Efficacy and safety of rimegepant for the preventive treatment of migraine in Japan: A double‐blind, randomized controlled trial

Abstract

Objectives/Background

This study was undertaken to compare the efficacy of the oral calcitonin gene‐related peptide receptor antagonist rimegepant relative to placebo as a preventive treatment for migraine in Japan. This was the first randomized placebo‐controlled trial of rimegepant for the preventive treatment of migraine to be conducted outside the United States and the second conducted globally.

Methods

In this phase 3, double‐blind, randomized, multicenter trial, conducted August 9, 2022 through January 18, 2024, adults in Japan with a history of 4–18 migraine attacks/month of moderate or severe pain intensity completed a 28‐day observation phase and then took rimegepant 75 mg or placebo every other day during the 12‐week double‐blind treatment phase. The primary endpoint was the mean change from the observation phase in the number of monthly migraine days in the last 4 weeks of the double‐blind treatment phase. Safety was assessed based on the frequency of adverse events and laboratory test abnormalities during the double‐blind treatment phase.

Results

A total of 484 (efficacy) and 496 (safety) treated participants were evaluable. During the observation phase, participants in the rimegepant and placebo groups, respectively, reported a mean (SD) of 9.3 (3.1) and 9.0 (3.1) monthly migraine days. The study met its primary endpoint with a statistically significant difference in mean change from the observation phase in the number of monthly migraine days in the last 4 weeks of the double‐blind treatment phase (difference rimegepant vs. placebo: −1.1 [95% confidence interval = −1.73 to −0.38], p = 0.002). In the rimegepant and placebo groups, respectively, 54.7% and 41.0% of participants reported adverse events and 0.8% and 0.4% reported serious adverse events during the double‐blind treatment phase. No signal of drug‐induced liver injury due to rimegepant was identified.

Conclusion

Rimegepant 75 mg every other day demonstrated efficacy superior to that of placebo for the preventive treatment of migraine, with a favorable safety profile. NCT05399485.

Plain Language Summary

This study tested the effectiveness of rimegepant for migraine prevention in Japan. Results showed that rimegepant was more effective than placebo in reducing monthly migraine days, with very few adverse effects. These results support the previous findings from a clinical study conducted in the United States and broaden them to a wider population.

Plain Language Summary: This study tested the effectiveness of rimegepant for migraine prevention in Japan. Results showed that rimegepant was more effective than placebo in reducing monthly migraine days, with very few adverse effects. These results support the previous findings from a clinical study conducted in the United States and broaden them to a wider population.

Abbreviations

AE

adverse event

ALT

alanine aminotransferase

AST

aspartate aminotransferase

CGRP

calcitonin gene‐related peptide

CI

confidence interval

DBT

double‐blind treatment

eDiary

electronic diary

EOD

every other day

EQ VAS

EQ‐5D‐5L visual analog scale

ICHD‐3

International Classification of Headache Disorders, 3rd edition

MIDAS

Migraine Disability Assessment

MMD

monthly migraine day

MSQoL

Migraine‐Specific Quality‐of‐Life Questionnaire

ODT

orally disintegrating tablet

OP

observation phase

SAE

serious adverse event

ULN

upper limit of normal

INTRODUCTION

Migraine is characterized by recurring headaches of moderate to severe pain intensity that are commonly associated with nausea, photophobia, and/or phonophobia. ¹ Affecting approximately 15% of people worldwide ² and 8.4% in Japan, ³ migraine is a leading cause of disability. ⁴ The burden for both the individual and society is considerable, ⁵ , ⁶ and more effective treatments for migraine would benefit both the individual and society globally. ⁷

Patients with migraine need an individualized management plan that often includes both acute treatment (to relieve pain and associated symptoms) and preventive treatment (to reduce attack frequency and severity). ⁸ Traditionally, patients have been prescribed a variety of medications (such as beta‐blockers, antidepressants, antiseizure medications, and calcium channel blockers) aimed at preventing migraine, ⁸ , ⁹ , ¹⁰ which have high discontinuation rates due to limited efficacy, delayed onset, or poor tolerability. ¹⁰ , ¹¹ Calcitonin gene‐related peptide (CGRP)–targeted treatments are the first preventive medications specifically developed for migraine. Following a review of the evidence, the American Headache Society recommended that CGRP‐targeted therapies (monoclonal antibodies and gepants) should be included in first‐line preventive treatment options for migraine. ¹² As elsewhere, ⁸ , ⁹ injectable CGRP monoclonal antibodies are recommended for migraine prophylaxis in Japan ¹³ ; however, oral CGRP receptor antagonists (gepants), such as rimegepant, have not yet been approved in Japan. Rimegepant has been shown to be effective for both acute ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ and preventive ¹⁹ treatment of migraine and offers several advantages over CGRP monoclonal antibodies. Oral agents are preferred over injections by many patients ²⁰ and allow for immediate cessation of therapy, which is not possible with CGRP monoclonal antibodies due to their long half‐lives.

During drug development, it is critically important to corroborate clinical trial findings across a broad study population, and for many countries, establishing efficacy and safety in the local population is a regulatory requirement. This was the first randomized placebo‐controlled trial of rimegepant for the preventive treatment of migraine to be conducted outside the United States and the second conducted globally. The primary objective of the study was to compare the efficacy of rimegepant relative to placebo as a preventive treatment for migraine in Japan as measured by the mean reduction in the number of migraine days per month in the last 4 weeks of the 12‐week double‐blind treatment (DBT) phase. The hypothesis was that rimegepant 75 mg every other day (EOD) would be superior to placebo in reducing the number of monthly migraine days (MMDs) from the observation phase (OP) to the last 4 weeks of the DBT phase.

METHODS

Study design

This phase 3 trial (study number C4951021 or BHV3000‐309; ClinicalTrials.gov identifier NCT05399485) was a double‐blind, randomized, multicenter evaluation of the efficacy and safety of rimegepant 75 mg orally disintegrating tablet (ODT) compared with placebo for the preventive treatment of migraine in Japan. A screening visit was followed by a 28‐day OP, then the baseline (randomization) visit; participants took rimegepant 75 mg or placebo EOD during the 12‐week DBT phase. This was followed by a 40‐week open‐label phase for participants who continued to meet all inclusion and exclusion criteria. Study visits occurred at weeks 2, 4, 8, and 12 during the DBT phase, and at weeks 14 and 16 then every 4 weeks through the open‐label phase. There was a final follow‐up safety visit 14 ± 2 days after the end of treatment visit.

The study was conducted at 44 study sites in Japan, in compliance with the Declaration of Helsinki, International Conference on Harmonization guidelines, Good Clinical Practice, and Good Laboratory Practice. All participants provided written informed consent, and these forms and the protocol received institutional review board/independent ethics committee approval prior to initiation of the study.

The current report summarizes the key efficacy and safety results in the 12‐week DBT phase based on the primary completion date database lock, which occurred after the last participant completed the week 12 visit. The DBT phase of the study was conducted August 9, 2022, through January 18, 2024. The open‐label phase of this study is ongoing; the results will be reported separately.

Study population

Males and females were eligible provided they were aged ≥18 years, had a ≥1‐year history of migraine (with or without aura) consistent with a diagnosis according to International Classification of Headache Disorders, 3rd edition (ICHD‐3), ¹ and onset of migraine before 50 years of age. Key inclusion criteria were migraine attacks lasting, on average, 4–72 h if untreated; 4–18 migraine attacks/month (4 weeks) of moderate or severe pain intensity within the last 3 months prior to the screening visit; four or more migraine days during the OP; not more than 18 headache days during the OP; and the ability to distinguish migraine attacks from tension‐type or cluster headache. Exclusions included individuals with a history of migraine with brainstem aura (basilar migraine), hemiplegic migraine, or retinal migraine, individuals with headache (migraine or nonmigraine) occurring 19 or more days per month in any of the 3 months prior to the screening visit, individuals with a history of systemic analgesic use (e.g., nonsteroidal anti‐inflammatory drugs or acetaminophen) on ≥15 days per month during the 3 months (12 weeks) prior to the screening visit, and individuals with uncontrolled, unstable, or recently diagnosed cardiovascular disease, uncontrolled hypertension, uncontrolled diabetes, or body mass index > 35 kg/m². Individuals with contraindications for triptans were eligible if they met all other study entry criteria. Full inclusion and exclusion criteria for the study can be found in the protocol in the Supplementary Appendix.

Participants could remain on one medication with possible migraine‐prophylactic effects regardless of indication, excluding CGRP antagonists (biologic or small molecule), provided the dose had been stable for at least 3 months (12 weeks) prior to the OP and was not expected to change. Any discontinuation of such medication must have been at least 90 days prior to the screening visit. Biologic CGRP antagonists had to be discontinued 6 months prior to screening and gepants discontinued 2 weeks prior to screening, and any prior rimegepant use was exclusionary.

Participants were allowed to take permitted rescue medication (standard of care) if needed for the acute treatment of migraine, including triptans (except during the open‐label phase after week 12), aspirin, nonsteroidal anti‐inflammatory drugs, baclofen, acetaminophen (up to 2000 mg/day for a maximum of 2 consecutive days at a time), antiemetics, and muscle relaxants.

Intervention, randomization, and blinding

At the baseline visit, participants were randomized 1:1 to receive rimegepant 75 mg ODT or matching placebo, stratified by use of preventive migraine medication through randomization (yes or no), using an interactive web response system, and triggering a container number for the study drug. Study drug was dispensed in wallets at study visits. Participants were instructed that the study drug was to be placed on top of or under the tongue until fully dissolved, then swallowed. The study was double‐blind, with both participants and investigators/study personnel blinded to treatment assignment.

Procedures

During the DBT phase, participants were instructed to take one dose of study drug (rimegepant 75 mg or placebo) every other calendar day, at around the same time, regardless of whether they had a migraine on that day.

Participants used an electronic diary (eDiary) daily to record migraine occurrence and characteristics (pain and associated symptoms) and any use of acute migraine medication (triptan, ergotamine, or other). At specified study visits, the Migraine‐Specific Quality‐of‐Life Questionnaire (MSQoL) v2.1, Migraine Disability Assessment (MIDAS), and EQ‐5D‐5L were completed using the eDiary. The MSQoL v2.1 is a 14‐item instrument, validated in three domains (role function‐restrictive, role function‐preventive, and emotional function), that assesses the impact of treatment on participant‐reported quality of life, ²¹ with higher scores indicating better quality of life. The MIDAS is a retrospective, participant‐reported, five‐item questionnaire that measures headache‐related disability as lost days due to headache from paid work or school, household work, and nonwork activities over a 3‐month period, ²² with higher scores indicating greater headache‐related disability. The EQ‐5D‐5L is a standardized measure of health status that includes the EQ‐5D‐5L visual analog scale (EQ VAS), a 20‐cm vertical scale with endpoints labeled “the best health you can imagine” and “the worst health you can imagine,” ²³ with higher scores indicating better health.

A migraine day was defined as any calendar day on which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined as a migraine with or without aura, lasting for ≥30 min, and associated with at least one symptom (nausea and/or vomiting, or photophobia and phonophobia) and/or two or more specified pain features (unilateral location, pulsating quality [throbbing], moderate or severe pain intensity, aggravated by or causing avoidance of routine physical activity [e.g., walking or climbing stairs]). Days on which acute migraine‐specific medication (i.e., triptan or ergotamine) was used were also considered migraine days, regardless of pain intensity or associated symptoms. The number of MMDs was calculated for each month (4 weeks) through the study.

Endpoints

The primary endpoint was the mean change from the OP in the number of MMDs in the last 4 weeks (weeks 9–12) of the DBT phase.

Secondary efficacy endpoints and outcomes research included the proportion of participants with ≥50% reduction from the OP in moderate to severe MMDs in the last 4 weeks (weeks 9–12) of the DBT phase; mean changes from the OP in MMDs over the entire (weeks 1–12) and the first 4 weeks (weeks 1–4) of the DBT phase; mean number of acute migraine‐specific medication days (triptans, ergotamine) per month in the last 4 weeks (weeks 9–12) of the DBT phase; and mean change from baseline at week 12 of the DBT phase in the MSQoL v2.1 role function‐restrictive domain score, MIDAS total score, and EQ VAS score.

Safety during the DBT phase was assessed based on adverse events (AEs), serious AEs (SAEs), and AEs leading to study drug discontinuation; occurrence of elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × upper limit of normal (ULN) concurrently with total bilirubin >2 × ULN; and prespecified hepatic‐related AEs. AEs could be spontaneously reported by the participant or elicited during open‐ended questioning, examination, or evaluation by a study investigator.

Statistical analyses

A sample size of approximately 490 randomized participants was estimated to provide approximately 225 evaluable participants per treatment group in the DBT migraine analysis set. Assuming rimegepant provides approximately a 1‐day advantage over placebo on the primary endpoint and a common SD of 3.75 days, the sample size provided approximately 80% power on the primary endpoint. The assumptions for this a priori sample size calculation were based on a previous study. ¹⁹

The primary endpoint was assessed in the DBT migraine analysis set, defined as participants who were randomized only once and took at least one dose of double‐blind study drug, with ≥14 days (not necessarily consecutive) of eDiary efficacy data in both the OP and ≥1 month (4‐week interval) of the DBT phase. The primary endpoint was analyzed using a linear mixed‐effect model with repeated measures that included the following variables: change from the OP in MMDs as the dependent variable; number of MMDs in the OP as a covariate; and fixed effects for treatment group, randomization stratum (i.e., preventive migraine medication use), month, and month‐by‐treatment group interaction. An unstructured covariance structure was used to model the within‐participant error, assumed to be homogenous across treatment groups. Migraine days were of any pain intensity. Months during the DBT phase were defined using 4‐week intervals as month 1 (weeks 1–4), month 2 (weeks 5–8), and month 3 (weeks 9–12). The number of MMDs was prorated to 28 days to account for days with missing eDiary migraine data. The difference estimate (rimegepant vs. placebo), SE, 95% confidence interval (CI), and p‐value were reported for the last 4 weeks (i.e., month 3). SE was estimated using the Huber–White robust “sandwich” estimator. ²⁴ , ²⁵ , ²⁶ The results by stable prophylactic migraine medication use through randomization and historical chronic migraine according to ICHD‐3 were also shown. Secondary continuous efficacy endpoints based on MMDs were analyzed similarly to the primary endpoint using linear mixed‐effect models with repeated measures. For the mean number of acute migraine‐specific medication days per month in the last 4 weeks (weeks 9–12) of the DBT phase, the number of acute migraine‐specific medication days per month was the dependent variable, and there was no covariate in the model.

The proportion of participants with ≥50% reduction from the OP in the number of moderate to severe MMDs in the last 4 weeks (weeks 9–12) of the DBT phase was analyzed using Mantel–Haenszel risk estimation ²⁷ with stratification by randomization stratum for the DBT migraine analysis set. Missing data were imputed as failure. The stratified difference estimate (rimegepant vs. placebo), SE, 95% CI, and p‐value were reported.

Changes in MSQoL role function‐restrictive domain score, MIDAS total score, and EQ VAS score at week 12 were analyzed for the DBT efficacy analysis set (i.e., participants who were randomized only once and took at least one dose of double‐blind study drug) with paired data (i.e., nonmissing scores at both baseline and week 12). Each outcomes research endpoint was analyzed using linear regression models with the following variables: week 12 change from baseline in the score as the dependent variable; baseline score as a covariate; and fixed effects for treatment group and randomization stratum. The week 12 difference estimate (rimegepant vs. placebo), SE, 95% CI, and p‐value were reported for each endpoint. SE was estimated using the Huber–White robust “sandwich” estimator.

Type 1 error was controlled using a hierarchical gatekeeping procedure. The significance of the primary efficacy endpoint was evaluated first at a two‐sided alpha level of 0.05; if it was significant, then the secondary efficacy and outcomes research endpoints were tested in a prespecified order, each at a two‐sided alpha level of 0.05: (1) proportion of participants with ≥50% reduction from the OP in the number of moderate to severe MMDs in the last 4 weeks (weeks 9–12) of the DBT phase; (2) mean change from the OP in MMDs over the entire (weeks 1–12) DBT phase; (3) mean change from the OP in MMDs over the first 4 weeks (weeks 1–4) of the DBT phase; (4) mean number of acute migraine‐specific medication days per month in the last 4 weeks (weeks 9–12) of the DBT phase; (5) mean change from baseline at week 12 of the DBT phase in the MSQoL v2.1 role function‐restrictive domain score; (6) mean change from baseline at week 12 of the DBT phase in the MIDAS total score; and (7) mean change from baseline at week 12 of the DBT phase in the EQ VAS score. Testing stopped at the first nonsignificant endpoint, with subsequent p‐values presented only for descriptive purposes.

The frequency of safety endpoints during the DBT phase was assessed descriptively for the DBT safety analysis set, comprising participants who took at least one dose of double‐blind study drug. AEs were coded using Medical Dictionary for Regulatory Activities version 26.1.

All statistical analyses were performed using SAS statistical software (SAS Institute, Cary, NC, USA) version 9.4 or higher.

RESULTS

Participant disposition and demographics

The DBT phase of the study was conducted August 9, 2022, through January 18, 2024. A total of 496 participants were randomized to rimegepant (n = 247) or placebo (n = 249), and all were treated with study drug (Figure 1). In the rimegepant group, 233 (94.3%) participants completed the DBT phase and 14 did not; in the placebo group, 238 (95.6%) participants completed the DBT phase and 11 did not (Figure 1).

FIGURE 1.

Disposition of study participants. DBT, double‐blind treatment.

The DBT migraine analysis set comprised 484 participants (rimegepant n = 240, placebo n = 244), the DBT efficacy analysis set comprised 496 participants (rimegepant n = 247, placebo n = 249), and the DBT safety analysis set comprised 496 participants (rimegepant n = 247, placebo n = 249).

The mean (SD) age of participants was 43.9 (10.2) years, 436 (90.1%) participants were female, and 161 (33.3%) were using stable preventive migraine medication through randomization in the DBT migraine analysis set. According to ICHD‐3 criteria, 146 (30.2%) participants had historical chronic migraine. Demographics and baseline characteristics were similar across treatment groups (Table 1). The percentage of participants with historical chronic migraine was similar between the population with stable prophylactic migraine medication use through randomization (31.7%) and the population without prophylactic medication use (29.4%).

TABLE 1.

Demographics and baseline characteristics.

Characteristic	Rimegepant 75 mg, n = 240	Placebo, n = 244	Overall, N = 484
Age, years	44.8 (9.6)	43.0 (10.7)	43.9 (10.2)
Sex
Female	220 (91.7)	216 (88.5)	436 (90.1)
Male	20 (8.3)	28 (11.5)	48 (9.9)
Height, cm	159.6 (6.4)	160.5 (6.7)	160.0 (6.5)
Weight, kg	56.5 (9.7)	56.4 (10.8)	56.4 (10.3)
Body mass index, kg/m2	22.2 (3.5)	21.8 (3.5)	22.0 (3.5)
Stable preventive migraine medication use through randomization	79 (32.9)	82 (33.6)	161 (33.3)
Chronic migraine according to ICHD‐3 criteria a	73 (30.4)	73 (29.9)	146 (30.2)
Age at migraine onset, years a	20.5 (9.5)	19.5 (8.3)	20.0 (8.9)
Number of moderate or severe migraine attacks per month in the past 3 months a	8.3 (3.0)	8.4 (2.8)	8.3 (2.9)
Duration of migraine attacks on average, untreated, h a	28.3 (19.3)	25.0 (18.5)	26.6 (19.0)
Primary migraine type a
Without aura	211 (87.9)	210 (86.1)	421 (87.0)
With aura	29 (12.1)	34 (13.9)	63 (13.0)

Note: DBT migraine analysis set, including participants who were randomized only once and took at least one dose of double‐blind study drug, with ≥14 days (not necessarily consecutive) of electronic diary efficacy data in both the observation phase and ≥1 month (4‐week interval) of the DBT phase. Data are provided as mean (SD) or n (%).

Abbreviations: DBT, double‐blind treatment; ICHD‐3, International Classification of Headache Disorders 3rd edition. ¹

^a Historical data collected at the screening visit.

Efficacy

During the OP, participants in the rimegepant and placebo groups, respectively, reported a mean (SD) of 9.3 (3.1) and 9.0 (3.1) MMDs, of which 6.4 (3.2) and 6.0 (3.0) MMDs were moderate or severe.

Mean (SD) exposure to the double‐blind study drug was 11.6 (2.0) weeks for rimegepant (n = 247) and 11.6 (2.0) weeks for placebo (n = 249) for the DBT safety analysis set.

The study met its primary endpoint, with a statistically significant greater mean reduction from the OP in MMDs in the last 4 weeks of the DBT phase for rimegepant versus placebo (difference in least squares mean change for rimegepant vs. placebo: −1.1 [95% CI −1.73 to −0.38]; p = 0.002; Table 2).

TABLE 2.

Key efficacy and outcomes research endpoints during the DBT phase.

Endpoint	Rimegepant 75 mg	Placebo	Difference (rimegepant – placebo)
Primary endpoint
Mean change from OP in the number of MMDs in the last 4 weeks of DBT phase a , b
OP, MMDs, mean (SD)	9.3 (3.1)	9.0 (3.1)	–
LS mean change (SE)	−2.4 (0.2)	−1.4 (0.2)	−1.1 (0.3)
95% CI	−2.93 to −1.96	−1.87 to −0.91	−1.73 to −0.38
p	–	–	0.002*
Secondary endpoints
Participants with ≥50% reduction from OP in the number of moderate to severe MMDs in the last 4 weeks of DBT phase a , c
OP, moderate or severe MMDs, mean (SD)	6.4 (3.2)	6.0 (3.0)	–
Response rate, % (n/N)	41.7 (100/240)	34.4 (84/244)	7.3
95% CI	35.5 to 47.9	28.5 to 40.4	−1.4 to 15.9
p	–	–	0.099
Mean change from OP in the number of MMDs over the entire DBT phase a , b
OP, MMDs, mean (SD)	9.3 (3.1)	9.0 (3.1)	–
LS mean change (SE)	−2.5 (0.2)	−1.1 (0.2)	−1.5 (0.3)
95% CI	−2.91 to −2.15	−1.47 to −0.64	−2.02 to −0.92
p	–	–	<0.001**
Mean change from OP in the number of MMDs in the first 4 weeks of the DBT phase a , b
OP, MMDs, mean (SD)	9.3 (3.1)	9.0 (3.1)	–
LS mean change (SE)	−2.7 (0.2)	−0.8 (0.2)	−1.9 (0.3)
95% CI	−3.11 to −2.20	−1.26 to −0.32	−2.51 to −1.23
p	–	–	<0.001**
Mean number of acute migraine‐specific medication days (triptans, ergotamine) per month in the last 4 weeks of the DBT phase a , d
LS mean (SE)	5.0 (0.3)	5.8 (0.3)	−0.8 (0.4)
95% CI	4.40 to 5.55	5.24 to 6.40	−1.64 to −0.05
p	–	–	0.037**
Mean change from baseline at week 12 of the DBT phase in the MSQoL v2.1 role function‐restrictive domain score e , f
Baseline score, mean (SD)	66.8 (15.4)	69.4 (15.3)	–
LS mean change (SE)	7.8 (0.8)	3.7 (0.8)	4.1 (1.1)
95% CI	6.20 to 9.44	2.05 to 5.36	1.89 to 6.33
p	–	–	<0.001**
Mean change from baseline at week 12 of the DBT phase in MIDAS total score e , f
Baseline score, mean (SD)	14.8 (16.7)	15.2 (19.0)	–
LS mean change (SE)	−4.0 (0.8)	−1.6 (1.2)	−2.4 (1.3)
95% CI	−5.57 to −2.42	−3.88 to 0.70	−4.98 to 0.17
p	–	–	0.067**
Mean change from baseline at week 12 of the DBT phase in EQ VAS score e , g
Baseline score, mean (SD)	77.1 (17.0)	78.8 (16.7)	–
LS mean change (SE)	3.5 (1.0)	0.8 (1.1)	2.7 (1.5)
95% CI	1.60 to 5.37	−1.40 to 3.02	−0.19 to 5.54
p	–	–	0.067**

Note: Rimegepant 75 mg was tested for superiority versus placebo at a two‐sided alpha level of 0.05 on the primary endpoint. If significant, the key secondary endpoints were evaluated using a hierarchical gatekeeping procedure, in the order shown, with each test conducted at a two‐sided alpha of 0.05. Testing stopped at the first nonsignificant endpoint, with subsequent nominal p‐values.

Abbreviations: CI, confidence interval; DBT, double‐blind treatment; EQ VAS, EQ‐5D‐5L visual analog scale; LS, least squares; MIDAS, Migraine Disability Assessment; MMD, monthly migraine day; MSQoL, Migraine‐Specific Quality‐of‐Life Questionnaire; OP, observation phase.

^a DBT migraine analysis set (rimegepant n = 240, placebo n = 244), including participants who were randomized only once and took at least one dose of double‐blind study drug, with ≥14 days (not necessarily consecutive) of electronic diary efficacy data in both the OP and ≥1 month (4‐week interval) of the DBT phase.

^b Linear mixed‐effects model with repeated measures. Number of MMDs in OP was a covariate; treatment group, randomization stratum (i.e., stable preventive migraine medication use through randomization), month, and month‐by‐treatment group interaction were fixed effects.

^c Stratified by randomization stratum using Mantel–Haenszel risk estimation.

^d Linear mixed‐effects model with repeated measures. Treatment group, randomization stratum, month, and month‐by‐treatment group interaction were fixed effects.

^e DBT efficacy analysis set (rimegepant n = 247, placebo n = 249), including participants who were randomized only once and took at least one dose of double‐blind study drug. Linear regression model: treatment group and randomization stratum were fixed effects and baseline score was a covariate. Paired data were used (i.e., nonmissing scores at both baseline and week 12).

^f Baseline: rimegepant n = 246, placebo n = 249. Participants with paired data at week 12: rimegepant n = 228, placebo n = 237.

^g Baseline: rimegepant n = 246, placebo n = 248. Participants with paired data at week 12: rimegepant n = 228, placebo n = 237.

^*Statistically significant in hierarchical gatekeeping procedure.

^**Nominal p‐value without formal hypothesis testing.

The response rates for the first secondary efficacy endpoint (i.e., participants with ≥50% reduction from the OP in moderate to severe MMDs in the last 4 weeks of the DBT phase) numerically favored rimegepant versus placebo and were 41.7% (95% CI = 35.5%–47.9%) in the rimegepant group and 34.4% (95% CI = 28.5%–40.4%) in the placebo group (p = 0.099; Table 2). Because the findings for the first secondary efficacy endpoint were not statistically significant, formal hypothesis testing did not proceed. Mean reductions in the number of MMDs over the entire DBT phase and in the first 4 weeks of the DBT phase were notably greater for rimegepant versus placebo (Table 2). All other secondary endpoints, including mean number of acute migraine‐specific medication days per month in the last 4 weeks of the DBT phase and mean changes at week 12 in the MSQoL v2.1 role function‐restrictive domain score, MIDAS total score, and EQ VAS score, also numerically favored rimegepant versus placebo (Table 2).

Subgroup analyses for the reduction from the OP in MMDs based on stable prophylactic migraine medication use through randomization (Table S1) and historical chronic migraine according to ICHD‐3 (Table S2) were consistent with the results for the whole population.

The rate of missing eDiary data was low, with >95% of participants being evaluable in the DBT efficacy analysis set for each month (that is, with ≥14 days of eDiary efficacy data) through the DBT phase. The results for the sensitivity analyses of the primary endpoint were consistently significant for rimegepant 75 mg versus placebo, including jump to reference analysis to impute missing data (data not shown).

Safety

During the DBT phase, AEs were reported by 54.7% of participants in the rimegepant group and 41.0% of participants in the placebo group. The most frequent AEs were nasopharyngitis, oropharyngeal pain, coronavirus infection, upper abdominal pain, COVID‐19, constipation, pyrexia, influenza, and back pain (Table 3). Most AEs were mild or moderate in severity. AEs were considered by the investigator to be related to blinded study drug in 9.7% of participants in the rimegepant group and 4.4% in the placebo group. SAEs were reported in 0.8% (n = 2) of participants in the rimegepant group and 0.4% (n = 1) of participants in the placebo group; all were considered unrelated to study drug. The SAEs comprised one participant with acute pancreatitis and one with COVID‐19 in the rimegepant group; in the placebo group, one participant had an SAE of appendicitis. AEs led to study drug discontinuation in 1.6% of participants in the rimegepant group and 0.8% in the placebo group (Table 3).

TABLE 3.

Summary of AEs during the DBT phase.

AE	Participants, n (%)
	Rimegepant 75 mg, n = 247	Placebo, n = 249
Any AE	135 (54.7)	102 (41.0)
PT ≥ 2% in any treatment group a
Nasopharyngitis	21 (8.5)	25 (10.0)
Oropharyngeal pain	9 (3.6)	8 (3.2)
Coronavirus infection	8 (3.2)	4 (1.6)
Abdominal pain, upper	8 (3.2)	2 (0.8)
COVID‐19	7 (2.8)	7 (2.8)
Constipation	7 (2.8)	1 (0.4)
Pyrexia	6 (2.4)	5 (2.0)
Influenza	5 (2.0)	5 (2.0)
Back pain	3 (1.2)	6 (2.4)
Mild AE	110 (44.5)	96 (38.6)
Moderate AE	24 (9.7)	6 (2.4)
Severe AE	1 (0.4)	0
SAE	2 (0.8)	1 (0.4)
AE related to study drug	24 (9.7)	11 (4.4)
SAE related to study drug	0	0
AE leading to study drug discontinuation	4 (1.6)	2 (0.8)
AE of special interest
Hepatic‐related AE b	3 (1.2)	4 (1.6)
Medication‐overuse headache AE c	0	0
Potential drug abuse AE b , d	4 (1.6)	5 (2.0)
Cardiovascular AE b	1 (0.4)	1 (0.4)
Suicidality AE e	0	0

Note: DBT safety analysis set, including participants who took at least one dose of double‐blind study drug.

Abbreviations: AE, adverse event; DBT, double‐blind treatment; MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term; SAE, serious AE; SOC, system organ class.

^a MedDRA version 26.1.

^b Based on standardized MedDRA queries.

^c PT of medication‐overuse headache; lowest level term of rebound headache.

^d Also based on clinical review of PTs in the depressant, stimulant, and psychotomimetic categories of the general disorders and administration site conditions SOC, nervous system disorders SOC, and psychiatric disorders SOC, as recommended in US Food and Drug Administration Guidance for Industry Assessment of Abuse Potential of Drugs section V.B (January 2017).

^e PTs include the following: completed suicide, suicide attempt, suicidal ideation.

Hepatic‐related AEs were reported in 1.2% (n = 3) of participants in the rimegepant group (the preferred terms included hepatic enzyme increase, liver function test increase, hepatic function abnormal, and hepatic steatosis [n = 1 each]) and 1.6% (n = 4) of participants in the placebo group (including ALT increase, AST increase, and hepatic steatosis [n = 1 each] and hepatic function abnormal [n = 2]).

Liver function test data were available for 241 (rimegepant) and 246 (placebo) participants during the DBT phase. No participants had AST or ALT levels >3 × ULN or total bilirubin >2 × ULN during the DBT phase.

DISCUSSION

This study is the first randomized placebo‐controlled trial of rimegepant for the preventive treatment of migraine to be conducted outside the United States and the second conducted globally. The findings demonstrated the efficacy and safety of rimegepant for the prevention of migraine in Japan, supporting the previous findings ¹⁹ and broadening them to a wider population.

The study met its primary objective by demonstrating a statistically significant greater reduction in MMDs for rimegepant compared with placebo during the last 4 weeks of the DBT phase. The results for all the secondary efficacy and outcomes research endpoints numerically favored rimegepant versus placebo, supporting the findings for the primary efficacy endpoint. A reduction of 1 day per month in headache frequency is often considered clinically meaningful ²⁸ and has been associated with better health‐related outcomes. ²⁹ , ³⁰ Reductions in MMDs for rimegepant versus placebo were observed during the first 4 weeks of the DBT phase and persisted throughout the 12‐week DBT phase. Benefits of rimegepant over placebo on quality of life, headache‐related disability, and health were observed in the greater improvements from baseline in MSQoL, MIDAS, and EQ VAS scores at week 12 of the DBT phase. The efficacy of rimegepant for the prevention of migraine in Japan supports and extends previous findings of a study conducted in the United States. ¹⁹ Overall, the findings suggest rimegepant reduces MMDs as early as the first 4–12 weeks after administration and decreases migraine severity, and its impact on quality of life in turn reduces the overall disease burden.

No new safety issues for rimegepant were identified, and the safety profile of rimegepant during the DBT phase of the current study was consistent with previous longer term studies. ¹⁹ , ³¹ Rimegepant was well tolerated, with a very low rate of AEs leading to study drug discontinuation and no evidence of drug‐induced liver injury.

Japanese treatment guidelines recommend considering preventive treatment for patients with more than two migraine attacks per month, patients with a history of headache interfering with daily activities more than 3 days per month, patients with lack of response to acute treatments for migraine, and patients for whom acute treatment medications are unsuitable. ¹³ Rimegepant is the only medication demonstrated to be effective for both acute ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ and preventive ¹⁹ treatment of migraine. With its oral route of administration, comparatively short half‐life (~10 h), ³² early onset of preventive efficacy, and good safety profile (in the current study and previously ¹⁹ ), rimegepant fulfills an unmet need for the preventive treatment of migraine. There is no evidence that gepants cause medication‐overuse headache. ⁸ , ³¹ Phase 3 studies of rimegepant for the acute treatment of migraine conducted in the United States ¹⁴ , ¹⁵ , ¹⁶ and Asia ¹⁷ demonstrated a durable therapeutic response through 48 h following a single dose, and EOD dosing was effective in reducing MMD versus placebo, suggesting an appropriate dosing regimen. ¹⁹ The current findings demonstrating the efficacy and safety of rimegepant ODT for the preventive treatment of migraine in Japan support the previous findings of the efficacy and safety of rimegepant oral tablets for the preventive treatment of migraine in a US population. ¹⁹ The rimegepant ODT and rimegepant oral tablets are bioequivalent. ³³

Limitations of this study include the relatively short duration of the DBT phase, which does not permit the longer term double‐blind evaluation of treatment effects; longer term data from the open‐label phase of the study will be reported separately. The exclusion criteria for the study, including unstable cardiovascular disease and higher headache frequency, somewhat limit the generalizability and external validity of the results for patients with complex medical histories or more severe migraine. The study did not include an active comparator, so relative effectiveness compared to existing standard‐of‐care preventive treatments cannot be evaluated; further head‐to‐head studies will be needed to further inform the position rimegepant in clinical practice. However, a 3‐month double‐blind comparison of rimegepant and galcanezumab demonstrated that both treatments were effective for episodic migraine, with no statistically significant difference in the primary endpoint (the proportion of participants with ≥50% reduction in MMDs from baseline across the 3‐month DBT period) between treatments. ³⁴

CONCLUSIONS

Rimegepant 75 mg EOD demonstrated efficacy superior to that of placebo for the preventive treatment of migraine, with a favorable safety profile. Numerical reductions in MMDs were observed in the first month and throughout the 12‐week DBT phase. The findings support the previous findings from the initial randomized placebo‐controlled trial of rimegepant for the preventive treatment of migraine and broaden them to a wider population. The open‐label extension phase of this study will assess the safety and effectiveness of rimegepant 75 mg EOD and as needed on nonscheduled dosing days for an additional 40 weeks.

AUTHOR CONTRIBUTIONS

Shigekazu Kitamura: Data curation; investigation; writing – review and editing. Yasuhiko Matsumori ‐ Data curation; investigation; writing ‐ review and editing. Toshimasa Yamamoto: Data curation; investigation; writing – review and editing. Tomofumi Ishikawa: Conceptualization; data curation; methodology; writing – review and editing. Yuko Hoshino: Data curation; writing – review and editing. Hiroki Yoshimatsu: Conceptualization; data curation; formal analysis; methodology; writing – review and editing. Alexandra Thiry: Conceptualization; data curation; formal analysis; methodology; writing – review and editing. Akio Arakawa: Conceptualization; methodology; supervision; writing – review and editing. Robert Croop: Conceptualization; data curation; methodology; supervision; writing – review and editing. Terence Fullerton: Conceptualization; data curation; methodology; supervision; writing – review and editing. Fumihiko Sakai: Conceptualization; data curation; investigation; methodology; writing – review and editing. Takao Takeshima: Data curation; investigation; writing – review and editing.

FUNDING INFORMATION

This study was sponsored by Biohaven Pharmaceuticals, which was acquired by Pfizer in October 2022.

CONFLICT OF INTEREST STATEMENT

Shigekazu Kitamura is a consultant for Eli Lilly Japan. Yasuhiko Matsumori received personal consultancy fees from Amgen Astellas BioPharma, Daiichi Sankyo Company, Eli Lilly Japan, and Otsuka Pharmaceutical Company during the conduct of the study. Toshimasa Yamamoto declares no conflicts of interest. Tomofumi Ishikawa is an employee of Pfizer and owns stock/options in Pfizer. Yuko Hoshino is an employee of Pfizer and owns stock/options in Pfizer. Hiroki Yoshimatsu is an employee of Pfizer and owns stock/options in Pfizer. Alexandra Thiry was an employee of Biohaven Pharmaceuticals, owns stock in Biohaven Pharmaceuticals, is an employee of Pfizer, and owns stock/options in Pfizer. Akio Arakawa is an employee of Pfizer and owns stock/options in Pfizer. Robert Croop was an employee of Biohaven Pharmaceuticals and Pfizer, owns stock/options in Biohaven Pharmaceuticals and Actio Biosciences, has received research payments from Pfizer, and provides services to Collima, which has had consulting agreements with Pfizer, Actio Biosciences, Aptose Biosciences, Biohaven Pharmaceuticals, Manistee Therapeutics, NVP Associates, Soleil Labs, and Vida Ventures Management Company. Terence Fullerton is an employee of Pfizer and owns stock/options in Pfizer. Fumihiko Sakai is a consultant for Amgen, Otsuka, and Eli Lilly. Takao Takeshima is an advisor for Sawai, Teijin, and Hedgcock MedTech, and reports honoraria (Otsuka, Amgen, Eli Lilly Japan, and Daiichi Sankyo) and grants for commissioned/joint research (Pfizer, Lundbeck, AbbVie, and Eli Lilly Japan).

Supporting information

Data S1.

Kitamura S, Matsumori Y, Yamamoto T, et al. Efficacy and safety of rimegepant for the preventive treatment of migraine in Japan: A double‐blind, randomized controlled trial. Headache. 2025;65:1403‐1412. doi: 10.1111/head.14995

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 deidentified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.