
Ho
T W
TW
Merck Research Laboratories, UG 4C-18, PO Box 1000, North Wales, PA 19454-1099, USA. tony_ho@merck.com
Mannix
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LK
Fan
X
X
Assaid
C
C
Furtek
C
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Jones
C J
CJ
Lines
C R
CR
Rapoport
A M
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D000284:Administration, Oral; D000328:Adult; D001381:Azepines / Q000008:administration & dosage* / Q000627:therapeutic use; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology; D013997:Time Factors
D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; D018015:Receptors, Calcitonin Gene-Related Peptide; C525458:telcagepant