Goadsby, Peter J

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. Objective To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program. Methods This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18–55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Results The ≥75% migraine responder rates over weeks 1–12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo ( p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo. Conclusions The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention. Trial Registration ClinicalTrials.gov identifier: NCT02275117.

Background Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab. Methods Interim analysis was undertaken from an ongoing five-year open-label treatment phase after all patients completed three years in the open-label treatment phase or discontinued the study. Adult patients with episodic migraine enrolled in the open-label treatment phase initially received 70 mg erenumab monthly. A protocol amendment increased the dosage to 140 mg monthly to assess long-term safety of the higher dose. Safety and tolerability were assessed by monitoring adverse events, electrocardiograms, laboratory assessments, and vital signs. Results Of 383 patients enrolled in the open-label treatment phase, at data cutoff 235 (61.3%) remained in the study, all received 140 mg for ≥1 year. Median (Q1, Q3) exposure (70 or 140 mg) for all patients enrolled was 3.2 (1.3, 3.4) years. The most frequent adverse events (≥4.0/100 patient-years) were reported as viral upper respiratory tract infection, sinusitis, influenza, and back pain. Exposure-adjusted serious adverse event rates were 4.2/100 patient-years. There was no increase in cardiovascular events over time. Conclusions In this long-term study of a CGRP-receptor antibody, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. Trial registration ClinicalTrials.gov NCT01952574

The quality of clinical trials is an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for controlled trials of drugs in migraine. Scientific and clinical developments in headache medicine led to second and third editions in 2000 and 2012, respectively. The current, fourth edition of the Guidelines retains the structure and much content from previous editions. However, it also incorporates evidence from clinical trials published after the third edition as well as feedback from meetings with regulators, pharmaceutical and device manufacturers, and patient associations. Its final form reflects the collective expertise and judgement of the Committee. These updated recommendations and commentary are intended to meet the Society's continuing objective of providing a contemporary, standardized, and evidence-based approach to the conduct and reporting of randomised controlled trials for the acute treatment of migraine attacks.

Objective To evaluate the efficacy and tolerability of single pulse transcranial magnetic stimulation (sTMS) for the preventive treatment of migraine. Background sTMS was originally developed for the acute treatment of migraine with aura. Open label experience has suggested a preventive benefit. The objective of this trial was to evaluate the efficacy and tolerability of sTMS for migraine prevention. Methods The eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (ESPOUSE) Study was a multicenter, prospective, open label, observational study. From December 2014 to March 2016, patients with migraine (n = 263) were consented to complete a 1-month baseline headache diary followed by 3 months of treatment. The treatment protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment. Patients reported daily headache status, medication use, and device use with a monthly headache diary. The primary endpoint, mean reduction of headache days compared to baseline, was measured over the 28-day period during weeks 9 to 12. The primary endpoint was compared to a statistically-derived placebo estimate (performance goal). Secondary endpoints included: 50% responder rate, acute headache medication consumption, HIT-6, and mean reduction in total headache days from baseline of any intensity. Results Of a total of 263 consented subjects, 229 completed a baseline diary, and 220 were found to be eligible based on the number of headache days. The device was assigned to 217 subjects (Safety Data Set) and 132 were included in the intention to treat Full Analysis Set. For the primary endpoint, there was a −2.75 ± 0.40 mean reduction of headache days from baseline (9.06 days) compared to the performance goal (−0.63 days) ( p < 0.0001). The 50% responder rate of 46% (95% CI 37%, 56%) was also significantly higher ( p < 0.0001) than the performance goal (20%). There was a reduction of −2.93 (5.24) days of acute medication use, headache impact measured by HIT-6, −3.1 (6.4) ( p < 0.0001), and total headache days of any intensity −3.16 days (5.21) compared to the performance goal (−0.63 days) ( p < 0.0001). The most common adverse events were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%). There were no serious adverse events. Conclusions This open label study suggests that sTMS may be an effective, well-tolerated treatment option for migraine prevention. Trial registration number NCT02357381

Background Quality clinical trials form an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. In 2008, the Committee published the first specific guidelines on chronic migraine. Subsequent advances in drug, device, and biologicals development, as well as novel trial designs, have created a need for a revision of the chronic migraine guidelines. Objective The present update is intended to optimize the design of controlled trials of preventive treatment of chronic migraine in adults, and its recommendations do not apply to trials in children or adolescents.

Background: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. Methods: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. Results: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom ( p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg ( p < .001) and nominally significant for 100 mg and 10 mg ( p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. Conclusions: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

Background: Medically intractable chronic migraine (CM) is a disabling illness characterized by headache ≥15 days per month. Methods: A multicenter, randomized, blinded, controlled feasibility study was conducted to obtain preliminary safety and efficacy data on occipital nerve stimulation (ONS) in CM. Eligible subjects received an occipital nerve block, and responders were randomized to adjustable stimulation (AS), preset stimulation (PS) or medical management (MM) groups. Results: Seventy-five of 110 subjects were assigned to a treatment group; complete diary data were available for 66. A responder was defined as a subject who achieved a 50% or greater reduction in number of headache days per month or a three-point or greater reduction in average overall pain intensity compared with baseline. Three-month responder rates were 39% for AS, 6% for PS and 0% for MM. No unanticipated adverse device events occurred. Lead migration occurred in 12 of 51 (24%) subjects. Conclusion: The results of this feasibility study offer promise and should prompt further controlled studies of ONS in CM.