Patient-Identified Most Bothersome Chronic Migraine Symptom: Promising Clinical Research Endpoint

The investigators of PROMISE-2 chose to assess the patient-identified most bothersome chronic migraine symptom and reported on this novel methodology in the current study.

Eptinezumab therapy for chronic migraine is associated with more improvement in patient-identified most bothersome symptoms compared with placebo, demonstrating that patient-identified most bothersome symptom is a novel, promising outcome measure for migraine clinical research, according to findings published in Headache.

The US Food and Drug Administration (FDA) recommendations for acute migraine clinical trials suggest the use of the absence of the most bothersome symptom — including nausea, photophobia, and phonophobia — as a coprimary study endpoint in order to align study outcomes with “the symptom(s) of primary importance to patients.” However, clinical studies focused on migraine preventives do not typically assess the most bothersome symptom.

The investigators of PROMISE-2, a phase 3, randomized, double-blind, placebo-controlled, parallel-group clinical trial ( Identifier: NCT02974153) chose to use a “broader and more patient-centered approach” to most bothersome symptom assessment — called the patient-identified most bothersome symptom — and reported on this novel methodology in the current study.

PROMISE-2 included adults with a migraine diagnosis established by 50 years of age, a chronic migraine history for at least 12 months before screening, and a report of at least 15 but no more than 26 headache days, including 8 or more migraine days during the course of a 28-day screening period.

Patients were randomly assigned 1:1:1 to receive eptinezumab 100 mg, eptinezumab 300 mg, or placebo intravenously on day 0 and at week 12. Participants were then stratified based on the number of migraine days experienced during the screening period (≤17 or fewer or >17) as well as by the use or nonuse of preventive migraine medication in the 3 months before screening. Participants were also required to complete an electronic diary daily and attend on-site visits at several timepoints.

The primary efficacy outcome was the change from baseline in monthly migraine days during weeks 1 through 12. The key outcome in the current analysis was patient-identified most bothersome symptom (a secondary PROMISE-2 endpoint) captured at screening and then evaluated at baseline and every 4 weeks thereafter through week 32.

The cohort included 1072 patients who received treatment (eptinezumab 100 mg, n=356; eptinezumab 300 mg, n=350; and placebo n=366). Between-group demographics and clinical characteristics were generally balanced across treatment groups; the average patient age was 40.5 years and average time since chronic migraine diagnosis was 11.8 years. Most patients were women (88.2%) and most were White (91%).

The mean number of headache days during the screening period was 20.5, with a mean of 16.1 migraine days.

A total of 23 unique patient-identified most bothersome symptoms were identified. For 27 patients (2.5%), this included more than 1 symptom type, while 0.7% of patients identified symptoms classified as “other.” The most common most bothersome symptoms were light sensitivity (18.7%), nausea and/or vomiting (15.1%), pain with activity (13.7%), pain (12.4%), headache (11.2%), sound sensitivity (7.3%), throbbing and/or pulsation (4.7%), cognitive disruption (4.1%), fatigue (2.4%), mood changes (1.5%), and sensitivity to smell (0.9%).

Nausea and/or vomiting, light sensitivity, and sound sensitivity are the 3 symptoms typically included in most bothersome symptom measurements; these symptoms were identified as the most bothersome symptom in 41.0% of patients. An expanded symptom list that included these 3 symptoms as well as aura and the other typical migraine pain features accounted for 83.7% of patient-identified most bothersome symptoms, with 16.3% of patients identifying symptoms beyond this list.

Those symptoms were inclusive of prespecified symptoms such as mental cloudiness, fatigue, and mood change (11.2%) and symptoms that were not prespecified such as sensitivity to smell, visual impact, pressure and/or tightness, anatomical pain, eye pain, neck pain, dizziness, allodynia, inactivity, sensory and/or sleep disturbance, speech difficulty, and multiple and/or other symptoms (5.1%).

More than 90% of patients reported no change in severity level of their most bothersome symptom at the end of the 28-day screening period (91.3%, 93.7%, and 92% in the eptinezumab 100- and 300-mg and placebo groups, respectively). This result indicated that the ranking of each patient-indicated most bothersome symptom was stable prior to treatment.

At 12 weeks, “much” or “very much” improvement in patient-indicated most bothersome symptom was reported by 53% of patients in the eptinezumab 100-mg group (a 19% difference from the placebo group) and by 61% of patients in the eptinezumab 300-mg group, a 27% difference from the placebo group, and by 34% of the placebo group. A higher percentage of those treated with eptinezumab reported either much or very much improvement in their most bothersome symptom as early as week 4 (45%, 47%, and 29% in the eptinezumab 100- and 300-mg groups and placebo group); rates increased for all treatment groups following the second dose.

Within 4 weeks of the second dose at week 16, much or very much improvement was noted by 58%, 65%, and 36% of patients in each group, respectively. By 20 weeks after the second dose — week 32 — the percentage of patients indicating improvement in their most bothersome symptom was similar to the rates observed at week 24.

Patient Global Impression of Change (PGIC) responses at the population level were similar to patient-identified most bothersome symptom at each timepoint. By week 12, 52% and 64% of patients in the eptinezumab 100-mg and 300-mg groups reported much or very much PGIC improvement — a 14% and 26% difference, respectively, from the placebo group.

By week 4, PGIC responses and patient-identified most bothersome symptom measures were “exactly the same” for 75.1% of the study population; 95.9% of patients had responses that “differed by no more than 1 category.” Results remained similar at weeks 12 and 24 (75.5% and 78.8%, respectively), while 97.2% and 96.6% had responses that differed by no more than 1 rating category.

Severity scores correlated strongly at each timepoint, with higher correlation coefficients than for the relationship between changes in monthly migraine days and PGIC scores.

Study limitations include the small sample size for most symptom categories identified in PROMISE-2, making it “not feasible” to evaluate the impact of eptinezumab therapy on specific symptoms.

“Patients treated with eptinezumab reported greater improvement in the severity of their [patient-indicated most bothersome symptom] than did patients who received placebo,” the researchers concluded. “These findings underscore the importance of evaluating outcomes beyond headache duration and frequency in patients with [chronic migraine].”

Disclosure: This clinical trial was supported by Lundbeck Seattle BioPharmaceuticals, Inc. Please see the original reference for a full list of authors’ disclosures.


Lipton LB, Dodick DW, Ailani J, McGill L, HIrman J, Cady R. Patient-identified most bothersome symptom in preventive migraine treatment with eptinezumab: a novel patient-centered outcome. Headache. 2021;61(5):766-776. doi:10.1111/head.14120