Original Article Cephalalgia 2019, Vol. 39(6) 687–710 Guidelines of the International Headache ! International Headache Society 2019 Article reuse guidelines: Society for controlled trials of acute sagepub.com/journals-permissions DOI: 10.1177/0333102419828967 journals.sagepub.com/home/cep treatment of migraine attacks in adults: Fourth edition Hans-Christoph Diener1,*, Cristina Tassorelli2,3,*, David W Dodick4, Stephen D Silberstein5, Richard B Lipton6, Messoud Ashina7, Werner J Becker8,9, Michel D Ferrari10, Peter J Goadsby11 , Patricia Pozo-Rosich12, Shuu-Jiun Wang13,14 and Jay Mandrekar15; on behalf of the International Headache Society Clinical Trials Standing Committee Abstract 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. Keywords Guidelines, controlled trials, acute treatment of migraine attacks in adults Date received: 12 December 2018; revised: 8 January 2019; accepted: 15 January 2019 10 Department of Neurology, Leiden University Medical Center, Leiden, 1 The Netherlands Department of Neurology, University Hospital Essen, Essen, Germany 11 2 National Institute for Health Research Wellcome Trust King’s Clinical Headache Science Center, IRCCS Mondino Foundation, Pavia, Italy 3 Research Facility, King’s College London, London, England Department of Brain and Behavioral Sciences, University of Pavia, Pavia, 12 Headache Research Group, Vall d’Hebron Institute of Research, Italy 4 Universitat Autònoma de Barcelona, Barcelona, Spain Department of Neurology, Mayo Clinic, Phoenix, AZ, USA 13 5 Headache & Craniofacial Pain Unit, Neurology Department, Hospital Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Universitari Vall d’Hebron, Barcelona, Spain PA, USA 14 6 Neurological Institute, Taipei Veterans General Hospital and Brain Montefiore Headache Center, Department of Neurology and Research Center, National Yang-Ming University, Taipei, Taiwan Department of Epidemiology and Population Health, Albert Einstein 15 Department of Health Sciences Research, Mayo Clinic Rochester, MN, College of Medicine, Bronx, NY, USA 7 USA Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of *These authors contributed equally to this work. Copenhagen, Glostrup, Denmark Corresponding author: 8 Department of Clinical Neurosciences, University of Calgary, Calgary, Hans-Christoph Diener, University of Essen, Hufeland Str 55, Essen, Alberta, Canada 45122 Germany. 9 Hotchkiss Brain Institute, University of Calgary, Calgary, Canada Email: hans.diener@uni-duisburg-essen.de 688 Cephalalgia 39(6) Introduction 1. Clinical trials for the acute treatment In 1991, the Clinical Trials Standing Committee of the of migraine attacks International Headache Society (IHS) published the 1.1. Subject selection first edition of the Guidelines for controlled trials of drugs in migraine (1). Its goal was to improve the qual- 1.1.1. Migraine definition ity of controlled clinical trials in migraine by encoura- Recommendation: ging the use of scientifically robust methods in clinical Eligible subjects should fulfil the diagnostic criteria research. To keep pace with developments in the scien- for migraine according to the most current version of tific and clinical understanding of acute treatment, the the International Classification of Headache Disorders Committee published a second edition of the Guidelines (ICHD) of the IHS (6). in 2000 (2) and a third edition in 2012 (3). The com- mitment to continuous improvement has been recog- Comments: nized; the Guidelines were considered in the 2018 Clinical trials of acute treatments for migraine can Guidance for industry (4) prepared by the Division of include subjects who have migraine without aura, Neurology Products in the Center for Drug Evaluation migraine with aura, and both migraine types, but the and Research at the Food and Drug Administration ICHD diagnostic criteria should be fulfilled to avoid (FDA), and they were adopted by the European population heterogeneity. In trials focusing on the Medicine Agency (EMA) in a 2016 concept paper acute treatment of migraine with aura, subjects with that represented an important milestone in its formal both migraine types can be included, as aura symptoms revision of the 2007 Guideline on clinical investigation of are recognizable, the attack types are distinguishable, medicinal products for the treatment of migraine (5). and most people who have migraine with aura also Since the 2012 update, multiple new acute treatments have attacks of migraine without aura (7). (Refer to have been developed, including small molecule calci- Section 2.1 for more information about migraine with tonin gene-related peptide (CGRP) receptor antagon- aura.) In trials enrolling participants with a history of ists, serotonin (5-HT1F) receptor agonists, triptan both types of attacks, the type of the treated attack reformulations, and neuromodulation approaches. should be classified according to ICHD criteria based Accordingly, the Guidelines of the International on the clinical features captured in a diary. Note that Headache Society for controlled trials of acute treatment this requirement may be impractical when subjects are of migraine attacks in adults: Fourth edition incorpor- instructed to treat early, because early treatment of ates data from clinical trials conducted since the third migraine can modify the clinical features of an attack edition of the Guidelines was published, as well as feed- and thereby prevent analysis by type (refer to Section back from meetings with representatives of the FDA 2.2 for more information about early intervention and EMA, pharmaceutical and device manufacturers, trials). In some instances, after efficacy and safety and patient associations. Although the Committee con- have been demonstrated in subjects with confirmed sidered the comments of pharmaceutical and device diagnoses of migraine without aura and migraine with manufacturers and members of the IHS on the first aura, trials targeting subjects with probable migraine – draft, the published version is an independent and migraine-like attacks missing one of the features unbiased reflection of the expertise and consensus required to fulfil all criteria for a type or subtype of judgement of its members. migraine (6) – may be appropriate. The present publication retains the structure of the third edition (3), with sub-sections for the selection of 1.1.2. Other primary headaches subjects, trial design, evaluation of results, statistics, Recommendations: and special issues, as well as a Toolbox, which provides 1.1.2.1. Individuals satisfying criteria for chronic readers with an index to content and summary state- migraine or with a history of chronic migraine in ments for each section. Several challenges in trial design the last 12 months should be excluded from pivotal that were raised in a preliminary statement in the third efficacy trials for the acute treatment of migraine. edition – specifically, the timing of acute treatment, In subsequent trials, exploration of the benefits of consistency of response, and participants who have new acute treatments in subjects with chronic migraine migraine with aura – have been addressed in Sections is needed. 1.2.9, 1.2.12, and 2.1, respectively. It is therefore hoped 1.1.2.2. Subjects with other concomitant primary that this edition of the Guidelines continues the trad- headache types (e.g. tension-type headache) are allowed ition of its predecessors by providing investigators with if attacks are infrequent (i.e. present on an average a contemporary, standardized, and evidence-based of < 1 day/month and < 12 days/year) (6) and can be approach to the conduct and reporting of clinical differentiated from migraine based on the quality of trials for the acute treatment of migraine attacks. pain and associated symptoms. Diener et al. 689 Comments: Comments: Individuals with chronic migraine are excluded from Because there are no objective signs or biomarkers the initial clinical trials of acute treatment because they for the diagnosis of migraine, and the 1-year require- may complicate analyses of efficacy in undifferentiated ment increases the specificity of the diagnostic criteria, populations (refer to (8) for guidance about trials eval- a minimum course of 1 year is advised to exclude uating preventive treatments in adults with chronic people with headache types that may mimic migraine. migraine). Subjects with migraine may have other pri- The history may be based on subject recall or physician mary headache types, including tension-type headache evaluation of medical records. At least five prior (2). Those experiencing primary headaches that cannot attacks of migraine without aura or two prior attacks be distinguished from ICHD-defined migraine without of migraine with aura are required for diagnoses using aura (6) should be excluded. ICHD criteria (6). 1.1.3. Secondary headaches 1.1.6. Age at onset Recommendation: Recommendation: Individuals with secondary headaches, including The age at onset of migraine should be less than 50 medication-overuse headache, should be excluded. years. Comments: Comments: Excessive use of acute medications for migraine does Few adults will be excluded by this criterion, as not necessarily lead to medication-overuse headache, migraine beginning after the age of 50 years is rare, and some individuals may fulfil IHS criteria for overuse and the prevalence of secondary headaches or organic of acute medications without suffering from a chronic diseases mimicking migraine increases after age 50. The pattern of headache. The secondary headache exclusion inclusion of subjects with onset of migraine after 50 also applies to these subjects. years of age can be considered in phase IV trials, as long as the migraine diagnosis is well established by 1.1.4. Frequency of attacks ICHD criteria, and secondary headaches have been Recommendations: ruled out. 1.1.4.1. Attacks of migraine should occur two to eight times per month. 1.1.7. Age at entry 1.1.4.2. The frequency of other headaches (including Recommendation: non-target) must be no greater than 1 day per month. Adult subjects participating in clinical trials should 1.1.4.3. There should be at least 48 hours of freedom be between 18 and 65 years of age at entry. from headache between attacks of migraine under study. 1.1.4.4. Subjects should experience fewer than 15 Comments: headache days per month. Only people who are at least 18 years old can pro- vide informed consent. The inclusion of subjects older Comments: than 65 years is encouraged in post-marketing surveil- A minimum of two attacks per month is recommended. lance studies. After age 65, those with migraine are The maximum frequency of eight attacks per month more likely to have (and be taking medications for) reduces the probability that those with incipient medica- coexistent conditions than a younger population, tion overuse, medication-overuse headache, or chronic which can confound assessments of safety and drug- migraine will be included in the trial. Allowing 48 hours drug interactions. Adverse health-related outcomes of freedom from headache between migraine attacks per- due to coexistent disease may be difficult to separate mits clear identification of individual attacks and distinc- from a complication of the treatment under tion from relapse, and it avoids the use of multiple investigation. treatments for a single prolonged attack. The evaluation of three to five consecutive attacks provides information 1.1.8. Sex on consistency of response and may attenuate the placebo Recommendation: effect on the first attack (refer to Section 1.2.12 for more 1.1.8.1. Males and females with migraine are eligible information about consistency of response). to participate in clinical trials of acute migraine medications. 1.1.5. Duration of migraine Recommendation: Comments: Migraine should be present for at least 1 year prior Migraine is at least three times more prevalent in to inclusion in a clinical trial. females than in males (9–12). Special caution should 690 Cephalalgia 39(6) be taken to avoid enrolling women who may be preg- attacks should also be excluded because the possible nant or lactating, unless they are the target of the trial. effects on pain can confound outcomes. People Partners of fertile-age women should practice effective known to be generally resistant to acute anti-migraine contraception (refer to Section 2.3 for information drugs may bias results if they are overrepresented in a about menstrual migraine). trial population. However, because factors such as inadequate dosing, treating late in the course of an 1.1.9. Concomitant drug use attack, inadequate trial, or frequent relapse may be Recommendations: perceived as drug failure or treatment resistance, inves- 1.1.9.1. Therapies not for migraine. Trials allowing tigators should establish the true nature of prior treat- participants to treat conditions other than migraine ment failures before excluding those who report them should pre-specify the permitted uses of concomitant from participation. therapies (i.e. open or restricted). The use of contracep- tive medication should also be pre-specified. In phase II 1.2. Trial design clinical trials, subjects should not be allowed to treat conditions other than migraine unless pharmacokinetic 1.2.1. Blinding (PK) and pharmacodynamic (PD) analyses have clearly Recommendation: shown a lack of interactions between the intervention Phase II and III efficacy trials of therapies for the being assessed for migraine and the concomitant ther- acute treatment of migraine should use a double-blind apy. In later development trials (i.e. phase III and IV), design. the treatment of concomitant and comorbid conditions may be specifically permitted with due precautions. Comments: 1.1.9.2. Acute migraine treatment. Investigational Drugs intended for the acute treatment of migraine treatments should not be administered until at least attacks can only be reliably evaluated in randomized, 48 hours after the use of other acute treatments for double-blind, placebo-controlled trials. Blinding may migraine, including over-the-counter (OTC) drugs, pre- not be required in long-term safety trials and natural- scription medications, and medical devices. istic trials. 1.1.9.3. Preventive migraine treatment. If considered exclusionary, the withdrawal of migraine preventive 1.2.2. Placebo control treatment should be completed and the last dose Recommendations: taken at least 1 month before enrolment. For partici- 1.2.2.1. Interventions under evaluation for the acute pants taking preventive drugs with a long half-life, at treatment of migraine should be compared with least five half-lives should elapse before enrolment. placebo. When the protocol permits migraine preventive drugs, 1.2.2.2. When two presumably active treatments are subjects should be on a stable dose of no more than one compared, a placebo control should be included for preventive agent for at least 2 months before enrolment assay sensitivity. to ensure a stable baseline. 1.1.9.4. Antipsychotics and antidepressants. People Comments: who have used antipsychotics on a regular basis The placebo effect is a genuine psychobiological phe- during the 3 months prior to consideration for enrol- nomenon that affects the results of clinical trials across ment should be excluded from phase II clinical trials. different disease states (14). In trials for the acute treat- Individuals co-medicating with antidepressants may be ment of migraine placebo response varies widely, from considered for inclusion. 6% to 56% for headache relief (15) and from 6% to 25% for pain freedom (16,17). This variability makes it Comments: difficult to interpret the results of active comparator Evaluating the potential for interactions is an trials that do not include placebo. Trials using historical important aspect of development prior to approval controls or active comparators lack assay sensitivity and marketing, especially in the case of small mol- and require large sample sizes to provide the narrow ecules. The absence of a clear understanding of PK confidence intervals (CIs) needed to ensure that new and PD profiles and possible drug-drug and drug- drugs are not inferior to controls (18). device interactions can obscure the interpretation of In the past, modified designs (e.g. exclusion of pla- treatment effects and adverse events (AEs). Persons cebo responders or sequential parallel designs) to with a substance use disorder, as defined by the reduce placebo response have proved poorly effective. Diagnostic and statistical manual of mental disorders, Nonetheless, particular care should be dedicated to fifth edition (13), should be excluded from clinical identify and mitigate placebo response risks as much trials. Individuals using cannabinoids to treat migraine as possible. Diener et al. 691 1.2.3. Design types blocks sizes of two, four, six, etc.) may be helpful in Recommendations: preventing participants from guessing treatment 1.2.3.1. Although both parallel-group and crossover assignments. designs may be used, parallel-group designs are preferred. 1.2.3.2. Limited to phase II trials, group-sequential, 1.2.5. Stratification adaptive treatment, and dose-defining designs may be Recommendations: appropriate. 1.2.5.1. There is usually no need for stratification in acute treatment trials. Comments: 1.2.5.2. Stratification may be considered when an The parallel-group design has the advantage of sim- imbalance between the treatment groups or an import- plicity. Parallel-group trials have successfully demon- ant factor may influence the results of a trial. strated both superiority and similarity among treatments. Multiple-attack, parallel-group designs Comments: can be used to assess intra-individual consistency of Randomization alone may not ensure full compar- response, although carry-over effects and intra-indivi- ability between subjects in different treatment groups, dual correlation must be taken into account (refer to especially in smaller trials, and stratified randomization Section 1.2.12 for information about consistency of is sometimes used to circumvent potential imbalances. response). With crossover trial designs, period and The EMA recommends that stratification variables carry-over effects may occur, and complexities may be usually be included as covariates in primary analyses, introduced if the tested treatment has notable side regardless of their prognostic value (25). In controlled effects. Crossover designs can also be used in multi- trials for migraine, the use of stratification by prognos- ple-attack trials to estimate intra-individual consistency tic factors should be limited to a few variables and only of response with placebo-control groups (19). In add- to those that have historically demonstrated effects on ition, crossover designs allow for the assessment of primary efficacy endpoint(s). Stratification variables acute treatment preferences. Subjects who have taken that have been used in acute treatment trials include more than one treatment can be asked which treatment age, body weight, headache intensity at baseline, they would prefer to take again. Reponses to this ques- migraine type (i.e. with or without aura), menstrual tion reflect subjects’ net assessment of benefits and tol- versus non-menstrual attacks, and concomitant pre- erability (20). Given the popularity of social media, ventive treatment (26–28). Given the preponderance participants in crossover trials should be instructed to of females with migraine, sex may also be used as a refrain from posting about the trial. stratification factor to control for imbalances in treat- Non-traditional clinical trial designs include step-wise, ment groups. adaptive, enriched designs and futility trials. Adaptive designs allow for the modification of aspects of a trial 1.2.6. Intention to treat (e.g. dosing) while in progress without undermining its Recommendations: scientific validity or integrity. For phase II evaluations 1.2.6.1. Randomized controlled trials of acute treat- of optimal dosing, randomised group-sequential, adaptive ments for migraine should follow the principle of inten- treatment, dose-defining, proof-of-concept (21–23) and tion to treat (ITT), which implies that analyses should two-stage, adaptive, dose-ranging (24) designs are appro- include all randomised subjects in the groups to which priate. The major advantage of these non-traditional they were randomly assigned, regardless of treatment designs is that they allow evaluation of the lowest effective received. dose and highest tolerated dose over a wide dose range in 1.2.6.2. The full analysis set may be modified to relatively few subjects. The chosen dose(s) can then be exclude subjects from the analysis if no treatment was confirmed as optimal in phase III clinical trials. taken or if no data points after treatment were rec- orded. A plan should be provided prospectively as to 1.2.4. Randomization how participants missing the 2-hour endpoint or who Recommendation: treat but do not record data will be handled. Those who Subjects enrolled in parallel-group and crossover treat but do not record data should probably be trials should be randomized at entry to the trial, counted as failures, and those who use rescue medica- except when considering adaptive randomization. tion before the 2-hour time assessment should be counted as failures. Comments: True randomization is crucial to avoid bias and, Comments: in large trials, to contribute to group matching. The ITT principle encourages, where reasonable, Block randomization using varying block sizes (e.g. the inclusion of subjects who withdrew, were lost to 692 Cephalalgia 39(6) follow-up, or did not fully adhere to trial protocol (29). 1.2.9. Timing of administration The ITT principle should be adhered to when the pri- Recommendations: mary outcome is a variable that measures a change 1.2.9.1. The timing of acute treatment should be from baseline to any post-dose time point or to the defined in the trial protocol. end of the trial. When the primary outcome is defined 1.2.9.2. Usually, participants are instructed to treat as a rate of change, and the analysis will therefore imply when migraine headache pain is of at least moderate a slope or rate of calculation, only subjects who have intensity, but alternatives include treating as soon as received at least one dose and recorded at least one data possible after headache onset, treating when pain inten- point should be included. sity is mild, and treating when pain intensity is severe. 1.2.9.3. The timing of acute treatment must be con- 1.2.7. Dose-response curves and dosage sistent with the objectives of the trial. Recommendations: 1.2.9.4. Subjects should record the time and pain 1.2.7.1. Dose-response curves should be defined intensity at the time of treatment in the trial diary. clearly in early (phase I and II) randomized, clinical trials of new chemical entities for the acute treatment Comments: of migraine. The head pain of migraine frequently begins with 1.2.7.2. Efficacy- and tolerability-based minimum mild intensity, progressively increases with variable effective and optimal doses should be determined. speed to a peak, and is followed by resolution; head- 1.2.7.3. Effective doses of a well-established or stand- ache pain can also fluctuate spontaneously during a ard drug should be utilized in comparative clinical migraine attack (41). These characteristics can pose trials, unless clinically inappropriate, in which case a challenges regarding the timing of treatment (e.g. clear justification for the particular dose selection early or when the attack is fully developed) and the should be given. evaluation of trial results. For example, healthcare pro- viders typically recommend treating early in the course Comments: of a migraine attack, while pain intensity is mild, New acute treatments for migraine should be tested because it can enhance efficacy (18,42,43). At the begin- against a standard comparator with established ning of an attack, however, migraine without aura can dose-response curves and optimal efficacy- and toler- be difficult to distinguish from non-migraine headaches. ability-based doses, such as rizatriptan, sumatriptan, Thus, subjects in migraine clinical trials who are or zolmitriptan (30–34); the CGRP receptor antagon- instructed to treat as soon as possible (i.e. at the first ists (i.e. gepants) ubrogepant and rimegepant (23,35); sign of migraine) may mistakenly treat other headache or the 5-HT1F receptor agonist lasmiditan (22). types. The potential for confusion is mitigated when The accepted optimal therapeutic dose of the com- attacks are allowed to fully develop. Having subjects parator should be used. wait until pain intensity is moderate or severe before treating increases the specificity of migraine diagnoses. 1.2.8. Route of administration Yet because this strategy conflicts with common clinical Recommendations: advice about early treatment, it is essential that partici- 1.2.8.1. When pre-clinical and PK data demonstrate pants in clinical trials receive clear instruction an acceptable PK profile in humans (i.e. good oral bio- about when to use acute treatment. In later stages of availability and rapid oral absorption), oral administra- development, depending on the specific objectives of tion of the test treatment is recommended because the the program, trials evaluating early intervention and oral route is preferred by most people with migraine (36). treatment when headache pain intensity is severe (e.g. 1.2.8.2. Alternative routes of administration, includ- for early morning migraine (44)) are encouraged when ing parenteral, inhalational, buccal, intranasal, and investigating the efficacy, safety, and tolerability of new rectal, can be utilized as circumstances dictate (e.g. treatments. severe nausea, status migrainosus). 1.2.10. Number of attacks treated Comments: Recommendations: Gastric absorption of orally-administered medica- 1.2.10.1. Determining the effect of an acute treat- tions can be delayed during migraine attacks (37–40). ment on the first migraine attack should be the primary In early phase I or II trials, therefore, it is advisable to objective. The attack to be considered should be clearly establish the intra- and interictal PK profile of oral specified in the protocol. treatments utilizing a crossover design in order to 1.2.10.2. If multiple attacks are treated, the first trea- gauge dose selection in later efficacy trials. ted attack or the attack that will be considered for Diener et al. 693 assessing the primary objective can be randomly least four attacks. The third design uses a combined selected. approach, with an initial 1-month double-blind phase (subjects use active treatment or placebo for the first Comments: attack) followed by a 1- or 2-month open-label phase, In most clinical trials of acute treatment, the first during which subjects treat at least three attacks with treated attack will be used in the evaluation of efficacy. the active intervention. Refer to Section 1.2.12 for information about multiple- Testing the effect of an acute treatment on several attack trials addressing consistency of response as a migraine attacks may increase the discriminative power primary objective (45–48). for efficacy when outcome measures are averaged across multiple attacks for each subject, provided that 1.2.11. Rescue medication all analysed subjects treat the same number of attacks. Recommendations: Using a generalized estimating equation or random- 1.2.11.1. The use of rescue medication should be effects modelling, all treated attacks can be used as a allowed at any time after the first primary efficacy basis for comparison (49,50). Generalized estimating time point, typically 2 hours after the initial adminis- equations control for intra-individual correlation, tration of treatment. whereas random-effects models treat each individual 1.2.11.2. Use of rescue medication before the 2-hour as a random effect. However, the increase in analytic endpoint should be considered a treatment failure power can be counterbalanced by a decrease in the unless an earlier time point for rescue was pre-specified number of subjects completing the trial. Relative to in the trial protocol. single-attack trials, multiple attack trials have higher dropout rates and may introduce an unmanageable Comments: bias if dropouts are related to tolerability issues or The time interval to using rescue medication can be lack of efficacy (51,52). Furthermore, repeated intake reduced when the primary efficacy time point is before 2 of placebo when a standard treatment is available raises hours, which is often the case in assessments of paren- ethical issues. teral drugs or trials involving paediatric subjects. Little Assessing intra-individual and population-level con- can be learned from delaying rescue medications sistency of response has been difficult in long-term beyond the primary efficacy time point. Furthermore, safety trials because they rarely include a placebo con- delays may unduly discomfort subjects and prolong the trol and often introduce selection bias when responders attack and associated disability, which are ethically from an efficacy trial are carried over (53). Long-term unacceptable. Rescue medication can be taken before trials should be used to evaluate the development of the time of the primary endpoint if subjects require it, tolerance (tachyphylaxis). but such use should be recorded as a treatment failure. 1.2.12. Consistency of response 1.3. Evaluation of results Recommendations: 1.3.1. Attack report form (diary) 1.2.12.1. Intra-individual consistency of response Recommendation: may be evaluated over multiple attacks in double- An easy-to-use electronic diary that captures prede- blind, placebo-controlled trials. fined endpoints should be used. Investigator-initiated 1.2.12.2. Response to at least four attacks should be trials may use paper diaries (54). assessed, and at least one of the four attacks should be treated with placebo in a randomized fashion. Comments: Headache characteristics and response to treatment Comments: are best recorded by means of electronic diaries with Population-level consistency of response refers to the time-stamp capabilities. Data for the index attack and proportion of treated subjects who achieve a trial end- the 2-hour time point should be entered in real time. point for the first, second, third, or nth treated attack. Adverse events may be collected in the diary or during This is best assessed in randomized controlled trials follow-up visits. Serious AEs need to be reported within evaluating multiple attacks (  4) using any of the fol- 24 hours. In settings where electronic diaries are not lowing three designs. In the first design, all subjects use available (e.g. investigator-initiated trials), paper dia- active treatment for at least three attacks, with placebo ries may be used. in one additional attack, in a randomized order. The With diaries, the quantity and quality of collected second design administers the active treatment for all data tend to be inversely proportional. Complicated attacks in most subjects, while a subset uses both active report forms with detailed description of symptoms treatment and placebo in a randomized manner for at may be difficult for subjects to fill out during attacks. 694 Cephalalgia 39(6) Some trials have been successful using algorithms to with no headache pain at 2 hours after treatment and ensure that the treated attack is a migraine (55,56). the proportion of subjects with absence of the most Familiarization with data capture on the trial diary bothersome associated symptom (MBS) at 2 hours is important. Subjects can complete the diary report for after treatment (4). The use of the MBS as a co-primary an attack whilst treating with their usual medication endpoint with pain freedom is an alternative to request- prior to entering the trial, and the data are reviewed ing demonstration of a positive treatment effect on all at the trial site. Subjects can also be asked to complete three migraine associated symptoms; it requires larger the diary at the randomization visit by recalling events sample sizes due to the need to consider the frequency of their most recent attack. The latter procedure is pref- of the symptoms. The MBS endpoint should be selected erable because it minimizes delays in trial participation. just prior to study drug administration and measured on a binary scale (present or absent) using either of two 1.3.2. Primary endpoint: Pain freedom at 2 hours suggested methods. One method allows subjects to Recommendation: select the MBS prior to randomization and then treat 1.3.2.1. The percentage of subjects who become pain only an attack that occurs with the pre-specified MBS. free at 2 hours after treatment, before the use of any The other is to use a time-locked recording device (e.g. rescue medication, should be the primary measure of an electronic diary) and have subjects record their MBS efficacy. at the onset of the treated attack and then record the effect on the MBS at 2 hours. The trial protocol should Comments: specify which of these approaches will be used by all Freedom from pain before the use of rescue medica- subjects in a clinical trial. tion is simple, clinically relevant, reflects patients’ It should be noted that an effect on associated symp- expectations (57,58), and is independent of the con- toms is very difficult to achieve in trials investigating founding effects of other therapies (e.g. rescue medica- early treatment, when headache is mild and associated tion). With respect to the 2-hour time point, it may be symptoms may not have appeared yet. Moreover, mea- argued that because some acute treatments have a slow suring the elimination of an associated symptom time to maximum or time to effective plasma concen- that was not present at the time treatment was taken, tration, an expectation of pain freedom within 2 hours especially for less common symptoms (e.g. nausea), of treatment is unrealistic. This position runs counter to substantially increases the required sample size and the principles of Good Clinical Practice (59), which give number of subjects that must be exposed. An alterna- the highest consideration to subject wellbeing; partici- tive approach would be to record the elimination of all pants in clinical trials should not be subjected to undue associated symptoms at 2 hours after treatment. harm, and the use of effective rescue therapies should not be delayed beyond 2 hours. Pain freedom at times 1.3.4. Secondary endpoints before 2 hours should be considered as an endpoint in trials of non-oral treatments (e.g. intravenous, intra- 1.3.4.1. Relapse muscular, subcutaneous, intranasal). Recommendations: 1.3.4.1.1. Relapse is a secondary treatment failure 1.3.3. Co-primary endpoint: Absence of the most bothersome that is defined as the occurrence of headache of any symptom severity within 48 hours of the administration of an Recommendation: investigational treatment among subjects who were Absence of the most bothersome migraine-asso- pain free 2 hours after the investigational treatment ciated symptom at 2 hours after treatment may be was administered. used as a co-primary endpoint. 1.3.4.1.2. A time interval of 24 hours may be con- sidered if the treatment under investigation has a short Comments: half-life. In addition to headache pain, migraine attacks are 1.3.4.1.3. Relapse rates should not be compared characterized by a number of associated symptoms, across trials, and it is recommended that investigators including nausea, vomiting, photophobia, and phono- evaluate the differential rates of relapse in comparative phobia (6). To align outcomes in controlled trials with trials only when primary efficacy rates are similar (60). symptom(s) of clinical significance, it is important to measure the effects of an acute treatment on all Comments: these features. For regulatory purposes, the FDA Relapse is a major problem with all effective recommends that efficacy analyses in acute trials use migraine treatments (61,62), and its incidence should as co-primary endpoints the proportion of subjects be recorded in all trials. Relapse was previously Diener et al. 695 known as ‘‘recurrence’’ and defined as initially obtain- Comments: ing pain freedom (refer to Section 1.3.2) or headache Total freedom from migraine is a combined efficacy relief (refer to Section 1.3.4.5) and subsequently experi- measure that addresses pain and associated symptoms. encing a moderate or severe headache or using rescue Statistically, it is up to four times more powerful than medication (even for mild headache pain) from the time analyses using four separate co-primary endpoints, as point of primary efficacy and up to 48 hours. The the majority of people with migraine do not exhibit all reported incidence of relapse under the older definition associated symptoms, and because these endpoints are varied considerably (e.g. from 6% to 50% with oral not necessarily independent (68). In a post-hoc analysis triptans (63,64)), and it is expected that estimates will based on pooled data from the rizatriptan clinical drug stabilize when analyses are based on the new definition. development program, rates of total freedom from migraine were 35% for rizatriptan and 8% for placebo 1.3.4.2. Sustained pain freedom (68). Rates of total freedom from migraine tend to be Recommendations: discouragingly low and often underestimate the benefits 1.3.4.2.1. Sustained pain freedom is defined as the of effective acute treatments. percentage of subjects who are pain free at 2 hours with no use of rescue medication or relapse within 24 1.3.4.4. Headache intensity or 48 hours of the initial treatment. Recommendations: 1.3.4.2.2. Sustained pain free is a recommended sec- 1.3.4.4.1. Subjects should note the intensity of head- ondary endpoint, and it is the primary endpoint in early ache immediately before the first use of the acute treat- intervention trials. ment being evaluated and at each subsequent pre- specified time point. Comments: 1.3.4.4.2. Headache intensity should be measured Sustained pain freedom is an important measure of on a 4-point scale where 0 ¼ no headache; 1 ¼ mild migraine treatment response. By integrating initial headache; 2 ¼ moderate headache; 3 ¼ severe headache. response, use of rescue medication, and relapse Alternatively, a 100-mm Visual Analogue Scale (60,61), the sustained pain-free rate is a more scientif- (VAS) or an 11-point numerical rating scale (NRS) ically robust outcome measure than the relapse rate can be used. alone. It is therefore recommended over relapse as an 1.3.4.4.3. Collecting data about headache intensity at endpoint in comparative trials (65). Investigators the primary efficacy time point (e.g. 2 hours) and before should be aware that the clinical success of acute treat- any rescue medication use is critical for the analysis of ment may be underestimated when using this narrowly- the pain-free primary efficacy outcome measure. defined efficacy outcome measure, but it has been 1.3.4.4.4. Headache intensity should be measured at useful in comparing triptans (66) and can be useful the time of treatment, every 30 minutes until 2 hours for non-triptan comparisons. Sustained pain freedom after treatment; hourly until 4 hours after treatment; can also be helpful in trials evaluating the use of at 12, 24, and 48 hours after treatment; and at the acute treatment in subjects with mild pain (e.g. early time of relapse. intervention trials). 1.3.4.4.5. If the time course of treatment effect on Sustained relief is a composite efficacy outcome headache intensity has been established in earlier measure based on concepts similar to those of sustained trials, fewer time points can be used (i.e. 1, 2, and 4 pain-free. It is defined as headache relief (not pain free- hours after treatment). dom) and absence of relapse or use of rescue medica- tion after the initial response (67). Sustained relief is not Comments: recommended as a secondary efficacy outcome The ordinal 4-point scale is the preferred instrument measure. for measuring headache intensity. It is easy to under- stand and use, and it can be employed in association 1.3.4.3. Total freedom from migraine with the VAS or 11-point NRS (54). The VAS has Recommendations: shown a very high level of concordance with the cat- 1.3.4.3.1. The absence of pain, nausea, vomiting, egorical scale (69), and the NRS is responsive and easy- photophobia, and phonophobia at the primary efficacy to-use in everyday practice; evidence from trials in time point (i.e. 2 hours after treatment in most other painful conditions suggests that the NRS may acute trials) is defined as total freedom from migraine. offer a higher discriminatory capability than a categor- This endpoint can be used as a secondary efficacy ical scale for pain exacerbations (70). Trials evaluating measure. the use of acute treatment for mild pain may use sus- 1.3.4.3.2. Freedom from headache and any migraine- tained pain free as a primary outcome measure, with associated symptoms may also be considered. pain intensity difference (PID) and sum of pain 696 Cephalalgia 39(6) intensity differences (SPID) considered as secondary improves the precision of time estimates relative to endpoints. Used widely in non-headache pain trials the fixed-interval assessments once commonly used in (71) and rarely in trials of acute migraine treatment migraine trials by providing data about treatment (72,73), PID and SPID have been shown to yield response over a clinically relevant period of time similar results to a 2-hour pain-free analysis (74), the instead of at pre-specified time points (e.g. 1, 2, or 4 4-point scale, and the VAS (75–77).) hours after treatment). Time stamping also allows diary entries for time to meaningful relief to be analysed by 1.3.4.5. Headache relief powerful statistical methods, such as survival analysis Recommendations: (82,83), that are superior to analyses based on fixed 1.3.4.5.1. Headache relief (45), defined as the intervals. decrease in headache pain from moderate or severe at baseline to mild or none at 2 hours after treatment and 1.3.4.7. Time to pain freedom before taking any rescue medication (refer to Section Recommendations: 1.2.11), should be used as a secondary efficacy measure. 1.3.4.7.1. Speed of onset of therapeutic effect can be 1.3.4.5.2. A time point before 2 hours after treatment evaluated using a survival analysis of pain freedom at can be used when testing parenteral treatments. time points earlier than 2 hours after treatment. 1.3.4.7.2. Time to pain freedom is a recommended Comments: secondary efficacy outcome measure. Headache relief should be used as an outcome meas- ure, but only as a secondary endpoint and mainly to Comments: facilitate comparison of the results of new clinical trials Time to pain freedom is a more exact measure than with those of previous programmes (30–32,61,74–78). time to meaningful relief. Ratings of headache intensity Since headache relief is associated with relief of disabil- at pre-defined time points before 2 hours (e.g. at 10- to ity, it can be used in clinical trials as a proxy for pain 15-minute intervals) can be used to analyse the speed of improvement and restoration of function. Headache onset of treatment response. Investigators should be relief is also useful for comprehensive cost of treatment aware that additional data recordings can complicate analyses. headache diaries and potentially lead to missing data. In older acute migraine clinical trials, headache relief Time-to-event analysis is the most appropriate stat- at 2 hours after treatment was used extensively as a istical method to assess speed of onset of therapeutic primary efficacy outcome (30,31,45,58,79) based on effect, using no headache when pain freedom is the out- the suggestion that patients may consider an acute come and mild or no headache when headache relief is treatment effective while residual headache pain persists the outcome. The difference between two treatments (45). The validity of this argument has been challenged should be expressed as a percentage, and because by evidence showing that patients do not believe a p-value calculations alone can be misleading, 95% CIs reduction in headache pain from moderate to mild con- should be given in order to better inform readers about stitutes success (80) and expect acute treatment to pro- the significance of the difference. Time-to-headache vide freedom from pain (57,58). In addition, the relief analyses have been used in previous trials headache relief endpoint assumes that the magnitude (77,78,84), but early response rates were relatively of change from severe pain to no pain is clinically small. Subcutaneous sumatriptan is an exception equivalent to the change from moderate pain to mild (85,86). pain, which is not the case (81). Finally, the verbal rating of pain intensity as 0 ¼ none, 1 ¼ mild, 2 ¼ mod- 1.3.4.8. Duration of attacks erate, and 3 ¼ severe assumes it is an interval variable in Recommendation: the absence of clinical validation. Duration of attacks should not be used as an efficacy measure. 1.3.4.6. Time to meaningful relief Recommendation: Comments: Time to meaningful relief can be used as a secondary The duration of a migraine attack can be influenced efficacy measure. by the effect of treatment, as well as by physiological factors (e.g. sleep) and external variables (e.g. use of Comments: rescue medication beyond 2 hours). Since these vari- Time to meaningful relief is most often assessed by ables cannot be controlled for in a clinical trial, they subjects using electronic diaries with time-stamp cap- prevent an accurate and scientifically sound interpret- abilities, which have largely replaced the use of stop- ation of the independent effect of an investigational watches (73,75). The time-stamped information intervention. The robustness of the pain freedom and Diener et al. 697 sustained pain freedom outcome measures mitigates the associated symptoms, as well as any adverse effects of need for attack duration as an efficacy measure. treatment. 1.3.4.9. Rescue medication Recommendation: Recommendations: 1.3.4.11.1. Subjects should assess functional disability 1.3.4.9.1. The percentage of patients taking rescue just before and up to 2 hours after the administration of medication 2 hours after intake of the test treatment acute treatment, before the use of rescue medication, can be used as a secondary efficacy measure. using a simple verbal, numerical scale. The following 1.3.4.9.2. The assessment of rescue use medication question is recommended: ‘‘How well can you function can be earlier if the primary outcome measure is speci- right now?’’ Response options should be: 0 ¼ no disabil- fied at a time earlier than 2 hours after treatment. ity (i.e. able to function normally); 1 ¼ mild disability (i.e. able to perform all activities of daily living but Comments: with some difficulty); 2 ¼ moderate disability (i.e. Theoretically, use of rescue medication at the primary unable to perform certain activities of daily living); efficacy time point reflects a judgement of the inefficacy 3 ¼ severe disability (i.e. unable to perform most to all of the test treatment, but subjects in clinical trials may activities of daily living or requiring bed rest). use rescue medication for conditions other than head- ache (e.g. anxiety, sleep, or associated symptoms). Rates Comments: of rescue medication usage have been found to be as Disability can be defined as a decrement in any of a sensitive as 2-hour pain-free rates in some trials range of domains (cognition, mobility, self-care, getting (86–88), but not in others (89). The use of rescue medi- along, life activities, or participation) or as the sum of cation should not be postponed beyond 2 hours after difficulties, impairment, and decreased productivity in treatment; its use may be permitted at 1 hour after treat- daily activities (93,94); HRQoL refers to the overall ment in paediatric trials and in trials where the primary effect of illness and its therapy on the perception of time point for efficacy is at 1 hour after treatment. the ability to live a useful and fulfilling life, including physical and mental components, general health per- 1.3.4.10. Global evaluation ception, and level of performance/participation in dif- Recommendations: ferent roles (95,96). Restoring the ability to function 1.3.4.10.1. Subjects’ global impression of acute treat- and improving quality of life are among the main ment effect can be used as a secondary outcome meas- objectives of acute migraine treatment (97,98), and ure. Efficacy and tolerability should be evaluated the global impact of migraine can be measured by con- separately. sidering functional disability and quality of life. 1.3.4.10.2. A simple Likert-type verbal scale is rec- However, it is important that the instruments employed ommended (e.g. very poor, poor, no opinion, good, are appropriate for assessing the global effect of treat- very good). ment on subjects’ quality of performance in different 1.3.4.10.3. Investigator’s impression of treatment roles and daily activities and sense of wellbeing. effect should not be used. Based on previous recommendations in IHS Guidelines (2,3), an NINDS-CDE recommendation as supplemental Comments: evaluation instrument (54), and continuing use in trials of Subject’s global impression of change from baseline — acute treatment of migraine, the Functional Impairment the global impression of an investigational treatment’s Scale (FIS) and the Migraine Physical Function Impact effect — is one of the most clinically relevant outcomes Diary (MPFID) are recommended instruments for assess- because it is a composite assessment of treatment effects ing functional disability (54). A simple numerical scale on headache, associated symptoms, and AEs (tolerabil- may be used to evaluate HRQoL, and of the global ity). Several scales, including the Patient Global impact assessment tools used in clinical trials of acute Impression of Change (PGI-C), have been used to treatment (88,99,100), only the 24-hour MSQoL and assess global impression of change in migraine trials Minor Symptoms Evaluation Profile (a self-administered, (22,90–92). Global impression of change is recommended 24-item instrument that uses a VAS to record perceived for use in phase III and IV trials, as well as for clinical symptoms of migraine) are well suited for assessing the trials comparing two or more active treatments. impact of acute treatment (101,102). 1.3.4.11. Global impact (functional disability and quality 1.3.4.12. Associated symptoms – nausea and vomiting of life). Functional disability and health-related quality Recommendation: of life (HRQoL) are important secondary global meas- The presence or absence of nausea should be rec- ures that account for the impact of headache and orded at the time trial treatment is administered and 698 Cephalalgia 39(6) at the time of assessment of the primary efficacy out- although verbal rating scales of severity can also be come (e.g. 2 hours). used (e.g. a 4-point scale where 0 ¼ none, 1 ¼ mild, 2 ¼ moderate, and 3 ¼ severe) (105). The presence or Comments: absence of phonophobia should also be recorded at 4, Nausea and vomiting are important associated 8, 12, 24, and 48 hours after treatment. symptoms of migraine, and acute migraine treatments should demonstrate efficacy against these symptoms. 1.3.4.15. Time between onset of headache and intake of Nausea and vomiting can also complicate treatment treatment when they occur as AEs, and therefore these variables Recommendation: should be recorded for at least 24 hours after treatment. Both timings should be recorded. When interpreting data about nausea or vomiting, investigators should consider that they can be attributed Comments: to (a) treatment efficacy effects; (b) treatment-induced The time interval between the onset of headache and adverse effects (i.e. treatment-emergent nausea or vomit- the use of an acute treatment is important for trials ing); and (c) use of rescue medication for nausea or investigating the efficacy of early intervention (refer to vomiting when applicable. Finally, it is important to Section 2.2 for information about early intervention). rate the severity of nausea in trials that include anti- emetics, either alone or in combination with other treat- 1.3.4.16. Treatment preference ments. A simple 4-point categorical verbal/numerical Recommendation: scale (e.g. 0 ¼ none, 1 ¼ mild, 2 ¼ moderate, or Subjects’ acute treatment preference is a useful 3 ¼ severe) can and has been used (103–105). exploratory and hypothesis-generating global assess- ment method (20,106–108) that is best suited for cross- 1.3.4.13. Associated symptoms – photophobia over trials. Recommendation: The presence or absence of photophobia should be Comments: recorded before treatment is administered and at Treatment preference is a subjective assessment that the time of assessment of the primary efficacy outcome considers treatment benefits and tolerability factors (2 hours). (109). It can be used to compare a new acute treatment with subjects’ usual treatment prior to the trial or, in a Comments: crossover trial, preference among treatments (20). Past Photophobia is very commonly associated with clinical trials have used a questionnaire with preference migraine attacks and can be disabling. Similar to scores graded from 0 to 5 (110,111). Reported preferences nausea and phonophobia, the effect of an acute treat- in clinical trials of acute migraine treatments have been ment of migraine on photophobia should be evaluated difficult to interpret because of the heterogeneity in sub- in migraine clinical trials. A simple assessment such as jects’ assessment of the balance between benefits and tol- presence or absence of photophobia is practical, erability issues; some patients prefer a more effective drug although verbal scales of severity can be used (e.g. a or dose at the expense of more AEs, if they are relatively 4-point scale where 0 ¼ none, 1 ¼ mild, 2 ¼ moderate, transient and mild, but others are willing to sacrifice a and 3 ¼ severe) (105). The presence or absence of minimal amount of efficacy for a better tolerability profile. photophobia should also be recorded at 4, 8, 12, 24, and 48 hours post-dose. 1.3.4.17. Blinding assessment Recommendation: 1.3.4.14. Associated symptoms – phonophobia It is important to determine how well a clinical trial Recommendation: is blinded. The presence or absence of phonophobia should be recorded before treatment is administered and at the Comments: time of assessment of the primary efficacy outcome The quality of blinding can be assessed using ques- (e.g. 2 hours). tionnaires. Indexes are available for the analysis of results (e.g. James’ Index or Bang Index (112,113)), Comments: though they are not totally free from bias (114). Migraine-associated phonophobia can be disabling. Similar to nausea and phonophobia, the effect of an 1.3.4.18. Treatment of relapse acute migraine treatment on photophobia should be Recommendation: evaluated in clinical trials. A simple assessment, such The efficacy of treatment for headache relapse as presence or absence of phonophobia, is practical should be measured by the percentage of subjects Diener et al. 699 with pain freedom 2 hours after the administration of details of trial-related AEs beyond those aforemen- treatment for headache relapse. tioned (59,116,117). Commonly used tools for analys- ing AEs include the chi-square test and Fisher’s Comments: exact test. Relapse of headache pain of any intensity can be treated with active treatment or placebo in a rando- mised, double-blind clinical trial. Participants should 1.4. Statistics be re-randomized to active treatment or placebo for 1.4.1. Hierarchy of endpoints. The following hierarchy of the second dose. Measured by the pain relief endpoint, endpoints should be adopted for trials investigating the the efficacy of certain acute medications (e.g. oral trip- efficacy, tolerability, and safety of interventions for the tans) is similar whether the primary or the relapsing acute treatment of migraine. headache is treated (34,78). Co-primary endpoints 1.3.5. Adverse events . Pain-free after 2 hours Recommendations: . Freedom from the most bothersome symptom at 2 1.3.5.1. Adverse events that occur during a clinical hours trial should be recorded contemporaneously in the trial diary. Secondary endpoints 1.3.5.2. Spontaneous real-time or synchronous . Supporting the primary endpoints reporting of AEs is recommended and should be sup-  Headache relief at 2 hours plemented by responses to open questions when  Sustained pain-free to 24 hours appropriate.  Total freedom from migraine 1.3.5.3. At a minimum, any subject experiencing an  Freedom from nausea and vomiting, photopho- AE in a clinical trial of an acute migraine treatment bia, or phonophobia should record event severity (mild, moderate, severe);  Time to pain freedom event seriousness (serious, non-serious); time of onset; . All other endpoints (i.e. tertiary or exploratory and time of resolution, as recommended by the endpoints) International Conference on Harmonisation’s  Intensity of headache Guideline for good clinical practice (59).  Headache relapse  Time to meaningful relief Comments:  Time to pain freedom Adverse events that occur during a clinical trial are  Rescue medication not necessarily related to the acute treatment being  Global evaluation evaluated (115), and investigators should determine  Global impact (disability and HRQoL) whether any AEs are believed to be treatment-related.  Time between headache onset and treatment intake Therefore, AEs should be recorded openly (i.e. spon-  Preference to treatment taneously), without a priori biases (to detect any unex-  Blinding assessment pected effects), and within 24 hours of intake of acute  Treatment of recurrence treatment (to mitigate problems of recall). The record- ing of AEs should also adhere to the nomenclature and The recommended co-primary efficacy measures for hierarchy of the Medical dictionary for regulatory activ- single-attack trials are the proportion of subjects who ities. Reports of AEs should include, at minimum, the are pain-free within 2 hours of treatment and the pro- following for each treatment arm: Subjects with one or portion of subjects who are free from the MBS within 2 more AE; subjects with any serious AE and details of hours of treatment. Inferences regarding differences can each serious AE, including causation; subjects who be assessed using standard statistical methods, such as withdrew because of AEs; subjects with individual, the chi-square test or Fisher’s exact test, assuming there pre-specified AEs based on a priori knowledge, if any, are no baseline imbalances or known potential con- of treatment or class tolerability profiles; severity of founders to account for by Cochran-Mantel-Haenszel. specific AEs; and a detailed table of individual AEs. If a baseline imbalance exists between the two groups Detailed tabulation of all AEs by organ system is rec- on any covariates, then analysis may be performed ommended over a listing of only AEs occurring in a using logistic regression, with subject status as pain- pre-specified percentage of subjects (commonly 3–5% free within 2 hours as a binary outcome of interest or greater) or with a frequency that significantly differs (yes, no) and treatment assignment as a primary pre- from another treatment arm. Finally, it is worth noting dictor with inclusion of other pre-specified covariates that many regulatory authorities require additional identified as imbalanced or confounders at baseline. 700 Cephalalgia 39(6) To properly calculate a sample size, investigators can be reported. For randomized controlled trials, need to take the following four steps, at a minimum: slope estimates between treatment arms can be com- estimate placebo response rates for the primary out- pared using a 2-sample t-test or a Wilcoxon rank sum come measure, based on well-founded assumptions test. If a baseline imbalance exists between treatment and meta-analyses (118); define a clinically relevant dif- groups on any covariates, then a regression analysis ference between active and placebo response rates for may be performed. the primary outcome measure; establish the a priori statistical errors (a- and ß); and determine an accept- able trial power (1-ß) (119). In addition, the appropri- 2. Special issues ateness of an adjustment for multiple comparisons must be considered in trials with more than one primary end- 2.1. Migraine with aura point. Investigators do not have to limit these adjust- Many people who have migraine without aura also ments to Bonferroni corrections, as there are various have attacks of migraine with aura (7). Both attack other alternatives available, notably the hierarchical or types have, in most cases, similar headache features gatekeeper approach (120,121). Adjustment for mul- and associated symptoms, and they may share the tiple comparisons may not be necessary for secondary same basic pain mechanisms. So far, no treatment has and tertiary endpoints. The required sample size may be been shown to be effective when administered in the much larger if the goal of the trial is to establish non- aura phase, either for reducing the duration of the inferiority or equivalence (122). Investigators need to aura or preventing the subsequent headache; in separ- pre-specify acceptable limits for such considerations. ate assessments of acute treatment given during the Standard statistical methods can also be used for aura phase, sumatriptan 6 mg SC and eletriptan 40 mg analysis of assessment measures in crossover and par- oral tablets had no effect on the aura or the headache allel-group trials. In addition to formal hypothesis test- (127,128). ing and reporting of p-values, CIs for differences The main challenge in clinical trials focused on sub- between an active treatment and placebo and between jects who have migraine with aura is diagnostic accur- two active treatments (123) are strongly recommended acy. The current ICHD classification (10) recognizes the to inform readers more fully of the meaning of the main type, migraine with typical aura (group 1.2.1), as results of the trial (124,125). A statement that two well as variants for typical aura followed by migraine drugs are equally effective without giving CIs is headache, typical aura followed by non-migraine head- unacceptable. Time to event (pain-free) analyses (126) ache, and aura not followed by headache. Since most or time to meaningful relief analyses can be performed acute treatment trials are carried out in mixed popula- using Kaplan-Meier survival curves or Cox propor- tions – subjects who have migraine with aura, subjects tional hazard regression methods to compare the who have migraine without aura, and subjects who have onset of action of two active treatments. Trials that attacks of both migraine types – investigators cannot collect data from multiple attacks within a subject or determine whether both types of attacks occurring in collect data at multiple time points may need to use a the same subject have similar or different responses to repeated measures or generalized estimating equations treatment unless each attack is separately classified as approach. migraine with aura or migraine without aura. The statistical analysis plan needs to specify hand- Therefore, a detailed recording of each aura symptom ling of missing data, with proper justification behind and the total duration of the aura is mandatory, and the choice of approach(es) for imputation. these should be based on uniform requirements (129). Investigators should refer to the guidelines of the To improve accuracy and ensure that response to agency or agencies funding the trial for information migraine-associated aura is being evaluated, diagnostic on how to handle missing data. and treatment diaries capable of recording specific aura Trials collecting intra-individual data at multiple symptoms and duration of aura should be used (130). time points may benefit from using a slope analysis, With these specialized instruments, an observation of which does not require imputation for missing data. blurred vision or visual snow (131), which might be With this method, slope for each subject can be esti- mistaken for aura with a standard diary, would not be mated using data collected over time by fitting a regres- enough to classify an attack as migraine with aura (132). sion line. The slope estimates then become the outcome Note that in trials designed to assess treatment of the of interest and allow the use of available data without aura phase, detailed instruction about the proper use of the need for any imputation, provided that at least one diaries is mandatory. post-baseline data point is available; they can be sum- Additional challenges hindering clinical trials for the marized as mean (standard deviation), and 95% CIs acute treatment of aura include the low incidence and Diener et al. 701 relatively short duration of aura, together with the high By this definition, individuals with headaches predom- inter-individual variability of aura characteristics inantly occurring at night or on waking in the morning, (133,134). The adoption of alternative trial designs as well as those who experience more than one head- may help to overcome these challenges and the conse- ache type and who are not able to differentiate migraine quent lack of specific treatments for migraine-asso- from other headaches, should be excluded from early ciated aura. As a first step, the trial protocol should intervention trials. clearly state if the objective is to abort or reduce the The specifics of an early intervention design depend length of the aura or to reduce or eliminate the head- on the purpose of the trial. If its objective is to show that ache, as these are distinct outcomes that most likely a drug is more effective than placebo when treating early have different neurobiologies. It should also specify in the mild phase (138), then a traditional parallel-group that participants have a history of at least one aura comparison or crossover design can be used (refer to or attack of migraine with aura per month. In trials Section 1.2.3 for more information about design where the expected effect of treatment is to prevent types). However, if its objective is to show that early the headache phase, the primary efficacy endpoint treatment (when pain is mild) is more effective than should be the number of headaches following the late treatment (when pain is moderate/severe), the the- aura, with pain freedom after 2 hours a secondary effi- oretically ideal design would be a multiple crossover trial cacy measure. When the focus is on headache preven- in which the same subject treats four attacks (early inter- tion in migraine with aura, a feasible compromise can vention with placebo, early intervention with active, late be aura followed by headache in at least 80% of the intervention with placebo, and late intervention with attacks. In trials where aura is the event of interest, active) in randomized order. Because a trial using this the primary efficacy measure should be the duration design would be complex, an acceptable option would be of the aura. a design used by Goadsby et al. (43), in which subjects in four parallel arms (early intervention with placebo, early intervention with active, late intervention with placebo, 2.2. Early intervention and late intervention with active) treat a single attack. To facilitate migraine diagnosis and assess whether Another suitable alternative would utilize a two-arm acute treatment will be effective when headache inten- parallel design, with treatment arms allocated to early sity is moderate or severe, subjects in clinical trials are intervention and late intervention, and subjects treating often required to wait until headache pain is of at least two attacks (one with placebo and one with active) in a moderate intensity before they treat an attack (45). This randomized order. is not how migraine attacks are treated in clinical prac- tice, where early intervention may be the most effective 2.2.2. Endpoints. The primary efficacy endpoint in early acute treatment strategy. With many oral triptans, for intervention trials should be pain-free at 2 hours after example, early intervention has been shown to lead to a treatment. However, as the aim of early intervention higher percentage of pain-free responses at 2 hours trials is also to evaluate efficacy on pain progression, after treatment than traditional administration (i.e. sustained pain-free to 24 or 48 hours (refer to when headache intensity is moderate or severe) (135): Section 1.3.4.2) should be used as a co-primary end- 57% versus 43% for zolmitriptan 2.5 mg (136), 68% point. The number of protocol violators (subjects versus 47% for eletriptan (137), 53% versus 38% for assigned to treat mild headache who treat moderate- almotriptan 12.5 mg (43), 58% versus 32% for suma- severe and vice versa) in early intervention trials can triptan 100 mg (138,139), and 66% versus 44% for riza- be substantial (43). As protocol violators, these subjects triptan 10 mg (140,141)). Early treatment while pain is can be excluded from the ITT analysis, but there is a mild has been associated with higher pain free rates for risk that analysis of the smaller sample will not be suf- non-triptan acute treatments as well. ficiently powered to detect treatment effects. An accept- able alternative is to reassign these subjects to their 2.2.1. Design. Early intervention trials were once char- actual treatment groups, as long as the re-allocation is acterized by wide variations in methodology and design done before the blind is broken. and important differences in the definition of an early intervention. As the time of treatment (how soon after onset treatment is taken) and headache intensity (treat- 2.3. Menstrual migraine ment is taken when pain is mild) are not necessarily In menstruating females, the peak incidence of migraine interchangeable (142), early intervention should be occurs in the interval beginning 2 days before and defined as the administration of treatment when pain extending through the first few days of menstruation intensity is mild and within 1 hour of headache onset. (143). The Appendix of ICHD-3 provides criteria for 702 Cephalalgia 39(6) pure menstrual migraine and menstrually-related speciality clinics and primary care facilities should be con- migraine. For both disorders, attacks occur on days sidered for enrolment in clinical trials, as long as they 2 to þ 3 of menstruation in at least two out of three meet eligibility criteria. Recruitment for phase II clinical menstrual cycles (6). For pure menstrual migraine, trials may be more readily conducted in speciality clinics attacks occur at no other time of the month, while in (where appropriate safety resources exist), whereas trials menstrually-related migraine attacks may occur at investigating generic or OTC drugs should try to recruit other times (6). Pure menstrual migraine is less subjects from pharmacies and primary care facilities, as common than menstrually-related migraine; in one well as via newspaper advertisements. The inclusion of study, only 7% of females had pure menstrual migraine people who habitually participate in migraine clinical while 34.5% had menstrually-related migraine (144). trials is discouraged. It is also recommended that investi- Migraine attacks occurring in association with men- gators establish a database of the number of migraine struation are generally noted to be severe, of long dur- trials of any kind in which a particular subject has parti- ation, and associated with higher relapse rates cipated in the 2 years preceding a clinical trial. Subject (145,146). Acute treatment trials might therefore inves- participation in earlier trials should be recorded and pre- tigate the efficacy of a new therapy by comparing its sented in the publication. Recruitment efforts and strate- rate of relapse with those of standard treatments in gies should also be disclosed in the publication. subjects with menstrually-related migraine, pure men- strual migraine, or both conditions. If the effect of an acute treatment on pure menstrual migraine is to be 2.6. Publication investigated, accurate diagnosis is essential; it is recom- Publication of trial results is necessary and should include mended that subjects record migraine attacks and men- all primary and secondary efficacy endpoints and all strual periods prospectively in a headache dairy for two safety data, whether positive or negative. Before any to three cycles before entering the trial and that inves- trial-related activities are initiated, a Steering tigators apply the strict definition provided above to Committee (refer to Section 2.9 for details) should distinguish them from subjects with menstrually-related agree on timelines for publication and, if possible, include migraine. Three months of prospective diary informa- them in the protocol; a Publication Committee may also tion may be needed to be certain of the diagnosis (147). be formed. At the initiation of the trial or at the end of If the aim is to assess the effect of a treatment on men- recruitment, a design paper with baseline data may be strually-related migraine attacks, it is recommended published. Authorship of trial-related publications (but not mandatory) that randomized subjects report should be based on the criteria of the International menstruation in the headache diary, treating at least Committee of Medical Journal Editors (148). one menstrually-related attack with the test treatment. In either population, subjects need careful instruction on allowable limits for the temporal relationship 2.7. Conflicts of interest between the migraine attack and the first day of men- To maintain the credibility of a trial, authors must struation. The primary efficacy measure should be the declare their conflicts of interest. A conflict of interest percentage of subjects who achieve freedom from pain exists whenever professional judgment concerning a pri- at 2 hours after treatment (refer to Section 1.3.2), but in mary interest (e.g. subject wellbeing or the validity of subjects experiencing these often long-lasting attacks research) may be influenced by a secondary interest with a high risk of recurrence, sustained pain-free (e.g. financial relationship to a trial sponsor). Financial (refer to Section 1.3.4.2.) is also an important measure. relationships that represent potential conflicts of interest include employment, consultancies, research grants, fees and honoraria, patents, royalties, stock or share owner- 2.4. Children and adolescents ship, and paid expert testimony. Investigators should Migraine attacks are usually short-lasting in children avoid agreements with sponsors, both for-profit and and adolescents, and the placebo response tends to be non-profit, that restrict access to trial data, limit its ana- high. The IHS is developing a separate set of recom- lysis and interpretation, or interfere with the independ- mendations for clinical trials of acute treatment of ent preparation and publication of manuscripts. Note migraine attacks in children and adolescents. that conflicts of interest extend to an investigator’s immediate family (partner and children). 2.5. Recruitment 2.8. Independent data safety monitoring board Investigators should recruit widely from the population expected to use the acute treatment being evaluated. For An independent data safety monitoring board and prede- example, all individuals being treated for migraine at fined stopping rules for futility or safety are recommended Diener et al. 703 for phase III trials. Independent interim analysis by the 2.10 Trial registration data safety monitoring board should be considered for Prior to the initiation, any trial should be pre-registered assessment of the pre-defined stopping rules. in a register acknowledged by regulatory authorities, such as clinicaltrials.gov, clinicaltrialsregister.eu, or a similar regional or national official database. 2.9. Steering committee For phase III trials sponsored by industry, the formation of a Steering Committee comprised of academics, statis- 2.10. Post-approval registries ticians, and (if appropriate) company representatives is The IHS recommends post-approval product registries recommended. For investigator-initiated trials (i.e. (i.e. prospective open-label observational studies) to developed and sponsored by independent investigators evaluate the use of newly approved acute treatments or academia), a Steering Committee is not necessary. in clinical practice. Registries generate real-world data Whether or not a committee is formed, investigators on long-term efficacy, tolerability, and safety. They also and sponsors are responsible for all aspects of a clinical measure compliance and adherence. Registries for trial, including conception; design; operational execu- acute migraine treatments may also include individuals tion; data handling; data analysis and interpretation; with relevant coexistent and comorbid diseases (e.g. subsequent reporting and publication; and compliance chronic pain syndromes, cardiovascular disease) who with all local laws and regulations. were excluded from clinical trials for acute migraine. 3. Toolbox Section number Summary guidance 1.1 Subject selection 1.1.1 Migraine definition Use ICHD diagnostic criteria 1.1.2 Other primary headaches Permitted if infrequent and clearly recognized by the patient 1.1.3 Secondary headaches Not permitted 1.1.4 Frequency of attacks 2–8 migraine attacks;  1 per month for other headache types (including non- target) 1.1.5 Duration of migraine  1 year 1.1.6 Age at onset < 50 years 1.1.7 Age at entry 18–65 years 1.1.8 Sex Females and males 1.1.9 Concomitant drug use See text 1.2 Trial design 1.2.1 Blinding Use double-blind 1.2.2 Placebo control Recommended 1.2.3 Design types Parallel-group and crossover 1.2.4 Randomization Recommended 1.2.5 Stratification Generally not necessary 1.2.6 Intention to treat Should be defined, see text 1.2.8 Route of administration Oral route is preferable if appropriate for the PK profile 1.2.9 Timing of administration Should be prospectively defined in the protocol 1.2.10 Number of attacks treated One, generally the first, see text 1.2.11 Rescue medication Allowed any time after the first primary efficacy time point 1.2.12 Consistency of response Evaluate  4 attacks, with  1 treated with placebo 1.3 Evaluation of results 1.3.1 Attack report form (diary) An easy-to-use electronic diary that captures predefined endpoints 1.3.2 Primary endpoint Pain freedom at 2 hours (continued) 704 Cephalalgia 39(6) Continued. Section number Summary guidance 1.3.3 Co-primary endpoint Absence of the most bothersome associated symptom at 2 hours 1.3.4 Secondary endpoints 1.3.4.1 Relapse Secondary endpoint, see text 1.3.4.2 Sustained pain-free Secondary endpoint, see text 1.3.4.3 Total freedom from migraine Secondary endpoint, see text 1.3.4.4 Headache intensity Secondary endpoint, on a 4-point verbal rating scale 1.3.4.5 Headache relief Secondary endpoint, see text 1.3.4.6 Time to meaningful relief Secondary endpoint, see text 1.3.4.7 Time to pain freedom Secondary endpoint, measured with a survival analysis of pain freedom at time points before 2 hours 1.3.4.8 Duration of attacks Not recommended 1.3.4.9 Rescue medication Secondary endpoint, see text 1.3.4.10 Global evaluation Secondary endpoint, see text 1.3.4.11 Global impact (functional dis- Secondary endpoint, on a 4-point verbal rating scale ability and quality of life) 1.3.4.12 Associated symptoms — Secondary endpoint, recorded at the time treatment is administered and at the nausea and vomiting time of assessment of the primary endpoint 1.3.4.13 Associated symptoms — Secondary endpoint, recorded at the time treatment is administered and at the photophobia time of assessment of the primary endpoint 1.3.4.14 Associated symptoms — Secondary endpoint, recorded at the time treatment is administered and at the phonophobia time of assessment of the primary endpoint 1.3.4.15 Time between headache onset Secondary outcome measure and treatment intake 1.3.4.16 Treatment preference Exploratory and hypothesis-generating global assessment method for crossover trials 1.3.4.17 Blinding assessment Secondary outcome measure 1.3.4.18 Treatment of relapse Secondary outcome measure, see text 1.3.4.19 Adverse events Record and report all events, see text 1.4 Statistics 1.4.1 Hierarchy of endpoints Recommended for use in trial design, conduct, and reporting ICHD, International Classification of Headache Disorders Clinical implications . The Guidelines of the International Headache Society for controlled trials of acute treatment of migraine attacks in adults: Fourth edition provides new information that will affect the design, conduct, and reporting of clinical trials in migraine. . The current edition supersedes the existing Guidelines and should be put to immediate use. Declaration of conflicting interests Weber. Financial support for research projects was provided The authors declared the following potential conflicts of inter- by Allergan, Electrocore, MSD and Pfizer. Headache research est with respect to the research, authorship, and/or publica- at the Department of Neurology in Essen is supported by the tion of this article: Hans-Christoph Diener has received German Research Council (DFG), the German Ministry of honoraria for participation in clinical trials, contribution to Education and Research (BMBF) and the European Union. advisory boards or oral presentations from: Alder, Allergan, H.C. Diener has no ownership interest and does not own Amgen, Autonomic Technology, Bristol-Myers Squibb, stocks of any pharmaceutical company. HCD serves on the CoLucid, Electrocore, Ipsen, Lilly, Medtronic, MSD, editorial boards of Cephalalgia and Lancet Neurology. HCD Novartis, Pfizer, Schaper and Brümmer, Teva and Weber & chairs the Clinical Guidelines Committee of the German Diener et al. 705 Society of Neurology and is member of the Clinical Trials Richard B Lipton is the Edwin S. Lowe Professor of Committee of the IHS. Neurology at the Albert Einstein College of Medicine in New Cristina Tassorelli received honoraria for participation in York. He receives research support from the NIH: 2PO1 clinical trials, contribution to advisory boards or scientific AG003949 (Program Director), 5U10 NS077308 (PI), 1RO1 presentations from: Allergan, Electrocore, Eli-Lilly, AG042595 (Investigator), RO1 NS082432 (Investigator), K23 Novartis, Teva and Medscape, LLC. CT has received inde- NS09610 (Mentor), K23AG049466 (Mentor). He also receives pendent support from the Italian Ministry of Health, Italian support from the Migraine Research Foundation and the Ministry of Research and European Community. CT has no National Headache Foundation. He serves on the editorial ownership interest and does not own stocks of any pharma- board of Neurology, senior advisor to Headache, and associate ceutical company. CT serves as Chief Section Editor of editor to Cephalalgia. He has reviewed for the NIA and Frontiers in Neurology – Section Headache Medicine and NINDS, holds stock options in eNeura Therapeutics and Facial Pain and on the editorial board of Journal of Biohaven Holdings; serves as consultant, advisory board Headache and Pain. CT is the chairman of the Clinical member, or has received honoraria from: American Academy Trials Committee of the IHS. of Neurology, Alder, Allergan, American Headache Society, David W Dodick has received compensation from serving Amgen, Autonomic Technologies, Avanir, Biohaven, on advisory boards and/or consulting within the past 5 years Biovision, Boston Scientific, Dr. Reddy’s, Electrocore, Eli for: Allergan, Amgen, Novartis, Alder, Arteaus, Pfizer, Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Pernix, Colucid, Merck, NuPathe, Eli Lilly and Company, Pfizer, Supernus, Teva, Trigemina, Vector, Vedanta. He receives Autonomic Technologies, Ethicon J&J, Zogenix, Supernus, royalties from Wolff’s Headache 7th and 8th Edition, Oxford Labrys, Boston Scientific, Medtronic, St Jude, Bristol-Myers Press University, 2009, Wiley and Informa. Squibb, Lundbeck, Impax, MAP, Electrocore, Tonix, Messoud Ashina received personal fees from Alder Novartis, Teva, Alcobra, Zosano, Insys, Ipsen, GBS/ Nocira, BioPharmaceuticals, Allergan, Amgen, Alder, Eli Lilly, Acorda, eNeura, Charleston Laboratories, Gore, Biohaven, Novartis and Teva. MA participated in clinical trials as the Bioventric, Magellan, Theranica, Xenon, Dr Reddy’s/ principal investigator for Alder ALD403-CLIN-011 (Phase Promius Pharma. Dr Dodick owns equity in Epien, GBS/ 3b), Amgen 20120178 (Phase 2), 20120295 (Phase 2), 20130255 Nocira, Second Opinion, Healint, and Theranica. Dr Dodick (OLE), 20120297 (Phase 3), GM-11 gammaCore-R trials, has received funding for travel, speaking, editorial activities, or Novartis CAMG334a2301 (Phase 3b), Amgen PAC1 royalty payments from IntraMed, SAGE Publishing, Sun 20150308 (Phase 2a), Teva TV48125-CNS30068 (Phase 3). Pharma, Allergan, Oxford University Press, American MA has no ownership interest and does not own stocks of any Academy of Neurology, American Headache Society, West pharmaceutical company. MA serves as associated editor of Virginia University Foundation, Canadian Headache Cephalalgia, co-editor of the Journal of Headache and Pain. Society, Healthlogix, Universal Meeting Management, MA is President-elect of the International Headache Society WebMD, UptoDate, Medscape, Oregon Health Science and General Secretary of the European Headache Federation. Center, Albert Einstein University, University of Toronto, Werner J Becker has received honoraria for service on med- Starr Clinical, Decision Resources, Synergy, MedNet LLC, ical advisory boards from Allergan, Amgen, and Novartis. He Peer View Institute for Medical Education, Medicom, has received speaker’s honoraria from Allergan and Amgen, and Chameleon Communications, Academy for Continued his university has received funding for clinical trials from Healthcare Learning, Haymarket Medical Education, Global Allergan and Amgen. He is on the board of the Canadian Scientific Communications, HealthLogix, Miller Medical, Headache Society, and an associate editor for Headache MeetingLogiX, Wiley Blackwell. Dr Dodick, through his Currents. employer, has consulting use agreements with Michel D Ferrari reports grants and consultancy or industry NeuroAssessment Systems and Myndshft. He holds board of support from Medtronic, Novartis, Lilly, TEVA, Amgen and director positions with KingDevick Technologies, and Epien Electrocore, and independent support from the European Inc. He holds the following Patent 17189376.1-1466:vTitle: Community, NWO, NIH and the Dutch Heart & Brain Botulinum Toxin Dosage Regimen for Chronic Migraine Foundations. Prophylaxis (no compensation). Peter J Goadsby reports grants and personal fees from Stephen Silberstein is the Director of the Jefferson Allergan, Amgen, and Eli-Lilly and Company; and personal Headache Center in Philadelphia, PA. As a consultant and/ fees from Akita Biomedical, Alder Biopharmaceuticals, Cipla or advisory panel member, he receives, or has received, honor- Ltd, Dr Reddy’s Laboratories, eNeura, Electrocore LLC, aria from Abide Therapeutics; Alder Biopharmaceuticals; Novartis, Pfizer Inc, Quest Diagnostics, Scion, Teva Allergan, Inc.; Amgen; Avanir Pharmaceuticals, Inc.; Pharmaceuticals, Trigemina Inc., Scion; and personal fees Biohaven Pharmaceuticals; Cefaly; Curelator, Inc.; Dr. from MedicoLegal work, Journal Watch, Up-to-Date, Reddy’s Laboratories; Egalet Corporation; GlaxoSmithKline Massachusetts Medical Society, Oxford University Press; and Consumer Health Holdings, LLC.; eNeura Inc.; electroCore in addition, PJG has a patent Magnetic stimulation for head- Medical, LLC; Impel NeuroPharma, Inc.; Lilly USA, LLC; ache assigned to eNeura without fee. Medscape, LLC; Novartis, Inc.; Satsuma Pharmaceuticals; Patricia Pozo-Rosich has received honoraria as a consultant Supernus Pharmaceuticals, Inc.; Teva Pharmaceuticals; and speaker for: Allergan, Almirall, Chiesi, Eli Lilly, Janssen Theranica; and Trigemina, Inc. Cilag, MSD, Novartis and Teva. Her research group has 706 Cephalalgia 39(6) received research grants from Allergan and has received funding of preventive treatment of chronic migraine in adults. for clinical trials from Alder, Boeringher Ingelheim, MSD, Cephalalgia 2018; 38: 815–832. Electrocore, Eli Lilly, Janssen Cilag, Novartis. She is a trustee 9. Rasmussen BK, Jensen R, Schroll M, et al. Epidemiology member of the board of the International Headache Society, she of headache in a general population – a prevalence study. is the Coordinator of the Spanish Headache Study Group of the J Clin Epidemiol 1991; 44: 1147–1157. Spanish Neurological Society. She is in the editorial board of 10. 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