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.
● Evaluation of Results
o Attack report form (diary): participants should use an easy-to-use electronic diary that records predefined endpoints. Investigator-initiated trials can use paper diaries.
o Primary endpoint: The percentage of participants who are pain-free 2 hours after treatment should be the primary measure of efficacy.
o Co-primary endpoints: Absence of the most bothersome migraine-associated symptom 2 hours after treatment can be used as a co-primary endpoint.
o Secondary endpoints
▪ Relapse: Relapse is defined as the occurrence of headache of any severity within 48 hours after administering an investigational treatment in participants who were pain-free 2 hours after treatment administration. If the treatment has a short half-life, a period of 24 hours may be used.
▪ Sustained pain freedom: Sustained pain freedom is defined as the percentage of participants who are pain-free at 2 hours and do not use rescue medication or relapse within 24 or 48 hours of initial treatment. This is a recommended secondary endpoint and is a primary endpoint for early intervention trials.
▪ Total freedom from migraine: Defined as the absence of pain, nausea, vomiting, photophobia, and phonophobia at the primary efficacy time point.
▪ Headache intensity: Participants should record the intensity of headache immediately before using the investigative treatment and at each specific time point. Headache intensity should be measured on a 4-point scale, a 100-mm Visual Analogue Scale (VAS), or an 11-point numerical rating scale (NRS).
▪ Headache relief: Defined as the decrease in headache pain from moderate or severe at baseline to mild or none at 2 hours after treatment.
▪ Time to meaningful relief: Time to meaningful relief can be used as a secondary efficacy measure.
▪ Time to pain freedom: A survival analysis of pain freedom can evaluate speed of onset of therapeutic effect. Time to pain freedom is a recommended secondary efficacy outcome measure.
▪ Duration of attacks: Duration of attacks should not be used as an efficacy measure.
▪ Rescue medication: The percentage of participants taking rescue medication 2 hours after intake of test treatment can be used as a secondary efficacy measure.
▪ Global evaluation: A simple Likert-type verbal scale can be used to assess participants’ global impression of acute treatment effect. This can be used as a secondary outcome measure.
▪ Global impact: Functional disability and health-related quality of life (HRQoL) are important secondary global measures.
▪ Associated symptoms:
● Nausea and vomiting: The presence or absence of nausea should be recorded at the time of treatment administration and at the primary efficacy endpoint.
● Photophobia: The presence or absence of photophobia should be recorded at the time of treatment administration and at the primary efficacy endpoint.
● Phonophobia: The presence or absence of phonophobia should be recorded at the time of treatment administration and at the primary efficacy endpoint.
▪ Time between onset of headache and intake of treatment: Both should be recorded.
▪ Treatment preference: Participants’ treatment preference is a useful exploratory global assessment method best suited for crossover trials.
▪ Blinding assessment: Determining how well a trial is blinded is important.
▪ Treatment of relapse: The efficacy of treatment of relapse should be measured by the percentage of participants with pain freedom 2 hours after administering medication for headache relapse.
▪ Adverse events: Participants should record adverse events that occur during the trial in the trial diary. These should be supplemented with responses to open questions when appropriate. Participants should record event severity, event seriousness, time of onset, and time of resolution.
● Hierarchy of endpoints: Trials assessing the efficacy, tolerability, and safety of interventions for the acute treatment of migraines should use the following hierarchy of endpoints:
● Pain-free after 2 hours
● Freedom from the most bothersome symptom at 2 hours
● Supporting the primary endpoints
● Headache relief at 2 hours
● Sustained pain-free to 24 hours
● Total freedom from migraine
● Freedom from nausea and vomiting, photophobia, or phonophobia
● Time to pain freedom
All other endpoints (tertiary or exploratory endpoints)
● Intensity of headache
● Headache relapse
● Time to meaningful relief
● Time to pain freedom
● Rescue medication
● Global evaluation
● Global impact (disability and HRQoL)
● Time between headache onset and treatment intake
● Preference of treatment
● Blinding assessment
● Treatment of recurrence
“It is therefore hoped that this edition of the Guidelines continues the tradition of its predecessors by providing investigators with a contemporary, standardized, and evidence-based approach to the conduct and reporting of clinical trials for the acute treatment of migraine attacks,” the researchers wrote.
Diener H, Tassorelli C, Dodick DW, et al. Guidelines of the International Headache Society for controlled trials of acute treatment of migraine attacks in adults: fourth edition [published online February 26, 2019]. Cephalagia. doi:10.1177/0333102419828967