[Skip to Content]
[Skip to Content Landing]

Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine PreventionA Randomized Clinical Trial

Educational Objective
To investigate the safety and efficacy of different doses of subcutaneous galcanezumab in the treatment of migraine prevention.
1 Credit CME
Key Points

Question  Is galcanezumab effective for prevention of migraine?

Findings  In this randomized clinical trial, administration of galcanezumab, 120 mg, once monthly to patients with a history of migraine who completed treatment significantly reduced the number of migraine headache days compared with placebo, with good tolerability and no emergent safety issues.

Meaning  Monoclonal antibodies against calcitonin gene-related peptide, such as galcanezumab, represent a novel approach in migraine prevention.

Abstract

Importance  Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention.

Objective  To assess whether at least 1 dose of galcanezumab was superior to placebo for episodic migraine prevention.

Design, Setting, and Participants  A randomized clinical trial was conducted in the United States (July 7, 2014, to August 19, 2015) in clinics of 37 licensed physicians with a specialty including, but not limited to, psychiatry, neurology, internal medicine, and primary care. Subcutaneous injections of galcanezumab, 5, 50, 120, or 300 mg, or placebo were given monthly during the 3-month treatment period. A total of 936 patients were assessed; 526 did not meet study entry or baseline criteria and 410 patients were randomly assigned to receive placebo or galcanezumab. Analyses were conducted on an intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study drug.

Interventions  Short-term migraine treatments were allowed as needed except for opioids or barbiturates.

Main Outcomes and Measures  To determine if at least 1 of the 4 doses of galcanezumab tested was superior to placebo for migraine prevention measured by the mean change from baseline in the number of migraine headache days 9 weeks to 12 weeks after randomization.

Results  Of the 936 patients assessed, 410 met entry criteria (aged 18-65 years with 4-14 migraine headache days per month and migraine onset prior to age 50 years) and were randomized to receive placebo or galcanezumab.For the primary end point, galcanezumab, 120 mg, significantly reduced migraine headache days compared with placebo (99.6% posterior probability −4.8 days; 90% BCI, −5.4 to −4.2 days vs 95% superiority threshold [Bayesian analysis] −3.7 days; 90% BCI, −4.1 to −3.2 days). Adverse events reported by 5% or more of patients in at least 1 galcanezumab dose group and more frequently than placebo included injection-site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea, and nausea.

Conclusions and Relevance  Monthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies. All dosages were safe and well tolerated for the preventive treatment of episodic migraine.

Trial Registration  clinicaltrials.gov Identifier: NCT02163993

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: David W. Dodick, MD, Department of Neurology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259 (dodick.david@mayo.edu).

Accepted for Publication: September 21, 2017.

Published Online: December 18, 2017. doi:10.1001/jamaneurol.2017.3859

Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

Correction: This article was corrected on February 12, 2018, to fix errors in the Conflict of Interest Disclosures.

Author Contributions: Drs Skljarevski and Zhang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Skljarevski, Oakes, Zhang, Ferguson, Johnson, Schacht, Goadsby, Dodick.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Skljarevski, Oakes, Zhang, Ferguson, Johnson, Carter, Goadsby, Dodick.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Zhang, Shan.

Obtained funding: Schacht.

Administrative, technical, or material support: Oakes, Ferguson, Carter, Schacht.

Conflict of Interest Disclosures: Drs Skljarevski, Oakes, Zhang, Ferguson, Martinez, Camporeale, Johnson, Shan, Carter, and Schacht are full-time employees of Eli Lilly and Company and/or one of its subsidiaries, and are stockholders. Dr Goadsby reports receiving consultant fees from Allergan, Amgen, and Eli-Lilly and Company; and personal fees from Akita Biomedical, Alder Biopharmaceuticals, Autonomic Technologies Inc, Avanir Pharma, Cipla Ltd, Colucid Pharmaceuticals, Ltd, Dr Reddy's Laboratories, eNeura, Electrocore LLC, Novartis, Pfizer Inc, Promius Pharma, Quest Diagnostics, Scion, Teva Pharmaceuticals, Trigemina Inc; MedicoLegal work, Journal Watch, UptoDate, and Oxford University Press. In addition, Dr Goadsby has a patent magnetic stimulation for headache pending assigned to eNeura. Dr Dodick has received compensation from serving on advisory boards and/or consulting within the past 5 years for Allergan, Amgen, Alder, Arteaus, Pfizer, Colucid, Merck, NuPathe, Eli Lilly and Company, Autonomic Technologies, Ethicon J&J, Zogenix, Supernus, Labrys, Boston Scientific, Medtronic, St Jude, Bristol-Myers Squibb, Lundbeck, Impax, MAP, Electrocore, Tonix, Novartis, Teva, Alcobra, Zosano, Insys, GBS/Nocira, Acorda, eNeura, Charleston Laboratories, Gore, Biohaven, Bioventric, Magellan, Theranica, Xenon, and Dr Reddy’s/Promius Pharma. Dr Dodick owns equity in Epien, GBS/Nocira, Second Opinion, Healint, and Theranica. Dr Dodick has received funding for travel, speaking, editorial activities, or royalty payments from IntraMed, SAGE Publishing, Sun Pharma, Allergan, Oxford University Press, American Academy of Neurology, American Headache Society, West Virginia University Foundation, Canadian Headache Society, HealthLogix, Universal Meeting Management, WebMD, UptoDate, Medscape, Oregon Health Science Center, Albert Einstein University, University of Toronto, Starr Clinical, Decision Resources, Synergy, MedNet LLC, Peer View Institute for Medical Education, Medicom, Chameleon Communications, Academy for Continued Healthcare Learning, Haymarket Medical Education, Global Scientific Communications, HealthLogix, Miller Medical, MeetingLogiX, and Wiley Blackwell. Dr Dodick, through his employer, has consulting use agreements with NeuroAssessment Systems and Myndshft. He holds board of director positions with King-Devick Technologies and Epien Inc. He holds the following Patent 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (no compensation). No other disclosures are reported.

Funding/Support: This study was sponsored and funded by Eli Lilly and Company, who also provided the study drug.

Role of the Funder/Sponsor: Eli Lilly and Company designed and conducted the study; managed collection of data, and oversaw any affiliated contracted research organizations in the process of conducting the study. All statistical analyses reported were performed by Eli Lilly and Company. All authors and Eli Lilly and Company prepared, reviewed, and approved the manuscript, and made the decision to submit the manuscript for publication.

Additional Contributions: The authors thank the patients, nurses, and physicians involved in this study.

References
1.
Global Burden of Disease Study 2013 Collaborators.  Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.  Lancet. 2015;386(9995):743-800.PubMedGoogle ScholarCrossref
2.
Hepp  Z, Dodick  DW, Varon  SF, Gillard  P, Hansen  RN, Devine  EB.  Adherence to oral migraine-preventive medications among patients with chronic migraine.  Cephalalgia. 2015;35(6):478-488.PubMedGoogle ScholarCrossref
3.
Silberstein  SD, Holland  S, Freitag  F, Dodick  DW, Argoff  C, Ashman  E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society.  Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society.  Neurology. 2012;78(17):1337-1345.PubMedGoogle ScholarCrossref
4.
Simpson  DM, Hallett  M, Ashman  EJ,  et al.  Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: report of the Guideline Development Subcommittee of the American Academy of Neurology.  Neurology. 2016;86(19):1818-1826.PubMedGoogle ScholarCrossref
5.
Goadsby  PJ.  Bench to bedside advances in the 21st century for primary headache disorders: migraine treatments for migraine patients.  Brain. 2016;139(pt 10):2571-2577.PubMedGoogle ScholarCrossref
6.
Ho  TW, Edvinsson  L, Goadsby  PJ.  CGRP and its receptors provide new insights into migraine pathophysiology.  Nat Rev Neurol. 2010;6(10):573-582.PubMedGoogle ScholarCrossref
7.
Goadsby  PJ, Edvinsson  L, Ekman  R.  Vasoactive peptide release in the extracerebral circulation of humans during migraine headache.  Ann Neurol. 1990;28(2):183-187.PubMedGoogle ScholarCrossref
8.
Goadsby  PJ, Edvinsson  L.  The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats.  Ann Neurol. 1993;33(1):48-56.PubMedGoogle ScholarCrossref
9.
Juhasz  G, Zsombok  T, Modos  EA,  et al.  NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release.  Pain. 2003;106(3):461-470.PubMedGoogle ScholarCrossref
10.
Lassen  LH, Haderslev  PA, Jacobsen  VB, Iversen  HK, Sperling  B, Olesen  J.  CGRP may play a causative role in migraine.  Cephalalgia. 2002;22(1):54-61.PubMedGoogle ScholarCrossref
11.
Hewitt  DJ, Aurora  SK, Dodick  DW,  et al.  Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine.  Cephalalgia. 2011;31(6):712-722.PubMedGoogle ScholarCrossref
12.
Ho  TW, Ferrari  MD, Dodick  DW,  et al.  Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial.  Lancet. 2008;372(9656):2115-2123.PubMedGoogle ScholarCrossref
13.
Olesen  J, Diener  H-C, Husstedt  IW,  et al; BIBN 4096 BS Clinical Proof of Concept Study Group.  Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine.  N Engl J Med. 2004;350(11):1104-1110.PubMedGoogle ScholarCrossref
14.
Marcus  R, Goadsby  PJ, Dodick  D, Stock  D, Manos  G, Fischer  TZ.  BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial.  Cephalalgia. 2014;34(2):114-125.PubMedGoogle ScholarCrossref
15.
Diener  HC, Barbanti  P, Dahlöf  C, Reuter  U, Habeck  J, Podhorna  J.  BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study.  Cephalalgia. 2011;31(5):573-584.PubMedGoogle ScholarCrossref
16.
Voss  T, Lipton  RB, Dodick  DW,  et al.  A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine.  Cephalalgia. 2016;36(9):887-898.PubMedGoogle ScholarCrossref
17.
Russo  AF.  Calcitonin gene-related peptide (CGRP): a new target for migraine.  Annu Rev Pharmacol Toxicol. 2015;55:533-552.PubMedGoogle ScholarCrossref
18.
Dodick  DW, Goadsby  PJ, Spierings  ELH, Scherer  JC, Sweeney  SP, Grayzel  DS.  Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study.  Lancet Neurol. 2014;13(9):885-892.PubMedGoogle ScholarCrossref
19.
Headache Classification Committee of the International Headache Society (IHS).  The International Classification of Headache Disorders, 3rd edition (beta version).  Cephalalgia. 2013;33(9):629-808.PubMedGoogle ScholarCrossref
20.
Cole  JC, Lin  P, Rupnow  MF.  Validation of the Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v. 2.1) for patients undergoing prophylactic migraine treatment.  Qual Life Res. 2007;16(7):1231-1237.PubMedGoogle ScholarCrossref
21.
Kawata  AK, Coeytaux  RR, Devellis  RF, Finkel  AG, Mann  JD, Kahn  K.  Psychometric properties of the HIT-6 among patients in a headache-specialty practice.  Headache. 2005;45(6):638-643.PubMedGoogle ScholarCrossref
22.
Monteith  D, Collins  EC, Vandermeulen  C,  et al.  Safety, tolerability, pharmacokinetics, and pharmacodynamics of the CGRP binding monoclonal antibody LY2951742 (galcanezumab) in healthy volunteers.  Front Pharmacol. 2017;8:740.PubMedGoogle ScholarCrossref
23.
Bigal  ME, Walter  S, Rapoport  AM.  Therapeutic antibodies against CGRP or its receptor.  Br J Clin Pharmacol. 2015;79(6):886-895.PubMedGoogle ScholarCrossref
24.
Bigal  ME, Dodick  DW, Rapoport  AM,  et al.  Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study.  Lancet Neurol. 2015;14(11):1081-1090.PubMedGoogle ScholarCrossref
25.
Diener  H-C, Schorn  CF, Bingel  U, Dodick  DW.  The importance of placebo in headache research.  Cephalalgia. 2008;28(10):1003-1011.PubMedGoogle ScholarCrossref
26.
Cernuda-Morollón  E, Larrosa  D, Ramón  C, Vega  J, Martínez-Camblor  P, Pascual  J.  Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine.  Neurology. 2013;81(14):1191-1196.PubMedGoogle ScholarCrossref
27.
Gupta  VK.  CSD, BBB and MMP-9 elevations: animal experiments versus clinical phenomena in migraine.  Expert Rev Neurother. 2009;9(11):1595-1614.PubMedGoogle ScholarCrossref
28.
Gursoy-Ozdemir  Y, Qiu  J, Matsuoka  N,  et al.  Cortical spreading depression activates and upregulates MMP-9.  J Clin Invest. 2004;113(10):1447-1455.PubMedGoogle ScholarCrossref
29.
Schankin  CJ, Maniyar  FH, Seo  Y,  et al.  Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate–induced migraine.  Brain. 2016;139(Pt 7):1994-2001.PubMedGoogle ScholarCrossref
30.
Lafata  JE, Tunceli  O, Cerghet  M, Sharma  KP, Lipton  RB.  The use of migraine preventive medications among patients with and without migraine headaches.  Cephalalgia. 2010;30(1):97-104.PubMedGoogle ScholarCrossref
31.
Evans  RW, Linde  M.  Expert opinion: adherence to prophylactic migraine medication.  Headache. 2009;49(7):1054-1058.PubMedGoogle ScholarCrossref
32.
de Hoon  J, Montieth  D, Vermeersch  S,  et al.  Safety, pharmacokinetics, and pharmacodynamics of LY2951742: a monoclonal antibody targeting CGRP.  Cephalalgia. 2013;33(8)(suppl):247.Google Scholar
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Topics
State Requirements