Efficacy and Tolerability of Rimegepant in Acute Migraine Treatment for Adults Contraindicated for Triptans: A Phase 4 Randomized, Double-Blind, Placebo-Controlled Trial

Trial ID: 2024-513269-37-00
Protocol: C4951004/BHV3000-406
Sponsor: Pfizer Inc.

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Diseases & Conditions

Migraine

Objectives

The primary objective of this study is to evaluate the **efficacy** of rimegepant compared to placebo in the acute treatment of migraine, specifically by assessing migraine headache pain relief at 2 hours postdose during the double-blind treatment (DBT) phase. This is clinically relevant as it aims to provide an alternative treatment option for patients with migraine attacks who are unsuitable for triptan use, potentially improving their quality of life by offering effective pain management.

Secondary objectives include:

Comparing rimegepant with placebo for migraine headache pain freedom at 2 hours postdose during the DBT phase.
Assessing the use of rescue medication within 24 hours postdose.
Evaluating the return to normal function, as measured by the functional disability scale, at 2 hours postdose.
Assessing sustained return to normal function from 2 to 24 hours and from 2 to 48 hours postdose.
Comparing sustained migraine headache pain relief from 2 to 24 hours and from 2 to 48 hours postdose.
Evaluating sustained migraine headache pain freedom from 2 to 24 hours and from 2 to 48 hours postdose.
Assessing freedom from the most bothersome symptom (MBS) associated with migraine at 2 hours postdose.

These secondary objectives aim to provide a comprehensive understanding of rimegepant's potential benefits in various aspects of migraine management, contributing to a holistic approach to treatment.

Participants

The clinical trial involves a total of **203 participants** who are being studied to evaluate the efficacy of rimegepant in the acute treatment of **migraine attacks with or without aura**. The study population includes both male and female subjects, aged 18 years and older, with a documented history of migraine attacks consistent with the International Classification of Headache Disorders, 3rd Edition. Participants were selected based on their ability to distinguish migraine attacks from tension headaches and their history of experiencing 4 to 14 migraine days per month on average in the three months prior to the screening visit. The trial includes individuals who are on stable doses of prophylactic migraine medication, excluding CGRP antagonists, for at least three months prior to the study. Participants must comply with restrictions on the use of certain medications and therapies. The trial population is not limited by gender, and both male and female subjects are included. The study also considers vulnerable populations, ensuring comprehensive representation. The sponsor has not provided specific information regarding lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the efficacy and tolerability of **rimegepant** for the acute treatment of **migraine** in adults unsuitable for triptan use. The trial is a Phase 4 study, with an estimated duration from March 2023 to July 2025. Participants will be randomly assigned to receive either 75 mg of rimegepant in the form of an oral lyophilisate or a placebo. The primary objective is to compare the efficacy of rimegepant with placebo, specifically measuring migraine headache pain relief at 2 hours post-dose during the double-blind treatment (DBT) phase. The primary endpoint is the percentage of subjects with a headache pain intensity of none or mild at 2 hours post-dose, assessed using a 4-point numeric rating scale.

The study will include several visits, starting with a screening visit to confirm eligibility based on criteria such as a documented history of migraine attacks and the ability to distinguish migraine from tension headaches. Participants must have experienced migraine attacks for more than one year, with an onset before the age of 50, and have 4 to 14 migraine days per month on average in the three months prior to screening. The baseline visit will occur before the dispensing of the investigational study drug, where women of childbearing potential must have a negative urine pregnancy test. Follow-up visits will monitor the participants' response to the treatment and adherence to the study protocol, including compliance with medication restrictions.

The expected length of participant involvement is up to 19 days, with conditions for early termination including non-compliance with the study protocol or adverse events that may compromise participant safety. Secondary endpoints include the percentage of subjects with a headache pain intensity of none at 2 hours post-dose, the use of rescue medication within 24 hours, and the assessment of functional disability levels at various time points post-dose. The study aims to provide comprehensive data on the effectiveness of rimegepant in treating acute migraine attacks, contributing to the understanding of its role in patients who cannot use triptans.

Treatment

The clinical trial involves the administration of **VYDURA 75 mg oral lyophilisate**, which contains the active substance **rimegepant**. This experimental medication is presented in the form of an oral lyophilisate, designed for oral administration. The dosage is set at 75 mg per administration, with a maximum daily dose of 75 mg. The treatment period is limited to a maximum of 19 days. Rimegepant is a chemical compound, also known by its synonyms BMS927711, BHV-3000, and BMS-927711. The chemical structure is described as (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta(b)pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridin-1-yl)piperidine-1-carboxylate. The pharmaceutical form and quality information are consistent with the commercial version of the 75 mg oral disintegrating tablet (ODT).

The study also includes a **placebo** for rimegepant 75 mg, which serves as the comparator treatment. The placebo is designed to match the experimental medication in appearance and administration route but does not contain any active substance. The placebo is utilized to maintain the double-blind nature of the trial, ensuring unbiased assessment of the efficacy and tolerability of rimegepant in the acute treatment of migraine in adults unsuitable for triptan use. The administration schedule for the placebo mirrors that of the active treatment, with compliance monitored throughout the trial period.

Efficacy

The efficacy of **rimegepant** in the acute treatment of migraine will be assessed in a Phase 4, randomized, double-blind, placebo-controlled trial. The primary endpoint for evaluating efficacy is the percentage of subjects experiencing a headache pain intensity of none or mild at 2 hours postdose during the double-blind treatment (DBT) phase. This will be measured using a 4-point numeric rating scale, where 0 indicates no pain, 1 indicates mild pain, 2 indicates moderate pain, and 3 indicates severe pain.

Secondary endpoints include the percentage of subjects with a headache pain intensity of none at 2 hours postdose, the percentage of subjects who take rescue medication within 24 hours after taking the study drug, and the percentage of subjects with a functional disability level of normal at 2 hours postdose. Functional disability will also be measured on a 4-point numeric rating scale, with 0 representing normal function and 3 indicating a requirement for bedrest. Additional secondary endpoints involve assessing the percentage of subjects with headache pain intensities of none or mild, and functional disability levels of normal at various time points from 2 to 48 hours postdose. The presence or absence of migraine-associated symptoms such as nausea, phonophobia, and photophobia will also be evaluated at 2 hours postdose.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Target Population: Minimum 1 year documented history of migraine attacks (with or without aura) consistent with a diagnosis according to the International Classification of Headache Disorders, 3rd Edition Per self-report, with confirmation from Investigator / supporting medication record, subjects must have: a. Migraine attacks present for more than 1 year with the age of onset prior to 50 years of age b. Migraine attacks, on average, lasting about 4 - 72 hours if untreated c. 4 to 14 migraine days per month on average across the 3 months prior to the Screening Visit (month is defined as 28 days for the purpose of this protocol) d. Subjects must be able to distinguish migraine attacks from tension headaches e. Subjects on prophylactic migraine medication (excluding CGRP antagonists) are permitted to remain on therapy if they have been on a stable dose for at least 3 months (12 weeks) prior to the Screening Visit, and if the dose is not expected to change during the course of the study
Triptan unsuitable
Age and Reproductive Status a. Subjects ≥ 18 years of age b. Subject meets reproductive criteria. Refer to Appendix 5 c. At the Baseline Visit prior to dispensing investigational study drug, WOCBP must have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG)
Subjects must be able to fully comply with the prohibitions and restrictions on the concomitant use of medications and therapies (including moderate to strong inhibitors and inducers of the CYP3A4 enzyme and strong inhibitiors of the P-gp transporter). For further inclusion criteria, please refer to the Protocol.

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Exclusion Criteria

Target Disease Exclusion a. History of cluster headaches, basilar migraine (with aura), or hemiplegic migraine b. Current medication overuse headaches c. Headaches occurring 15 or more days per month (migraine or nonmigraine) in any of the 3 months prior to Screening Visit (SV) d. 7 or more non-migraine headache days per month, on-average, across the 3-months prior to the Screening Visit
Medical History and Current Diseases: a. History of gastric or small intestinal surgery or disease or conditions that causes malabsorption b. BMI ≥ 35kg/m2 c. Alcohol or drug abuse within the past 12 months or subjects with any significant substance use disorder within the 12 months from the SV d. Current diagnosis schizophrenia, bipolar, or borderline personality disorder e. History or current evidence of other major psychiatric disorder that might interfere with the ability to properly report clinical outcomes f. Major depressive (MDD) or any anxiety disorder which requires more than 1 daily medication for each disorder, or major depressive episode within last 12 months g. Active chronic pain syndrome h. Other pain syndromes, dementia, or significant neurological disorders (other than migraine) i. Current diagnosis of MDD requiring treatment with atypical antipsychotics j. History with current evidence of uncontrolled, unstable or recently diagnosed cardiovascular disease during 24 weeks prior to SV k. Systolic blood pressure >150 mmHg or diastolic blood pressure > 100 mmHg after 10 minutes of rest l. History or current evidence of any unstable medical conditions m. Positive for drugs of abuse that in the investigator's judgment is medically significant, in that it would impact the safety of the subject or the interpretation of the study results
Allergies and Adverse Drug Reactions: History of drug or other allergy which, in the opinion of the investigator, makes the subject unsuitable for participation in the study. Rimegepant is contraindicated in subjects with hypersensitivity to any component of its formulation.
Sex and Reproductive Status: a.WOCBP who are unwilling or unable to use required contraception b. Women who are pregnant, lactating or breastfeeding c. Women with a positive pregnancy test at SV or prior to study drug administration
ECG and Laboratory Test Findings a. Any clinically significant abnormality identified on the medical, ECG or laboratory evaluation. A subject with a clinical abnormality or laboratory parameters outside the reference range may be included only if the Investigator considers the finding not clinically significant, that it will not introduce additional risk, nor interfere with the study procedures (not including exclusion criteria listed in Section 5.3). b. Estimated glomerular filtration rate (eGFR) according to the re-expressed abbreviated (four-variable) Modification of Diet in Renal Disease (MDRD) Study equation <30 ml/min/1.73m2. c. Total bilirubin >1.5 x ULN (For Gilbert’s syndrome, direct bilirubin >ULN is exclusionary). d. AST and ALT >2 x ULN. e. Serum albumin <2.8g/dL f. Neutrophil count ≤ 1000/µL (or equivalent) g. HbA1c >7.5% h. Evidence of organ dysfunction or any clinically significant deviation from normal on physical examination, vital signs, 12-lead electrocardiogram (ECG), or clinical laboratory determinations beyond what is consistent with the target population
Prohibited Medications and Devices a. Non-Narcotic Analgesics taken at least 15 days per month for a nonheadache indication during the 12 weeks prior to SV b) Other CGRP antagonists (beyond rimegepant), including: i. CGRP antagonist monoclonal antibodies taken within 24 weeks prior SV ii. CGRP antagonist small molecules taken within 10 days prior SV c. Botulinum toxin injections (e.g., Botox®) used for the prevention of migraine taken within 3 months (12 weeks) prior to the SV d. Cefaly or any other device for migraine treatment or prevention used within 12 weeks prior SV e. Ergotamine taken at least 10 days per month on a regular basis for at least 12 weeks in the year prior SV f. Narcotics, such as opioids or barbiturates taken at least 4 days per month during 12 weeks prior SV g. Permitted acute migraine medication taken at least 15 days per month for a non-migraine indication during 12 weeks prior SV.For further exclusion criteria, please refer to the Protocol.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	23 Mar 2023	12
Belgium	Not Recruiting	23 Mar 2023	38
Denmark	Not Recruiting	23 Mar 2023	9
Finland	Not Recruiting	23 Mar 2023	8
France	Not Recruiting	23 Mar 2023	38
Germany	Not Recruiting	23 Mar 2023	32
Italy	Not Recruiting	23 Mar 2023	36
Poland	Not Recruiting	23 Mar 2023	155
Spain	Not Recruiting	23 Mar 2023	26
Sweden	Not Recruiting	23 Mar 2023	43