BACKGROUND: The calcitonin gene-related peptide (CGRP) pathway is a promising 
target for preventive therapies in patients with migraine. We assessed the 
safety and efficacy of AMG 334, a fully human monoclonal antibody against the 
CGRP receptor, for migraine prevention.
METHODS: In this multicentre, randomised, double-blind, placebo-controlled, 
phase 2 trial, patients aged 18-60 years with 4 to 14 migraine days per month 
were enrolled at 59 headache and clinical research centres in North America and 
Europe, and randomly assigned in a 3:2:2:2 ratio to monthly subcutaneous 
placebo, AMG 334 7 mg, AMG 334 21 mg, or AMG 334 70 mg using a sponsor-generated 
randomisation sequence centrally executed by an interactive voice response or 
interactive web response system. Study site personnel, patients, and the sponsor 
study personnel were masked to the treatment assignment. The primary endpoint 
was the change in monthly migraine days from baseline to the last 4 weeks of the 
12-week double-blind treatment phase. The primary endpoint was calculated using 
the least squares mean at each timepoint from a generalised linear mixed-effect 
model for repeated measures. Safety endpoints were adverse events, clinical 
laboratory values, vital signs, and anti-AMG 334 antibodies. The study is 
registered with ClinicalTrials.gov, number NCT01952574. An open-label extension 
phase of up to 256 weeks is ongoing and will assess the long-term safety of AMG 
334.
FINDINGS: From Aug 6, 2013, to June 30, 2014, 483 patients were randomly 
assigned to placebo (n=160), AMG 334 7 mg (n=108), AMG 334 21 mg (n=108), or AMG 
334 70 mg (n=107). The mean change in monthly migraine days at week 12 was -3·4 
(SE 0·4) days with AMG 334 70 mg versus -2·3 (0·3) days with placebo (difference 
-1·1 days [95% CI -2·1 to -0·2], p=0·021). The mean reductions in monthly 
migraine days with the 7 mg (-2·2 [SE 0·4]) and the 21 mg (-2·4 [0·4]) doses 
were not significantly different from that with placebo. Adverse events were 
recorded in 82 (54%) patients who received placebo, 54 (50%) patients in the AMG 
334 7 mg group, 54 (51%) patients in the AMG 334 21 mg group, and 57 (54%) 
patients in the AMG 334 70 mg group. The most frequently reported adverse events 
were nasopharyngitis, fatigue, and headache. Serious adverse events were 
reported for one patient in the AMG 334 7 mg group (ruptured ovarian cyst) and 
one patient in the AMG 334 70 mg group (migraine and vertigo); these events were 
judged to be unrelated to AMG 334 treatment. Nine (3%) of 317 patients had 
neutralising antibodies. No apparent association was recorded between patients 
with positive anti-AMG 334 antibodies and adverse events. No clinically 
significant vital signs, laboratory, or electrocardiogram findings were 
recorded.
INTERPRETATION: These results suggest that AMG 334 70 mg might be a potential 
therapy for migraine prevention in patients with episodic migraine and support 
further investigation of AMG 334 in larger phase 3 trials.
FUNDING: Amgen.