Supported by evidence-based practice and validated methodologies, the International Headache Society (IHS) and regulatory bodies published a new series of recommendations intended to guide the design, conduct, and reporting of well-controlled trials of preventive treatment of migraine in children and adolescents. This report was published in Cephalalgia.
The investigators developed these recommendations as an outgrowth of the preventive trial guidelines for adults and addressed major issues specific to clinical trials in children and adolescents with migraine. Recommendations were the product of consultations with members of the Clinical Trials and the Child and Adolescent Standing Committees, roundtable discussions with stakeholders (lay people and pharmaceutical professionals), and open consultation with IHS members.
Recommendations for Participants
Carefully defined inclusion and exclusion criteria are recommended for the appropriate identification of participants. Criteria should specify the diagnoses, demographic features, concomitant health conditions, and treatments of the population to be studied.
Diagnosis of migraine types and subtypes should follow the most recent version of the International Classification of Headache Disorders (ICHD), which distinguishes specific features of pediatric migraine, including shorter duration, frontotemporal location, and parental observation allowance. The investigators note that it may be difficult to recruit children aged under 12 years for studies on chronic migraine as no reliable data are available on the prevalence of chronic migraine in children. If medication-overuse headache is included in clinical trials of children and adolescents, the pattern of overuse must remain stable through screening, baseline, and treatment phases. Finally, patients with missing criteria to fulfill a defined migraine type or subtype may still be included in chronic migraine trials if they meet the ICHD criteria for chronic migraine.
History of Migraine
Participants should report the presence of recurrent migraine headache for at least 6 months prior to trial inclusion, ensuring its primary nature rather than as a migraine variant, which may initially occur in children and adolescents.
Age at Onset
The IHS recommends accurately recording the age of migraine onset to assure a stable history of primary headache disorder; it is important to note that the initial presentation of migraine in young children may be a variant.
Age at Entry
Clinical trial designs should assure adequate age stratification, defining children as participants aged 6 to 11 years and adolescents as participants aged 12 to 17 years.
Participants enrolled in clinical trials must fulfill all predefined eligibility criteria, which should be documented at baseline and confirmed prior to randomization. The guidelines further limit a participant’s enrollment to 1 clinical trial at a time. Enrolled participants and their parents or guardians should be given clear information regarding the trial purpose, their role in its conduct, and the risks they will assume.
Adolescent women who are pregnant, may become pregnant, or are breastfeeding should be excluded from participation in a clinical trial; adolescent women included in a trial should adhere to effective contraceptive measures throughout the trial duration.
All coexistent conditions, including psychiatric disorders, should be assessed prior to inclusion in a clinical trial. Patients with conditions that may have an impact on the conduct or results of a trial should be excluded from participation.
Patients with a history of treatment failure, defined as insufficient efficacy following adequate treatment doses and duration or tolerability/safety concerns, may be included in clinical trials.
Recommendations for Trial Design
To establish the efficacy, safety, and tolerability of treatments for the prevention of migraine in children and adolescents, investigators must use double-blind trial designs; blinding further helps eliminate investigator and participant bias.
Clinical trials should compare the preventive intervention with placebo, sham, attention control, or an active comparator. Most migraine trials in pediatric populations have already been performed successfully in adults, and certain expectations may contribute to an increased placebo response in studies with children and adolescents.
The IHS recommends parallel-group trial designs over crossover designs: crossover designs include the possibility of a carryover effect and require longer study periods, which increases the chance of participants dropping out. Additionally, certain novel trial designs may be considered, including Sequential Multiple Assignment Randomized Trial or Multiphase Optimization Strategy.
An established method of randomization should be specified prior to trial initiation, and random assignment of participants should occur following the baseline phase. As trial participants are part of the intention-to-treat population, randomized positions should not be reassigned during the trial period.
To overcome potential confounding, stratification of participants by age, gender, comorbidity, and medication use should be included in parallel-group trial designs.
Well-designed data collection systems should be used to gather essential data regarding headache characteristics, medication use, adverse events, and intervention adherence.
A baseline period of 28 days up to 56 days is recommended to confirm the eligibility of enrolled participants. A headache diary used during this period can capture important diagnostic information, including migraine attack frequency, duration, intensity, and associated symptoms (such as nausea, photophobia, and phonophobia).
Duration of Treatment
The IHS recommends a minimum treatment period of 84 days (12 weeks). Although treatment periods extending beyond 12 weeks risk identifying a separation between intervention and control, longer treatment periods may be used to evaluate the cumulative or sustained benefit and to identify additional adverse events.
Ideally, participants should continue to record any perceived adverse events in a daily diary after the randomized treatment period. Follow-up is recommended to evaluate long-term safety risks and potential rebound phenomena after treatment termination.
Dosage or Procedure
Trial results in adult populations and known pharmacokinetics and pharmacodynamics should guide the widest possible range of doses used in preventive treatment phase II trials involving children and adolescents. Dosing in phase III trials should be administered according to weight and match the participants’ stage of development.
Participants and their guardians should record all treatments used for headache in their trial diaries, including type and frequency of acute medications. Concomitant therapies that are permitted should be pre-specified upon enrollment; therapies with potentially preventive capabilities for migraine, however, should not be allowed unless dosage has been stabilized for at least 2 months prior to randomization.
Regular monitoring of participants in clinical trials is recommended throughout the trial phases: face-to-face visits are recommended every 4 to 8 weeks and telephone or video contact between visits may be used to encourage treatment adherence. Smart packaging, pill counts, and device reminders may be considered to monitor adherence.
Recommendations for Outcome Measures and End Points
Primary End Points
Primary efficacy end points in preventive treatment trials should either measure headache frequency or 50% responder rate, which are defined by the number of migraine days a patient experiences during the treatment period or the absolute reduction in headache frequency, respectively.
Secondary End Points
Secondary outcomes to consider include the effect of treatment on specific headache characteristics (headache intensity, headache hours per 28 days, frequency of migraine aura), depression and anxiety, and disability and functioning.
Exploratory Outcome Measures
These outcomes are captured by measures deemed clinically meaningful and which correlate to primary and secondary end points, including number of headache-free days, number of symptom-free days, and presence of biomarkers.
Pharmacoeconomic End Points
The economic value of preventive treatments for migraine should be captured by assessing the direct and indirect costs of treatment, including the price of the treatment and time lost from school or work.
The IHS recommends that participants and investigators document all adverse events and serious adverse events occur during a clinical trial openly as not all events are related to treatment. Documentation of adverse events should follow the nomenclature and hierarchy of the Medical Dictionary for Regulatory Activities.
Recommendations for Statistics
In reporting statistics, it is recommended that investigators preplan their statistical analysis and define a priori issues, including measurement time to determine study outcomes, primary efficacy end points, modalities of data collection to evaluate change in efficacy variables, sample size required to achieve appropriate study power, baseline and treatment phase comparisons as primary or secondary end points, protocol for imputation of missing data, and methods of comparing treatment groups.
Recommendations for trial registration, publication of results, ethics, conflicts of interest, independent data safety monitoring board, steering committee, post-approval registries, and health technology assessment follow those published by the IHS Guidelines for trials of preventive treatments of migraine in adults.
Abu-Arafeh I, Hershey AD, Diener HC, Tassorelli C; on behalf of the Clinical Trials Standing Committee and the Child and Adolescent Standing Committee of the International Headache Society. Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine in children and adolescents, 1st edition [published online April 4, 2019]. Cephalalgia. doi: 10.1177/0333102419842188