Use of pain freedom and freedom from most bothersome symptom (MBS) as primary endpoints could reduce samples sizes required to achieve significance, compared with past trials using 4 primary endpoints, according to a review of acute treatment of migraine trial results with new FDA endpoints. Researchers analyzed phase 3 randomized, placebo-controlled, double-blind acute migraine treatment trials that use pain freedom and MBS freedom as primary of planned secondary endpoints. They conducted a review of observed placebo responses, drug effect sizes, and sample sizes to better inform the design of future trials. Among the findings:
- The mean placebo response rate for 2-hour pain freedom was 16.75% and treatment effect ranged from 5.0% to 27.2%.
- For 2-hour MBS freedom, the mean placebo response rate was 32.8% and the range of treatment effect was 8.9% to 25.4%.
- The use of these 2 endpoints may allow the enrollment of fewer trial participants than have been used in the past.
- However, these initial trials had enrollment of more patients than would have been minimally required.
Hindiyeh NA, Kellerman DJ, Schmidt PC. Review of acute treatment of migraine trial results with the new FDA endpoints: Design implications for future trends. [Published online ahead of print April 6, 2019]. Headache. doi:10.1111/head.13511.
Assessing efficacy for acute treatment of migraine has changed since the 1990’s triptan studies. Initially, the sole primary regulatory acute endpoint was “2-hour headache response”, also called headache relief or pain relief. This occurred when pain moved to zero or mild pain at 2-hours. The International Headache Society guidelines suggested that the primary endpoint for acute trials should be 2-hour pain freedom. The FDA countered with 4 co-primary 2-hour endpoints listed above. Hitting all 4 endpoints ended up requiring large studies and even then, some studies sometimes missed one of the co-primary endpoints. Accordingly, the FDA invented the new 2-hour MBS, allowing patients to choose what was most noxious to them besides pain, to be evaluated in addition to 2-hour pain freedom. Powering of studies using MBS is still being calculated, as MBS has a higher placebo response rate than 2-hour pain freedom. Interestingly, every study using the MBS endpoint has reported that photophobia is the most bother symptom. —Stewart J. Tepper, MD, FAHS, Professor of Neurology, Geisel School of Medicine at Dartmouth, Director, Dartmouth Headache Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH.