Phase 4 Randomized Double-Blind Placebo-Controlled Study on Rimegepant Efficacy and Tolerability in Migraine Prophylaxis for Adults with Inadequate Oral Preventive Response

Trial ID: 2024-513270-21-00
Protocol: C4951012/BHV3000-407
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 as an every-other-day (EOD) dosing regimen for the prophylaxis of **migraine headaches with or without aura** in adults. This is specifically targeted at individuals with a history of inadequate response to 2-4 categories of recognized, orally-administered migraine preventive medications. The clinical relevance of this objective lies in its potential to offer an effective preventive treatment option for patients who have not achieved satisfactory results with existing oral preventive therapies. The primary outcome measure is the mean reduction in the number of migraine days per month over the entire double-blind treatment (DBT) phase.

Secondary objectives include:

Comparing the proportion of subjects achieving a ≥50% reduction in the number of migraine days with moderate or severe headache pain intensity per month over the entire DBT Phase (Weeks 1 to 12) between rimegepant and placebo.
Comparing the mean reduction in the number of migraine days per month in the first 4 weeks of the DBT Phase between rimegepant and placebo.
Comparing the mean reduction in the number of migraine days per month in the last 4 weeks of the DBT Phase between rimegepant and placebo.
Comparing the mean change from baseline in the Migraine-Specific Quality-of-Life Questionnaire v 2.1 (MSQ) restrictive role function domain score at Week 12 of the DBT Phase between rimegepant and placebo.
Comparing the mean change from baseline in the Migraine Interictal Burden Scale (MIBS) score at Week 12 of the DBT Phase between rimegepant and placebo.

These secondary objectives aim to provide a comprehensive assessment of the impact of rimegepant on migraine frequency, severity, and quality of life, further elucidating its potential benefits in migraine management.

Participants

The clinical trial involves a total of **130 participants** who are adults with a documented history of **migraine headaches with or without aura**. The study population includes both male and female subjects, aged 18 years and older, who have experienced migraine attacks for more than one year, with the onset of migraines occurring before the age of 50. Participants were selected based on their history of inadequate response to orally-administered migraine preventive medications across 2-4 categories. The trial population is characterized by individuals who experience 4 to 14 migraine days per month, both prior to and during the observation phase. Participants must be able to distinguish migraine attacks from tension headaches. The study includes individuals who meet specific reproductive criteria, and women of childbearing potential must have a negative pregnancy test before receiving the investigational study drug. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across a diverse group of individuals.

Plans and Procedures

The clinical trial is a **Phase 4**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and tolerability of **rimegepant** for the prevention of **migraine headaches with or without aura** in adults with a history of inadequate response to oral preventive medications. The trial aims to compare the efficacy of rimegepant to placebo as an every-other-day dosing regimen, focusing on the mean reduction in the number of migraine days per month over the entire double-blind treatment (DBT) phase. The trial is expected to last until July 2025, with recruitment having commenced in March 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a documented history of migraines, age of onset, and prior inadequate response to preventive medications. Following the screening, eligible participants will enter an observation phase to establish baseline migraine frequency. The DBT phase will then commence, during which participants will be randomly assigned to receive either rimegepant or placebo. Study visits will occur at regular intervals to monitor efficacy and safety, with primary endpoints including the mean change in migraine days per month and secondary endpoints assessing reductions in headache pain intensity and quality of life measures.

The expected length of participant involvement is approximately 24 weeks, encompassing the observation and DBT phases. Conditions that may lead to early termination from the study include adverse events, non-compliance with study procedures, or withdrawal of consent. The end-of-study visit will involve a final assessment of migraine frequency and overall health status, concluding the participant's involvement in the trial.

Treatment

The clinical trial involves the administration of **Rimegepant**, marketed under the name VYDURA 75 mg oral lyophilisate. This experimental medication is formulated as an oral lyophilisate, designed for oral administration. The active substance, Rimegepant, is a chemical compound with the chemical name (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 dosage for this trial is set at 75 mg, with a maximum daily dose of 75 mg, administered every other day (EOD) for a maximum treatment period of 24 weeks. The pharmaceutical form is specifically designed to ensure ease of administration and patient compliance. The product is authorized under the marketing authorization number EU/1/22/1645/002 and is manufactured by Pfizer Europe MA EEIG.

The study also includes a **placebo** control, which is designed to match the experimental medication in appearance and administration route. The placebo for Rimegepant 75 mg is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered orally, following the same dosing schedule as the active treatment, to provide a valid comparison for evaluating the efficacy and tolerability of Rimegepant in the prevention of migraine in adults with a history of inadequate response to oral preventive medications. Compliance with the dosing regimen is monitored throughout the study to ensure adherence and accurate assessment of the treatment outcomes.

Efficacy

The efficacy of **rimegepant** in the prevention of migraine will be assessed through a randomized, double-blind, placebo-controlled Phase 4 clinical trial. The primary endpoint for evaluating efficacy is the mean change from the Observation Phase in the number of migraine days per month over the entire double-blind treatment (DBT) Phase. Secondary endpoints include the proportion of subjects achieving a ≥ 50% reduction in the number of migraine days with moderate or severe headache pain intensity per month during the DBT Phase, as well as the mean change in migraine days per month during the first 4 weeks (Weeks 1 to 4) and the last 4 weeks (Weeks 9 to 12) of the DBT Phase. Additionally, changes from baseline in the Migraine-Specific Quality of Life Questionnaire (MSQ) restrictive role function domain score and the Migraine Interictal Burden Scale (MIBS) score at Week 12 of the DBT Phase will be evaluated.

Efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, including baseline and at Weeks 1 to 12. The trial will utilize validated scales and patient-reported outcomes to measure changes in migraine frequency and severity. The data collected will be analyzed to determine the effectiveness of rimegepant compared to placebo in reducing the frequency of migraine days and improving quality of life for participants with a history of inadequate response to oral preventive medications.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Target Population: Minimum 1 year documented history of migraines (with or without aura) consistent with a diagnosis according to the International Classification of Headache Disorders, 3rd Edition.3 Per self-report, with confirmation from Investigator / supporting medical record, subjects must have: a. Migraine attacks present for more than 1 year from the Screening Visit b. Age of onset prior to 50 years of age c. Migraine attacks lasting about 4–72 hours, if untreated d. 4 to 14 migraine days, on average, across the 3 months prior to the Screening Visit e. 4 to 14 migraine days during the 28-day Observation Phase f. Subjects must be able to distinguish migraine attacks from tension headaches g. Prior inadequate response, within 10 years of the Screening Visit, to agents across 2-4 categories of recognized, orally-administered migraine-preventive medications where at least one example of prior inadequate response is due to lack of efficacy or prior intolerance (not contraindication)
Age and Reproductive Status: a) Subjects ≥18 years-old b) Subject meets reproductive criteria. Refer to Section 16.6 c) At the Baseline Visit, prior to dispensing investigational study drug, WOCBP must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) before dosing with study drug. 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) 15 or more headache days (migraine or non-migraine) per month in any of the 3-months prior to the Screening Visit or during the 28-day Observation Phase d) 7 or more non-migraine headache days per month, on-average, across the 3-months prior to the Screening Visit or during the 28-day Observation Phase e) Inadequate response to agents across > 4 categories of recognized, orally administered, migraine-preventive medications
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 past 12 months from the date of the Screening Visit d) Current diagnosis of major depressive disorder requiring treatment with an atypical antipsychotic e) Current diagnosis of schizophrenia, bipolar disorder, or borderline personality disorder f) Other major psychiatric disorder that might interfere with the ability to properly report clinical outcomes g) Major depressive disorder or any anxiety disorder which requires more than 1 daily medication for each disorder. h) Major depressive episode within last 12 months prior to the Screening Visit. i) Subjects who meet criteria for C-SSRS Suicidal Ideation Items 4 or 5 within the last 12 months prior to the Screening Visit, OR subjects who endorse any of the 5 C-SSRS Suicidal Behavior Items within the last 10 years prior to the Screening Visit, OR subjects who present a serious risk of suicide j) Active chronic pain syndromes k) Other pain syndromes (including trigeminal neuralgia), dementia, significant neurological disorders other than migraine l) Current evidence of uncontrolled, unstable or recently diagnosed cardiovascular disease m) Myocardial infarction, acute coronary syndrome (ACS), percutaneous coronary intervention (PCI), cardiac surgery, stroke or transient ischemic attack within 6 months prior to the Screening Visit n) Uncontrolled hypertension (high blood pressure). o) Any unstable medical conditions (e.g., history of congenital heart disease, arrhythmia, or cancer) p) Positive drug screen 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.
Sex and Reproductive Status WOCBP who are unwilling or unable to use required contraception a) Women who are pregnant or breastfeeding b) Women with a positive pregnancy test at Screening Visit
ECG and Laboratory Test Findings - as specified in the protocol.
Prohibited Medications and Devices a) Recognized migraine-preventive medication taken within 30 days prior the Screening (with exceptions) b) Non-Narcotic Analgesics or paracetamol taken 15 days per month during the 3 months prior to the Screening Visit c) Any device for migraine prevention or treatment within 3 months prior to the Screening Visit d) Ergotamine taken 10 days per month on a regular basis for 3 months in the year prior to the Screening Visit e) Narcotic, such as opioid or barbiturate taken for 4 days per month during the 3 months prior to the Screening Visit f) Permitted acute migraine medication taken 15 days per month for a non-headache indication during the 3 months (12 weeks) prior to the SV
Other a) Non-compliance with or inability to complete eDiary during Observation Phase. Subjects with less than 24 completed eDiary reports during 28 days in the Observation Phase b) Exposure to non-biological investigational agents within 30 days prior to the Screening c) Exposure to biological investigational agents within 6 months prior to the Screening d) Previous enrollment in any multiple dose BHV3000 (rimegepant) study. Subjects may be considered for BHV3000-407 if the subject participated in any of the following single-dose studies: BHV3000-301, BHV3000-302, BHV3000-303, but did not participate in any multiple dose rimegepant study. e) Participation in any other clinical study while participating in this clinical study. f) Past participation in a clinical study within 30 days prior to the Screening Visit g) Failure to complete the Baseline Visit within the timeframe specified in the schedule of assessments h) The subject is clinically unsuitable to participate i) Site staff directly involved in the conduct of the study and their family, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members. 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	6
Belgium	Not Recruiting	23 Mar 2023	32
Denmark	Not Recruiting	23 Mar 2023	22
Finland	Not Recruiting	23 Mar 2023	41
Germany	Not Recruiting	23 Mar 2023	35
Italy	Not Recruiting	23 Mar 2023	44
Poland	Not Recruiting	23 Mar 2023	179
Spain	Not Recruiting	23 Mar 2023	94
Sweden	Not Recruiting	23 Mar 2023	17