Robert Croop, Richard B Lipton, David Kudrow, David A Stock, Lisa Kamen, Charles M Conway, Elyse G Stock, Vladimir Coric, Peter J Goadsby
Summary
Background Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine.
Methods We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9–12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638.
Findings Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9–12. The change from the observation period in mean number of migraine days per month during weeks 9–12 was -4·3 days (95% CI –4·8 to –3·9) with rimegepant and -3·5 days (–4·0 to –3·0) with placebo (least squares mean difference -0·8 days, 95% CI -1·46 to -0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died.
Interpretation Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted.
Funding Biohaven Pharmaceuticals.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Introduction Migraine pharmacotherapy is generally classified into
Migraine is a chronic neurological condition characterised two types: acute treatments for relief of attacks when
by recurrent attacks of headache that are typically they occur; and preventive treatments to reduce attack
unilateral, throbbing, and associated with photophobia, frequency and severity. Each type of treatment has
1More than 1 billion 6 and separate guidelines.7–9 Since almost
people worldwide have migraine, three-quarters of whom every individual with migraine needs acute treatment,
2Migraine is the leading cause of disability prescribing preventive treatment will necessarily entail
3Almost two- polypharmacy, because different drugs are used to relieve
thirds (63%) of people with migraine have relatively infre- attacks (acute) and reduce the frequency and severity
4and of attacks (preventive). Most traditional oral preventive
treatment can be uncomplicated. However, for individuals treatments (eg, β blockers, antiepileptic drugs, and
who experience more frequent attacks (ie, more than tricyclic antidepressants) were developed for indications
four per month), or for whom infrequent attacks are other than migraine. They typically have suboptimal
incapacitating, accounting for roughly a third (38%) of the 10 and adherence is gen-
total migraine population, adding a regularly scheduled erally poor (≤20% of patients persist on treatment after
5 11
Published Online December 15, 2020 https://doi.org/10.1016/
S0140-6736(20)32544-7 See Online/Comment https://doi.org/10.1016/
S0140-6736(20)32624-6 Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA (Prof R B Lipton MD);
NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College Hospital/SLaM Biomedical Research Centre, King’s College London, UK
(Prof P J Goadsby MD); University of California,
Los Angeles, Los Angeles, CA, USA (Prof P J Goadsby); California Medical Clinic for Headache, Santa Monica, CA, USA (D Kudrow MD); Biohaven Pharmaceuticals, New Haven, CT, USA (R Croop MD,
D A Stock PhD, L Kamen MHA,
C M Conway PhD, E G Stock MD, V Coric MD)
Correspondence to:
Dr Robert Croop, Biohaven Pharmaceuticals, New Haven, CT 06510, USA robert.croop@ biohavenpharma.com
Research in context
Evidence before this study
We did an unrestricted PubMed search with the terms “migraine”, “acute”, and “prevention”, with a filter for clinical trials; this search returned 750 articles. Few drugs have been shown to provide benefits for acute and preventive treatment of migraine, and no drug has regulatory approval for both indications. Five studies of drugs with an indication for acute treatment of migraine showed benefits in migraine prevention. A non-steroidal anti-inflammatory drug (ibuprofen) was effective for prevention of migraine, and three triptans (frovatriptan, naratriptan, and zolmitriptan) showed modest benefits for short-term prevention of menstrual migraine. However, all these drugs are associated with medication
overuse headache, which limits their use as preventive agents. Rimegepant is an oral calcitonin gene-related peptide receptor antagonist that has shown tolerability and efficacy for acute treatment of migraine. Findings of an uncontrolled open-label study suggested that regular intermittent dosing of rimegepant might be effective for preventive treatment of migraine.
Added value of this study
The findings of our randomised placebo-controlled trial showed that orally administered rimegepant is safe, tolerable, and efficacious as a preventive treatment for migraine. The primary efficacy endpoint was change from a 4-week pretreatment observation period in the mean number of migraine days per month in the last 4 weeks of a double-blind treatment phase
(weeks 9–12). Participants assigned rimegepant had a significantly greater change than those assigned placebo (–4·3 [95% CI –4·8 to –3·9] days vs –3·5 [-4·0 to -3·0] days). Moreover, participants treated with rimegepant showed a significant benefit over placebo with respect to secondary
efficacy endpoints of at least a 50% reduction from the 4-week observation period in the mean number of moderate or severe migraine days per month in weeks 9–12 (49% [95% CI 44 to 54]
vs 41% [36 to 47]) and change from the 4-week observation period in the mean number of total migraine days per month in weeks 1–12 of the double-blind treatment phase (-3·6 [95% CI
-4·0 to -3·2] days vs -2·7 [-3·1 to -2·3] days). Use of
rimegepant as a preventive and acute treatment could provide a simple comprehensive approach to the treatment of migraine.
Implications of all the available evidence
In clinical trials, rimegepant has shown efficacy and a favourable safety and tolerability profile. The drug has a convenient oral administration and its pharmacokinetic profile (half-life around 11 h) provides clinicians with greater flexibility for treatment compared with monoclonal antibodies (which have half-lives around 1 month). The short half-life of rimegepant relative to monoclonal antibodies is especially useful for patients who
have a planned or unplanned pregnancy or adverse events that might require rapid cessation of drug exposure. Additional research could help to clarify the role of rimegepant for contemporaneous preventive and acute treatment of migraine.
Rimegepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist approved in the USA for
12 The 75 mg dose of rimegepant was safe and efficacious in multiple
13–15 Four monoclonal antibodies that target the CGRP receptor or ligand have been established as preventive treatments
16–20 Since injectable and orally administered
21and a reduction in migraine days per month was recorded with rimegepant 75 mg dosed every other day in a long-
22we postulated that this dose regimen of rimegepant would be safe and effective for preventive treatment of migraine. Demonstration of sustained benefit for 48 h after one 75 mg dose of
15 suggested that daily dosing would not be needed for a preventive effect. Since CGRP monoclonal antibodies have shown efficacy in episodic migraine and chronic migraine, treatment effects with rimegepant were expected to be evident in both conditions; thus, a study population with a broad range of attack frequency would be appropriate. The aim of our study was to compare the safety, tolerability, and efficacy of rimegepant taken every other day with placebo for preventive treatment of migraine.
Methods
Study design and participants
We did a multicentre, randomised, double-blind, placebo-controlled trial to assess the safety and efficacy of rimegepant for preventive treatment of migraine at 92 study centres in the USA. The study comprised three phases: a screening phase, which included a 4-week observation period; a 12-week double-blind treatment phase; and a 52-week open-label extension phase. We report here findings from the 4-week observation period and the 12-week double-blind treatment phase; the 52-week open-label extension will be reported separately.
Eligible participants were men and women aged 18 years and older with at least a 1-year history of migraine with aura, migraine without aura, or chronic migraine, as defined by the International Classification
1 and an initial presentation of migraine before age 50 years. Participants also had to have at least four, and not more than 18, migraine attacks of moderate or severe intensity per month (1 month defined as 4 weeks) over the 3-month period before the screening visit and at least 6 migraine days during the lead-in 4-week observation period. Participants had to be able to distinguish migraine attacks from attacks of tension-type and cluster head- ache. During the 12-week double-blind treatment phase
of the study, participants were allowed to take one preventive migraine drug, excluding CGRP receptor antagonists and CGRP monoclonal antibodies, provided that the dose was stable for at least 3 months before the 4-week observation period and did not change during the observation period or the double-blind treatment phase. Participants were required to use two reliable means of contraception to avoid pregnancy throughout the study; women of childbearing potential had to have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) before receiving any study drug. Participants also had to have normal findings on medical and laboratory assessments; those with a clinical abnormality or laboratory parameters outside the reference range could be eligible for the study if the finding was judged not to be clinically significant by the investigator and did not introduce additional risk factors or interfere with the study procedures.
Individuals were excluded if they had more than 18 headache days (migraine or non-migraine) during the 4-week observation period or had a history of non- response to more than two drug categories for preventive treatment of migraine. We also excluded individuals if investigators believed they had a history or current evidence of any medical condition that would expose them to undue risk of a significant adverse event or interfere with assessments of safety or efficacy; if they had been treated for or showed evidence of alcohol or drug abuse within the past 12 months (48 weeks); if they had a history of drug or other allergy that made them unsuitable for participation; or if they had an electro- cardiogram or laboratory test finding that raised safety or tolerability concerns. Complete exclusion criteria are available in the appendix (pp 52–56).
Our study was done in accordance with Good Clinical Practice guidelines, the Declaration of Helsinki, and all applicable local regulations. The protocol was approved by a central Institutional Review Board (Advarra IRB, Columbia, MD, USA) and an Institutional Review Board at one study site (MedStar Georgetown Headache– Georgetown University, McLean, VA, USA). The study protocol is available in the appendix (pp 6–96). Partici- pants provided written informed consent before they were screened for the study. An independent panel of three liver experts was engaged to periodically review the hepatic safety of the entire clinical programme and selected cases, including liver function test abnormalities. This study did not make use of a Data Safety Monitoring Committee because the long-term safety of rimegepant 75 mg dosed at least every other day was previously
22
Randomisation and masking
Immediately after written informed consent was obtained and before any study-related procedures were undertaken, site staff obtained a participant identification
number by entering a new participant into an interactive web response system (Rave Randomization and Trial Supply Management, Medidata Solutions, New York, NY, USA). At the baseline visit, eligible participants were randomly allocated (1:1) either rimegepant or placebo; randomisation was stratified by use of preven- tive migraine medications (yes or no). After confirming participant eligibility, registering a participant for randomisation triggered a container number for study medication. The study drug was dispensed at baseline and as needed at study visits. To achieve masking of random assignments, placebo tablets were matched to rimegepant tablets by appearance. Participants, inves- tigators, and study personnel were unaware of treatment assignments.
Procedures
During the 4-week observation period, participants used an electronic diary to document the occurrence and severity of migraine attacks and a paper diary to record use of all migraine treatments and, if a woman, daily menstrual cycle information. 4 days before the baseline (randomisation) visit, individuals returned to the study site for a prerandomisation (laboratory) visit. At this visit, safety laboratory tests and a serum pregnancy test for women of childbearing potential were done, and diary compliance was assessed.
At the baseline visit, before participants were ran- domised and given study medication, eligibility for con- tinued participation was assessed. Participants meeting all inclusion criteria and none of the exclusion criteria were given 30 tablets of either rimegepant 75 mg or matching placebo and instructed to take one tablet every other calendar day, independent of their migraine headache status on that day. Individuals were told to continue using the electronic diary to document the occurrence and severity of migraine attacks and the paper diary to record use of standard migraine drugs and menstrual cycle information (women only). In addition to study medication, participants could continue using one additional protocol-specified drug for migraine prevention (eg, topiramate, amitriptyline, or propranolol) as long as the dose was stable for at least 3 months before the start of the 4-week observation period and was not expected to change throughout the study. Individuals were also instructed to record their use of rescue medication in the paper diary; permitted rescue medications during the 12-week double-blind treatment phase included triptans, non-steroidal anti-inflammatory drugs, paracetamol up to 1000 mg/day for a maximum of 2 consecutive days (including a fixed combination con- taining paracetamol 250 mg, aspirin 250 mg, and caffeine 65 mg), baclofen, antiemetics, and muscle relaxants. Rimegepant was not permitted as a rescue medication. Participants who had migraine attacks during the 12-week double-blind treatment phase could use these rescue medications while maintaining regular every-other-day
See Online for appendix
dosing of the assigned study drug. At the baseline visit and week 12, participants completed or were administered via paper forms the Migraine-Specific Quality-of-Life
23 and the Migraine
24
After the baseline visit, participants returned to the study site at weeks 2, 4, 8, and 12 for review by study personnel of the electronic and paper diaries, assessment of study medication compliance, and monitoring of tolerability and safety, including vital signs, laboratory tests, and electrocardiography. At completion of the 12-week double-blind treatment phase, and with labora- tory results within acceptable ranges per protocol, participants were assessed for entry into an open-label extension phase (to be reported separately). Those who did not complete the double-blind treatment phase completed an end-of-treatment visit and 2-week and 8-week follow-up safety visits.
Outcomes
The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9–12).
Secondary efficacy endpoints were achievement of at least a 50% reduction from the 4-week observation period in the mean number of moderate or severe migraine days (moderate or severe headache pain intensity) per month in the last 4 weeks of the double- blind treatment phase (weeks 9–12); change from the 4-week observation period in the mean number of migraine days per month across the double-blind treatment phase (weeks 1–12); mean number of rescue medication days per month in the last 4 weeks of the double-blind treatment phase (week 9–12); and change from the 4-week observation period in the mean number of migraine days per month in the first 4 weeks of the double-blind treatment phase (weeks 1–4). Secondary endpoints related to disability were change from baseline in MSQ role function (restrictive domain score) at week 12 of the double-blind treatment phase and change from baseline in MIDAS total score at week 12 of the double- blind treatment phase.
Secondary endpoints related to safety and tolerability were the frequency of unique participants with: adverse events; serious adverse events; adverse events leading to discontinuation; clinically significant laboratory test abnormalities; increases in aspartate aminotransferase or alanine aminotransferase greater than three times the upper limit of normal (ULN) concurrently with bilirubin elevations greater than two times the ULN; and hepatic-related adverse events and hepatic-related adverse events leading to discontinuation of treatment.
Statistical analysis
With a sample size of roughly 800 participants random- ised, we anticipated that approximately 370 participants
per group would be included in the efficacy dataset. We assumed that if rimegepant provided approximately a 1-day advantage over placebo with respect to the primary efficacy endpoint, using a common SD of 3·75 days, the study would have approximately 95% power (nQuery version 8.0). Estimates for the change in migraine days per month and the SD accord with publicly available information from another investigational oral CGRP
25
The efficacy analysis was done in the efficacy-evaluable population, comprising all randomised participants who received at least one dose of their assigned study medication (rimegepant or placebo) during the 12-week double-blind treatment phase and who had at least 14 days of electronic diary efficacy data from the 4-week obser- vation period and for at least one 4-week interval during the 12-week double-blind treatment phase (4-week intervals comprised weeks 1–4, weeks 5–8, and weeks 9–12). The change from baseline primary efficacy endpoint was tested for superiority of rimegepant to placebo using a generalised linear mixed-effect model that included participant as a random effect and number of migraine days during the 4-week observation period as a covariate (SAS version 9.4 or higher). The model included fixed effects for treatment group; stratification factor (use of preventive migraine medication); study month in the double-blind treatment phase (month 1 was weeks 1–4, month 2 was weeks 5–8, and month 3 was weeks 9–12); and the month-by-treatment group interaction. Evaluation of migraine days per month was based on data from the previous visit to the current visit (ie, 4-week intervals) and was prorated to account for missing diary data. We computed migraine days per month, prorated to 28 days, for participants in the efficacy analysis set who provided at least 14 days of electronic diary data during any reporting period (ie, the 4-week observation period or a 4-week interval during the 12-week double-blind treatment phase). Difference esti- mates (rimegepant – placebo), 95% CIs, and p values were reported for weeks 9–12 of the 12-week double-blind treatment phase.
The number of participants who had at least a 50% reduction in the mean number of moderate or severe migraine days per month in the last 4 weeks of the 12-week double-blind treatment phase (weeks 9–12) was analysed using a stratified Cochran-Mantel-Haenszel test after individuals with missing data in this period were imputed to be non-responders. The change from baseline in the mean number of migraine days per month over the entire double-blind treatment phase (weeks 1–12) was assessed with the same statistical model used to analyse the primary efficacy endpoint. Use of rescue medications (mean number of days per month) in weeks 9–12 of the double-blind treatment phase was assessed using a generalised linear mixed-effects model similar in structure to that used for the primary efficacy analysis. The change from baseline in the mean number of migraine days per month during weeks 1–4 of the
double-blind treatment phase was assessed with the same statistical model used to analyse the primary effi- cacy endpoint. The changes from baseline in MSQ role function (restrictive domain score) and MIDAS total score at week 12 were analysed using generalised linear models that included the baseline score as a covariate and fixed effects for treatment group and stratification factor (use of preventive migraine medication).
Type I error was controlled using hierarchical testing. The significance of the primary efficacy endpoint was evaluated at the 0·05 level. If the primary efficacy endpoint was significant then the six secondary efficacy endpoints were tested hierarchically in the following order, each at the 0·05 level: (1) proportion of participants with at least a 50% reduction in the mean number of moderate or severe migraine days per month in the last 4 weeks of the double-blind treatment phase; (2) change from baseline in the mean number of migraine days per month over the entire course of the double-blind treatment phase; (3) use of rescue medications (mean number of days per month) in the last 4 weeks of the double-blind treatment phase; (4) change from baseline in the mean number of migraine days per month in the first 4 weeks of the double-blind
based on grade 3–4 clinical laboratory assessments, graded using version 5.0 of Common Terminology Criteria for Adverse Events. The frequency of unique participants with alanine aminotransferase or aspartate aminotransferase levels greater than three times the ULN and total bilirubin greater than two times the ULN on the same laboratory test occasion were tabulated and presented with descriptive statistics and exact CIs.
This study is registered at ClinicalTrials.gov, NCT03732638.
Role of the funding source
The funder had a role in study design, data collection, data analysis, data interpretation, and writing of the report. RC, DAS, LK, CMC, EGS, and VC are employed by the funder. All authors had full access to all data in the study and had final responsibility for the decision to submit for publication.
Results
Between Nov 14, 2018, and Aug 30, 2019, 1591 par- ticipants were recruited and assessed for eligibility
treatment phase; (5) change from baseline in the MSQ role function (restrictive domain score) at week 12 of the double-blind treatment phase; and (6) change from baseline in the MIDAS total score at week 12 of the double- blind treatment phase. A secondary efficacy endpoint was tested only if the preceding endpoint in the hierarchy was determined to be significant.
A post-hoc exploratory analysis was done to assess separately the treatment effects of rimegepant in partici- pants with episodic migraine and chronic migraine on a key secondary endpoint (achievement of at least a 50% reduction from the observation period in the mean number of moderate or severe migraine days per month in the last 4 weeks of the double-blind treatment phase).
The safety endpoints reported are for the double- blind treatment phase. The safety analysis population included participants who received at least one dose of study drug. Investigators determined the severity of adverse events and the relation of adverse events to study treatment; no independent assessment was done. The investigators’ terms were coded and grouped by system organ class using version 21.1 of the Medical Dictionary for Regulatory Activities. If a participant had an adverse event of different severity over time, then only the worst severity was reported. Tabulations were made for the frequency of unique participants with adverse events (by severity, by relation to study drug, and overall), serious adverse events, adverse events leading to treatment discontinuation, hepatic-related adverse events (by severity, by relation to study drug, and overall), and hepatic-related adverse events leading to treatment discontinuation.
The frequency of unique participants with clinically
significant laboratory test abnormalities was tabulated Figure: Trial profile
Rimegepant (n=370)
Placebo (n=371)
Total (n=741)
recorded by electronic diary during the 12-week double- blind treatment period. The mean number of tablets
Age, years 41·3 (13·0) 41·1 (13·1) 41·2 (13·1)
Gender
Women 300 (81%) 313 (84%) 613 (83%)
Men 70 (19%) 58 (16%) 128 (17%)
Ethnicity
Hispanic or Latino 105 (28%) 98 (26%) 203 (27%)
Not Hispanic or Latino 265 (72%) 273 (74%) 538 (73%)
Race
White 295 (80%) 309 (83%) 604 (82%)
Black or African American 62 (17%) 49 (13%) 111 (15%)
Asian 1 (<1%) 7 (2%) 8 (1%)
Multiple 6 (2%) 2 (1%) 8 (1%)
American Indian or Alaska Native 6 (2%) 1 (<1%) 7 (1%)
Native Hawaiian or other Pacific islander 0 3 (1%) 3 (<1%)
Weight, kg 73·5 (13·3) 72·3 (13·0) 72·9 (13·1)
Height, cm 165·9 (8·7) 165·9 (8·5) 165·9 (8·6)
Body-mass index, kg/m² 26·6 (3·8) 26·2 (3·9) 26·4 (3·8)
Age at disease onset, years 18 (14–28) 18 (13–28) 18 (13–28)
Duration of untreated attacks, h 24 (12–48) 24 (12–48) 24 (12–48)
Moderate or severe attacks per month, n 7·8 (2·8) 7·8 (2·7) 7·8 (2·7)
History of chronic migraine
Yes 78 (21%) 95 (26%) 173 (23%)
No 292 (79%) 276 (74%) 568 (77%)
Primary migraine type
Without aura 220 (59%) 226 (61%) 446 (60%)
With aura 150 (41%) 145 (39%) 295 (40%)
Migraine days per month in the 4-week 10·3 (3·2) 9·9 (3·0) 10·1 (3·1) observation period, days*
Data are mean (SD), n (%), or median (IQR). *In efficacy-evaluable participants, 348 assigned rimegepant and 347 assigned placebo.
used per month was similar for individuals assigned rimegepant (13·8 [SD 1·6]) and placebo (13·9 [1·8]). The mean number of cumulative tablets used was also similar between groups (38·3 [SD 10·3] vs 37·9 [11·5]).
The treated population (n=741) had a mean age of 41·2 (SD 13·1) years (table 1). 613 (83%) participants were women and 604 (82%) were of white race. Mean bodyweight of participants was 72·9 (SD 13·1) kg and mean body-mass index was 26·4 (3·8) kg/m². The treated population (n=741) reported a history of moderate or severe attacks per month of mean 7·8 (SD 2·7). 446 (60%) participants had a primary migraine type without aura, and 173 (23%) were assessed as having chronic migraine by history. Without treatment, attacks lasted for a median of 24 (IQR 12–48) h. During the observation period, efficacy-evaluable participants in the rimegepant (n=348) and placebo (n=347) groups had a mean of 10·3 (SD 3·2) and 9·9 (3·0) migraine days per month, respectively.
Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9–12. The least squares mean difference between the rimegepant and placebo treatment groups was -0·8 days (95% CI-1·46 to -0·20; p=0·0099), with reductions of -4·3 days (–4·8 to –3·9) for rimegepant and -3·5 days (–4·0 to –3·0) for placebo (table 2).
Rimegepant was more effective than placebo for the percentage of participants with at least a 50% reduction in the mean number of moderate or severe migraine days per month in the last month of double-blind treatment with rimegepant and placebo (49% [95% CI 44 to 54] vs
Table 1: Demographics and baseline characteristics in the treated population
(figure). The most frequent reasons for screen failure and non-randomisation were non-compliance with or inability to complete the electronic diary during the 4-week observation period (n=180), not having at least 6 migraine days during the 4-week observation period (n=108), and exclusionary aminotransferase results (n=76). 747 participants were randomly allocated either rimegepant (n=373) or placebo (n=374); 741 individuals received study medication and were included in the safety analysis (370 received rimegepant and 371 received placebo). 695 participants who received at least one dose of their assigned study medication were categorised as evaluable for the efficacy analysis, 348 (94%) who were assigned rimegepant and 347 (94%) who were assigned placebo.
Mean time on double-blind treatment was similar for participants assigned rimegepant (11·2 weeks [SD 2·8]) and placebo (11·1 weeks [3·3]). 335 (91%) of 370 par- ticipants who received rimegepant and 335 (90%) of 371 who received placebo were at least 90% adherent with every-other-day dosing, based on average tablet use
41% [36 to 47]; p=0·044). Rimegepant was also superior to placebo for the least squares mean change in mean number of total migraine days per month over the 3-month treatment period (-3·6 [95% CI -4·0 to -3·2] vs
-2·7 [-3·1 to -2·3]; p=0·0017). The rimegepant and placebo treatment groups did not statistically differentiate with respect to the least squares mean days of rescue medication per month in the last month of the double- blind phase (3·7 [95% CI 3·3 to 4·2] vs 4·0 [3·5 to 4·4], p=0·39). Because of the hierarchical nature of the analysis plan for efficacy, further statistical testing was not done; all secondary efficacy endpoint results are presented in table 2.
The post-hoc analysis of participants with or without a history of chronic migraine showed evidence for a treatment effect of rimegepant in both subgroups with respect to the proportion of participants with at least a 50% reduction in the mean number of moderate or severe migraine days per month in weeks 9–12 of the double-blind treatment phase (appendix p 5).
Participants who received rimegepant and placebo were equally likely to have an adverse event, with 133 (36%) individuals in each treatment group reporting
Rimegepant (n=348)
Placebo (n=347)
Least squares mean difference between groups (95% CI)
p value
n Point estimate (95% CI) n Point estimate (95% CI)
Change in mean number of migraine days per month during weeks 9–12, days (primary efficacy outcome)†
348
–4·3 (–4·8 to –3·9) 347
–3·5 (–4·0 to –3·0) –0·8 (–1·5 to –0·2) 0·0099
≥50% reduction in mean number of moderate or severe migraine days per month during weeks 9–12
171
49% (44 to 54)
144
41% (36 to 47)
8% (0 to 15)
0·044
Change in mean number of total migraine days per month during weeks 1–12, days†
348
-3·6 (-4·0 to -3·2)
347
-2·7 (-3·1 to -2·3)
–0·8 (–1·3 to –0·3)
0·0017
Rescue medication days per month during weeks 9–12, days†
348
3·7 (3·3 to 4·2)
347
4·0 (3·5 to 4·4)
–0·2 (–0·8 to 0·3)
0·39‡
Change in mean number of total migraine days per month during weeks 1–4, days†
348
-2·9 (-3·3 to -2·5)
347
-1·7 (-2·2 to -1·3)
–1·2 (–1·7 to –0·6)
<0·0001‡
Change in MSQ role function (restrictive domain score) at week 12†§
269
18·0 (15·5 to 20·6)
266
14·6 (12·1 to 17·1)
3·5 (0·2 to 6·7)
0·036‡
Change in MIDAS total score at week 12†§ 269 -11·8 (-15·4 to -8·2) 266 -11·7 (-15·3 to -8·1) –0·1 (–4·7 to 4·5) 0·96‡
MSQ=Migraine-Specific Quality-of-Life Questionnaire. MIDAS=Migraine Disability Assessment. *Evaluable participants had ≥14 days of electronic diary efficacy data (not necessarily consecutive) in the 4-week observation period and data for at least 1 month (4-week interval) in the 12-week double-blind treatment phase. To control the type I statistical error rate at 0·05, a preplanned hierarchical testing procedure was applied; endpoints are presented in the sequence in which they were evaluated. †Analysed using a generalised linear mixed-effects model with treatment group, preventive migraine medication use at randomisation, study month, and month-by-treatment group interaction as fixed effects and participant as random effect. ‡Nominal p value in hierarchical testing. §Analysis only included participants who completed the MIDAS or MSQ questionnaire within the prespecified efficacy analysis window (weeks 10–13).
Table 2: Efficacy outcomes assessed in the efficacy-evaluable population*
an adverse event (table 3). Adverse events occurring in at
least 2% of rimegepant-treated participants were naso- pharyngitis, nausea, urinary tract infection, and upper respiratory tract infection (table 3). Nearly all adverse events were mild or moderate in severity. 40 (11%) patients who received rimegepant and 32 (9%) who received placebo had an adverse event considered (by investigators who were unaware of treatment assignments) to be related to study treatment. One participant who received placebo had a serious adverse event (pyelonephritis) that was deemed related to study treatment; no treatment- related serious adverse events were reported in the rimegepant group. The rate of discontinuation from the study due to an adverse event was low in both treatment groups; seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued due to an adverse event (table 3).
Four (1%) participants who were treated with rime- gepant and two (1%) who were treated with placebo had concentrations of alanine aminotransferase or aspartate
Rimegepant Placebo
(n=370) (n=371)
aminotransferase One participant
greater than three times the ULN. in the rimegepant group (<1%) had
Table 3: Summary of adverse events in the safety population
asymptomatic elevation of aminotransferases, with ala-
nine aminotransferase greater than ten times the ULN; alkaline phosphatase and bilirubin levels were always within normal limits. One (<1%) other participant in the rimegepant group had bilirubin levels greater than two times the ULN and was diagnosed with a hereditary liver disorder (Gilbert syndrome) after genotyping.
Discussion
The findings of our multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial showed efficacy of
rimegepant with respect to the primary efficacy endpoint of change from the 4-week observation period in the mean number of total migraine days per month in the last 4 weeks of the 12-week double-blind treatment phase. A positive response to rimegepant was also seen during the first 4 weeks of treatment, which indicates early onset of preventive effects. Rimegepant also showed a benefit in the proportion of participants with at least a 50% reduction in the mean number of moderate or severe migraine days per month in the last
4 weeks of the 12-week double-blind treatment phase, which corroborates the clinical importance of the reductions in the primary endpoint. These benefits were also evident in subgroups of participants with episodic and chronic migraine, but this analysis was post hoc and, therefore, not tested.
Our findings add to evidence that oral CGRP receptor antagonists can provide a targeted novel approach to
25,26 They also show, for the first time, that orally administered rimegepant 75 mg is effective as a preventive treatment over 12 weeks. Thus, rimegepant has shown efficacy as both an acute treatment and a
14,15
The safety and tolerability of rimegepant across the 12-week double-blind treatment phase was similar to that seen with placebo. These findings accord with the safety
14,15 and extend the favourable safety profile of rimegepant. The adverse events that did occur were mostly mild or moderate; no serious adverse events were related to treatment with rimegepant; and few participants in the rimegepant group (n=7) discontinued the study due to adverse events. Liver function tests showed low rates of increased enzymes in both treatment groups. One participant in the rimegepant group had asymptomatic aminotransferase elevations, with alanine aminotransferase greater than ten times the ULN. Aminotransferase levels rapidly decreased and returned to normal amounts even though the participant took two additional doses of rimegepant shortly after identification of the increased levels. The site principal investigator deemed the increases not related to study drug, and an independent panel of liver experts concluded that the relation to study medication was not probable. There were no cases of concurrent alanine aminotransferase or aspartate aminotransferase eleva- tions greater than three times the ULN and bilirubin elevation greater than two times the ULN. There were no Hy’s law cases (ie, serious drug-induced liver injury, based on markers of hepatocellular injury with jaundice). Overall, the safety results from our trial align with
22
No current drug is indicated for both acute and preventive treatment of migraine. Four injectable CGRP pathway-targeted monoclonal antibodies are available for preventive treatment of migraine, and two drugs in the
14,15,27,28
Rimegepant provides an alternative CGRP pathway- targeted approach to migraine prevention that might have advantages for some patients. First, research has shown that more than half (52%) of patients with migraine prefer orally administered treatments instead of injectable treatments because of convenience and fear
29 Second, rimegepant has a half-life of 11 h by comparison with approximately 1-month half-lives of CGRP monoclonal 30 If an adverse event occurs (eg, a hypersensitivity reaction) and clinicians want to rapidly reduce or eliminate drug exposure, the
difference in half-lives between rimegepant and a CGRP monoclonal antibody could be important. Moreover, because migraine is frequently seen in women of childbearing potential, rimegepant’s relatively short half- life could facilitate family planning or drug withdrawal in the event of a planned or unplanned pregnancy.
A constantly high exposure to a CGRP receptor antagonist might not be necessary for all patients. In view
31
even over relatively short periods, orally administered rimegepant might give patients the option to adjust drug use to meet individual needs—ie, regularly for prevention and as-needed for acute treatment. For appropriately
32approach to treatment of migraine might help in reaching several goals common to acute and preventive treatment, such as reducing disability, avoiding excessive use of medication and other health-care resources, and enhancing patients’ sense of
6 Previous studies have shown the safety and efficacy of rimegepant for acute
14,15 with no sign of medication-
22 Emerging preclinical science supports observations that prolonged antagonism of the CGRP pathway is not associated with
33Thus, the results of our study show the potential for use of rimegepant in preventive treatment of migraine. Use of rimegepant for acute and preventive treatment of migraine might reduce the overall burden of illness associated with migraine, and this idea merits further investigation.
The strengths of our study include: enrolment of a large diverse sample that was representative of adults with migraine; inclusion of participants with episodic migraine and chronic migraine; and use of guideline-recom- mended methods for assessment of preventive migraine treatments from the International Headache Society and the European Medicines Agency. The limitations of our study include: its relatively short duration; the relatively small sample of participants with chronic migraine (ie, people with more than 3 months of headache on at least 15 days per month, with features of migraine on at least 8 days per month); exclusion of individuals with more than 18 headache days during the observation period; and no active comparator. Subsequent trials addressing these limitations might facilitate drug selection in the context of existing medications, allow for assessment of long-term treatment effects among rimegepant-treated participants, and provide more definitive estimates of efficacy in a broad population with chronic migraine.
Contributors
All authors contributed to study design, data interpretation, and writing of the report. RC and LK oversaw study conduct. DK was a site principal investigator. DAS was responsible for all statistical analyses.
Declaration of interests
RBL declares research support from the US National Institutes of Health; support from the Migraine Research Foundation and the National Headache Foundation; has reviewed for the National Institute on Aging and the National Institute of Neurological Disorders and
Stroke; holds stock options in Biohaven Holdings; serves as a consultant, advisory board member, or has received honoraria from the American Academy of Neurology, Allergan, the American Headache Society, Amgen, Avanir, Biohaven, Biovision, Boston Scientific, Dr Reddy’s (Promius), Electrocore, Eli Lilly, eNeura Therapeutics, Equinox, GlaxoSmithKline, Lundbeck (Alder), Merck, Pernix, Pfizer, Supernus, Teva, Trigemina, Vector, and Vedanta; and receives royalties from Oxford University Press, Wiley, and Informa. DK declares advisory board fees from Lundbeck, Biohaven, Eli Lilly, Amgen, Novartis, and Xoc; speaker’s bureau fees from Teva, Amgen, Novartis, Eli Lilly, Lundbeck,
and Allergan; and research support from Amgen, Novartis, Eli Lilly, Teva, Alder, Biohaven, Biogen, and Roche-Genentech. RC, VC, EGS, CMC, DAS, and LK are employed by and own stock in Biohaven Pharmaceuticals. PJG declares grants and personal fees from Amgen and Eli Lilly; grants from Celgene; personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals, Clexio, Electrocore, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, Lundbeck, MundiPharma, Novartis, Pfizer, Sanofi, Santara Therapeutics, Teva Pharmaceuticals, Trigemina, WL Gore, MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic
stimulation for headache assigned to eNeura without fee. Data sharing
Biohaven Pharmaceuticals will provide access to deidentified patient-level data that underlies the results in this Article in response to scientifically valid research proposals. Data from this study will be made available beginning 9 months and ending 24 months after the publication of this Article. Biohaven will consider requests from qualified researchers for access to the data. Proposals should be directed to the corresponding author. Biohaven will review the request using an internal committee composed of Biohaven staff who are responsible for the programme, including a clinician, a statistician, and a data-sharing professional. Biohaven will make reasonable efforts to fulfil all data requests for legitimate research purposes, but there might be instances in which retrieval or delivery of data is not feasible, such as those involving,
for example, patient privacy, requirements for permissions, contractual obligations, and conflicts of interest. All those receiving access to data will be required to enter into a data use agreement provided by Biohaven, which will contain the terms under which the data will be provided.
Acknowledgments
This clinical trial was supported by Biohaven Pharmaceuticals, developer of rimegepant. Medical writing services were provided by Christopher Caiazza and supported by Biohaven Pharmaceuticals.
We thank the patients, investigators, and site staff who participated in this study; Alexandra Thiry (Biohaven Pharmaceuticals) for statistical contributions; Michael Hanna (Biohaven Pharmaceuticals) for medical monitoring of the trial; and Francine Healy and Christopher Jensen (Biohaven Pharmaceuticals) for careful reviews and helpful comments on the manuscript.
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