Study to Evaluate the Efficacy and Safety of Erenumab (AMG 334) Compared to Placebo in Migraine Prevention (ARISE)

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention

To evaluate the effect of erenumab compared to placebo on the change from baseline in monthly migraine days, in adults with episodic migraine.

Study Overview

• Status: Completed
• Conditions: Migraine
• Intervention / Treatment: Drug: Placebo; Drug: Erenumab

Detailed Description

Adults with a history of migraine with or without aura for ≥ 12 months and who experience ≥ 4 to < 15 migraine days per month with < 15 headache days per month will be randomized 1:1 to placebo or erenumab. Double-blind erenumab or placebo will be administered during the 12-week double-blind treatment phase and open-label erenumab will be administered during the 28-week open-label treatment phase.

• Study Type: Interventional
• Enrollment (Actual): 577
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Research Site
  • Ballerup, Denmark, 2750
    • Research Site
  • Glostrup, Denmark, 2600
    • Research Site
  • Vejle, Denmark, 7100
    • Research Site
• France
  • Bordeaux Cedex, France, 33076
    • Research Site
  • Nice cedex 1, France, 06003
    • Research Site
  • Paris, France, 75010
    • Research Site
  • Paris, France, 75014
    • Research Site
  • Pringy Cedex, France, 74374
    • Research Site
• Greece
  • Athens, Greece, 11521
    • Research Site
  • Athens, Greece, 11525
    • Research Site
  • Athens, Greece, 16675
    • Research Site
  • Thessaloniki, Greece, 54645
    • Research Site
• Portugal
  • Amadora, Portugal, 2720-276
    • Research Site
  • Lisboa, Portugal, 1649-035
    • Research Site
  • Lisboa, Portugal, 1500-650
    • Research Site
  • Torres Vedras, Portugal, 2560-280
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 121467
    • Research Site
  • Moscow, Russian Federation, 119435
    • Research Site
  • Novosibirsk, Russian Federation, 630091
    • Research Site
  • Saint Petersburg, Russian Federation, 197022
    • Research Site
  • Ufa, Russian Federation, 450083
    • Research Site
• Spain
  • Madrid, Spain, 28040
    • Research Site
  • Aragón
    • Zaragoza, Aragón, Spain, 50009
      • Research Site
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Research Site
  • Castilla León
    • Valladolid, Castilla León, Spain, 47005
      • Research Site
  • Cataluña
    • Barcelona, Cataluña, Spain, 08035
      • Research Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Research Site
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Research Site
  • Galicia
    • Santiago de Compostela, Galicia, Spain, 15706
      • Research Site
• Switzerland
  • Bad Zurzach, Switzerland, 5330
    • Research Site
  • Biel, Switzerland, 2502
    • Research Site
  • Geneve, Switzerland, 1205
    • Research Site
  • Lugano, Switzerland, 6903
    • Research Site
  • St Gallen, Switzerland, 9007
    • Research Site
  • Zollikon, Switzerland, 8702
    • Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35216
      • Research Site
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Research Site
  • California
    • Culver City, California, United States, 90230
      • Research Site
    • Long Beach, California, United States, 90806
      • Research Site
    • Sacramento, California, United States, 95821
      • Research Site
    • San Diego, California, United States, 92103
      • Research Site
    • Santa Monica, California, United States, 90404
      • Research Site
    • Walnut Creek, California, United States, 94598
      • Research Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Research Site
  • Connecticut
    • Fairfield, Connecticut, United States, 06824
      • Research Site
  • Florida
    • Hollywood, Florida, United States, 33021
      • Research Site
    • Jacksonville, Florida, United States, 32216
      • Research Site
    • Orlando, Florida, United States, 32806
      • Research Site
    • Oviedo, Florida, United States, 32765
      • Research Site
    • Palm Beach Gardens, Florida, United States, 33410
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Research Site
  • Illinois
    • Gurnee, Illinois, United States, 60031
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46256
      • Research Site
  • Kansas
    • Lenexa, Kansas, United States, 66214
      • Research Site
  • Kentucky
    • Lexington, Kentucky, United States, 40513
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21208
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02131
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48104
      • Research Site
    • Kalamazoo, Michigan, United States, 49009
      • Research Site
  • New Jersey
    • Princeton, New Jersey, United States, 08540
      • Research Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Research Site
  • New York
    • Williamsville, New York, United States, 14221
      • Research Site
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Research Site
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45245
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19114
      • Research Site
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • Research Site
  • South Carolina
    • Mount Pleasant, South Carolina, United States, 29464
      • Research Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • Research Site
  • Texas
    • Austin, Texas, United States, 78759
      • Research Site
    • Dallas, Texas, United States, 75214
      • Research Site
  • Utah
    • Salt Lake City, Utah, United States, 84121
      • Research Site
  • Virginia
    • Virginia Beach, Virginia, United States, 23454
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98105
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• History of migraines (with or without aura) for ≥ 12 months
• Migraine frequency: ≥ 4 and < 15 migraine days per month on average acrossthe 3 months prior to screening
• Headache (ie, migraine and non-migraine headache) frequency: < 15 headache days per month on average across the 3 months prior to screening
• Demonstrated compliance with the eDiary

Exclusion Criteria:

• Older than 50 years of age at migraine onset.
• History of cluster headache or hemiplegic migraine headache.
• Unable to differentiate migraine from other headaches
• No therapeutic response with > 2 categories for prophylactic treatment of migraine after an adequate therapeutic trial.
• Concomitant use of 2 or more medications with possible migraine prophylactic effects within 2 months prior to the start of the baseline phase or during the baseline phase. If only 1 prophylactic medication is used, the dose must be stable within 2 months prior to the start of the baseline phase and throughout the study
• Used a prohibited medication, device, or procedure within 2 months prior to the start of the baseline phase or during the baseline phase.
• Received botulinum toxin
• Anticipated to require any excluded medication, device, or procedure during the study.
• Active chronic pain syndromes (such as fibromyalgia and chronic pelvic pain).
• History of major psychiatric disorder.
• History of seizure disorder or other significant neurological conditions other than migraine.
• Human immunodeficiency virus (HIV) infection by history.
• Myocardial infarction (MI), stroke, transient ischemic attack (TIA), unstable angina, or coronary artery bypass surgery or other revascularization procedure within 12 months prior to screening.
• The subject is at risk of self-harm or harm to others. Previously randomized into an AMG 334 study.
• Unlikely to be able to complete all protocol required study visits or procedures, and/or to comply with all required study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the open-label treatment phase.	Drug: Placebo; Administered once a month by subcutaneous injection
Experimental: Erenumab; Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the open-label treatment phase.	Drug: Erenumab; Administered once a month by subcutaneous injection; Other Names: AMG 334; Aimovig™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Monthly Migraine Days at Week 12	A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine with or without aura. The change from baseline in monthly migraine days was calculated as the number of migraine days during the last 4 weeks of the 12-week double-blind treatment phase - the number of migraine days during the 4-week baseline phase.	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12	A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine without aura or a migraine with aura. Monthly migraine days were calculated as the number of migraine days in the 4-week baseline phase and during the last 4 weeks of double-blind treatment. At least a 50% reduction from baseline in monthly migraine days was determined if the change in monthly migraine days from the 4-week baseline phase to the last 4 weeks of the 12-week double-blind treatment phase * 100 / baseline monthly migraine days was less than or equal to -50%.	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days at Week 12	Monthly acute migraine-specific medication treatment days is the number of days on which migraine specific medications were used between monthly doses of study drug. Migraine-specific medications includes two categories of medications: triptan-based migraine medications and ergotamine-based migraine medications. The change from baseline in monthly acute migraine-specific treatment days was calculated as the number of migraine-specific treatment days during the last 4 weeks of the 12-week double-blind treatment phase - the number of migraine-specific treatment days during the 4-week baseline phase.	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
Percentage of Participants With at Least a 5-point Reduction From Baseline in Average Impact on Everyday Activities Domain Score Measured by MPFID at Week 12	The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from "Without any difficulty" (1) to "Unable to do" (5) and frequency items ranging from "None of the time" (1) to "All of the time" (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Achievement of at least a 5 point reduction from baseline in the monthly average domain score was calculated as (monthly average domain score during the last 4 weeks of the 12-week double-blind treatment phase - baseline monthly average domain score) was ≤ -5.	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
Percentage of Participants With at Least a 5-Point Reduction From Baseline in Average Impact on Physical Impairment Domain Score Measured by MPFID at Week 12	The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from "Without any difficulty" (1) to "Unable to do" (5) and frequency items ranging from "None of the time" (1) to "All of the time" (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Achievement of at least a 5 point reduction from baseline in the monthly average domain score was calculated as (monthly average domain score during the last 4 weeks of the 12-week double-blind treatment phase - baseline monthly average domain score) was ≤ -5.	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
Number of Participants With Adverse Events	Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4, where: Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; Grade 4 = Life-threatening consequences; urgent intervention indicated Grade 5 = Death related to AE.	From first dose of study drug up to 12 weeks after the last dose. The double-blind treatment phase was 12 weeks and the open-label treatment phase was 28 weeks.
Number of Participants Who Developed Antibodies to Erenumab	Blood samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect anti-drug antibodies (ADA) against erenumab. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based bioassay to determine neutralizing activity against erenumab (Neutralizing Antibody Assay). Developing antibody incidence indicates participants with a negative or no result at baseline and a positive result at any time post-baseline. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. Transient indicates a negative result at the participant's last time point tested, for those participants with a positive binding/neutralizing result post-baseline.	Baseline (the period prior to the first dose erenumab 70 mg) and post-baseline (the period after the first dose of erenumab 70 mg until 12 weeks after last dose, up to 48 weeks total)

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Lampl C, Kraus V, Lehner K, Loop B, Chehrenama M, Maczynska Z, Ritter S, Klatt J, Snellman J. Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials. J Headache Pain. 2022 Aug 18;23(1):104. doi: 10.1186/s10194-022-01470-4.
• Zhou Y, Zhang F, Starcevic Manning M, Hu Z, Hsu CP, Chen PW, Peng C, Loop B, Mytych DT, Paiva da Silva Lima G. Immunogenicity of erenumab: A pooled analysis of six placebo-controlled trials with long-term extensions. Cephalalgia. 2022 Jul;42(8):749-760. doi: 10.1177/03331024221075621. Epub 2022 Mar 10.
• Cheng S, Picard H, Zhang F, Eisele O, Mikol DD. Efficacy and safety of erenumab for migraine prevention: an overview. Japanese Journal of Headache. 2019; 45 : 493-505.
• Ashina M, Kudrow D, Reuter U, Dolezil D, Silberstein S, Tepper SJ, Xue F, Picard H, Zhang F, Wang A, Zhou Y, Hong F, Klatt J, Mikol DD. Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions. Cephalalgia. 2019 Dec;39(14):1798-1808. doi: 10.1177/0333102419888222. Epub 2019 Nov 10.
• Kudrow D, Pascual J, Winner PK, Dodick DW, Tepper SJ, Reuter U, Hong F, Klatt J, Zhang F, Cheng S, Picard H, Eisele O, Wang J, Latham JN, Mikol DD. Vascular safety of erenumab for migraine prevention. Neurology. 2020 Feb 4;94(5):e497-e510. doi: 10.1212/WNL.0000000000008743. Epub 2019 Dec 18. Erratum In: Neurology. 2020 Jun 9;94(23):1052.
• Ashina M, Goadsby PJ, Dodick DW, Tepper SJ, Xue F, Zhang F, Brennan F, Paiva da Silva Lima G. Assessment of Erenumab Safety and Efficacy in Patients With Migraine With and Without Aura: A Secondary Analysis of Randomized Clinical Trials. JAMA Neurol. 2022 Feb 1;79(2):159-168. doi: 10.1001/jamaneurol.2021.4678.
• Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, Palmer K, Picard H, Mikol DD, Lenz RA. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018 May;38(6):1026-1037. doi: 10.1177/0333102418759786. Epub 2018 Feb 22.
• Kawata AK, Ladd MK, Lipton RB, Buse DC, Bensink M, Shah S, Hareendran A, Mannix S, Mikol D. Reducing the physical, social, and emotional impact of episodic migraine: Results from erenumab STRIVE and ARISE phase III randomized trials. Headache. 2022 Feb;62(2):159-168. doi: 10.1111/head.14258. Epub 2022 Feb 8.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2015
• Primary Completion (Actual): July 11, 2016
• Study Completion (Actual): March 20, 2017

Study Registration Dates

• First Submitted: June 12, 2015
• First Submitted That Met QC Criteria: June 24, 2015
• First Posted (Estimate): June 29, 2015

Study Record Updates

• Last Update Posted (Actual): October 12, 2022
• Last Update Submitted That Met QC Criteria: October 3, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Migraine; Headache; Prevention; Prophylaxis; Episodic
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Calcitonin Gene-Related Peptide Receptor Antagonists; Erenumab
• Other Study ID Numbers: 20120297; 2014-004463-20 (EudraCT Number)