Inconsistencies in End Points, Study Design Identified in Migraine Treatment Trials

Author(s):

Investigators noted that empirical work is needed to determine if change from baseline, fixed time point assessments, and responder definitions, or other approaches optimize power and sensitivity to change.

Richard B. Lipton, MD

A systematic review of clinical trials that evaluated preventive migraine pharmacologic and device treatments revealed inconsistencies across study design, end point definitions, and how end points and outcomes were measured.

The study evaluated a subset of 268 publications that fulfilled the targeted criteria of being randomized, blinded, and focused on the aforementioned treatments. Despite showing some commonalities among outcomes and end points, there was no clear “standardized” set of end points and outcomes that emerged.

"The inconsistencies in end points and outcomes within this literature suggest that the development of a uniform set of outcomes and end points could improve the clinical meaningfulness of clinical trial results, facilitate cross-trial comparisons and better inform patient care,” the study authors concluded.

Study author Richard Lipton, MD, director, Montefiore Headache Center, and colleagues found that 68.7% (184 of 268) of the publications examined 1 or more migraine-specific outcome, 39.6% (106 of 268) examined 1 or more headache-specific outcome, and 50.7% (136 of 268) examined 1 or more acute/rescue medication use outcome.

Furthermore, the results also showed that 40.3% (108 of 268) of the publications examined 1 or more headache-related patient-reported outcome measure (PROM) whereas 22.0% (59 of 268) examined 1 or more non-headache specific PROM.

Predetermined terms were searched in PubMed on October 28, 2019, with each literature undergoing a pre-specified protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). In addition to the classification of outcomes into 5 broad categories, end points were classified as either change from baseline, fixed timepoint, and responder definitions (≥50% reduction, ≥75% reduction, 100% reduction, other definitions).

When classifying these end points, Lipton et al noted, “empirical work is required to determine if these approaches or other approaches optimize power and sensitivity to change. Novel approaches could include analysis of trajectories of change, time to event analysis, or regression adjustment for baseline differences.”

There were various combinations of outcomes used across publications, none more common than using an only migraine-focused outcome strategy (47 of 268; 17.5%). Migraine-focused outcomes paired with 1 or more acute/rescue medication use outcome was the next most common strategy, representing 14.9% of publications (40 of 268).

Of the 184 publications evaluating 1 or more migraine-focused outcomes, 69.0% (127 of 184) examined migraine attacks, 51.1% (94 of 184) evaluated migraine days, and 48.4% (89 of 184) evaluated migraine pain.

With respect to timing of end points, the majority of the publications (160 of 184; 87%) evaluated change from baseline and a somewhat limited number of publications (55 of 184; 29.9%) examined between-group differences within a pre-specified, fixed time interval.

Among the 106 publications that utilized 1 or more headache-focused outcome, 74.5% (79 of 106) examined headache days, 28.3% (30 of 106) examined headache attacks, and 38.7% (41 of 106) evaluated headache pain. Almost 90% of the 106 publications examined change from baseline in 1 or more headache-focused outcomes (93 of 106; 87.7%) while 28.3% (30 of 106) examined group differences at fixed times.

As for the 108 publications that used headache-related PROMs, the Migraine Disability Assessment Test (MIDAS; 53 of 108; 49.1%), Migraine-specific Quality of Life (MSQ; 34 of 108; 31.5%), and the 6-item Headache Impact Test short form (HIT-6) were the most frequently encountered measures used as outcomes. Notably, few publications examined headache-related PROMs in conjunction with 1 or more responder definitions (13 of 108; 12%).

"Taken together, a standardization process that is designed to integrate the voices of patients with rigorous methodological techniques could improve evaluations of preventive migraine treatments, capture outcomes most meaningful to patients, facilitate cross-trial comparisons, and better inform clinical decision-making,” Lipton et al concluded.

REFERENCE

McGinley JS, Houts CR, Nishida TK, et al. Systematic review of outcomes and endpoints in preventive migraine clinical trials. Migraine. Published online February 18, 2021. doi: 10.1111/head.14069