Efficacy and Tolerability of Rimegepant for the Acute Treatment of Migraine in Adults Unsuitable for Triptan Use

Participants recorded their migraine headache pain intensity using 4-point numeric rating scale (0=none, 1=mild, 2=moderate, 3=severe). Pain relief at 2 hours post-dose was defined as pain intensity of none or mild at that time point.

Participants recorded their migraine headache pain intensity using 4-point numeric rating scale (0=none, 1=mild, 2=moderate, 3=severe). Pain freedom at 2 hours post-dose was a pain intensity of none at that time point.

Post 24 hours after dosing with study medication and after the 24-hour assessments were completed on the e-diary, participants were permitted to use the following rescue medications (non-study medications) such as: 1) non-steroidal anti-inflammatory drug like acetaminophen or aspirin, ibuprofen, naproxen; 2) antiemetics like metoclopramide, promethazine; 3) other like baclofen; 4) other approved pharmacological treatment with established efficacy in the acute treatment of migraine, including locally recognized standard of care, unless otherwise specified.

Functional disability level was measured on a 4-point numeric rating scale (0= normal,1= mildly impaired, 2= severely impaired, 3= required bedrest). Functional disability was defined as a functional disability level of mildly impaired, severely impaired, or required bedrest. Return to normal function at 2 hours post-dose was defined as functional disability score of normal at that time point for participants with functional disability at the time of dosing.

Functional disability level was measured on a 4-point numeric rating scale (0= normal,1= mildly impaired, 2= severely impaired, 3= required bedrest). Functional disability was defined as a functional disability level of mildly impaired, severely impaired, or required bedrest. Sustained return to normal function, from 2 to 24 hours post-dose was defined as functional disability levels of normal at all time points from 2 to 24 hours post-dose in participants with functional disability at the time of dosing.

Functional disability level was measured on a 4-point numeric rating scale (0= normal,1= mildly impaired, 2= severely impaired, 3= required bedrest). Functional disability was defined as a functional disability level of mildly impaired, severely impaired, or required bedrest. Sustained return to normal function, from 2 to 48 hours post-dose was defined as functional disability levels of normal at all time points from 2 to 48 hours post-dose in participants with functional disability at the time of dosing.

Participants recorded their migraine headache pain intensity using 4-point numeric rating scale (0=none, 1=mild, 2=moderate, 3=severe). Sustained pain relief from 2 to 24 hours post-dose was defined as a pain intensity of none or mild at all time points from 2 to 24 hours post-dose.

Participants recorded their migraine headache pain intensity using 4-point numeric rating scale (0=none, 1=mild, 2=moderate, 3=severe). Sustained pain relief from 2 to 48 hours post-dose was defined as a pain intensity of none or mild at all time points from 2 to 48 hours post-dose.

Participants recorded their migraine headache pain intensity using 4-point numeric rating scale (0=none, 1=mild, 2=moderate, 3=severe). Sustained pain freedom from 2 to 24 hours post-dose was defined as a pain intensity of none at all time points from 2 to 24 hours post-dose.

Participants recorded their migraine headache pain intensity using 4-point numeric rating scale (0=none, 1=mild, 2=moderate, 3=severe). Sustained pain freedom from 2 to 48 hours post-dose was defined as a pain intensity of none at all time points from 2 to 48 hours post-dose.

MBS freedom was defined as MBS reported before dosing that was absent post-dose at the specified time point. MBS reported before dosing was nausea, photophobia, or phonophobia. Each symptom (nausea, photophobia, or phonophobia) was measured post-dose using 0= absent or 1= present. Participants who had symptom score of 0 (absent) aligning with MBS reported before dosing were considered to have MBS freedom.

Reliability of rimegepant effect during OLE Phase achieved when difference between (1) percentage of participants randomized to rimegepant with response to single EQMA in DBT phase and(2) percentage of participants with response to >=4 of first 5 EQMAs >=23 hours(h) apart in OLE phase was <=7%. Statistical analysis reports difference between (1) and (2) for each first 5 EQMAs >=23h apart in OLE phase. Response: category of "moderately better" or"very much better" for Migraine Quality of Life Questionnaire(MQoL)Question(Q) 16 (overall change in migraine symptoms since taking study medication) at 24h post-dose. EQMA:evaluable qualifying migraine attack (migraine attack of moderate/severe pain intensity,first treated with rimegepant, not other acute headache medication) with nonmissing MQoL Q16 value at 24h post dose. Percentage of participants with response after single EQMA in DBT phase randomized to rimegepant and each of first 5 EQMA in OLE phase are reported in descriptive section.

Mean change from historical baseline in the number of migraine days per month by headache pain intensity (total; moderate or severe) at each specified month and over the entire OLE Phase is reported in this outcome measure. A migraine day was defined as either 1) a day on which participant experienced migraine headache pain intensity of mild, moderate, or severe as reported in eDiary or 2) an acute migraine-specific medication day. Total historical baseline is defined as the number of migraine days per month of any pain intensity in the 3 months prior to screening from the migraine history case report form (CRF). Moderate or severe historical baseline was defined as the number of migraine days per month of moderate or severe pain intensity in the 3 months prior to screening from the migraine history CRF.

Percentages of participants with >= 50% reduction from historical baseline in the number of migraine days per month by headache pain intensity (total; moderate or severe) in each month and over the entire OLE Phase is reported in this outcome measure. A migraine day was defined as either 1) a day on which participant experienced migraine headache pain intensity of mild, moderate, or severe as reported in eDiary or 2) an acute migraine-specific medication day. Total historical baseline is defined as the number of migraine days per month of any pain intensity in the 3 months prior to screening from the migraine history CRF. Moderate or severe historical baseline was defined as the number of migraine days per month of moderate or severe pain intensity in the 3 months prior to screening from the migraine history CRF.

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

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participants or clinical investigation participant administered an investigational (medicinal) product and that does not necessarily have a causal relationship with the treatment. A serious AE is 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 a participant who received rimegepant or other important medical events.

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

Laboratory tests included hematology and serum chemistry. All laboratory tests except glucose were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0, where Grade 3=severe events which require hospitalization or prolongation of hospitalization and Grade 4=life-threatening consequences requiring urgent intervention. Glucose was graded according to Division of Acquired Immune Deficiency Syndrome table for Grading Severity of Adult and Pediatric Adverse Events v2.1.

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

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participants or clinical investigation participant administered an investigational (medicinal) product and that does not necessarily have a causal relationship with the treatment. A serious AE is 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 a participant who received rimegepant or other important medical events.

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

Laboratory tests included hematology and serum chemistry. All laboratory tests except glucose were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0, where Grade 3=severe events which require hospitalization or prolongation of hospitalization and Grade 4=life-threatening consequences requiring urgent intervention. Glucose was graded according to Division of Acquired Immune Deficiency Syndrome table for Grading Severity of Adult and Pediatric Adverse Events v2.1.

MIBS was a 4-item self-administered questionnaire that measured interictal migraine related burden in the past 4 weeks on days when participants were not having an attack, using 4 domains: impairment in work or school; impairment in family and social life; difficulty making plans or commitments; emotional/affective and cognitive distress. The questionnaire specifically asked about the effect of the disease over the past 4 weeks on days without a headache attack. Response options included: don't know/not applicable (0), never (0), rarely (1), some of the time (2), much of the time (3), or most or all of the time (3). Each response associated with numerical score were summed across all 4 items resulting in a total MIBS score ranging from 0 to 12, and the level of interictal burden being categorized into the following: 0 for none and 12 for severe. Higher scores indicate worse interictal burden.