Elsevier

The Lancet Neurology

Volume 19, Issue 10, October 2020, Pages 814-825
The Lancet Neurology

Articles
Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial

https://doi.org/10.1016/S1474-4422(20)30279-9Get rights and content

Summary

Background

Many patients who require migraine preventive treatment have not been able to tolerate or have not responded to multiple previous preventive medications. We aimed to assess the safety and efficacy of galcanezumab, an antibody to calcitonin gene-related peptide, in patients with migraine who had not benefited from preventive medications from two to four categories.

Methods

CONQUER was a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial done at 64 sites (hospitals, clinics, or research centres) in 12 countries (Belgium, Canada, Czech Republic, France, Germany, Hungary, Japan, the Netherlands, South Korea, Spain, the UK, and the USA). Patients were 18–75 years of age, with episodic or chronic migraine, with migraine onset before the age of 50 years, who had a documented failure of preventive medications from two to four drug categories in the past 10 years owing to lack of efficacy or tolerability, or both. Patients were randomised 1:1 to receive subcutaneous placebo or galcanezumab 120 mg per month (with a 240 mg loading dose administered as two 120 mg injections) for 3 months. For masking purposes, patients receiving placebo also received two injections during the first dosing visit. Randomisation was done by a computer-generated random sequence by means of an interactive web-response system stratified by country and migraine frequency (low frequency episodic migraine, four to fewer than eight migraine headache days per month; high frequency episodic migraine, eight to 14 migraine headache days per month and fewer than 15 headache days per month; chronic migraine, at least eight migraine headache days per month and at least 15 headache days per month). The primary endpoint was the overall mean change from baseline in number of monthly migraine headache days during the 3-month treatment period in all patients who were randomly assigned and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03559257, and is now completed.

Findings

Between Sept 10, 2018, and March 21, 2019, 462 participants with episodic (269 [58%]) or chronic (193 [42%]) migraine were randomly assigned and received at least one injection with placebo (n=230) or galcanezumab (n=232). Galcanezumab-treated patients had significantly greater reduction in migraine headache days versus placebo across months 1–3. The galcanezumab group had on average 4·1 fewer monthly migraine headache days compared with baseline (13·4), while the placebo group had on average 1·0 fewer than at baseline (13·0; between-group difference −3·1 [95% CI −3·9 to −2·3]; p<0·0001; effect size=0·72). Types and number of treatment-emergent adverse events were similar between galcanezumab and placebo. Treatment-emergent adverse events were reported in 122 (53%) of 230 patients in the placebo group and 119 (51%) of 232 patients in the galcanezumab group. There were four serious adverse events during the study, two (1%) reported in the placebo group and two (1%) reported in the galcanezumab group.

Interpretation

Galcanezumab was superior to placebo in the preventive treatment of migraine and was safe and well tolerated in patients for whom multiple previous standard-of-care preventive treatments had failed. Galcanezumab might represent an important treatment option for patients who have not benefited from or tolerated previous standard-of-care treatments.

Funding

Eli Lilly.

Introduction

Migraine is a neurological disease characterised by severe, intermittent headaches with associated symptoms including nausea, vomiting, phonophobia, and photophobia.1 According to the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, migraine is the second leading cause of years lived with disability.2 Despite the availability of preventive medications for migraine, which are meant to reduce the frequency of migraine attacks, many patients do not respond to these treatments or are unable to tolerate them. A study reviewing the treatments of patients with migraine in France, Germany, Japan, and the USA showed that 43% of the patients taking preventive migraine medications had a history of medication failures or switching medications.3 Adherence to preventive medication among patients with chronic migraine is worse, reported at 26%−29% at 6 months in a US study.4 Among patients with either episodic or chronic migraine who are undergoing oral preventive treatment, side-effects and a lack of efficacy are the most common reasons for discontinuation.5, 6 When migraine is not adequately managed, the negative effect on patient functioning increases, leading to losses in work or school and home productivity, missed or restricted family and social activities, overall decrease in quality of life,7, 8, 9, 10 and increased health-care costs.11, 12, 13 Therefore, new, more effective, and better tolerated treatments might help to improve these outcomes, particularly for those patients who have previously not benefited from treatment with multiple migraine preventive medications.

Research in context

Evidence before this study

We searched PubMed with the keywords “migraine AND preventive”, “CGRP”, “calcitonin gene-related peptide”, and “migraine preventives randomised controlled clinical trials”, for articles and clinical studies published in English in the past 10 years from Jan 1, 2010, to March 1, 2020. Several studies have shown that calcitonin gene-related peptide (CGRP) plays a role in the pathophysiology of headache disorders such as migraine. Galcanezumab is a humanised monoclonal antibody that potently and selectively binds to CGRP and prevents its biological activity without blocking the CGRP receptor. The prescription of CGRP monoclonal antibodies is approved in multiple countries for the preventive treatment of migraine. Publications of post-hoc analyses and two previous phase 3 trials (one with erenumab and one with fremanezumab) indicated that CGRP monoclonal antibodies might also be a safe and effective preventive option for patients who had multiple previous treatment failures.

Added value of this study

The results of this phase 3b, multicentre, randomised, placebo-controlled, double-blind, parallel trial show that monthly galcanezumab was safe and effective in patients for whom treatments had failed in two to four standard-of-care migraine preventive medication categories. More patients treated with galcanezumab had at least 75% and 100% reduction in monthly migraine headache days and greater improvement in functioning compared with patients treated with placebo. This study represents an important addition to the literature on galcanezumab and to the existing set of studies of CGRP antibodies as it not only included patients with both episodic and chronic migraine, but also included patients up to 75 years of age, thereby extending the age range previously evaluated for galcanezumab and the age range evaluated for the other CGRP monoclonal antibodies in a population for whom previous treatments had failed. This study also extends the results of previous studies in this population as it used a more stringent definition for treatment failure such that patients had to have actually tried the medications before they could be considered treatment failures; avoidance of a medication because of contraindication or unsuitability did not count toward the treatment-failure inclusion criterion.

Implications of all the available evidence

Galcanezumab 120 mg per month (with a 240-mg loading dose) is well tolerated and efficacious in the prevention of migraine in patients who had treatment failures of two to four categories of standard-of-care migraine preventive medications. Galcanezumab might represent an important treatment option for patients who have not benefited from or tolerated previous standard-of-care treatments.

Advances in migraine preventive treatment have led to the approval of multiple monoclonal antibodies which target calcitonin gene-related peptide (CGRP) or its receptor, and these treatments might represent an important migraine preventive treatment option for patients for whom previous treatments have failed. Galcanezumab, a humanised monoclonal antibody that potently and selectively binds to CGRP and prevents its biological activity without blocking the CGRP receptor,14 has been proven to be safe, well tolerated, and efficacious in patients with episodic or chronic migraine.15, 16, 17, 18, 19, 20 Post-hoc analyses in patients from previous galcanezumab phase 3 trials who had not benefited from at least two previous migraine preventive medications owing to safety and efficacy reasons showed a reduction in monthly migraine headache days after galcanezumab treatment compared with placebo.21, 22 However, those phase 3 trials excluded patients who had not responded to more than three classes of migraine preventive treatment with level A or level B efficacy23 or onabotulinum toxin A or B. Two studies with other CGRP monoclonal antibodies—one study with erenumab24 in patients with episodic migraine and one study with fremanezumab25 in patients with episodic or chronic migraine—have shown tolerability and efficacy in patients with previous migraine preventive treatment failures. In the CONQUER study, we aimed to evaluate the safety and efficacy of galcanezumab in patients with episodic or chronic migraine who had experienced treatment failures from two to four standard-of-care migraine preventive medication categories.

Section snippets

Study design and participants

CONQUER was a multicentre, randomised, double-blind, parallel, placebo-controlled, phase 3b study done by 65 investigators at 64 sites (hospitals, clinics, or research centres) in 12 countries (Belgium, Canada, Czech Republic, France, Germany, Hungary, Japan, the Netherlands, South Korea, Spain, the UK, and the USA; appendix p 1).

Eligible participants were 18–75 years of age with a diagnosis of migraine with aura or without aura, or chronic migraine defined by the International Classification

Results

Between Sept 10, 2018, and March 21, 2019, 610 participants were screened, of whom 462 (76%) participants with episodic (269 [58%]) or chronic (193 [42%]) migraine were randomly assigned and received their first injection with placebo (n=230) or galcanezumab (n=232). Note that 463 participants were randomly assigned, but one patient who was inadvertently randomly assigned and did not receive treatment was excluded from the analysis population (n=462). Eleven patients discontinued from the

Discussion

This phase 3b study found galcanezumab to be superior to placebo in reducing monthly migraine headache days in patients who had not benefited from two to four categories of standard-of-care migraine preventive treatments. Patients in this study had a baseline of 13·2 migraine headache days per month and severe disability and functional impairment as evidenced by baseline MIDAS total and MSQ-RFR domain scores. Galcanezumab treatment reduced the mean number of monthly migraine headache days by

Data sharing

Eli Lilly provides access to all individual participant data collected during the trial, after anonymisation, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is set once data are made available. Access is provided after a proposal has been approved by an independent review committee

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