Abstract and Introduction
Objective: To assess the utility of the novel patient-identified (PI) most bothersome symptom (MBS) measure from PROMISE-2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine.
Background: Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI-MBS could improve clinical decision-making.
Methods: In PROMISE-2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses (n = 1072). PI-MBS was an exploratory outcome requiring each patient to self-report their MBS in response to an open-ended question. At baseline and week 12, patients rated overall improvement in PI-MBS. The relationships among PI-MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9–12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6-item Headache Impact Test total, EuroQol 5-dimensions 5-levels visual analog scale, and 36-item Short-Form Health Survey component scores were assessed.
Results: Treatment groups had similar baseline characteristics and reported a total of 23 unique PI-MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI-MBS at week 12 correlated with changes in MMDs (ρ = −0.49; p < 0.0001) and other patient-reported outcomes. Controlling for changes in MMDs, PI-MBS improvement predicted other patient-reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI-MBS were 0.31 (p < 0.0001 vs. placebo) and 0.54 (p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively.
Conclusions: Improvement in PI-MBS at week 12 was associated with improvement in other patient-reported outcome measures, and PI-MBS may be an important patient-centered measure of treatment benefits in patients with chronic migraine.
Migraine attacks are characterized by pain features (e.g., exacerbation of pain by activity), canonical associated symptoms (nausea, phonophobia, and photophobia), and other symptoms (e.g., cognitive disruption, fatigue, changes in mood, sensitivity to smell).[1–10] Given this vast array of symptoms, establishing priorities for assessing endpoints in clinical trials is essential. One approach was to designate the same set of symptoms as primary endpoints for everyone. This approach was used in acute treatment trials which required statistically significant separation on four co-primary endpoints: pain, photophobia, phonophobia and nausea. This approach was viewed as problematic for several reasons. First, not everyone has every symptom so statistical power for nausea, present in perhaps 60% of patients, is lower than the power for pain, present in 100% of patients. Second, requiring significant differences on four co-primaries is a high bar which increases the risk of failure due to chance alone. Third, this approach does not incorporate patient priorities regarding their symptoms. Regulator guidance was modified in 2018; the number of co-primary endpoints was reduced from four to two. Pain was retained but the associated symptoms were replaced with freedom from the patient-designated most bothersome symptom (MBS), selected from among nausea, photophobia, and phonophobia.[12–14] Allowing the patient to select their MBS from a circumscribed list has some advantages: It reduces the number of statistical comparisons required if pain, nausea, photophobia, and phonophobia were all co-primary endpoints in migraine trials, and it prioritizes the symptoms that generally are considered the most bothersome to the patient, providing a more patient-centered measure. However, this approach also has a major disadvantage: For some patients, their MBS is not nausea, photophobia, or phonophobia, and limiting the available choices renders the measure less patient-centered. An alternative approach to the limited MBS selection is an open-ended question to identify, without restriction, the migraine-related symptom each patient finds most bothersome, which was used in the PROMISE-2 study.[15,16] We refer to this measure as the patient-identified most bothersome symptom (PI-MBS).
In the PROMISE-2 migraine prevention study in chronic migraine (CM), patients described their PI-MBS at screening and were asked to rate overall improvement in the PI-MBS using a 7-point ordinal scale after treatment with eptinezumab or placebo. These exploratory analyses were designed to determine the potential research and clinical utility of the PI-MBS measure for future trials and clinical practice. It was hypothesized that PI-MBS would correlate with changes on other related patient-reported outcome measures (PROMs), add unique clinical information above and beyond change in monthly migraine days (MMDs), and be sensitive to differences across treatment groups.
Headache. 2022;62(6):690-699. © 2022 Blackwell Publishing