Efficacy and Safety Trial of Rimegepant for Migraine Prevention in Adults

Study Overview
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Brief Summary
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The purpose of this is study is to compare the efficacy of BHV-3000 (rimegepant) to placebo as a preventive treatment for migraine, as measured by the reduction in the number of migraine days per month.

Official Title
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A Phase 2/3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Rimegepant in Migraine Prevention

Conditions
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Migraine

Intervention / Treatment
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* Drug: Rimegepant
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has at least 1 year history of migraine (with or without aura) consistent with a diagnosis according to the International Classification of Headache Disorders, 3rd Edition, including the following: Age of onset of migraines prior to 50 years of age Migraine attacks, on average, lasting 4 - 72 hours if untreated Per subject report, 4 - 18 migraine attacks of moderate to severe intensity per month within the last 3 months prior to the Screening Visit 6 or more migraine days during the Observation Period Not more than 18 headache days during the Observation Period Ability to distinguish migraine attacks from tension/cluster headaches Subjects on prophylactic migraine medication are permitted to remain on 1 medication with possible migraine-prophylactic effects if the dose has been stable for at least 3 months prior to the Screening Visit, and the dose is not expected to change during the course of the study. Exclusion Criteria: Subject with a history of HIV disease Subject history with current evidence of uncontrolled, unstable or recently diagnosed cardiovascular disease, such as ischemic heart disease, coronary artery vasospasm, and cerebral ischemia. Subjects with Myocardial Infarction (MI), Acute Coronary Syndrome (ACS), Percutaneous Coronary Intervention (PCI), cardiac surgery, stroke or transient ischemic attack (TIA) during the 6 months prior to screening Uncontrolled hypertension (high blood pressure), or uncontrolled diabetes (however subjects can be included who have stable hypertension and/or diabetes for at least 3 months prior to screening). Subjects with major depressive episode within the last 12 months, major depressive disorder or any anxiety disorder requiring more than 1 medication for each disorder. Medications to treat major depressive disorder or an anxiety disorder must have been at a stable dose for at least 3 months prior to the Screening visit. Subjects with other pain syndromes, psychiatric conditions, dementia, or significant neurological disorders (other than migraine) that, in the Investigator's opinion, might interfere with study assessments Subject has a history of gastric, or small intestinal surgery (including Gastric Bypass, Gastric Banding, Gastric Sleeve, Gastric Balloon, etc.), or has disease that causes malabsorption Body mass index ≥ 33 kg/m2 Subject has current diagnosis of major depressive disorder requiring treatment with atypical antipsychotics, schizophrenia, bipolar disorder, or borderline personality disorder History of gallstones or cholecystectomy. The subject has a history or current evidence of any unstable medical conditions (e.g., history of congenital heart disease or arrhythmia, known or suspected infection, hepatitis B or C, or cancer) that, in the investigator's opinion, would expose them to undue risk of a significant adverse event (AE) or interfere with assessments of safety or efficacy during the course of the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DBT Rimegepant/OL Rimegepant<br>DBT Phase (Weeks 1 through 12): Participants received a single oral dose of rimegepant 75 mg tablet every other day (EOD) for 12 weeks. OLE Phase (Weeks 13 through 64): Participants who continued to meet study entry criteria and had acceptable laboratory test results per protocol, entered the OLE phase and received a single oral dose of rimegepant 75 mg tablet EOD for 52 weeks. If participants had a migraine on a day that they were not scheduled to dose with rimegepant, they could take one tablet of rimegepant 75 mg on that calendar day to treat a migraine (as needed [PRN] dosing). After completing the OLE phase, participants had follow-up safety visits 2 and 8 weeks after the End-of-Treatment (EOT) visit. Participants who did not complete the DBT phase and/or did not enter or complete the OLE phase were to complete the EOT visit, the 2-week follow-up safety visit, and the 8-week follow-up safety visit after their early discontinuation. | Drug: Rimegepant<br>* Rimegepant 75 mg tablet EOD<br>* Other names: BHV-3000;|
| Placebo Comparator: DBT Placebo/OL Rimegepant<br>DBT Phase (Weeks 1 through 12): Participants received a single oral dose of placebo matching to rimegepant tablet EOD for 12 weeks. OLE Phase (Weeks 13 through 64): Participants who continued to meet study entry criteria and had acceptable laboratory test results per protocol, entered the OLE phase and received a single oral dose of rimegepant 75 mg tablet EOD for 52 weeks. If participants had a migraine on a day that they were not scheduled to dose with rimegepant, they could take one tablet of rimegepant 75 mg on that calendar day to treat a migraine (PRN dosing). After completing the OLE phase, participants had follow-up safety visits 2 and 8 weeks after the End-of-Treatment (EOT) visit. Participants who did not complete the DBT phase and/or did not enter or complete the OLE phase were to complete the EOT visit, the 2-week follow-up safety visit, and the 8-week follow-up safety visit after their early discontinuation. | Drug: Rimegepant<br>* Rimegepant 75 mg tablet EOD<br>* Other names: BHV-3000;Drug: Placebo<br>* Placebo tablet to match rimegepant tablet EOD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Mean Number of Total Migraine Days Per Month in the Last 4 Weeks of the DBT Phase | A migraine day: any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache: a migraine with or without aura, lasting for ≥30 minutes, and meeting at least 1 of the following criteria (a and/or b): a) ≥2 of the following: unilateral location, pulsating quality, moderate to severe pain intensity, aggravation by or causing avoidance of routine physical activity; b) ≥1 of the following: nausea and/or vomiting, photophobia, and phonophobia. If the participant took a migraine-specific medication during aura or to treat headache on a calendar day, it was counted as a migraine day regardless of the duration and pain features/associated symptoms. Months were defined as 28-day intervals. The change from baseline was calculated as the number of monthly migraine days during the last 4 weeks of the DBT phase (Weeks 9 to 12) minus number of monthly migraine days during the OP. | OP and Weeks 9 to 12 of the DBT phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had ≥ 50% Reduction in Moderate or Severe Migraine Days Per Month in the Last 4 Weeks of the DBT Phase | A migraine day was any calendar day in which the participant experienced a qualified migraine headache (as previously described). If the participant took a migraine-specific medication during aura or to treat headache on a calendar day, it was counted as a migraine day regardless of the duration and pain features/associated symptoms. A moderate or severe migraine day was a migraine day of moderate or severe pain intensity. Months were defined as 28-day intervals. A reduction of at least 50% in the mean number of moderate or severe monthly migraine days was determined if the number of moderate or severe monthly migraine days in the last 4 weeks of the DBT (Weeks 9 to 12) was less than or equal to half (50%) of the number of moderate or severe monthly migraine days in the OP. | OP and Weeks 9 to 12 of the DBT phase | 
| Change From Baseline in the Mean Number of Migraine Days Per Month Over the Entire Course of the DBT Phase | A migraine day was any calendar day in which the participant experienced a qualified migraine headache (as previously described). If the participant took a migraine-specific medication during aura or to treat headache on a calendar day, it was counted as a migraine day regardless of the duration and pain features/associated symptoms. Months were defined as 28-day intervals. The change from baseline was calculated as the number of monthly migraine days during the DBT phase (Weeks 1 to 12) minus the number of monthly migraine days during the OP. | OP and Weeks 1 to 12 of the DBT phase | 
| Frequency of Use of Rescue Medication Days Per Month in the Last Month of the DBT Phase | A rescue medication day was a day on which the participant took triptan, ergotamine, or other permitted medication to acutely treat headache or aura. Months were defined as 28-day intervals. | Weeks 9 to 12 of the DBT phase | 
| Change From Baseline in the Mean Number of Total Migraine Days Per Month in the First Month of the DBT Phase | A migraine day was any calendar day in which the participant experienced a qualified migraine headache (as previously described). If the participant took a migraine-specific medication during aura or to treat headache on a calendar day, it was counted as a migraine day regardless of the duration and pain features/associated symptoms. Months were defined as 28-day intervals. The change from baseline was calculated as the number of monthly migraine days during the first 4 weeks of the DBT phase (Weeks 1 to 4) minus the number of monthly migraine days during the OP. | OP and Weeks 1 to 4 of the DBT phase | 
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Study Drug Discontinuation in the DBT Phase | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition on-treatment in a patient or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. An SAE was defined as any event that met any of the following criteria: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received rimegepant; other important medical events that may not have resulted in death, be life-threatening, or required hospitalization, based upon appropriate medical judgment, they may have jeopardized the participant and may have required medical or surgical intervention. | Weeks 1 to 12 of the DBT phase | 
| Number of Participants With AEs, SAEs, AEs Leading to Study Drug Discontinuation in the OLE Phase | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition on-treatment in a patient or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. An SAE was defined as any event that met any of the following criteria: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received rimegepant; other important medical events that may not have resulted in death, be life-threatening, or required hospitalization, based upon appropriate medical judgment, they may have jeopardized the participant and may have required medical or surgical intervention. | OLE Phase (Weeks 13 through 64) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities in the DBT Phase | Clinically significant laboratory abnormalities were defined as Grade 3 to 4 laboratory test results according to numeric laboratory test criteria found in Common Technical Criteria for Adverse Events (CTCAE) Version 5.0 (2017) if available; otherwise, according to Division of Acquired Immune Deficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1 (2017) for glucose, LDL-cholesterol, uric acid, and urinalysis. Laboratory test groups of clinical interest included hematology, serum chemistry, and urinalysis. Participants must have had a non-missing measurement in the DBT phase to be included for a given parameter. | Weeks 1 to 12 of the DBT phase | 
| Number of Participants With Clinically Significant Laboratory Abnormalities in the OLE Phase | Clinically significant laboratory abnormalities were defined as Grade 3 to 4 laboratory test results according to numeric laboratory test criteria found in CTCAE Version 5.0 (2017) if available; otherwise, according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1 (2017) for glucose, LDL-cholesterol, uric acid, and urinalysis. Laboratory test groups of clinical interest included hematology, serum chemistry, and urinalysis. Participants must have had a non-missing measurement in the OLE phase to be included for a given parameter. | OLE Phase (Weeks 13 through 64) | 
| Number of Participants With Elevations of AST or ALT > 3 x Upper Limit of Normal (ULN) Concurrent With Total Bilirubin (TBL) > 2 x ULN During the DBT Phase | Elevations of AST or ALT > 3 x ULN concurrent with TBL > 2 x ULN were defined as elevations on the same collection date. Participants must have had a non-missing AST, ALT, or TBL measurement in the OLE phase to be included. | Weeks 1 to 12 of the DBT phase | 
| Percentage of Participants With Elevations of AST or ALT > 3 x ULN Concurrent With TBL > 2 x ULN During the OLE Phase | Elevations of AST or ALT > 3 x ULN concurrent with TBL > 2 x ULN were defined as elevations on the same collection date. Participants must have had a non-missing AST, ALT, or TBL measurement in the DBT phase to be included. | OLE Phase (Weeks 13 through 64) | 
| Number of Participants With Hepatic-related AEs and Hepatic-related AEs Leading to Discontinuation During the DBT Phase | Hepatic AEs were defined as all preferred terms in the DBT phase under the Hepatic Disorders Standardized Medical Dictionary (Version 21.1) for Regulatory Activities Query (SMQ), except those preferred terms in the Congenital, Familial, Neonatal and Genetic Disorders of the Liver SMQ. | Weeks 1 to 12 of the DBT phase | 
| Number of Participants With Hepatic-related AEs and Hepatic-related AEs Leading to Discontinuation During the OLE Phase | Hepatic AEs were defined as all preferred terms in the OLE phase under the Hepatic Disorders SMQ, except those preferred terms in the Congenital, Familial, Neonatal and Genetic Disorders of the Liver SMQ. | OLE Phase (Weeks 13 through 64) | 
| Mean Change From Baseline in the Migraine Specific Quality of Life (MSQoL) Role Function-Restrictive Domain Score at Week 12 of the DBT Phase | The Migraine Specific Quality of Life (MSQoL) is a self-administered, 14-item instrument that has been validated in 3 domains: role restriction, role prevention, and the emotional function. The role function-restrictive domain consists of 7 items that describe how migraine limits one's daily social and work-related activities. Participants respond to items using a 6-point scale: none of the time, a little bit of the time, some of the time, a good bit of the time, most of the time, and all of the time, which are assigned scores of 1 to 6, respectively. Item scores are recoded using (7 - original score). Next, raw dimension scores are computed as a sum of recoded item scores and rescaled from a 0 to 100 scale such that higher scores indicate better quality of life. The change from baseline was calculated as the MSQoL restrictive role function domain score at Week 12 of the DBT phase minus the MSQoL restrictive role function domain score at baseline. | Baseline, Week 12 of the DBT Phase | 
| Mean Change From Baseline in the Migraine Disability Assessment (MIDAS) Total Score at Week 12 of the DBT Phase | The Migraine Disability Assessment (MIDAS) is a retrospective, self-administered, 5-item questionnaire that measures headache-related disability as lost time due to headache from paid work or school, household work, and non-work activities. Participants provide the number of missed work or school days; missed household chores days; missed social or leisure activity days; and days at work or school, and separately at home, where productivity was reduced by half or more in the last 3 months (scale: 0 - 90 for each of 5 subscales). The 5 subscale scores are summed to compute the MIDAS total score (scale: 0 - 450). Lower scores indicate less headache-related disability. The change from baseline was calculated as the MIDAS total score at Week 12 of the DBT phase minus the MIDAS total score at baseline. | Baseline, Week 12 of the DBT Phase | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Migraine, Prevention, Prophylaxis