Efficacy and Safety Study of Rimegepant in Episodic Migraine Prevention With Multiple Dosing Regimens

A migraine day was defined as any calendar day in 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 minutes, and meeting either \>=2 of the pain features: unilateral location; pulsating quality; moderate or severe pain intensity; aggravation by or causing avoidance of routine physical activity OR \>=1 of the associated symptoms: nausea and/or vomiting; photophobia and phonophobia. The number of migraine days per month were prorated to 28 days and derived for a month in on-DBT efficacy analysis period as follows: 28\*(total number of migraine days through Month 3 \[Weeks 1 to 12\]/ (total number of e-diary efficacy data days through Month 3 \[Weeks 1 to 12\]). Mean change in number of migraine days per month in DBT phase as compared to OP phase was calculated and reported in this outcome measure.

Time frame: Observation phase (from 31 days prior to randomization), DBT phase (through Month 3 [Week 1 to 12])

Population: Double-blind treatment efficacy (Migraine) analysis set included participants in the full analysis set who were randomized only once and took \>= 1 dose of double-blind study drug (rimegepant or placebo) and had \>=14 days of eDiary efficacy data (not necessarily consecutive) in both the OP and \>=1 month (4-week interval) in the DBT Phase.

MSQoL is a self-administered, 14-item instrument validated in 3 domains: role restriction, role prevention, and the emotional function. The restrictive role function domain consisted of 7 items that described how migraine limited one's daily social and work-related activities. Participants were required to respond to items using a 6-point scale ranging from 1 to 6, where 1: none of the time, 2: a little bit of the time, 3: some of the time, 4: a good bit of the time, 5: most of the time, and 6: all of the time,. Item scores were recoded using (7 - original score). Raw dimension scores for restrictive role function domain were computed as a sum of recoded item scores and rescaled from a 0 to 100 scale such that lower score (0) indicated poor quality of life and higher scores (100) indicated better quality of life.

Time frame: Baseline (Day 1), Week 12 of the DBT phase

Population: Double-blind treatment efficacy analysis set included participants in the full analysis set who were randomized only once and took \>= 1 dose of double-blind study drug. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.

A migraine day was defined as any calendar day in 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 minutes, and meeting either \>=2 of the pain features: unilateral location; pulsating quality; moderate or severe pain intensity; aggravation by or causing avoidance of routine physical activity OR \>=1 of the associated symptoms: nausea and/or vomiting; photophobia and phonophobia. The number of migraine days per month were prorated to 28 days and derived a month (i.e., 4-week interval) in on-DBT efficacy analysis period as follows: 28\*(total number of migraine days in the month / (total number of e-diary efficacy data in the month. Mean change in number of migraine days per month in the first 4 weeks of DBT phase as compared to OP phase was calculated and reported in this outcome measure.

Time frame: Observation phase (from 31 days before randomization), Week 1 to Week 4 of the DBT phase

Population: Double-blind treatment efficacy (Migraine) analysis set included participants in the full analysis set who were randomized only once and took \>= 1 dose of double-blind study drug (rimegepant or placebo) and had \>=14 days of eDiary efficacy data (not necessarily consecutive) in both the OP and \>=1 month (4-week interval) in the DBT Phase. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.

A migraine day was defined as any calendar day in 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 minutes, and meeting either \>=2 of the pain features: unilateral location; pulsating quality; moderate or severe pain intensity; aggravation by or causing avoidance of routine physical activity OR \>=1 of the associated symptoms: nausea and/or vomiting; photophobia and phonophobia. The number of migraine days per month were prorated to 28 days and derived a month (i.e., 4-week interval) in on-DBT efficacy analysis period as follows: 28\*(total number of migraine days in the month) / (total number of e-diary efficacy data in the month). Mean change in number of migraine days per month in the last 4 weeks of DBT phase as compared to OP phase was calculated and reported in this outcome measure.

Time frame: Observation phase (from 31 days before randomization), Week 9 to Week 12 of the DBT phase

Population: Double-blind treatment efficacy (Migraine) analysis set included participants in the full analysis set who were randomized only once and took \>= 1 dose of double-blind study drug (rimegepant or placebo) and had \>=14 days of eDiary efficacy data (not necessarily consecutive) in both the OP and \>=1 month (4-week interval) in the DBT Phase. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.

An acute migraine-specific medication day was defined as any calendar day during which the participant took a migraine-specific medication (i.e., triptan or ergotamine). The number of acute migraine-specific medication days per month were prorated to 28 days and derived for on-DBT efficacy analysis period as follows: 28\*(total number of acute migraine-specific medication days through Month 3/ (total number of e-Diary efficacy data days through Month 3).

Time frame: DBT phase (through Month 3 [Week 1 to 12])

Population: Double-blind treatment efficacy (Migraine) analysis set included participants in the full analysis set who were randomized only once and took \>= 1 dose of double-blind study drug (rimegepant or placebo) and had \>=14 days of eDiary efficacy data (not necessarily consecutive) in both the OP and \>=1 month (4-week interval) in the DBT Phase.

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. In this outcome measure, participants with adverse events leading to study drug discontinuation were reported.

Time frame: DBT: From Week 1 to Week 12

Population: Double-blind treatment safety population included participants in the enrolled analysis set who took \>= 1 dose of double-blind study drug (rimegepant or placebo).

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. In this outcome measure, participants with adverse events leading to study drug discontinuation were reported.

Time frame: OLE: From Week 12 to Week 24

Population: Open-label rimegepant safety population included participants in the enrolled analysis set who took \>= 1 dose of open-label rimegepant.

Number of participants with AST or ALT \>3\*ULN concurrent with TBL \>2\*ULN in DBT phase were reported in this outcome measure.

Time frame: DBT: From Week 1 to Week 20

Population: Double-blind treatment safety population included participants in the enrolled analysis set who took \>= 1 dose of double-blind study drug (rimegepant or placebo). Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.

Number of participants with AST or ALT \>3\*ULN concurrent with TBL \>2\*ULN in DBT phase were reported in this outcome measure.

Time frame: OLE: From Week 12 to Week 32

Population: Open-label rimegepant safety population included participants in the enrolled analysis set who took \>= 1 dose of open-label rimegepant. Here Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.

The laboratory parameters were graded according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) version 5.0 and using division of AIDS (DAIDS) toxicity grading scale version 2.1 (glucose, low density lipoprotein \[LDL\] cholesterol, uric acid and urinalysis) and for other parameters (eosinophils, hemoglobin, leukocytes, albumin, lymphocytes, neutrophils, platelets, alanine aminotransferase, alkaline phosphatase ,aspartate aminotransferase, bicarbonate, bilirubin, calcium, cholesterol, creatine kinase, creatinine, lactate dehydrogenase, potassium, sodium, triglycerides) CTCAE version v5.0 was used. Severity were graded as Grade 1=mild AE, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening consequences; urgent intervention indicated. Number of participants according to Grade 3 or 4 laboratory abnormalities are reported. Only laboratory abnormalities with non-zero values in any of the treatment arms are reported.

Time frame: DBT: From Week 1 to Week 20

Population: Double-blind treatment safety population included participants in the enrolled analysis set who took \>= 1 dose of double-blind study drug (rimegepant or placebo). All participants under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here Number Analyzed refers to the number of participants evaluable for the specified rows.

The laboratory parameters were graded according to the NCI CTCAE version 5.0 and using DAIDS toxicity grading scale version 2.1 (glucose, LDL cholesterol, uric acid and urinalysis). And for other parameters (eosinophils, hemoglobin, leukocytes, albumin, lymphocytes, neutrophils, platelets, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bicarbonate, bilirubin, calcium, cholesterol, creatine kinase, creatinine, lactate dehydrogenase, potassium, sodium, triglycerides) CTCAE version v5.0 was used. Severity was graded as Grade 1=mild AE, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening consequences; urgent intervention indicated. Number of participants according to Grade 3 or 4 laboratory abnormalities are reported. Only laboratory abnormalities with non-zero values in any of the treatment arms are reported.

Time frame: OLE: From Week 12 to Week 32

Population: Open-label rimegepant safety population included participants in the enrolled analysis set who took \>= 1 dose of open-label rimegepant. All participants under 'Overall Number of Participants Analyzed' contributed data to the table; however, may not have evaluable data for every row. Here Number Analyzed refers to the number of participants evaluable for the specified rows.

\\An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. Hepatic-related AEs included: alanine aminotransferase and aspartate aminotransferase increased, liver function test abnormal, liver function test increased, bilirubin conjugated increased, blood bilirubin increased, transaminases increased and hyperbilirubinemia. Number of participants with any hepatic-related AEs in the DBT phase were reported in this outcome measure.

Time frame: DBT: From Week 1 to Week 20

Population: Double-blind treatment safety population included participants in the enrolled analysis set who took \>= 1 dose of double-blind study drug (rimegepant or placebo).

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. Hepatic AEs included: alanine aminotransferase and aspartate aminotransferase increased, liver function test abnormal, bilirubin conjugated, hepatic enzyme increased, blood bilirubin unconjugated increased, blood bilirubin and transaminases increased and hepatic function abnormal. Number of participants with any hepatic-related AEs in the OLE phase were reported in this outcome measure.

Time frame: OLE: From Week 12 to Week 32

Population: Open-label rimegepant safety population included participants in the enrolled analysis set who took \>= 1 dose of open-label rimegepant.

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. Hepatic-related AEs included: alanine aminotransferase and aspartate aminotransferase increased, liver function test and blood bilirubin increased. Number of participants with any hepatic-related AEs leading to study drug discontinuation is reported in this outcome measure.

Time frame: DBT: From Week 1 to Week 12

Population: Double-blind treatment safety population included participants in the enrolled analysis set who took \>= 1 dose of double-blind study drug (rimegepant or placebo).

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. Hepatic-related AEs included: aspartate aminotransferase increased and liver function test abnormal. Number of participants with any hepatic-related AEs leading to study drug discontinuation is reported in this outcome measure.

Time frame: OLE: From Week 12 to Week 24

Population: Open-label rimegepant safety population included participants in the enrolled analysis set who took \>= 1 dose of open-label rimegepant.

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. AEs were categorized as mild: usually transient and required only minimal treatment or therapeutic intervention. The event did not generally interfere with usual activities of daily living. Moderate: was usually alleviated with additional specific therapeutic intervention. The event interfered with usual activities of daily living, causing discomfort but posed no significant or permanent risk of harm to the participant. Severe: Interrupted usual activities of daily living, significantly affected clinical status, or required intensive therapeutic intervention. AEs included both non-SAEs and serious adverse events (SAEs).

Time frame: DBT: From Week 1 to Week 20

Population: Double-blind treatment safety population included participants in the enrolled analysis set who took \>= 1 dose of double-blind study drug (rimegepant or placebo).

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. AEs were categorized as mild: usually transient and required only minimal treatment or therapeutic intervention. The event did not generally interfere with usual activities of daily living. Moderate: was usually alleviated with additional specific therapeutic intervention. The event interfered with usual activities of daily living, causing discomfort but posed no significant or permanent risk of harm to the participant. Severe: Interrupted usual activities of daily living, significantly affected clinical status, or required intensive therapeutic intervention. AEs included both non-SAEs and SAEs.

Time frame: OLE: From Week 12 to Week 32

Population: Open-label rimegepant safety population included participants in the enrolled analysis set who took \>= 1 dose of open-label rimegepant.

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. An SAE was any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of the participant who received rimegepant and other important medical events.

Time frame: OLE: From Week 12 to Week 32

Population: Open-label rimegepant safety population included participants in the enrolled analysis set who took \>= 1 dose of open-label rimegepant.

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. An SAE was any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of the participant who received rimegepant and other important medical events.

Time frame: DBT: From Week 1 to Week 20

Population: Double-blind treatment safety population included participants in the enrolled analysis set who took \>= 1 dose of double-blind study drug (rimegepant or placebo).

Percentage of participants with \>= 50% reduction from OP, in number of migraine days (moderate or severe) in the overall DBT phase is reported in this outcome measure. The number of migraine days per month were prorated to 28 days and derived for a month in on-DBT efficacy analysis period as follows: 28\*(total number of migraine days through Month 3 \[Weeks 1 to 12\]/ (total number of e-diary efficacy data days through Month 3 \[Weeks 1 to 12\]).

Time frame: DBT phase (through Month 3 [Week 1 to 12])

Population: Double-blind treatment efficacy (Migraine) analysis set included participants in the full analysis set who were randomized only once and took \>= 1 dose of double-blind study drug (rimegepant or placebo) and had \>=14 days of eDiary efficacy data (not necessarily consecutive) in both the OP and \>=1 month (4-week interval) in the DBT Phase.