title: Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial.
abstract: BACKGROUND
  Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered humanised anti-CGRP antibody, for migraine prevention.
  
  
  METHODS
  In this randomised, double-blind, placebo-controlled, exploratory, proof-of-concept phase 2 trial, patients aged 18-55 years with five to 14 migraine days per 28-day period were randomly assigned (1:1) via an interactive web response system to receive an intravenous dose of ALD403 1000 mg or placebo. Site investigators, patients, and the sponsor were masked to treatment allocation during the study. The primary objective was to assess safety at 12 weeks after infusion. The primary efficacy endpoint was the change from baseline to weeks 5-8 in the frequency of migraine days, as recorded in patient electronic diaries. Patients were followed up until 24 weeks for exploratory safety and efficacy analyses. Safety and efficacy analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, NCT01772524.
  
  
  RESULTS
  Between Jan 28, 2013, and Dec 23, 2013, of 174 patients randomly assigned at 26 centres in the USA, 163 received either ALD403 (n=81) or placebo (n=82). Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 in the placebo group. The most frequent adverse events were upper respiratory tract infection (placebo 6 [7%] patients vs ALD403 7 [9%] patients), urinary tract infection (4 [5%] vs 1 [1%]), fatigue (3 [4%] vs 3 [4%]), back pain (4 [5%] vs 3 [4%]), arthralgia (4 [5%] vs 1 [1%]), and nausea and vomiting (2 [2%] vs 3 [4%]). Six serious adverse events were reported by three patients and were judged to be unrelated to study drug: in the ALD403 group, one patient had four serious adverse events and one had one serious adverse event, and in the placebo group, one patient had one serious adverse event. There were no differences in vital signs or laboratory safety data between the two treatment groups. The mean change in migraine days between baseline and weeks 5-8 was -5·6 (SD 3·0) for the ALD403 group compared with -4·6 (3·6) for the placebo group (difference -1·0, 95% CI -2·0 to 0·1; one-sided p=0·0306).
  
  
  CONCLUSIONS
  No safety concerns were noted with an intravenous dose of ALD403 1000 mg. This study also provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days.
  
  
  BACKGROUND
  Alder Biopharmaceuticals.
authors.affiliation: Department of Neurology, Mayo Clinic, Phoenix, AZ, USA. Electronic address: dodick.david@mayo.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Dodick
authors.affiliation: NIHR-Wellcome Trust Clinical Research Facility, King's College London, London, UK; Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Goadsby
authors.affiliation: Department of Neurology, Thomas Jefferson University, Jefferson Headache Center, Philadelphia, PA, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Silberstein
authors.affiliation: Department of Neurology and the Montefiore Headache Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lipton
authors.affiliation: Danish Headache Center and Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jes
authors.initials: J
authors.lastname: Olesen
authors.affiliation: Danish Headache Center and Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Messoud
authors.initials: M
authors.lastname: Ashina
authors.affiliation: MD Clinical, Hallandale Beach, FL, USA.
authors.forename: Kerri
authors.initials: K
authors.lastname: Wilks
authors.affiliation: California Medical Clinic for Headache, Santa Monica, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kudrow
authors.affiliation: Women's Clinical Research Center, Seattle, WA, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Kroll
authors.affiliation: Miami Research Associates, South Miami, FL, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Kohrman
authors.affiliation: Boston Clinical Trials, Boston, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bargar
authors.affiliation: Pacific Northwest Statistical Consulting, Woodinville, WA, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Hirman
authors.affiliation: Alder BioPharmaceuticals, Bothell, WA, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Smith
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000175:diagnosis* / Q000517:prevention & control*; D015202:Protein Engineering / Q000379:methods; D012141:Respiratory Tract Infections / Q000139:chemically induced / Q000175:diagnosis; D013997:Time Factors; D016896:Treatment Outcome; D014552:Urinary Tract Infections / Q000139:chemically induced / Q000175:diagnosis
chemical_list: D000911:Antibodies, Monoclonal; D015740:Calcitonin Gene-Related Peptide