The International Headache Society (IHS) Clinical Trials Standing Committee has released the updated fourth edition of their guidelines for controlled trials of drugs in migraine, which has been published in Cephalagia.
The new guidelines use the structure and much of the content from previous editions. However, the fourth edition includes evidence from newly-published clinical trials, as well as feedback from meetings with regulators, pharmaceutical manufacturers, and patient associations.
The Committee recommends the following guidelines for conducting a randomized controlled trial for the acute treatment of migraine attacks:
● Guidelines for subject selection
o Migraine definition: participants should meet the diagnostic criteria for migraine according to the most recent version of the International Classification of Headache Disorders (ICHD) of the IHS.
o Chronic migraine: participants who meet the diagnostic criteria for chronic migraine or who have a history of chronic migraine within the past 12 months should be excluded from efficacy trials for the acute treatment of migraine.
o Other primary headache types: participants with other concomitant primary headache types are eligible if attacks are infrequent and can be differentiated from migraine based on pain and symptoms.
o Secondary headaches: participants with secondary headaches including medication-overuse headache should be excluded.
o Frequency of migraine: Participants should have attacks 2 to 8 times per month, ≤1 day per month of other headaches, at least 48 hours of freedom from headache between attacks, and <15 headache days per month.
▪ Duration of migraine: Participants should have migraines for at least 1 year.
o Age at onset: Participants should be aged <50 at onset of migraine.
o Age at entry: Participants should be between aged 18 and 65.
o Sex: Men and women with migraine are both eligible for studies.
o Concomitant drug use:
▪ Treatments not for migraine: If a trial allows participants to treat conditions other than migraine, the permitted use of concomitant therapies should be pre-specified. Phase 2 clinical trial participants should generally not be allowed to treat conditions other than migraine.
▪ Acute migraine treatment: Researchers should administer investigational treatments only after 48 hours have passed since the participants have last used another acute treatment for migraine.
▪ Preventative migraine treatment: If exclusionary, participants should withdraw from migraine preventative treatment at least 1 month before treatment. If the protocol allows preventative treatment, participants should be on a stable dose of no more than 1 preventative agent for at least 2 months before the study.
▪ Antipsychotics and antidepressants: Participants using antipsychotics regularly during the 3 months before enrollment should be excluded from phase 2 trials, but patients co-medicating with antidepressants can be considered.
● Trial Design
o Blinding: Phase 2 and 3 efficacy trials should use a double-blind design.
o Placebo control: Interventions should be compared with placebo. If 2 active treatments are being compared, a placebo control should be included for assay sensitivity.
o Design types: Both parallel-group and crossover designs can be used, but parallel-group designs are preferred. Limited to phase 2 trials, group-sequential, adaptive treatment, and dose-defining designs may be appropriate.
o Randomization: Participants in parallel-group and crossover trials should be randomized at entry to trial unless the researchers are considering adaptive randomization.
o Stratification: Acute treatment trials generally don’t need stratification. It may be considered when an imbalance between the treatment groups or factors may influence the trial’s results.
o Intention to treat: Randomized controlled trials of acute treatments for migraine should follow the principle of intention to treat (ITT). The full analysis set may be modified to exclude participants from analysis if no treatment was received or if no data points after treatment were recorded.
o Dose-response curves and dosage: Early (phase 1 and 2) randomized clinical trials of new chemical treatments should define dose-response curves; determine efficacy- and tolerability-based minimum effective and optimal doses; and use effective doses of a well-established drug for comparative clinical trials.
o Route of administration: Oral administration is recommended if pre-clinical and pharmacokinetic (PK) data show an acceptable PK profile in humans. Alternative routes of administration include parenteral, inhalational, buccal, intranasal, and rectal.
o Timing of administration: The trial protocol should defined the timing of acute treatment and must be consistent with the trial’s objectives. Participants should record the time and pain intensity at the time of treatment.
o Number of attacks treated: The primary objective should be determining the effect of an acute treatment on the first migraine attack. If multiple attacks are treated, the first treatment attack or the attack used to assess the primary objective can be randomly selected.
o Rescue medication: After the first primary efficacy endpoint (usually 2 hours after the initial administration of treatment), the use of rescue medication should be allowed. Use of rescue medication before the first primary efficacy endpoint should be considered a treatment failure.
o Consistency of response: Intra-individual consistency of response can be evaluated over multiple attacks in double-blind, placebo-controlled trials. Responses to ≥4 attacks should be assessed with at least 1 attack treated with placebo in a randomized fashion.
This article originally appeared on Neurology Advisor