Efficacy and Safety Evaluation of Atogepant in Acute Migraine Treatment: A Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-506029-12-00
Protocol: M24-305
Sponsor: AbbVie Deutschland GmbH & Co. KG

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Diseases & Conditions

Migraine Migraine without aura Migraine with aura

Objectives

The primary objective of this study is to evaluate the **efficacy** of a single dose of atogepant compared to placebo for the acute treatment of a single migraine attack. This is clinically relevant as it aims to determine the effectiveness of atogepant in providing relief from migraine symptoms, which can significantly impact patients' quality of life.

The secondary objectives are to assess the **safety** and **tolerability** of atogepant for the acute treatment of migraine, both for a single attack and across multiple migraine attacks. Additionally, the study aims to evaluate the consistency of effect across multiple attacks. These objectives are crucial for understanding the overall risk-benefit profile of atogepant in the management of migraine, ensuring that it is not only effective but also safe for repeated use.

Participants

The clinical trial involves a total of **545 participants** who are being evaluated for the efficacy of a single dose of atogepant compared to placebo for the acute treatment of a single **migraine** attack. The study population includes both male and female subjects aged between 18 to 75 years, with a history of migraines lasting between 4 to 72 hours when untreated or treated unsuccessfully. Participants have experienced 2 to 8 migraine attacks per month with moderate to severe headache pain in the three months prior to screening. The trial population was selected based on specific inclusion criteria, including the ability to read, understand, and complete study questionnaires and eDiary. Participants are required to have a history of migraine onset before the age of 50 and must not be pregnant or breastfeeding. The study considers lifestyle factors such as the use of prescription or nonprescription medication for acute migraine treatment, with stable prophylactic treatment for at least three months prior to randomization. The trial includes a vulnerable population, ensuring comprehensive evaluation across diverse demographic groups.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study with an open-label extension to evaluate the efficacy, safety, tolerability, and consistency of effect of **atogepant** for the acute treatment of **migraine**. The trial aims to assess the efficacy of a single dose of atogepant compared to placebo for the acute treatment of a single migraine attack. The study will involve multiple phases, including a screening phase, a double-blind treatment phase, and an open-label extension phase. The estimated duration of the trial is from April 2024 to November 2025, with participant involvement expected to last up to 24 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, such as a history of migraines and the ability to comply with study procedures. Following successful screening, participants will be randomized to receive either atogepant or placebo. The double-blind treatment phase will involve regular follow-up visits to monitor efficacy and safety outcomes, including pain freedom and relief at specified time points post-dose. The open-label extension phase will allow all participants to receive atogepant, providing further data on long-term safety and tolerability.

The primary endpoint is pain freedom at 2 hours after the double-blind dose for the first attack, with secondary endpoints including sustained pain relief and freedom, absence of migraine-associated symptoms, and the use of rescue medication. Participants are expected to adhere to the study protocol, including the use of specified birth control methods for female participants of childbearing potential. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent. The trial is conducted in accordance with ethical guidelines, and informed consent is obtained from all participants prior to any study-specific procedures.

Treatment

The clinical trial involves the administration of **Atogepant**, an experimental medication, for the acute treatment of migraine. **Atogepant** is provided in the form of a **tablet** and is administered **orally**. The pharmaceutical formulation is developed by Allergan Sales, LLC, a subsidiary of AbbVie Inc. The active substance, **atogepant**, is of chemical origin. The trial aims to evaluate the efficacy of a single dose of **atogepant** compared to a placebo. The maximum treatment period for the study is 24 hours, and the dosage is determined based on the study protocol, although specific dosage details are not provided in the source data.

The study also includes a **placebo** group, which serves as a comparator to the experimental treatment. The placebo is designed to mimic the **atogepant** tablets in appearance but does not contain any active pharmaceutical ingredients. The placebo is used to ensure the double-blind nature of the trial, allowing for an unbiased assessment of the efficacy and safety of **atogepant**. Participants are randomly assigned to receive either the experimental medication or the placebo, and compliance with the dosing schedule is monitored throughout the study to ensure the integrity of the trial results.

Efficacy

The efficacy of Atogepant for the acute treatment of **migraine** will be assessed in a randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is pain freedom, defined as a reduction in headache severity from moderate/severe at baseline to no pain, measured at 2 hours after the double-blind dose for the first migraine attack. Secondary endpoints include the absence of the most bothersome symptom (MBS) at 2 hours, pain relief at 2 hours, sustained pain relief from 2 to 24 hours and 2 to 48 hours, use of rescue medication within 24 hours, ability to function normally at 2 and 8 hours, absence of photophobia and phonophobia at 2 hours, pain freedom at 8 hours, and absence of nausea at 2 hours after the double-blind dose for the first attack.

These efficacy parameters will be collected and analyzed at specified timepoints, including 30 minutes, 1 hour, 2 hours, and 8 hours post-dose. The assessments will be conducted using validated scales and patient-reported outcomes to ensure accuracy and reliability. The trial will focus on the first migraine attack during the double-blind treatment period to determine the efficacy of a single dose of Atogepant compared to placebo.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subjects must voluntarily sign and date an informed consent, approved by an IEC/IRB, prior to the initiation of any screening or study-specific procedures.
Female subjects (or individuals) of childbearing potential must practice at least 1 protocol-specified method of birth control, from 30 days prior to Visit 2/Randomization until 30 days after the last dose of study drug. Female subjects of nonchildbearing potential do not need to use birth control.
Has used prescription or nonprescription medication for the acute treatment of migraine in the past.
Oral migraine medications used for prophylaxis on-label or off-label (e.g., topiramate, amitriptyline, beta blockers, flunarizine, venlafaxine, etc.), and injectable onabotulinum toxin A and other therapies used for migraine prevention are permitted provided that the treatment is stable for at least 3 months prior to Visit 2/Randomization and continues without change in dose throughout the study.
Subjects enrolling in the Triptan-Unsuitable substudy (applicable only after completion of enrollment in the main study) must meet all the inclusion criteria listed for the main study and must not meet any of the exclusion criteria listed for the main study. In addition, subjects must meet the following inclusion criterion: Subject must be ""triptan-unsuitable"" defined as meeting 1 of the 2 following criteria: -has a contraindication to triptans based upon local label and investigator judgment, irrespective of prior triptan use OR meets the following triptan failure definition for ≥2 different triptans: Currently uses a triptan or has used a triptan in the past and has not achieved pain relief (defined as the reduction of a moderate/severe migraine headache to a mild headache or no headache) at 2 hours postdose in ≥2 out of 4 attacks based upon subject interview and investigator judgment OR -Used a triptan in the past but no longer uses a triptan due to AEs based upon subject interview and investigator judgment.
Ability and willingness to read, understand, and complete study questionnaires and eDiary.
Aged 18 to 75 years, inclusive, at Visit 1/Screening (subjects must also meet the legal age of majority per local law).
History of migraine (with or without aura) according to the ICHD-3 for ≥12 months prior to Visit 1/Screening.
Migraine onset before the age of 50.
History of migraines lasting between 4 to 72 hours when untreated or treated unsuccessfully and migraine episodes separated by at least 48 hours of headache pain freedom.
History of 2 to 8 migraine attacks per month with moderate to severe headache pain in each of the 3 months prior to Visit 1/Screening per investigator judgment.
Female subjects who are not pregnant or breastfeeding, and are not planning to become pregnant or donate eggs during the study and for approximately 30 days after the last dose of study drug.
Female subjects (or individuals) of childbearing potential must have a negative serum pregnancy test at Visit 1/Screening and a negative urine pregnancy test at Visit 2/Randomization. Subjects with a borderline serum pregnancy test at Visit 1/Screening must have absence of clinical suspicion of pregnancy or other pathological causes of borderline results and a serum pregnancy test ≥3 days later to document continued lack of a positive result (unless prohibited by local requirements). Subjects with a urine pregnancy test at Visit 2/Randomization that is borderline or ambiguous must have a serum pregnancy test. In such cases, the subjects must be excluded from participation if the serum pregnancy result is positive.

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Exclusion Criteria

Subject has difficulty in distinguishing migraine headache from tension-type or other headaches per the investigator's judgment.
History of an average of 15 or more headache days per month in the 6 months prior to Visit 1/Screening per the investigator's judgment, or a current diagnosis of chronic migraine as defined by ICHD-3. (Note: subjects with a diagnosis of chronic migraine who, in the opinion of the investigator, have fewer than 15 headache days per month due to concomitant prophylactic treatment are allowed to participate in the study).
Current diagnosis of new persistent daily headache, trigeminal autonomic cephalalgia (e.g., cluster headache), and painful cranial neuropathy as defined by ICHD-3.
Subject required hospital/emergency room treatment for migraine attacks on 3 or more occasions within 6 months prior to Visit 1/Screening.
ECG with clinically significant abnormalities at Visit 1/Screening, as determined by the investigator.
QTcF > 450 msec for males or QTcF > 470 msec for females at Visit 1/Screening based on the report of the central reviewer.
Hypertension defined as sitting systolic blood pressure > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg at Visit 1/Screening or Visit 2/Randomization. Blood pressure measurements that exceed these limits may be repeated only once.
Clinically significant abnormalities in the physical examination as determined by the investigator.
Clinically significant laboratory abnormalities as determined by the investigator, or laboratory values meeting any of the following criteria at Visit 1/Screening: ALT or AST > 1 × ULN; Total bilirubin > 1 × ULN (except for subjects with a diagnosis of Gilbert's disease); Serum albumin < 2.8 g/dL [4.06 µmol/L]
Positive result on the urine drug screen at Visit 1/Screening unless explained by allowed concomitant medication use (e.g., opioids prescribed for migraine pain, use of benzodiazepines for insomnia).
Positive result on the hepatitis B surface antigen or the anti-hepatitis C antibody testing at Visit 1/Screening.
Presence of other confounding pain syndromes, confounding psychiatric conditions, dementia, epilepsy and other significant neurological disorders other than migraine per investigator judgment.
Presence of chronic, nonheadache pain condition requiring daily pain medication.
Clinically significant cardiovascular, cerebrovascular, hematologic, endocrine, pulmonary, renal, hepatic, gastrointestinal, psychiatric, or neurologic disease. -If there is a history of such disease but the condition has been stable for more than 6 months prior to Visit 1/Screening and is judged by the investigator as not likely to interfere with the subject's participation in the study, the subject may be included. -Subjects on dialysis for renal failure are not allowed to participate in the study.
Significant risk of self-harm, based on clinical interview or responses on the C-SSRS, or harm to others per the opinion of the investigator; subjects must be excluded if they report suicidal ideation with intent, with or without a plan (i.e., Type 4 or 5 on the C-SSRS) in the past 6 months or report suicidal behavior in the last 6 months prior to Visit 1/Screening or Visit 2/Randomization.
History of malignancy in the 5 years prior to Visit 1/Screening, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
History of any prior gastrointestinal conditions (e.g., diarrhea syndromes, inflammatory bowel disease) that may affect the absorption or metabolism of study drug. -Subjects with prior gastric bariatric interventions (e.g., Lap Band) which have been reversed may participate.
History of acute hepatitis within 6 months of Visit 1/Screening or any history of chronic liver disease (including nonalcoholic fatty liver disease, viral chronic hepatitis, and cirrhosis).
History of hypersensitivity or clinically significant adverse reaction to a CGRP receptor antagonist.
Subject is an employee or immediate family member (parents, spouses, siblings, or children) of one of the investigators, study staff, or AbbVie.
Subject has condition or situation, which the investigator feels will compromise the safety of the subject or the quality of the data and renders the subject an unsuitable candidate for the study.
Subject has taken medication for acute treatment of headache (including acetaminophen, NSAIDs, triptans, ditans, ergotamine, opioids, gepants, or combination analgesics) 10 or more days per month in any of the 3 months prior to Visit 2/Randomization.
Subject has taken strong CYP3A4 inhibitors, including but not limited to systemic (oral/IV) itraconazole, ketoconazole, clarithromycin, telithromycin, nefazodone, and HIV protease inhibitors within 30 days or 5 half-lives of the drug (whichever is longer) prior to Visit 2/Randomization.
Subject has taken strong or moderate CYP3A4 inducers, including but not limited to barbiturates (e.g., phenobarbital and primidone), efavirenz, carbamazepine, phenytoin, rifampin, and St John's wort within 30 days or 5 half-lives of the drug (whichever is longer) prior to Visit 2/Randomization.
Subject has taken strong OATP1B1/OATP1B3 inhibitors (e.g., cyclosporine, telmisartan) within 30 days or 5 half-lives (whichever is longer) of the drug prior to Visit 2/Randomization.
Subject has taken drugs with narrow therapeutic margins with theoretical potential for CYP drug interactions (e.g., warfarin) within 30 days or 5 half-lives (whichever is longer) of the drug prior to Visit 2/Randomization.
Subject has been exposed to any gepant within 30 days prior to Visit 2/Randomization.
Subject has been exposed to injectable monoclonal antibodies blocking the CGRP pathway within 6 months prior to Visit 2/Randomization.
History of clinically significant drug or alcohol abuse or dependency in the 12 months prior to Visit 1/Screening, or subject had concomitant cannabis or ingested CBD oil use, either recreational or for medical reasons, within 30 days prior to Visit 2/Randomization.
Subject has been treated with any investigational drug within 30 days or 5 half-lives of the drug (whichever is longer) prior to Visit 2/Randomization or is currently enrolled in another clinical study or was previously enrolled in this study.
Subject has been treated with oral herbal medicine including, but not limited to, traditional Chinese medicine within 30 days or 5 half-lives (whichever is longer) prior to Visit 2/Randomization.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Apr 2024	84
Czechia	Not Recruiting	01 Apr 2024	204
Germany	Not Recruiting	01 Apr 2024	81
Hungary	Not Recruiting	01 Apr 2024	89
Italy	Not Recruiting	01 Apr 2024	118
Poland	Not Recruiting	01 Apr 2024	177
Portugal	Not Recruiting	01 Apr 2024	70
Slovakia	Not Recruiting	01 Apr 2024	101
Spain	Not Recruiting	01 Apr 2024	66
Sweden	Not Recruiting	01 Apr 2024	23