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Figure 1.  Flow Diagram of Patients Initially Assessed for Eligibility and Completed Study Period 3 by Treatment Group
Flow Diagram of Patients Initially Assessed for Eligibility and Completed Study Period 3 by Treatment Group
Figure 2.  Change in the Number of Migraine Headache Days During Study Period 3 From Baseline to End Point (Month 3 of Study Period 3) Among Patients Who Received Placebo or Galcanezumab
Change in the Number of Migraine Headache Days During Study Period 3 From Baseline to End Point (Month 3 of Study Period 3) Among Patients Who Received Placebo or Galcanezumab

LS indicates least square; error bars, SE.

aP ≤ .05.

bP < .01.

Figure 3.  Change From Baseline in the Level of Functional Impact at End Point (Month 3 of Study Period 3) Among Patients Treated With Placebo or Galcanezumab Represented by Migraine-Specific Quality of Life, Version 2.1 Total Composite Scores
Change From Baseline in the Level of Functional Impact at End Point (Month 3 of Study Period 3) Among Patients Treated With Placebo or Galcanezumab Represented by Migraine-Specific Quality of Life, Version 2.1 Total Composite Scores

For galcanezumab, 5 mg: 95% CI, 22.6-32.5; P = .03; galcanezumab, 120 mg: 95% CI, 25.1-35.3; P = .002; and galcanezumab, 300 mg: 95% CI, 22.6-32.4; P = .03. LS indicates least square.

Table 1.  Baseline Characteristics of Patients Randomly Assigned to Either Placebo or Galcanezumab for Prevention of Migrainea
Baseline Characteristics of Patients Randomly Assigned to Either Placebo or Galcanezumab for Prevention of Migrainea
Table 2.  TEAEs Reported During the Double-blind Treatment Period by 5% or More of Galcanezumab Patientsa
TEAEs Reported During the Double-blind Treatment Period by 5% or More of Galcanezumab Patientsa
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
Original Investigation
February 2018

Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine Prevention: A Randomized Clinical Trial

Author Affiliations
  • 1Eli Lilly and Company, Indianapolis, Indiana
  • 2Eli Lilly Italia, Sesto Fiorentino, Italy
  • 3National Institute for Health Research-Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK
  • 4Department of Neurology, University of California, San Francisco
  • 5Department of Neurology, Mayo Clinic, Scottsdale, Arizona
JAMA Neurol. 2018;75(2):187-193. doi:10.1001/jamaneurol.2017.3859
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

Introduction

Migraine is a chronic neurologic disease that negatively affects patients’ daily functioning.1,2 Currently, there are 5 US Food and Drug Administration–approved medications for migraine prevention, none of which was developed for migraine or with any mechanistic understanding of their action in migraine.3,4 Treatment responses are variable; adherence over time is low, especially with oral preventive drugs; and all of the currently available drugs have well-established and troublesome adverse effects in some patients.5 New treatment options with improved efficacy and tolerability are needed for patients with migraine; ideally, those options would be developed specifically for the disease and reflect a better understanding of its pathophysiology.

Advances in the understanding of migraine have unveiled several potential pharmacologic targets for both acute treatment and prevention.5Quiz Ref ID Calcitonin gene-related peptide (CGRP), found in peripheral trigeminal sensory and the central nervous system,6 was found to be elevated in the plasma of migraineurs during an attack7-9 and is a promising target believed to play an integral role in the pathophysiology of migraine.5-10 As a pharmacologic target, CGRP was clinically validated with -gepants, a class of small-molecule CGRP receptor antagonists that were efficacious in acute relief of migraine11-16; 2 were discontinued owing to hepatic toxic effects.5,11 Understanding the fundamental role of CGRP in migraine and advancing the application of therapeutic biologics led to the development of monoclonal antibodies against CGRP.17 One of these monoclonal antibodies against CGRP is galcanezumab (LY2951742), a humanized monoclonal antibody that potently and selectively binds to CGRP. In a phase 2a study, galcanezumab, 150 mg, twice monthly was efficacious and well tolerated for the prevention of migraine.18

In the phase 2b study reported herein, the safety and efficacy of 4 different doses of monthly galcanezumab compared with placebo for the prevention of migraine were assessed. Adverse events (AEs) are the only safety components reported here; a second article will provide a comprehensive review of safety data.

Methods
Study Design and Patients

This was a phase 2b study of galcanezumab and placebo in patients with episodic migraine conducted by 37 licensed physicians in the United States. The trial comprised 4 study periods (SPs) between July 7, 2014, and August 19, 2015: (1) screening and washout, (2) a prospective baseline period for determining the frequency of migraine headache days (MHDs), (3) double-blind treatment period (months 1, 2, and 3), and (4) posttreatment period.

Study period 1 (5-45 days) included initial screening for eligibility and washout of migraine prevention treatments. Study period 2 (28-38 days) established a baseline for the frequency of MHDs. During SP 2, patients called into an electronic patient-reported outcome interactive voice response system (ePRO) daily to record their headache information.

Study period 3 was a 3-month time during which the treatments were administered. If eligible, the patient was randomized to 1 of 5 treatment groups (2:1:1:1:1 ratio) to receive either placebo or 1 galcanezumab dose level (5, 50, 120, or 300 mg), respectively. Quiz Ref IDGalcanezumab or placebo was administered by subcutaneous (SC) injection once monthly during office visits (visits 3, 5, and 7). All patients received two 1.5-mL injections at each dosing visit; sites were instructed to use a 25- or 27-gauge needle. Galcanezumab was supplied as a lyophilized formulation in glass vials, and placebo was administered as sodium chloride, 0.9%, for injection. Patients continued calling into ePRO daily to record their headache information. If a patient discontinued the study early during SP 3, that patient immediately entered SP 4. Study period 4 was a 3-month posttreatment period during which patients received neither of the treatments. Daily ePRO call-ins continued, and office visits occurred every 6 weeks. During the study, acute migraine treatments were allowed as needed (opioids or barbiturates were not permitted). Concomitant medications allowed included acetaminophen, nonsteroidal anti-inflammatory drugs, aspirin, triptans, corticosteroids (periodic topical or inhaled but not oral or injected), and ergotamines and their derivatives. Preventive treatments were permitted only during SP 4, when migraine preventive medications were allowed at the discretion of the investigator.

The patient population consisted of men and women aged 18 to 65 years with a history of migraine, with or without aura, for at least 1 year prior to enrollment. For enrollment, patients had to experience a frequency of 4 to 14 MHDs and at least 2 migraine attacks in a 28-day period during SP 2. Migraine onset must have occurred prior to age 50 years. Use of botulinum toxin A and B administered in the head or neck area must have been discontinued at least 4 months prior to SP 2. Patients were excluded from study participation for any of the following reasons: currently enrolled in or discontinued within the last 30 days from a clinical trial using any investigational drug or device; any current or previous exposure to a CGRP or nerve growth factor antibody; history of hemiplegic, ophthalmoplegic, or basilar-type migraine; history or presence of other medical illness indicating a medical problem that would preclude study participation; failure to respond to more than 2 effective migraine preventive treatments as defined by the American Academy of Neurology/American Headache Society treatment guidelines level A and B evidence3; evidence of significant active psychiatric disease; and pregnancy or lactation. For evidence of adequate adherence, patients should have completed at least 80% of the ePRO daily headache entries during SP 2. All patients provided written informed consent prior to initiating any study procedures; financial compensation was provided. The study was approved by the Quorum Review Inc and Dean Foundation for Health Research and Education. The trial protocol is available in the Supplement.

Randomization and Blinding

Patients were assigned by a computer-generated randomization sequence using an interactive web-response system to placebo or galcanezumab, 5, 50, 120, or 300 mg (2:1:1:1:1) administered by SC injection once monthly for 3 months. Patients, investigators, and all other personnel involved in the conduct of the study were blinded to individual treatment assignments.

Outcomes

The primary objective was to assess whether at least 1 dose of galcanezumab was superior to placebo in the prevention of migraine. Superiority was determined when the posterior probability of greater improvement for any galcanezumab dose group compared with placebo measured by the mean change from baseline in the number of MHDs in month 3 was 95% or more. Secondary outcome measures reported herein included changes from baseline in the number of MHDs plus probable MHDs, probable MHDs, headache days, migraine attacks, and the proportion of patients reporting 50% and 100% reduction in the number of MHDs during SP 3. An MHD was defined according to the diagnostic criteria of the “International Classification of Headache Disorders” (3rd edition, beta version)19 modified for headache duration, as any calendar day in which a migraine headache lasted 30 minutes or longer (regardless of duration, a day with use of acute treatment was not automatically counted as an MHD). A headache day was defined as any calendar day in which a migraine, probable migraine, or nonmigraine headache (any headache lasting ≥30 minutes but not fulfilling migraine or probable migraine criteria) occurred lasting 4 hours or longer. Probable migraines were headaches that lasted 30 minutes or longer on a given calendar day, with or without aura, but were missing 1 of the features needed to fulfill all migraine criteria. A migraine attack was defined as beginning on any day that a migraine was recorded and ending when a migraine-free day (in this case, a 24-hour period) occurred. The scale indicating the severity of migraine for patients with 1 or more migraine headaches per month was 1 indicating mild; 2, moderate; and 3, severe.

The effect of galcanezumab on functional impact owing to monthly MHDs was assessed using changes from baseline in the Migraine-Specific Quality of Life Questionnaire, version 2.1 (MSQ)20 and Headache Impact Test-6 (HIT-6)21 responses. Safety end points reported herein included the occurrence of spontaneously reported treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and discontinuation rates.

Statistical Analyses
Sample Size

A planned sample size of at least 134 patients in the placebo group and 67 in each of the galcanezumab dose groups was expected to provide approximately 90% power to show that at least 1 galcanezumab dose arm had at least a 95% posterior probability of greater improvement in MHDs over placebo. This sample size calculation was based on a Bayesian dose-response model.

Efficacy

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. Two statistical tests were used to evaluate the primary objective. The primary analyses were performed using a Bayesian dose-response model during SP 3; 90% Bayesian credible intervals (BCIs) were calculated for the posterior mean change from baseline in MHDs. There was no prespecified multiplicity adjustment for the primary efficacy analysis. Because the Bayesian dose-response model provided only estimates of treatment effect at month 3, a supporting analysis (mixed-model repeated measures; the multiplicity-adjusted P value with the step-down Dunnett procedure was calculated using a 2-sided α level of .05) was used for the primary efficacy measure to provide an estimate of treatment effect at each of the 3 months in SP 3, as well as overall across the 3 months. Analyses were conducted using SAS software, version 9.2 (SAS Institute Inc).

Continuous variables for secondary outcomes were analyzed using a repeated measures analysis. Response rates (50% and 100%) were analyzed using a categorical, pseudo-likelihood–based repeated measures analysis. Change from baseline to end point using last observation carried forward for MSQ and HIT-6 was analyzed using the analysis of covariance model. No multiplicity adjustments were made for any secondary end points.

Safety and Tolerability

Adverse events were coded according to Medical Dictionary for Regulatory Activities, version 17.1 (meddra.org) criteria. Categorical safety measures were analyzed using the Fisher exact test.

Results
Patient Disposition and Baseline Characteristics

Of 936 patients entering SP 1 (Figure 1), 410 were randomized to study treatments where they received at least 1 dose of any of the study treatments (galcanezumab, 273; placebo, 137). Patients not meeting study entry criteria were discontinued. Overall, 375 (91.5%) of randomized patients completed SP 3 (galcanezumab, 249 [91.2%]; placebo, 126 [92.0%]). There were 238 (87.2%) galcanezumab- and 120 (87.6%) placebo-treated patients who completed both SP 3 and SP 4.

Baseline demographic and clinical characteristics were not statistically significantly different between any treatment groups (Table 1). The patient population was primarily female (340 [83.0%]) and white (307 [75.0%]), with a mean (SD) age of 40.2 (12.0) years.

There were no statistically significant differences in discontinuation rates for any reason between galcanezumab and placebo in SP 3 or 4. Thirty-five of 410 patients (8.5%) discontinued the study during SP 3; the leading cause was patient decision. Two galcanezumab-treated patients withdrew owing to an AE: a patient receiving 5 mg reported seeing spots in the right eye that the investigator judged were related to treatment; a consulting ophthalmologist differed and reported that the event was related to migraine. The second patient (300-mg group) had preexisting abdominal pain; the patient withdrew for that reason. The investigator determined that the event was not related to treatment. During SP 4, that same patient reported a prolapsed uterus and urinary tract infection, which were considered unrelated to galcanezumab. One patient who received placebo discontinued the study during SP 4 owing to an AE (upper limb fracture) that the investigator judged was not related to treatment. Nineteen of 380 patients (5.0%) withdrew during SP 4; patient decision was again the leading cause.

Efficacy

The 120-mg dose of galcanezumab met the primary objective. The posterior probability of greater improvement (Bayesian analysis) in MHDs with galcanezumab, 120 mg (99.6%; −4.8 MHDs, 90% BCI, −5.4 to −4.2 MHDs) compared with placebo (−3.7 MHDs, 90% BCI, −4.1 to −3.2 MHDs) was greater than the specified threshold (95%) for the mean change from baseline in the number of MHDs at month 3. Figure 2 shows the change from baseline in MHDs during SP 3 for patients treated with galcanezumab compared with placebo using results from mixed-model repeated measures supporting analysis. Galcanezumab, 5 mg (−3.8 MHDs; 95% CI, −4.5 to −3.1 MHDs; P = .045), 50 mg (−4.0 MHDs; 95% CI, −4.6 to −3.3 MHDs; P = .02), and 300 mg (−4.2 MHDs; 95% CI, −4.8 to −3.5 MHDs; P = .004) were associated with a statistically significant reduction of MHDs at month 1 compared with placebo (−3.0 MHDs; 95% CI, −3.5 to −2.5 MHDs); galcanezumab, 300 mg (−4.5 MHDs; 95% CI, −5.2 to −3.8 MHDs; P = .03) also statistically significantly reduced MHDs compared with placebo (−3.6 MHDs; 95% CI, −4.1 to −3.1 MHDs) at month 2. The overall change from baseline in the number of MHDs during SP 3 was statistically significantly different for both the 120-mg (−4.3 MHDs; 95% CI, −4.9 to −3.7 MHDs; P = .02) and 300-mg (−4.3 MHDs; 95% CI, −4.9 to −3.7 MHDs; P = .02) galcanezumab dose groups compared with placebo (−3.4 MHDs; 95% CI, −3.8 to −2.9 MHDs).

Least square (LS) mean change from baseline for secondary outcomes was statistically significantly different between galcanezumab, 120 mg, and placebo at month 3 except for headache days: migraine plus probable MHDs (−5.9; 95% CI, −6.7 to −5.1; P < .001) vs placebo (−4.0; 95% CI, −4.6 to −3.4), probable MHD (−0.9; 95% CI, −1.3 to −0.6; P = .049) vs placebo (−0.5; 95% CI, −0.8 to −0.3), migraine attacks (−3.5; 95% CI, −3.9 to −3.0; P = .003) vs placebo (−2.7; 95% CI, −3.0 to −2.3), 50% response rate (47/62 [75.8%]; P = .03) vs placebo (78/126 [61.9%], and 100% response rate (22/62 [35.5%]; P = .04) vs placebo (29/126 [23.0%]).

Functional impact owing to monthly migraine headaches, assessed by the MSQ and HIT-6 scales, was significantly improved by galcanezumab compared with placebo. Figure 3 displays the results of MSQ total composite scores. Only patients who received galcanezumab, 120 mg, had statistically significantly greater LS mean changes (−10.0; 95% CI, −12.2 to −7.7; P = .04) than placebo (−7.3; 95% CI, −8.8 to −5.7) of HIT-6 composite scores.

Safety and Tolerability

A similar frequency of TEAEs was reported in both the placebo- (70 [51.1%]) and galcanezumab- (140 [53.1%]) treated patients during SP 3. The percentages of TEAEs that were considered possibly related to treatment by the investigator among the galcanezumab and placebo groups were not significantly different; there was no significant correlation between galcanezumab dose and the incidence of TEAEs. The most frequently reported TEAE by 5% or more of patients in all galcanezumab dose groups and more frequently than placebo are reported in Table 2. Injection-site pain was self-limited, usually resolved during the day of injection, and was reported as mild to moderate by all but 2 patients (both resolved in 1 day). During SP 4, other TEAEs that occurred more frequently among galcanezumab-treated than placebo patients included back pain, sinusitis, bronchitis, urinary tract infection, influenza, neck pain, and pain in extremity.

There were no deaths during the study. One SAE was reported during SP 3 by a patient in the galcanezumab, 120-mg group. This patient was hospitalized for appendicitis, which resulted in an appendectomy; the event was noted as resolved but the patient did not return to the study site and was declared lost to follow-up. Two SAEs were noted during SP 4 in patients assigned to galcanezumab: Crohn disease was reported in 1 patient (galcanezumab, 5 mg; patient completed SPs 3 and 4) and suicidal ideation was documented in 1 patient with a medical history of depression and 2 prior suicide attempts (galcanezumab, 300 mg; patient discontinued the study during SP 3 because of a protocol violation). Following the database lock, an additional SAE (congenital ankyloglossia in a male infant) was reported; the infant’s father received galcanezumab, 300 mg. None of the SAEs was considered to be related to galcanezumab.

Discussion

In this phase 2b randomized clinical trial, galcanezumab administered in monthly SC injections for 3 months was efficacious and well tolerated for the prevention of episodic migraine. Quiz Ref IDCompared with placebo, 120-mg galcanezumab doses significantly reduced the mean number of MHDs during the study treatment period (Bayesian analysis). The overall change from baseline to month 3 in the number of MHDs was significant for both the 120-mg and 300-mg dose groups compared with placebo. Galcanezumab, 120 mg, was also superior to placebo at month 3 for all secondary outcomes except headache days.

Quiz Ref IDThe most common AEs for galcanezumab were injection-site pain, upper respiratory tract infections, nasopharyngitis, dysmenorrhea, and nausea; most were mild to moderate in intensity. Only 2 patients among those who received galcanezumab withdrew during the treatment phase owing to an AE. The overall safety profile of galcanezumab in this study was consistent with that established in previous clinical studies.18,22

Galcanezumab is 1 of 4 monoclonal anti-CGRP antibodies being developed for the preventive treatment of migraine.23 The long-term safety of monoclonal antibodies directed against CGRP or the CGRP receptor is unknown at present.18 In previous phase 2 studies using CGRP monoclonal antibodies, single and multiple SC doses were well tolerated; no clinically relevant changes were reported for vital signs, laboratory test results, or electrocardiograms.18,24 Although this phase 2b study was rigorous in its design and included a sufficient sample size for initial testing in patients with episodic migraine, the efficacy and safety results should be regarded as preliminary and the number of patients as insufficient to detect rare or uncommon SAEs.

The sample size for doses of galcanezumab did not allow for definitive conclusions regarding short- or long-term safety. The placebo response rates in this study were relatively high and could be owing in part to heightened awareness and expectations of patients enrolled in a trial with a new compound developed specifically for the prevention of migraine, especially after the public release of early efficacy results from phase 2 studies of galcanezumab and other monoclonal antibodies in this same class.25 Monthly clinic visits, SC treatment administration, and the 4-to-2 active to placebo randomization ratio study design were also factors that could have contributed to a high placebo response rate.25 Despite these limitations, the tolerability and preliminary efficacy results of this study are promising and justified the initiation of larger studies.

Levels of CGRP have been reported to be elevated in the plasma of patients with migraine6-8 and may also function as a biomarker for migraine diagnosis.26 Monoclonal antibodies do not readily penetrate the blood-brain barrier18; only 0.1% to 0.5% of the plasma concentration of antibodies cross the intact blood-brain barrier.24 Previous studies in acute migraine with CGRP small-molecule receptor antagonists that likewise do not cross the blood-brain barrier,11-14,17 along with the results of the present study, suggest a peripheral site of action. Still others27,28 have concluded that the blood-brain barrier might be more permeable during migraine attacks and that there may be sufficient exposure to central sites of action. A more recent study29 has reported that the blood-brain barrier was not permeable to dihydroergotamine during acute glyceryl trinitrate-induced migraine attacks. The present study adds to an escalating body of evidence that supports the concept that CGRP plays a critical role in the pathogenesis of migraine.

Effective, safe, and well-tolerated treatment for the prevention of migraine will fulfill a serious, presently unmet medical need. The AE profiles of currently approved treatments are considerable, with variable efficacy rates and high nonadherence rates.2,30,31 Antibody treatment is becoming an attractive option for various reasons, including high target specificity, less frequent dosing, and minimal off-target toxic effects.17,18,23Quiz Ref ID Galcanezumab has a long elimination half-life of 28 days,32 a favorable AE profile, and is administered by SC injection. These characteristics could potentially increase adherence to this preventive treatment.

Limitations and Strengths

A limitation of this study was its relatively short duration, though a 3-month double-blind period is routine in migraine prevention trials. In addition, the baseline period (28 days), while standard in prevention trials, may not be of sufficient duration to establish an accurate baseline of headache frequency. The secondary end points were not corrected for multiple comparisons and should therefore be interpreted with caution and viewed as preliminary. This was, however, a dose-finding phase 2b study, and the clinical design and end points were standard; missing data were imputed with the same rigorous methods as those used for regulatory approval.

Conclusions

Physicians and patients are seeking more effective and better tolerated treatments for migraine prevention than those currently approved and prescribed. These results provided sufficient efficacy, tolerability, and safety data to justify further development of galcanezumab, 120 mg and 240 mg, in larger phase 3 clinical trials.

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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
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