Migraine Headaches Elimination With Patent Foramen Ovale-Directed Therapy (COMFORT-PFO)

June 1, 2026 updated by: Robert Sommer, Columbia University

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?

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

32

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10032
        • Columbia University Medical Center
        • Contact:
        • Contact:
        • Principal Investigator:
          • Robert J Sommer, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Group A - Thienopyridine only
16 patients will be randomized to this group. Thienopyridine medication (prasugrel) which was demonstrated to reduce headache frequency during study screening phases, will be continued for 6 months and then stopped. Post-therapy headache frequency will be compared with the patient's baseline headache frequency. After completion of the study procedures, patients in this group will be given the opportunity to get the PFO closure procedure.
Drug: Prasugrel 5mg
Six months of daily prasugrel therapy following randomization.
Other Names:
  • Prasugrel Hydrochloride
Active Comparator: Group B - PFO closure plus thienopyridine
16 patients will be randomized to this group. After demonstrating thienopyridine (prasugrel) benefit for migraine symptoms in the screening phases of the study, patients in this arm will undergo PFO closure, a non-surgical outpatient catheter procedure. They will remain on prasugrel for an additional 6 months. The medication will then be stopped. Post-therapy headache frequency will be compared with the patient's baseline headache frequency.
Drug: Prasugrel 5mg
Six months of daily prasugrel therapy following randomization.
Other Names:
  • Prasugrel Hydrochloride
Device: Transcatheter Closure of Patent Foramen Ovale
A standard transcatheter closure of PFO will be performed in the Group B cohort. During this non-surgical procedure, the GORE Cardioform Septal Occluder will be used to close the PFO (it is FDA-approved for exactly this purpose for prevention of recurrent stroke) but will be used here in an off-label fashion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Reduction in Monthly Migraine Days (MMD)
Time Frame: upon completion of the 56-day Post-Therapy monitoring session
The primary efficacy endpoint is the proportion of randomized subjects maintaining a clinically meaningful migraine response, defined as a ≥50% reduction in Monthly Migraine Days (MMD) in the Post-Therapy monitoring session, compared with the Baseline monitoring session (following discontinuation of prasugrel).
upon completion of the 56-day Post-Therapy monitoring session

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effect Persistence (EP)
Time Frame: upon completion of the 56-day Post-Therapy monitoring session

Effect Preservation (EP) is a constructed metric which defines the extent to which the clinical benefit of migraine reduction observed during thienopyridine therapy is maintained following discontinuation of therapy.

EP is calculated for each randomized subject as the proportion of the On-Therapy reduction in Monthly Migraine Days (MMD) that is preserved during the Post-Therapy period, expressed as a percentage.

For each subject, EP is defined as:

EP = (Post-Therapy Reduction in MMD / On-Therapy Reduction in MMD) × 100 where:

Post-Therapy Reduction in MMD = Baseline MMD - Post-Therapy MMD

On-Therapy Reduction in MMD = Baseline MMD - On-Therapy MMD

EP provides a continuous, subject-level measure of treatment durability, allowing comparison of the extent to which the initial treatment effect is maintained following therapy discontinuation.
upon completion of the 56-day Post-Therapy monitoring session
Responder-based Endpoints
Time Frame: upon completion of the 56-day Post-Therapy monitoring session

Responder-based endpoints will assess higher thresholds of clinical response and will include the proportion of subjects achieving:

  • ≥75% reduction in MMD from Baseline during the Post-Therapy monitoring period
  • ≥90% reduction in MMD from Baseline, representing near complete elimination of migraine days
  • 100% reduction in MMD from Baseline, representing complete elimination of migraine days.
upon completion of the 56-day Post-Therapy monitoring session
Absolute reduction in MMD from Baseline to Post-Therapy
Time Frame: upon completion of the 56-day Post-Therapy monitoring session
This measure will calculate the absolute difference in MMD between the Baseline monitoring session and the Post-Therapy monitoring session.
upon completion of the 56-day Post-Therapy monitoring session
Percent reduction in MMD from Baseline to Post-Therapy
Time Frame: upon completion of the 56-day Post-Therapy monitoring session
This measure will assess the percentage difference in MMD between the Baseline monitoring session and the Post-Therapy session.
upon completion of the 56-day Post-Therapy monitoring session
Change in MSQ 2.1 Score (Baseline Score - Post-thienopyridine Score)
Time Frame: Baseline and upon completion of the 56-day Post-Therapy monitoring session
The Migraine-Specific Quality of Life Questionnaire (MSQ) Version 2.1 is a 14-item patient-reported questionnaire to evaluate the impact of migraines on a patient's quality of life across 3 domains: Role Function-Restrictive (measures how migraines limit daily, social, and work-related activities), Role Function-Preventive (measures how migraines prevent these daily activities from happening altogether), and Emotional Function (assesses the emotional toll, frustration, and helplessness caused by migraines). In this modified version, the minimum score is 0, and the maximum score is 70, with each answer to the 14 questions receiving from 0 to 5 points. The cumulative score will be assessed at Baseline and after Treatment. The lower the score, the better Quality of Life. The absolute difference in the cumulative score will be compared, with a reduction from baseline indicating an improvement in quality of life.
Baseline and upon completion of the 56-day Post-Therapy monitoring session
Change in HIT-6 Score (Baseline Score - Post-thienopyridine Score)
Time Frame: Baseline and upon completion of the 56-day Post-Therapy monitoring session
The HIT-6 (Headache Impact Test) is a 6-item patient-reported questionnaire that measures how severely headaches impact daily life, social functioning, and ability to concentrate. Scores range from 36 to 78, with higher numbers indicating greater headache-related disability. This measure will assess the difference from the Baseline (at enrollment) HIT-6 score, to the HIT-6 score after completion of the Post-Therapy monitoring session. A decrease in the HIT-6 score reflects a reduction of the life impact imposed by migraines.
Baseline and upon completion of the 56-day Post-Therapy monitoring session

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Columbia University

Collaborators

W.L.Gore & Associates
Occlutech International AB

Investigators

  • Principal Investigator: Robert J Sommer, MD, Columbia University
  • Principal Investigator: Jessica Ailani, MD, MedStar Georgetown University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2026

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

March 1, 2028

Study Registration Dates

First Submitted

May 22, 2026

First Submitted That Met QC Criteria

June 1, 2026

First Posted (Actual)

June 5, 2026

Study Record Updates

Last Update Posted (Actual)

June 5, 2026

Last Update Submitted That Met QC Criteria

June 1, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACYY1211

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Upon completion, all study information will be de-identified, and shared with our colleagues at the Centro Cardiologico Monzino (Milan, Italy), Dr. Daniela Trabattoni. Dr. Trabattonia and her colleagues are performing a parallel trial with the same protocol, but using a PFO closure device not available in the United States.

IPD Sharing Time Frame

Starting April 2026, all supportive information is being shared collaboratively. No IPD will be shared until the study is completed at both sites (estimated 2028).

IPD Sharing Access Criteria

The two principal investigators (Sommer and Trabattoni) will have access to the de-identified data and supporting information, as well as their dedicated research teams. Outcome data from the two sites will be compared and potentially combined into a single report.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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