Evaluation of Efficay & Safety of Galcanezumab in the Prevention of Episodic Migraine- the EVOLVE-2 Study (EVOLVE-2)

• ClinicalTrials.gov Identifier: NCT02614196
• Recruitment Status: Completed
• First Posted: November 25, 2015
• Results First Posted: January 7, 2019
• Last Update Posted: June 17, 2020
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: November 23, 2015
• First Posted Date: November 25, 2015
• Results First Submitted Date: August 23, 2018
• Results First Posted Date: January 7, 2019
• Last Update Posted Date: June 17, 2020
• Actual Study Start Date: December 4, 2015
• Actual Primary Completion Date: March 29, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 12, 2018)

Overall Mean Change From Baseline in the Number of Monthly Migraine Headache Days [ Time Frame: Baseline, Month 1 through Month 6 ]

Migraine Headache Day (MHD):A calendar day on which a migraine headache or probable migraine headache occurred. Migraine Headache : A headache, with or without aura, of ≥30 minutes duration with both of the following required features (A and B): A) At least 2 of the following headache characteristics: Unilateral location; Pulsatile quality; Moderate or severe pain intensity; Aggravation by or causing avoidance of routine physical activity; AND B) During headache at least one of the following: Nausea and/or vomiting; Photophobia and phonophobia; Overall mean is derived from the average of months 1 to 6 from mixed model repeated measures (MMRM) model. Least Square (LS) mean was calculated using mixed model repeated measures (MMRM) model with treatment, pooled country, month, and treatment by month, baseline, and baseline by month as fixed effects.

• Original Primary Outcome Measures (submitted: November 23, 2015): Mean Change from Baseline in the Number of Monthly Migraine Headache Days [ Time Frame: Baseline, Month 6 ]

Current Secondary Outcome Measures (submitted: December 12, 2018)

• Mean Percentage of Participants With Reduction From Baseline ≥50%, ≥75%, and 100% in Monthly Migraine Headache Days [ Time Frame: Baseline, Month 1 through Month 6 ]
  Migraine Headache Day (MHD): A calendar day on which a migraine headache or probable migraine headache occurred. Mean is derived from the average of months 1 to 6 from generalized linear mixed model repeated measures. Mean percentages of participants were calculated with a generalized linear mixed model repeated measures method with treatment, month and treatment by month, baseline.
• Mean Change From Baseline in the Migraine-Specific Quality of Life Questionnaire (MSQ) Version 2.1 Role Function Restrictive Domain [ Time Frame: Baseline, Month 4 through Month 6 ]
  MSQ v2.1 was developed to address physical & emotional limitations of specific concern to individuals with migraine. It consists of 14 items that address 3 domains:(1) Role Function-Restrictive (items 1-7);(2) Role Function- Preventive (items 8-11);&(3) Emotional Function (items 12-14).Response options range from "none of the time" (value 1) to "all of the time" (value 6), & are reverse-recoded (value 6 to 1) before the domain scores are calculated.Total raw scores for each domain is the sum of the final item value for all of the items in that domain.After the total raw score is computed for each domain, they are transformed to a 0-100 scale with higher scores indicating a better health status & a positive change in scores reflecting functional improvement. Mean is derived from the average of months 4 to 6 from MMRM model. LSMean was calculated using MMRM model with treatment, pooled country, month, treatment by month, baseline by month & baseline MHD category as fixed factors.
• Overall Mean Change From Baseline in the Number of Monthly Migraine Headache Days Requiring Medication for the Acute Treatment of Migraine or Headache [ Time Frame: Baseline, Month 1 through Month 6 ]
  Migraine Headache Day (MHD):A calendar day on which a migraine headache or probable migraine headache occurred. Overall mean is derived from the average of months 1 to 6 from MMRM model.LSMean was calculated using MMRM model with treatment, pooled country, month, treatment by month, baseline, baseline by month, and baseline MHD category as fixed effects.
• Mean Change From Baseline in Patient Global Impression of Severity (PGI-S) Rating [ Time Frame: Baseline, Month 4 through Month 6 ]
  The PGI-S scale is a participant-rated instrument that measures patients own global impression of their illness severity. The participant was instructed as follows: "Considering migraine as a chronic condition, how would you rate your level of illness?" Response options were from 1 ("normal, not at all ill") to 7 ("extremely ill"). Mean is derived from the average of months 4 to 6 from MMRM model. LSMean was calculated using MMRM model with treatment, pooled country, month, treatment by month, baseline, baseline by month, and baseline MHD category as fixed factors.
• Overall Mean Change From Baseline in Headache Hours [ Time Frame: Baseline, Month 1 through Month 6 ]
  Headache Hours is calculated as the total number of headache hours on which a headache occurred. Overall mean is derived from the average of months 1 to 6 from MMRM model. LSMean was calculated using MMRM model with treatment, pooled country, month, treatment by month, baseline, baseline by month and baseline MHD category.
• Mean Change From Baseline in the Migraine Disability Assessment Test (MIDAS) Total Score [ Time Frame: Baseline, Month 6 ]
  The MIDAS is a participant-rated scale which was designed to quantify headache-related disability over a 3-month period. This instrument consists of five items that reflect the number of days reported as missing or with reduced productivity at work or home, and the number of days of missed social events. Each item has a numeric response range from 0 to 90 days, if days are missed from work or home they are not counted as days with reduced productivity at work or home. The numeric responses are summed to produce a total score ranging from 0 to 270, in which a higher value is indicative of more disability. LSMean was calculated using MMRM model with treatment, pooled country, month, treatment by month, baseline, baseline by month, and baseline MHD category as fixed factors.
• Percentage of Participants Developing Anti-drug Antibodies (ADA) to Galcanezumab [ Time Frame: Month 1 through Month 6 ]
  Treatment emergent (TE) ADA evaluable participant is considered to be TE ADA+ if the subject has at least one post-baseline titer that is a 4-fold or greater increase in titer from baseline measurement. If baseline result is ADA Not Present, then the participant is TE ADA+ if there is at least one post-baseline result of ADA present with titer >= 1: 20.
• Pharmacokinetics (PK): Serum Concentrations of Galcanezumab [ Time Frame: Month 6 ]
  Pharmacokinetics (PK): Serum Concentrations of Galcanezumab.
• Plasma Concentration of Calcitonin Gene-Related Peptide (CGRP) [ Time Frame: Month 6 ]
  Plasma Concentration of Calcitonin Gene-Related Peptide (CGRP).

Original Secondary Outcome Measures (submitted: November 23, 2015)

• Proportion of Participants with Reduction from Baseline ≥50%, ≥75%, and 100% in Monthly Migraine Headache Days [ Time Frame: Month 6 ]
• Mean Change from Baseline on the Migraine-Specific Quality of Life Questionnaire [ Time Frame: Baseline, Month 6 ]
• Mean Change from Baseline in the Number of Monthly Migraine Headache Days Requiring Medication for the Acute Treatment of Migraine or Headache [ Time Frame: Baseline, Month 6 ]
• Mean Change from Baseline in the Patient Global Impression of Severity (PGI-S) Score [ Time Frame: Baseline, Month 6 ]
• Mean Change from Baseline in Headache Hours [ Time Frame: Baseline, Month 6 ]
• Mean Change from Baseline on the Migraine Disability Assessment Test (MIDAS) Total Score [ Time Frame: Baseline, Month 6 ]
• Percentage of Participants Developing Anti-drug Antibodies to LY2951742 [ Time Frame: Baseline through Month 6 ]
• Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of LY2951742 [ Time Frame: Baseline through Month 6 ]
• Plasma Concentration of Calcitonin Gene-Related Peptide (CGRP) [ Time Frame: Baseline through Month 6 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Efficay & Safety of Galcanezumab in the Prevention of Episodic Migraine- the EVOLVE-2 Study
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of LY2951742 in Patients With Episodic Migraine - the EVOLVE-2 Study
• Brief Summary: The main purpose of this study is to evaluate the efficacy and safety of the study drug known as galcanezumab in participants with episodic migraine.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:

Sponsor is also masked.

Primary Purpose: Treatment

• Condition: Migraine

Intervention

• Drug: Galcanezumab
  Administered SC
  Other Name: LY2951742
• Drug: Placebo
  Administered SC

Study Arms

• Experimental: Galcanezumab 120mg
  Galcanezumab 240mg given as loading dose at first dosing visit followed by galcanezumab 120mg once a month for 5 months by subcutaneous (SC) injection.
  Intervention: Drug: Galcanezumab
• Experimental: Galcanezumab 240mg
  Galcanezumab 240mg given by SC injection once a month for 6 months.
  Intervention: Drug: Galcanezumab
• Placebo Comparator: Placebo
  Placebo given by SC injection once a month for 6 months.
  Intervention: Drug: Placebo
• Experimental: Galcanezumab 120mg Maximum Extended Enrollment Cohort
  Galcanezumab 240mg given as loading dose at first dosing visit followed by galcanezumab 120mg once a month for 5 months by subcutaneous (SC) injection.
  Intervention: Drug: Galcanezumab
• Experimental: Galcanezumab 240mg Maximum Extended Enrollment Cohort
  Galcanezumab 240mg given by SC injection once a month for 6 months.
  Intervention: Drug: Galcanezumab
• Placebo Comparator: Placebo Maximum Extended Enrollment Cohort
  Placebo given by SC injection once a month for 6 months.
  Intervention: Drug: Placebo

Publications *

• Dodick DW, Doty EG, Aurora SK, Ruff DD, Stauffer VL, Jedynak J, Dong Y, Pearlman EM. Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine. Cephalalgia. 2020 Nov 3:333102420966658. doi: 10.1177/0333102420966658. [Epub ahead of print]
• Ailani J, Andrews JS, Rettiganti M, Nicholson RA. Impact of galcanezumab on total pain burden: findings from phase 3 randomized, double-blind, placebo-controlled studies in patients with episodic or chronic migraine (EVOLVE-1, EVOLVE-2, and REGAIN trials). J Headache Pain. 2020 Oct 17;21(1):123. doi: 10.1186/s10194-020-01190-7.
• Stauffer VL, Turner I, Kemmer P, Kielbasa W, Day K, Port M, Quinlan T, Camporeale A. Effect of age on pharmacokinetics, efficacy, and safety of galcanezumab treatment in adult patients with migraine: results from six phase 2 and phase 3 randomized clinical trials. J Headache Pain. 2020 Jun 23;21(1):79. doi: 10.1186/s10194-020-01148-9.
• Bangs ME, Kudrow D, Wang S, Oakes TM, Terwindt GM, Magis D, Yunes-Medina L, Stauffer VL. Safety and tolerability of monthly galcanezumab injections in patients with migraine: integrated results from migraine clinical studies. BMC Neurol. 2020 Jan 17;20(1):25. doi: 10.1186/s12883-020-1609-7. Erratum in: BMC Neurol. 2020 Mar 13;20(1):90.
• Kielbasa W, Quinlan T. Population Pharmacokinetics of Galcanezumab, an Anti-CGRP Antibody, Following Subcutaneous Dosing to Healthy Individuals and Patients With Migraine. J Clin Pharmacol. 2020 Feb;60(2):229-239. doi: 10.1002/jcph.1511. Epub 2019 Sep 4.
• Silberstein SD, Stauffer VL, Day KA, Lipsius S, Wilson MC. Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2). J Headache Pain. 2019 Jun 28;20(1):75. doi: 10.1186/s10194-019-1024-x. Erratum in: J Headache Pain. 2019 Dec 27;20(1):118.
• Stauffer VL, Wang S, Voulgaropoulos M, Skljarevski V, Kovacik A, Aurora SK. Effect of Galcanezumab Following Treatment Cessation in Patients With Migraine: Results From 2 Randomized Phase 3 Trials. Headache. 2019 Jun;59(6):834-847. doi: 10.1111/head.13508. Epub 2019 Apr 3.
• Förderreuther S, Zhang Q, Stauffer VL, Aurora SK, Láinez MJA. Preventive effects of galcanezumab in adult patients with episodic or chronic migraine are persistent: data from the phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2, and REGAIN studies. J Headache Pain. 2018 Dec 29;19(1):121. doi: 10.1186/s10194-018-0951-2.
• Nichols R, Doty E, Sacco S, Ruff D, Pearlman E, Aurora SK. Analysis of Initial Nonresponders to Galcanezumab in Patients With Episodic or Chronic Migraine: Results From the EVOLVE-1, EVOLVE-2, and REGAIN Randomized, Double-Blind, Placebo-Controlled Studies. Headache. 2019 Feb;59(2):192-204. doi: 10.1111/head.13443. Epub 2018 Nov 21.
• Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia. 2018 Jul;38(8):1442-1454. doi: 10.1177/0333102418779543. Epub 2018 May 31.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 12, 2018): 986
• Original Estimated Enrollment (submitted: November 23, 2015): 825
• Actual Study Completion Date: October 5, 2018
• Actual Primary Completion Date: March 29, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Have a diagnosis of migraine as defined by International Headache Society (IHS) International Classification of Headache Disorders (ICHD)-3 beta version (1.1 or 1.2) (ICHD-3 2013), with a history of migraine headaches of at least 1 year prior to screening, migraine onset prior to age 50 and MONTHLY frequency of 4-14 MHD.

Exclusion Criteria:

• Are currently enrolled in or have participated within the last 30 days or within 5 half-lives (whichever is longer) in a clinical trial involving an investigational product.
• Current use or prior exposure to galcanezumab or another Calcitonin Gene-Related Peptide (CGRP) antibody.
• Known hypersensitivity to multiple drugs, monoclonal antibodies or other therapeutic proteins, or to galcanezumab.
• History of persistent daily headache, cluster headache or migraine subtypes including hemiplegic (sporadic or familial) migraine, ophthalmoplegic migraine, and migraine with brainstem aura (basilar-type migraine) defined by IHS ICHD-3 beta.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Czechia, Germany, Israel, Korea, Republic of, Mexico, Netherlands, Puerto Rico, Spain, Taiwan, United Kingdom, United States
• Removed Location Countries: Brazil, Czech Republic

Administrative Information

• NCT Number: NCT02614196
• Other Study ID Numbers: 15768; I5Q-MC-CGAH ( Other Identifier: Eli Lilly and Company ); 2015-001882-17 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Responsible Party: Eli Lilly and Company
• Study Sponsor: Eli Lilly and Company
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: June 2020