A First Step in Standardizing Endpoints and Outcomes in Acute Migraine Trials

Outcomes and endpoints used in acute migraine clinical trials vary significantly, but developing a core set of patient-centered outcomes and endpoints may improve individual trials and facilitate informed treatment decisions. This is according to research published in Headache.

To provide an overview of the current acute migraine clinical trial literature, with the goal of aiding future endpoint selection and outcome assessments and facilitating the development of new treatments, researchers conducted a systematic literature review focused on the range and frequency of specific concepts, endpoints, and outcomes.

Acute migraine clinical trial outcomes were grouped into 1 of 4 broad categories: pain-related outcomes (including pain relief and freedom, general pain, headache recurrence, use of medication, and meaningful relief); nonpain-associated symptoms (including most bothersome symptom, nausea, vomiting, photophobia, phonophobia, and aura); disability and/or impairment; and patient-reported outcome measures (PROMs, including headache-and nonheadache-specific PROMs).

In total, 1567 publications were identified; 705 were included for the final analysis. Article publication dates ranged from 1972 to 2019, and the average inter-rater agreement for descriptive variables — age, sex, migraine characteristics, and trial design, among others — had a kappa estimate of 0.86.

To focus on more recent pharmacologic and device-related acute migraine literature, the researchers identified a subset of studies (n=451) for evaluation.

Within this subset, the median total sample size was 243 participants per study. The average age was 39.1 (±3.9) years, 82.9% of participants were women, and 85.1% were White. Most of these publications (90.1%) evaluated a general migraine population rather than a specific subgroup, such as those having menstrual, episodic, or chronic migraines.

Investigators found that 95.3% of publications evaluated 1 or more pain-related outcomes, while 67.2% evaluated 1 or more associated symptoms or most bothersome symptom. Just over 41% of studies evaluated disability and impairment outcomes, and 35.3% examined 1 or more PROMs.

The most commonly seen pain-related outcomes included pain relief, pain freedom, general pain, headache recurrence, and rescue medication use (72.1%, 64.9%, 34%, 44.8%, and 61.6%, respectively). A majority of publications examining pain relief used an ordinal response scale (94.2%), while others used a continuous response scale such as the visual analog scale (VAS) or numerical rating scale (NRS; 4.5% total; 71.4% VAS). Endpoints varied widely and ranged from 10 minutes to 24 hours post-treatment, with 2 hours being the most commonly used time point.

The majority of studies focusing on pain freedom used an ordinal scale, while the majority of studies reporting on general pain used a 4-category response scale. Studies evaluating headache recurrence used a 24-hour cutoff and the presence of at least 1 pain-related outcome, and rescue medication studies used at least 1 pain-related outcome as the primary endpoint.

Disability and impairment studies primarily used an ordinal response scale with 4 response categories. The most common endpoint type was fixed time point analysis; 44.6% of publications examined change from baseline, 2.7% evaluated both fixed time points and change from baseline, and 1.1% evaluated other endpoints.

PROMs were combined across all studies, with 35.3% of publications evaluating 1 or more PROMs. Most of these studies (n=159) evaluated 1 or more nonmigraine or headache-specific patient-reported outcome.

Headache-related PROMs were used in acute migraine trials infrequently. Only 28 publications examined 1 or more migraine- or headache-related patient-reported outcomes; of these, over half (60.7%) used the 24-hour Migraine-Specific Quality of Life Questionnaire and 17.9% used the Patient Perception of Migraine Questionnaire-Revised. The most common nonheadache-specific PROMs were related to treatment satisfaction, efficacy, and preference, measured using 4- or 7-category ordinal scales, 4- or 5-category ordinal scales, and a binary scale or a 3-category ordinal scale, respectively.

Study limitations include the potential for publication bias and an inability to investigate several relevant methodological and clinical topics due to the scope of the project.

“Current trials of acute treatments for migraine exhibit a large amount of variability in outcomes and the ways in which outcomes are used to define endpoints,” the researchers concluded. “Standardization of the outcomes and endpoints…will facilitate cross-trial comparisons and facilitate communication with patients about the benefits of treatment alternatives.”

“Future work should rigorously evaluate existing PROMs against prespecified criteria, and to explore other criteria domains, such as physical and cognitive function,” they added. “Based on ongoing qualitative work and feedback from the [US Food and Drug Administration], the development of measures of cognitive function may also be informative.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Houts CR, McGinley JS, Nishida TK, et al. Systematic review of outcomes and endpoints in acute migraine clinical trials. Headache. 2021;61(2):263-275. doi:10.1111/head.14067