Abstract
Objective
This post hoc subgroup analysis was conducted using pooled data from three US‐based clinical trials to compare efficacy and safety of rimegepant 75 mg versus placebo in acute migraine in adults who are Black or African American.
Background
Migraine, characterized by recurring moderate‐to‐severe unilateral head pain, affects approximately 13% of the population and in the United States affects Black or African American and White populations at similar rates. Despite this, there is stark underrepresentation of Black or African American patients in clinical trials. Rimegepant, an oral small molecule calcitonin gene‐related peptide receptor blocker or antagonist, is approved for acute migraine treatment in the United States; however, treatment has not previously been analyzed in Black or African American adults.
Methods
Using pooled data from three US‐based, double‐blind, randomized, placebo‐controlled, multicenter clinical trials (ClinicalTrials.gov, NCT03235479; NCT03237845; NCT03461757), efficacy analyses were conducted on a modified intent‐to‐treat population including all participants who received study medication, had a migraine attack of moderate or severe pain intensity at the time of dosing, and provided ≥1 efficacy datapoint after receiving study treatment. Trials were conducted July 2017 to January 2018 (NCT03235479, NCT03237845) or February 2018 to October 2018 (NCT03461757). The coprimary efficacy endpoints of each trial were freedom from pain (score 0 = none on a 4‐point pain scale) and freedom from most bothersome symptom (MBS) at 2 h post dose. Safety was assessed through reported on‐treatment adverse events, defined as events occurring on or after treatment was received. Analyses were performed in the Black or African American population, in the White population, and in the overall pooled study population (including Black or African American, White, Asian, American Indian or Alaskan Native, Native Hawaiian or other Pacific Islander, and multiple races).
Results
Overall, 3551 treated participants were in the pooled population; 696 (19.6%) were Black or African American; 2700 (76.0%) were White. In the Black or African American population, rimegepant showed improvements versus placebo in the two coprimary endpoints. For pain freedom 2 h post dose, the stratified risk was 24.4% (88/359) for rimegepant and 18.2% (59/323) for placebo in Black or African American participants; risk difference was 6.2% (95% confidence interval [CI]: 0.1, 12.3; p = 0.047). For MBS freedom 2 h post dose, the stratified risk was 43.1% (155/359) for rimegepant and 35.5% (115/323) for placebo in Black or African American participants; risk difference was 7.6% (95% CI: 0.3, 14.9; p = 0.041). The risk difference was similar in White participants: 7.9% (95% CI: 5.2, 10.6; p < 0.001) for pain freedom 2 h post dose and 9.9% (95% CI: 6.5, 13.4; p < 0.001) for MBS freedom 2 h post dose. Adverse event rates among Black or African American participants treated with rimegepant were 10.7% (39/365) and 7.9% (26/331) in participants receiving placebo.
Conclusion
This pooled analysis showed rimegepant 75 mg was effective and well tolerated for migraine treatment in Black or African American adult participants.
Keywords: African American, calcitonin gene‐related peptide, clinical trials, migraine, rimegepant, treatment
Plain Language Summary
Migraine affects Black or African American people at a similar rate as White people; however, medical studies for migraine therapies often do not include many Black or African American people. We conducted this analysis using data from three separate studies of the drug rimegepant (a drug approved for treating acute migraine) to see how safe and effective it is for Black or African American people. This analysis shows that rimegepant is better than placebo (a tablet that contains no drug) in improving migraine pain and other related symptoms in Black or African American people with migraine.
Abbreviations
- AE
adverse event
- BMI
body mass index
- CGRP
calcitonin gene‐related peptide
- CI
confidence interval
- MBS
most bothersome symptom
- SD
standard deviation
INTRODUCTION
In the United States, prevalence estimates for severe headaches or migraine are similar among Black or African American (14.5%) and White (15.5%) populations. 1 There are, however, racial/ethnic discrepancies in migraine care. For example, Black or African American patients with headache are less likely to seek help from healthcare providers, less likely to have a specific diagnosis of migraine, and less likely to be prescribed migraine‐specific treatment compared with White patients. 1 , 2 Black or African American individuals are also persistently underrepresented in clinical trials of migraine, which often include patient populations that are predominantly White. 3 Underrepresentation of Black or African American patients in clinical trials of migraine is concerning because racial‐/ethnic‐based differences in the efficacy and/or safety of medications have been observed across a range of other therapeutic areas such as the cardiovascular system. 4 , 5 , 6 , 7
The pathophysiology of migraine is not fully understood; however, research has identified a crucial role for calcitonin gene‐related peptide (CGRP), which impacts the trigeminal nerve complex. 8 As a result, treatments for migraine aiming to either block CGRP directly, or at its receptor, have been developed. 9 Rimegepant is an oral small molecule CGRP receptor blocker or antagonist that has been approved by the US Food and Drug Administration for the acute treatment of migraine (with or without aura) as well as the preventive treatment of episodic migraine in adults. The efficacy and safety of rimegepant for the acute treatment of migraine was established in three pivotal phase 3 clinical trials. 10 , 11 However, the treatment effects of rimegepant have not been previously evaluated in a population comprised exclusively of Black or African American adults. The objective of this post hoc subgroup analysis, therefore, was to compare the efficacy and safety of rimegepant (75 mg) with placebo for the acute treatment of migraine in adults who are Black or African American.
METHODS
Data sources
Data were pooled from three US‐based, double‐blind, randomized, placebo‐controlled, multicenter, phase 3 pivotal trials of rimegepant for the acute treatment of migraine (ClinicalTrials.gov, NCT03235479; NCT03237845; NCT03461757; full study details have been published previously). 10 , 11 The duration of each trial was approximately 11 weeks, including a screening period of 3 to 28 days, an acute treatment phase of up to 45 days in which to treat one attack, and an end‐of‐treatment visit. The trials were conducted in July 2017 to January 2018 (NCT03235479, NCT03237845) or February 2018 to October 2018 (NCT03461757). Because all trials included in this study were conducted in the United States, each racial group reflects a US‐based population.
Ethics
Each trial was conducted in accordance with the principles of the Guidelines for Good Clinical Practice, the Declaration of Helsinki, and all applicable local regulations. Study protocols were approved by independent ethics committees and/or institutional review boards at each study center. Before any study‐related procedures were undertaken, participants in all three trials provided written informed consent to participate.
Participants
Key inclusion criteria in each trial included age ≥18 years; a ≥1‐year history of headache consistent with a diagnosis of migraine (with or without aura) according to the International Classification of Headache Disorders, 3rd edition; 2 to 8 attacks of moderate or severe pain intensity per month; migraine attacks that last an average of 4 to 72 h if untreated; and <15 headache days per month during the 3 months before screening. Participants were excluded if they had any medical condition that might interfere with study assessments of efficacy and safety or expose them to undue risk of adverse events (AEs). Participants with a history of migraine with brainstem aura or hemiplegic migraine were excluded. Participants with contraindications to triptans were eligible if they met all other entry criteria. Participants on preventive migraine medication were permitted to remain on preventive therapy provided dosing was stable for ≥3 months prior to screening. Further details on inclusion/exclusion criteria can be found in the primary publications and at ClinicalTrials.gov.
Study treatment
Participants were randomized, in a double‐blind manner, via an Interactive Web Response System (Synteract [Carlsbad, CA, USA] for NCT03235479 and NCT03237845, and Almac [Sounderton, PA, USA] for NCT03461757), in a 1:1 ratio to either rimegepant 75 mg or matching placebo treatment. Randomization in each study was stratified by use of prophylactic migraine medication (yes/no) but not by racialized groups. Participants were provided a single, oral dose of study medication (rimegepant 75 mg or matching placebo) to treat a single migraine attack of moderate or severe pain intensity sometime in the following 45 days. Participants who had not experienced a migraine attack of moderate or severe pain intensity within 45 days of randomization returned unused study medication to the study center.
Assessments
Participants were instructed to treat a migraine attack with pain of moderate or severe intensity immediately after answering electronic diary (eDiary) questions about their current pain level and other migraine symptoms. Participants were asked to rate their current pain level (from 0 = none to 3 = severe) and identify their other most bothersome symptom (MBS) from among phonophobia, photophobia, or nausea and rate their level of functional disability (from 0 = normal to 3 = requires bed rest). Participants completed the eDiary for up to 48 h after taking study medication to rate pain intensity; the presence or absence of migraine‐associated symptoms; and functional disability at 15, 30, 45, 60, and 90 min and at 2, 3, 4, 6, 8, 24, and 48 h after dosing. Data on “race” classification were collected using the minimum categories for federal statistics and administrative reporting employed by the US Census, which include American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, and White.
Endpoints
The coprimary efficacy endpoints of each trial were freedom from pain (score of 0 = none on pain scale) and freedom from the MBS (symptom was absent) at 2 h post dose. Secondary efficacy endpoints in each study included pain relief (score of 0 = none or 1 = mild on the pain scale) at 2 h post dose, normal function (score of 0 = normal on the functional disability scale) at 2 h post dose, sustained pain relief from 2 to 24 h and from 2 to 48 h post dose, sustained pain freedom from 2 to 24 h and from 2 to 48 h post dose, use of rescue medication within 24 h post dose, nausea freedom at 2 h post dose, photophobia freedom at 2 h post dose, phonophobia freedom at 2 h post dose, and pain relapse from 2 to 48 h post dose (pain severity score of 1, 2, or 3 among those with pain freedom at 2 h post dose).
Safety was assessed through reporting of on‐treatment AEs, which were defined as those with onset date on or up to 7 days after the study medication date. AEs were summarized descriptively, with severity and relationship to study treatment determined by site investigators. AEs were coded using Medical Dictionary for Regulatory Activities v21.1.
Data analysis
Given the similarities in study design and inclusion/exclusion criteria across the three studies, and accessibility to the study datasets as a sponsor for the trials, patient‐level data were pooled for efficacy analyses and safety summaries.
Demographics and baseline characteristics of participants were presented by racialized group (the Black or African American population, the White population, and the overall pooled study population [that includes other racialized groups]) and treatment group, using summary statistics (mean and standard deviation for continuous data, n [%] for categorical data).
Efficacy analyses were performed on the modified intent‐to‐treat population, which included all randomized participants who received study medication, had a migraine attack of moderate or severe pain intensity at the time of dosing, and provided at least one efficacy datapoint after receiving study treatment. Endpoints were evaluated using Mantel–Haenszel risk estimation stratified by use of preventive medication (and study for the overall population). Stratified risk with 95% confidence intervals (CIs) was presented for rimegepant and placebo treatments. Risk differences (rimegepant − placebo) with 95% CIs are also presented, with treatment comparisons based on nominal p values. Analyses were performed in each of the racialized groups. Statistical testing was two‐tailed and considered significant at p < 0.05. Data were analyzed using SAS software, v9.4 or later (SAS Institute, Cary, NC, USA). 12
Post hoc analysis was conducted to test for interaction between the Black or African American and White racialized groups in the coprimary efficacy endpoints. Because the primary analysis methodology does not allow incorporation of an interaction term, a separate Breslow‐Day test for homogeneity of odds ratios across the two groups was conducted. Additionally, forest plots were constructed.
RESULTS
Participants
Among 3551 treated participants in the pooled population, 696 (19.6%) were Black or African American and 2700 (76.0%) were White. The remaining 155 participants in the overall pooled study population were of other racialized backgrounds (e.g., Asian, American Indian or Alaskan Native, Native Hawaiian or other Pacific Islander, and multiple races reported). The three trials used for the pooled analysis were relatively homogeneous. All three trials were run in the United States and were designed and conducted in a similar manner, and in accordance with regulatory guidelines for acute treatment migraine trials. Although formal statistical comparison was not conducted, demographics and clinical characteristics of Black or African American participants were generally similar to White participants (Table 1). Black or African American participants, however, had a slightly higher mean baseline weight and body mass index (BMI) than White participants, and had a slightly higher percentage of male participants compared with the White subgroup. Additionally, nausea (as the historical MBS) and prior use of preventive migraine medications were somewhat lower among Black or African American participants than White participants.
TABLE 1.
Demographics and baseline characteristics of all treated participants.
| Demographic | Black or African American (N = 696) | White (N = 2700) | Overall a (N = 3551) | |||
|---|---|---|---|---|---|---|
| Rimegepant (n = 365) | Placebo (n = 331) | Rimegepant (n = 1322) | Placebo (n = 1378) | Rimegepant (n = 1769) | Placebo (n = 1782) | |
| Mean (SD) age, y | 39.2 (10.7) | 39.2 (10.5) | 41.4 (12.5) | 41.2 (12.5) | 40.8 (12.1) | 40.7 (12.1) |
| Sex, n (%) | ||||||
| Female | 313 (85.8) | 266 (80.4) | 1146 (86.7) | 1209 (87.7) | 1527 (86.3) | 1534 (86.1) |
| Male | 52 (14.2) | 65 (19.6) | 176 (13.3) | 169 (12.3) | 242 (13.7) | 248 (13.9) |
| Race, n (%) | ||||||
| White | 0 | 0 | 1322 (100.0) | 1378 (100.0) | 1322 (74.7) | 1378 (77.3) |
| Black or African American | 365 (100.0) | 331 (100.0) | 0 | 0 | 365 (20.6) | 331 (18.6) |
| Other | 0 | 0 | 0 | 0 | 82 (4.6) | 73 (4.1) |
| Mean (SD) weight, kg | 90.5 (22.5) | 93.1 (24.7) | 83.2 (22.7) | 83.1 (22.4) | 84.8 (22.9) | 84.6 (23.1) |
| Mean (SD) BMI, kg/m2 | 32.72 (7.92) | 33.12 (8.67) | 30.20 (7.86) | 30.32 (7.89) | 30.76 (7.94) | 30.71 (8.06) |
| Mean (SD) duration of untreated attacks, h | 29.2 (22.1) | 28.5 (21.9) | 30.6 (22.0) | 31.7 (21.7) | 30.2 (22.0) | 30.9 (21.7) |
| Mean (SD) number of moderate‐to‐severe attacks per month | 4.8 (1.8) | 4.9 (1.7) | 4.6 (1.8) | 4.6 (1.8) | 4.6 (1.8) | 4.6 (1.8) |
| Primary migraine type, n (%) | ||||||
| Without aura | 239 (65.5) | 214 (64.7) | 914 (69.1) | 935 (67.9) | 1206 (68.2) | 1199 (67.3) |
| With aura | 126 (34.5) | 117 (35.3) | 408 (30.9) | 443 (32.1) | 563 (31.8) | 583 (32.7) |
| Historically MBS, b n (%) | ||||||
| Photophobia | 224 (61.4) | 193 (58.3) | 751 (56.8) | 761 (55.2) | 1024 (57.9) | 997 (55.9) |
| Phonophobia | 74 (20.3) | 66 (19.9) | 217 (16.4) | 250 (18.1) | 296 (16.7) | 331 (18.6) |
| Nausea | 65 (17.8) | 72 (21.8) | 354 (26.8) | 366 (26.6) | 447 (25.3) | 453 (25.4) |
| Use of preventive migraine medication, n (%) | 47 (12.9) | 34 (10.3) | 221 (16.7) | 242 (17.6) | 275 (15.5) | 282 (15.8) |
Abbreviations: BMI, body mass index; MBS, most bothersome symptom; SD, standard deviation.
Includes Black or African American, White, Asian, American Indian or Alaskan Native, Native Hawaiian or other Pacific Islander, and multiple races reported.
Two Black or African American rimegepant participants and one White placebo participant did not have a historical MBS reported.
Efficacy
Rimegepant demonstrated improvements over placebo on the coprimary endpoints of pain freedom and MBS freedom at 2 h post dose in Black or African American participants. For pain freedom at 2 h post dose (Figure 1A), the stratified risk was 24.4% (88/359) for rimegepant and 18.2% (59/323) for placebo in Black or African American participants, with a risk difference of 6.2% (95% CI: 0.1, 12.3; p = 0.047). For MBS freedom at 2 h post dose (Figure 1B), the stratified risk was 43.1% (155/359) for rimegepant and 35.5% (115/323) for placebo in Black or African American participants, with a risk difference of 7.6% (95% CI: 0.3, 14.9; p = 0.041). The risk differences were similar to effects seen in White participants, which were 7.9% (95% CI: 5.2, 10.6; p < 0.001) for pain freedom at 2 h post dose and 9.9% (95% CI: 6.5, 13.4; p < 0.001) for MBS freedom at 2 h post dose (Figure 1). Breslow‐Day tests for homogeneity of odds ratios across the groups supported no interaction (pain freedom 2 h post dose: p = 0.231; MBS freedom 2 h post dose: p = 0.364). See also Figure 2.
FIGURE 1.
Analysis of coprimary efficacy endpoints in the mITT population.a CI, confidence interval; diff, difference; MBS, most bothersome symptom; mITT, modified intent‐to‐treat population; Pbo, placebo; Rim, rimegepant. aSee methods for more details on mITT criteria. Risk was stratified by prophylactic migraine medication use (and by study for the overall population) with Mantel–Haenszel weighting. Participants with missing data at 2 h or who used rescue medication prior to 2 h were classified as failures. Risk difference is rimegepant − placebo.
FIGURE 2.
Pain freedom (A) and MBS (B) at 2 h post dose. Diff, difference; MBS, most bothersome symptom.
Rimegepant also demonstrated improvements over placebo in Black or African American participants on secondary efficacy endpoints (Table 2). In the Black or African American population, the risk difference was 9.1% (95% CI: 1.6, 16.5; p = 0.017) for pain relief at 2 h post dose, 6.8% (95% CI: −0.5, 14.1; p = 0.066) for normal function at 2 h post dose, 1.0% (95% CI: −8.9, 11.0; p = 0.840) for freedom from nausea at 2 h post dose, 4.5% (95% CI: −4.9, 13.9; p = 0.346) for freedom from phonophobia at 2 h post dose, and 9.9% (95% CI: 2.2, 17.7; p = 0.012) for freedom from photophobia at 2 h post dose. Risk difference was −9.0% (95% CI: −14.9, −3.1; p = 0.003) for use of rescue medication within 24 h post dose, 5.8% (95% CI: 0.9, 10.6; p = 0.019) for sustained pain freedom from 2 to 24 h post dose, 7.8% (95% CI: 0.7, 14.8; p = 0.031) for sustained pain relief from 2 to 24 h post dose, 3.7% (95% CI: −0.8, 8.2; p = 0.110) for sustained pain freedom from 2 to 48 h post dose, 3.9% (95% CI: −2.9, 10.6; p = 0.263) for sustained pain relief from 2 to 48 h post dose, and −2.5% (95% CI: −18.9, 13.8; p = 0.761) for pain relapse from 2 to 48 h post dose. Across all endpoints, Black or African American participants met nominal statistical significance (p < 0.05) in 5 of 11, whereas White participants met nominal statistical significance in 10 of 11 (Table 2). Risk differences across endpoints were typically smaller for Black or African American participants compared with White participants.
TABLE 2.
Summary of secondary efficacy endpoints in the mITT population. a
| Endpoint | Black or African American | White | Overall | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Stratified risk (%) (95% CI) | Risk difference (%) (95% CI) b | Stratified risk (%) (95% CI) | Risk difference (%) (95% CI) b | Stratified risk (%) (95% CI) | Risk difference (%) (95% CI) c | ||||
| Rimegepant (n = 359) | Placebo (n = 323) | Rimegepant (n = 1307) | Placebo (n = 1364) | Rimegepant (n = 1749) | Placebo (n = 1758) | ||||
| Pain relief at 2 h post dose | 55.3 (50.1, 60.4) | 46.2 (40.8, 51.6) |
9.1 (1.6, 16.5) p = 0.017 |
58.7 (56.0, 61.4) | 43.4 (40.8, 46.1) |
15.3 (11.5, 19.0) p < 0.001 |
57.9 (55.6, 60.2) | 43.9 (41.6, 46.2) |
14.1 (10.8, 17.3) p < 0.001 |
| Normal function at 2 h post dose | 41.6 (36.4, 46.7) | 34.8 (29.6, 39.9) |
6.8 (−0.5, 14.1) p = 0.066 |
33.1 (30.5, 35.6) | 21.3 (19.1, 23.4) |
11.8 (8.4, 15.1) p < 0.001 |
34.9 (32.7, 37.2) | 23.8 (21.8, 25.8) |
11.1 (8.1, 14.1) p < 0.001 |
| Freedom from nausea at 2 h post dose d | 52.9 (46.1, 59.8) e | 51.9 (44.7, 59.2) f |
1.0 (−8.9, 11.0) p = 0.840 |
48.9 (45.5, 52.3) g | 42.4 (39.1, 45.7) h |
6.5 (1.7, 11.2) p = 0.008 |
48.8 (45.9, 51.8) i | 43.5 (40.6, 46.5) j |
5.3 (1.1, 9.5) p = 0.013 |
| Freedom from phonophobia at 2 h post dose k | 38.2 (31.7, 44.7) l | 33.7 (26.9, 40.5) m |
4.5 (−4.9, 13.9) p = 0.346 |
39.5 (36.3, 42.7) n | 28.8 (25.9, 31.7) o |
10.7 (6.4, 15.0) p < 0.001 |
39.2 (36.4, 42.0) p | 29.3 (26.8, 31.9) q |
9.8 (6.0, 13.7) p < 0.001 |
| Freedom from photophobia at 2 h post dose r | 41.9 (36.4, 47.4) s | 32.0 (26.5, 37.5) t |
9.9 (2.2, 17.7) p = 0.012 |
33.2 (30.5, 35.9) u | 22.3 (19.9, 24.6) v |
10.9 (7.4, 14.5) p < 0.001 |
35.1 (32.7, 37.5) w | 23.9 (21.8, 26.0) x |
11.2 (8.0, 14.4) p < 0.001 |
| Use of rescue medication within 24 h post dose | 14.7 (11.0, 18.3) | 23.7 (19.1, 28.3) |
−9.0 (−14.9, −3.1) p = 0.003 |
19.1 (17.0, 21.3) | 34.7 (32.2, 37.3) |
−15.6 (−18.9, −12.3) p < 0.001 |
18.2 (16.4, 20.0) | 32.4 (30.2, 34.5) |
−14.1 (−17.0, −11.3) p < 0.001 |
| Sustained pain relief from 2 to 24 h post dose | 38.0 (32.9, 43.0) | 30.2 (25.2, 35.2) |
7.8 (0.7, 14.8) p = 0.031 |
45.2 (42.5, 47.9) | 26.8 (24.4, 29.1) |
18.4 (14.9, 22.0) p < 0.001 |
43.5 (41.2, 45.8) | 27.4 (25.3, 29.5) |
16.1 (12.9, 19.2) p < 0.001 |
| Sustained pain freedom from 2 to 24 h post dose | 15.1 (11.4, 18.8) | 9.3 (6.1, 12.5) |
5.8 (0.9, 10.6) p = 0.019 |
13.9 (12.1, 15.8) | 6.4 (5.1, 7.7) |
7.5 (5.3, 9.8) p < 0.001 |
14.1 (12.5, 15.8) | 6.8 (5.7, 8.0) |
7.3 (5.3, 9.3) p < 0.001 |
| Sustained pain relief from 2 to 48 h post dose | 30.7 (25.9, 35.5) | 26.8 (22.0, 31.6) |
3.9 (−2.9, 10.6) p = 0.263 |
39.9 (37.2, 42.5) | 23.4 (21.2, 25.7) |
16.4 (13.0, 19.9) p < 0.001 |
37.8 (35.5, 40.0) | 24.0 (22.0, 26.0) |
13.8 (10.7, 16.8) p < 0.001 |
| Sustained pain freedom from 2 to 48 h post dose | 12.1 (8.7, 15.4) | 8.4 (5.4, 11.4) |
3.7 (−0.8, 8.2) p = 0.110 |
11.7 (10.0, 13.5) | 5.8 (4.6, 7.0) |
5.9 (3.8, 8.1) p < 0.001 |
11.8 (10.3, 13.3) | 6.2 (5.0, 7.3) |
5.6 (3.8, 7.5) p < 0.001 |
| Pain relapse from 2 to 48 h post dose y | 51.4 (41.0, 61.8) z | 54.0 (41.3, 66.6) aa |
−2.5 (−18.9, 13.8) p = 0.761 |
37.8 (31.8, 43.9) bb | 47.0 (39.0, 55.0) cc |
−9.2 (−19.2, 0.9) p = 0.074 |
41.7 (36.5, 46.8) dd | 50.0 (43.3, 56.6) ee |
−8.3 (−16.7, 0.1) p = 0.053 |
Abbreviations: CI, confidence interval; mITT, modified intent‐to‐treat population.
See methods for details on the mITT population.
Risk was stratified by prophylactic migraine medication use with Mantel–Haenszel weighting. Participants with missing data at the specified time point or who used rescue medication prior to the specified time point (except for the use of rescue medication endpoint) were classified as failures. Risk difference is rimegepant − placebo.
Risk was stratified by study and prophylactic migraine medication use with Mantel–Haenszel weighting. Participants with missing data at the specified time point or who used rescue medication prior to the specified time point (except for the use of rescue medication endpoint) were classified as failures. Risk difference is rimegepant − placebo.
Among those with nausea at baseline: e n = 204, f n = 179,g n = 810, h n = 865, i n = 1070, j n = 1088.
Among those with phonophobia at baseline: l n = 212,m n = 184, n = 894, o = 955, p n = 1158,q n = 1187.
Among those with photophobia at baseline: s n = 312, t n = 277, u n = 1172, v n = 1232, w n = 1552, x n = 1571.
Among those with pain freedom at baseline: z n = 88, aa n = 59, bb n = 246, cc n = 149, dd n = 351, ee n = 215.
Safety
The rate of AEs among Black or African American participants was 10.7% (39/365) among those treated with rimegepant and 7.9% (26/331) among those treated with placebo (Table 3). The rate of severe AEs was low and comparable among Black or African American participants treated with rimegepant or placebo (n = 1; 0.3% in both cohorts). AEs occurring in ≥0.5% (i.e., n > 1) of Black or African American participants treated with rimegepant included nausea (n = 4; 1.1%), increased blood creatine phosphokinase (n = 4; 1.1%), abdominal pain (n = 3; 0.8%), urinary tract infection (n = 2; 0.5%), somnolence (n = 2; 0.5%), dysgeusia (n = 2; 0.5%), muscle spasm (n = 2; 0.5%), hypertension (n = 2; 0.5%), and generalized pruritus (n = 2; 0.5%). The AE profile of rimegepant in Black or African American participants was similar to the profile in White participants (Table 3), where the overall AE rate was 10.4% (138/1322) and the rate of severe AEs was 0.4% (5/1322).
TABLE 3.
Summary of on‐treatment AEs in all treated participants.
| n (%) of participants | Black or African American (N = 696) | White (N = 2700) | Overall a (N = 3551) | |||
|---|---|---|---|---|---|---|
| Rimegepant (n = 365) | Placebo (n = 331) | Rimegepant (n = 1322) | Placebo (n = 1378) | Rimegepant (n = 1769) | Placebo (n = 1782) | |
| ≥1 AE | 39 (10.7) | 26 (7.9) | 138 (10.4) | 121 (8.8) | 192 (10.9) | 154 (8.6) |
| ≥1 mild AE | 28 (7.7) | 18 (5.4) | 99 (7.5) | 86 (6.2) | 136 (7.7) | 108 (6.1) |
| ≥1 moderate AE | 12 (3.3) | 9 (2.7) | 44 (3.3) | 46 (3.3) | 61 (3.4) | 58 (3.3) |
| ≥1 severe AE | 1 (0.3) | 1 (0.3) | 5 (0.4) | 2 (0.1) | 7 (0.4) | 3 (0.2) |
| Most common AEs b | ||||||
| Increased blood creatine phosphokinase | 4 (1.1) | 2 (0.6) | 4 (0.3) | 6 (0.4) | 9 (0.5) | 8 (0.4) |
| Nausea | 4 (1.1) | 2 (0.6) | 18 (1.4) | 12 (0.9) | 26 (1.5) | 14 (0.8) |
| Abdominal pain | 3 (0.8) | 0 | 1 (0.1) | 0 | 4 (0.2) | 0 |
| Urinary tract infection | 2 (0.5) | 2 (0.6) | 10 (0.8) | 4 (0.3) | 14 (0.8) | 6 (0.3) |
| Somnolence | 2 (0.5) | 1 (0.3) | 4 (0.3) | 4 (0.3) | 7 (0.4) | 5 (0.3) |
| Generalized pruritus | 2 (0.5) | 0 | 0 | 0 | 2 (0.1) | 0 |
| Dysgeusia | 2 (0.5) | 0 | 0 | 1 (0.1) | 2 (0.1) | 1 (0.1) |
| Muscle spasms | 2 (0.5) | 0 | 1 (0.1) | 1 (0.1) | 3 (0.2) | 1 (0.1) |
| Hypertension | 2 (0.5) | 0 | 0 | 2 (0.1) | 2 (0.1) | 2 (0.1) |
| Diarrhea | 1 (0.3) | 3 (0.9) | 8 (0.6) | 6 (0.4) | 9 (0.5) | 9 (0.5) |
| Dizziness | 1 (0.3) | 0 | 9 (0.7) | 11 (0.8) | 11 (0.6) | 13 (0.7) |
| Dry mouth | 0 | 2 (0.6) | 2 (0.2) | 2 (0.1) | 2 (0.1) | 4 (0.2) |
| Sinusitis | 0 | 2 (0.6) | 2 (0.2) | 1 (0.1) | 2 (0.1) | 3 (0.2) |
| Chest pain | 0 | 2 (0.6) | 1 (0.1) | 1 (0.1) | 1 (0.1) | 3 (0.2) |
Abbreviation: AE, adverse event.
Includes Black or African American, White, Asian, American Indian or Alaskan Native, Native Hawaiian or other Pacific Islander, and multiple races reported.
AEs occurring in ≥0.5% of participants in any treatment group and sorted according to frequency in Black or African American participants treated with rimegepant.
DISCUSSION
The Black or African American population has been, and continues to be, persistently underrepresented in clinical trials of migraine. 3 Although rimegepant is indicated for both acute and preventive treatment of migraine, its use has not been evaluated in a population comprising exclusively of Black or African American adults. While there are no known ethnic/racial differences in the migraine pathophysiological process that would predict the likelihood of notable rimegepant treatment response heterogeneity between Black and non‐Black patients, the presence of other demographic confounders and/or the potential differences in previous experience with health care systems and in treatment expectations between the study subpopulations could influence trial results, given the subjective nature of the patient‐reported outcome measures used in the source clinical trials. Therefore, this post hoc subgroup analysis of three large controlled rimegepant clinical trials was undertaken with the intent of providing insights into this clinically important question. Research is needed to better understand if there are racial/ethnic differences in the pathophysiological processes and an explanation of observed disparities in people living with migraine disease. 13 This analysis demonstrated that rimegepant 75 mg is effective and well tolerated for the acute treatment of migraine in Black or African American adults. Of note, this analysis did not compare against other migraine treatments or evaluate use of rimegepant as a preventative migraine treatment.
The efficacy of rimegepant was demonstrated across several different endpoints. Most notably, rimegepant demonstrated improvements over placebo on the coprimary endpoints of pain freedom and MBS freedom at 2 h post dose in Black or African American participants. Rimegepant also demonstrated improvement, or was observed to move toward improvement, in measures of pain relief, sustained pain relief and pain freedom, other migraine symptoms (photophobia and phonophobia), use of rescue medication, and overall functioning. Improvement in photophobia and phonophobia is notable because their presence alters behavior and mood and contributes to migraine‐related disability. 14 , 15 Overall, efficacy findings in this study suggest acute treatment with rimegepant provides a clinically meaningful benefit to Black or African American adults with migraine by reducing pain and other bothersome symptoms.
These efficacy findings in Black or African American participants are in broad agreement with efficacy findings in White participants. However, effect sizes were typically smaller in the Black or African American cohort, and nominal p values were >0.05 for ~50% of the secondary endpoints in Black or African American participants, compared with ~10% in White participants. These discrepancies may, in part, be a result of relatively small sample sizes for some endpoints in the Black or African American population compared with the White subgroup. Whereas 359 Black or African American participants treated with rimegepant were included in the efficacy analyses set, this is much fewer than the number of White participants receiving rimegepant included in the efficacy analysis set (n = 1307). Further, although most efficacy endpoints utilized the full efficacy analyses set, some secondary endpoints were based on a subset of patients, and evaluable sample size was reduced even further. For example, the freedom from photophobia, phonophobia, and nausea endpoints were based on subsets of participants who reported the symptom at migraine onset. Thus, although the number of evaluable Black or African American participants treated with rimegepant was 312 for photophobia freedom, the numbers were only 212 for phonophobia freedom and 204 for nausea freedom. Likewise, only 88 Black or African American participants treated with rimegepant were evaluated for the pain relapse endpoint. Finally, there appeared to be a greater response to placebo, and often to rimegepant, for many efficacy endpoints in the Black or African American population than in the White population. A greater placebo response among Black or African American participants has been observed previously for pain, MBS, and functional disability endpoints in studies of lasmiditan for the acute treatment of migraine. 16 The reasons for this effect with lasmiditan—and observed in this pooled analysis of rimegepant—are unknown, but it has been suggested that perceptions and expectations of the clinical experience may impact outcomes and such perceptions vary between Black or African American participants and White participants. 17 Placebo rates vary among pain indicators, 18 , 19 , 20 and in this analysis there appeared to be a greater placebo effect. Further work is needed to understand the impact of placebo and nocebo among underrepresented groups in clinical trials.
The AE profile of rimegepant in Black or African American participants was similar to the profile in White participants. Both populations reported a similar number of participants with AEs (10% to 11%); few participants reported a severe AE (0.4% in White and 0.3% in Black or African American participants), and the most commonly reported AEs were generally similar in both groups. Some AEs were reported more frequently in Black or African American participants than White participants (e.g., increased blood creatine phosphokinase, abdominal pain), whereas others were reported less frequently in Black or African American participants (e.g., diarrhea, dizziness). However, the overall low number of these individual events makes it impossible to conclude whether true differences exist between groups. Although these events appeared very infrequently, it adds to research of AEs experienced by Black or African American participants taking rimegepant and may help identify AEs more likely to be experienced by individuals in certain populations. Overall, these findings demonstrate treatment with rimegepant was well tolerated in Black or African American participants.
Although no formal statistical comparisons were performed, some differences in the demographics and clinical characteristics of Black or African American participants and White participants in this analysis were observed. It is therefore possible that some of these factors could represent potential confounders in the final interpretation of this analysis. For example, mean BMI was slightly higher (2 to 3 kg/m2) in Black or African American participants, and slightly more participants were male 21 than in the White subgroup. Fewer Black or African American participants reported prior use of preventive migraine medications than White participants, which has been reported in other clinical trials of acute migraine treatment and may reflect racial/ethnic differences in migraine prescribing patterns. 16 Finally, whereas the number and duration of migraine attacks was similar among Black or African American participants and White participants, nausea (as the historical MBS) was reported less frequently among Black or African American participants. Interestingly, previous studies have also found that Black or African American individuals are less likely to report nausea with a migraine attack. 22 It is possible that decreased nausea among Black or African American participants may be related to the phenotypical expression of migraine disease, which has complex pathophysiology. Further research on this topic is needed. Moreover, it highlights the need for more diverse populations in migraine studies, including epidemiological studies, to better characterize differences in phenotypical presentation of migraine disease among historically underrepresented racial/ethnic groups. Taken together, race is a social construct as opposed to biological construct; therefore, further work is needed to assess therapeutic differences in minoritized populations and interactions with other social factors (i.e., social determinants of health).
This study has several limitations. Because the trials were limited to treatment of a single migraine attack, conclusions cannot be made on the repeated long‐term use of rimegepant in Black or African American participants. Additionally, sample size was relatively small in this post hoc analysis of the available Black or African American population in these studies. Even with pooling across the three studies, the sample size of the Black or African American population is smaller than that for any of the individual studies that were powered for efficacy analysis. Analysis of other ethnicities was not possible due to the small sample sizes across the three studies. Differences between subgroups, such as BMI and preventative medication use, were not statistically tested and could have impacted the findings. As all participants were located in the United States, the results of this analysis may not be generalizable to Black populations in other geographic areas. The analysis, however, is strengthened by the similarities in design across the three studies, allowing for pooling of Black or African American participants who were enrolled and treated using similar criteria and methods. Of note, for the participants across the three studies included in this pooled analysis, 19.6% were Black or African American compared with the overall US population percentage of 13.7%. The more varied a group of clinical trial participants, the more we can learn about the safety and efficacy of a potential medicine or vaccine for people who have characteristics similar to the trial participants.
CONCLUSION
This pooled analysis demonstrates that rimegepant is effective and well tolerated for the acute treatment of migraine in Black or African American adults compared with placebo. This analysis did not compare against other migraine treatments or evaluate use of rimegepant as a preventative migraine treatment. Although study design elements limit conclusions, the percentage of Black or African American participants enrolled was above the current US average and provides insight into acute migraine treatment with rimegepant for this population. These results highlight that further research is warranted to better understand this population's response to preventive treatment, especially in light of observed differences in baseline characteristics, including body weight, baseline MBS, and prior exposure to preventive therapies.
AUTHOR CONTRIBUTIONS
Larry Charleston 4th: Writing – original draft; writing – review and editing. Cynthia E. Armand: Conceptualization; resources; writing – original draft; writing – review and editing. Teshamae S. Monteith: Writing – original draft; writing – review and editing. Hope L. O'Brien: Writing – original draft; writing – review and editing. Chandra C. Abbott: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; writing – original draft; writing – review and editing. Glenn C. Pixton: Methodology; validation; writing – original draft; writing – review and editing. Terence Fullerton: Conceptualization; data curation; formal analysis; funding acquisition; methodology; resources; visualization; writing – original draft; writing – review and editing.
FUNDING INFORMATION
This study was sponsored by Pfizer.
CONFLICT OF INTEREST STATEMENT
Larry Charleston IV has received personal compensation for serving as a consultant for AbbVie, Accolade, Amgen, Amneal, Aurene, Haleon, LinPharma, Lundbeck, Pfizer, and Satsuma. He is on the advisory panel for Mi‐Helper Inc. (stock options) and received grant/research support from the Disparities in Headache Advisory Council and Amgen (paid to Michigan State University). He has received Continuing Medical Education (CME) honoraria from the American Headache Society, American Academy of Neurology, BrainWeekend, MedSpoke, Migraine360 CME Program, NeurologyWeek, Continuing Education Health Interactive, and Primary Care Education Consortium. He serves on the speaker bureau of Axsome Therapeutics. He is a non‐compensated associate editor for Headache: The Journal of Head and Face Pain; serves as a non‐compensated Board of Directors as Treasurer/Secretary for the Clinical Neurological Society of America and a non‐compensated Board of Director of the American Headache Society as Chair of the American Headache Society's Equity Diversity and Inclusion Advisory Council (non‐voting). Cynthia E. Armand is on the editorial board of Journal of the American Medical Association Neurology. She has served as a consultant for Teva, Biohaven, AbbVie, Pfizer, Tonix Medicines, and LinPharma. She has received CME honoraria from the American Headache Society and the American Academy of Neurology. Teshamae S. Monteith is the clinical trial site principal investigator for studies sponsored by Eli Lilly, Ipsen, and AbbVie (all paid to the institution); advisory board/consultancy for AbbVie, Teva, Axsome, LinPharma, e‐Neura, Novartis, Merz, Lundbeck, and Pfizer; has received educational grants from Amgen and AbbVie; has received personal fees from Medscape, Massachusetts Medical Society, American Headache Society, American Academy of Neurology, AbbVie, and Novartis; and is unpaid coauthor for research funded by AbbVie, Pfizer/Biohaven, and Theranica. Editorial work includes serving as associate editor for Cephalalgia/Cephalalgia Reports, Confinia Cephalalgica, and Continuum Audio; deputy editor for Neurology Minute; and serving on the editorial board for Neurology, New England Journal of Medicine Journal Watch, American Migraine Foundation, and Brain and Life Magazine. She has provided unpaid service on the board of directors for the International Headache Society (2021 to 2023) and is currently on the executive board for the Florida Society of Neurology. Hope L. O'Brien received indirect funding to institution for serving as consultant for AbbVie, Cefaly, Lilly, and Pfizer. She has received personal compensation for consultation services from Tonix Medicines and Guidepoint. The institution has also received funds for Dr. O'Brien's participation on the speaker bureau for AbbVie, Lilly, Pfizer, Amgen (2021), BDSI (2021), and Biohaven (2022). She has also received indirect industry funding to institution for research/clinical trial (site PI) support from AbbVie, Lilly, and Ipsen. She has received royalty fees for editorial services from UpToDate. She is on the board of the National Headache Society and Cincinnati Eye Institute Foundation, and serves on committee vice chair of the American Academy of Neurology and United Counsel of Neurological Subspecialties. Other compensated speaking activities are for Medscape, Gather‐ed, American Headache Society, and American Academy of Neurology. Glenn C. Pixton is an employee of Pfizer and owns stock/stock options. He also owns stock in AbbVie. Terence Fullerton and Chandra C. Abbott are employees or former employees of Pfizer and own stock/stock options.
ACKNOWLEDGMENTS
Medical writing support was provided by Alex Frings, PharmD, CMPP, of Engage Scientific Solutions, and was funded by Pfizer.
DATA AVAILABILITY STATEMENT
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.