Migraine Headaches Elimination With Patent Foramen Ovale-Directed Therapy

Cessation of Migraine Headaches With Patent Foramen Ovale-Directed Therapy (COMFORT - PFO): An Investigator-Initiated Study

Migraine is a common and often disabling condition, but its exact causes are not fully understood. Some people with migraines have a small opening in the heart wall called a patent foramen ovale (PFO). In some of these patients, closing this opening or taking a medication that inhibits blood platelets (prasugrel) has been shown to reduce migraines. However, not everyone benefits, and it is unclear why. This study is being done to better understand whether closing a PFO can provide lasting migraine relief - especially in patients whose migraines improve with prasugrel.

The goal of this study is to find out whether, in patients whose migraines improve while taking prasugrel, closing the PFO along with 24 weeks of prasugrel leads to better long-term migraine relief after stopping the medication, than by taking prasugrel for 24 weeks alone.

Participants will track their migraines daily using an electronic diary, then take prasugrel and compare their migraines while on the medication. Only patients whose migraines improve on this medication will continue in the study. Eligible participants will be randomly assigned (like flipping a coin) to one of two groups: 1) Medication-only group: Continue prasugrel for 24 weeks. 2) Procedure group: Undergo a minimally invasive procedure to close the PFO and continue prasugrel for 24 weeks. After treatment, the medication will be stopped in both groups, and participants will again track their migraines for about 8 weeks.

The main question is: Do patients who have PFO closure continue to have fewer migraines after stopping prasugrel compared with those who did not have the procedure?

The hypothesis of the COMFORT-PFO Study is that a subset of migraine patients with PFO have an underlying platelet-mediated migraine mechanism in which byproducts of platelet activation or aggregation enter the cerebral circulation via the PFO at supraphysiologic levels, thereby triggering migraine.

Inhibition of platelet activity with thienopyridine therapy is expected to reduce the generation of these byproducts in the systemic venous circulation and, consequently, their passage to the cerebral circulation. Similarly, transcatheter closure of the PFO eliminates the right-to-left pathway, resulting in reduced exposure of the brain to these platelet-derived factors. In this context, a response to thienopyridine therapy may serve as a clinical marker to identify patients in whom the PFO plays a mechanistic role in migraine pathophysiology.

The primary objective of this study is to evaluate whether the clinical benefit in migraine reduction observed during initial thienopyridine therapy is maintained after treatment withdrawal, comparing subjects assigned to transcatheter PFO closure with those managed with medical therapy alone. Thienopyridine-responsiveness will be assessed using prasugrel hydrochloride in this study.

Patient Inclusion Criteria:

• Age: ≥18 and <55 at time of screening
• Migraine headache with aura, or migraine headache without aura, fulfilling conditions of the Neurology Screening Tool (meeting ICHD-3 criteria)
• Diagnosis of migraine for ≥ 1 year; onset of migraine symptoms < 40 years of age
• By history, an average headache burden of greater than one migraine headache day per week:
• without current preventative therapy, OR
• despite preventative therapy, OR
• with reason to come off effective therapy (e.g. cost, aversion to injections, side effects)
• If patient is taking preventive migraine medications, dose must be stable for at least 3 months prior to the screening visit. Patient agrees to continue preventive medication at the current dosage throughout the duration of the Baseline and On-treatment monitoring periods (Study Weeks 1 - 17).
• Female patients capable of becoming pregnant agree to use two forms of birth control or abstinence during their participation in the study.

Patient Exclusion Criteria:

Exclusions due to underlying patient medical issues:

• Headache disorder other than migraine with aura, or migraine without aura
• Patient has history of stroke, TIA, or intracranial hemorrhage.
• Patient has a history of thrombocytopenia within one year, or platelet count <100,000/mm3 identified during the screening laboratory evaluation.
• Patient has severe hepatic impairment with reduced synthetic function as documented by prolongation of PT/PTT, or with total bilirubin >3.0 mg/dL identified during the screening laboratory evaluation.
• Patient has previously implanted pacemaker, IVC filter, PFO closure device, ASD closure device, or left atrial appendage closure device or any cardiac history which, in the investigator's opinion, would preclude them from study participation.
• Patient has documented right-to-left shunt source in addition to PFO such as atrial septal defect or pulmonary arteriovenous malformation.
• Patient has a history of clinically significant bleeding within 6 months of the screening visit, any active bleeding, or active peptic ulcer disease.
• Patient has an uncontrolled arrhythmia, or if on therapy, has evidence of arrhythmia control failure within the past 90 days (e.g., supraventricular tachycardia or atrial fibrillation while under rhythm control).
• Patient has elevated PVR which in the opinion of the implanting physician precludes safe PFO closure.
• Patient has active infection at the time of screening that cannot be treated.
• Patient is planning surgery during the study timeframe.
• A female patient is pregnant or is planning pregnancy during the anticipated duration of the study. Urine or blood pregnancy screening will be performed as part of the screening laboratory evaluation.
• Patient has documented nickel allergy/sensitivity
• Patient has a documented history of non-compliance with medical care, which would preclude them, in the opinion of the study team

Exclusion Due to Medication Restrictions:

• Patient has known hypersensitivity or contraindication to thienopyridines
• Patient has another medical condition requiring chronic antithrombotic therapy with antiplatelet, oral anticoagulant or injectable agents
• Patient has need for daily use of NSAIDs other than for treatment of migraines