Migraine Headaches Elimination With Patent Foramen Ovale-Directed Therapy

NCT07629635 | Not Yet Recruiting Phase 3 DMC FDA Drug FDA Device

• 1 other identifier: ACYY2573
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

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?

Conditions

Migraine Disease; Patent Foramen Ovale

Keywords

Migraine Headaches; Patent Foramen Ovale; Thienopyridine; COMFORT-PFO; Prasugrel

Outcome Measures

Primary Outcomes (1)

• Reduction in Monthly Migraine Days (MMD)

  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 Outcomes (6)

• Effect Persistence (EP)

  upon completion of the 56-day Post-Therapy monitoring session

• Responder-based Endpoints

  upon completion of the 56-day Post-Therapy monitoring session

• Absolute reduction in MMD from Baseline to Post-Therapy

  upon completion of the 56-day Post-Therapy monitoring session

• Percent reduction in MMD from Baseline to Post-Therapy

  upon completion of the 56-day Post-Therapy monitoring session

• Change in MSQ 2.1 Score (Baseline Score - Post-thienopyridine Score)

  Baseline and upon completion of the 56-day Post-Therapy monitoring session

Study Arms (2)

Group A - Thienopyridine only

ACTIVE COMPARATOR

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

Group B - PFO closure plus thienopyridine

ACTIVE COMPARATOR

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; Device: Transcatheter Closure of Patent Foramen Ovale

Interventions

Prasugrel 5mg DRUG

Six months of daily prasugrel therapy following randomization.

Also known as: Prasugrel Hydrochloride

Group A - Thienopyridine only; Group B - PFO closure plus thienopyridine

Transcatheter Closure of Patent Foramen Ovale DEVICE

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.

Group B - PFO closure plus thienopyridine

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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
• Patient has known hypersensitivity or contraindication to thienopyridines

Sponsors & Collaborators

• W.L.Gore & Associates: collaborator
• Columbia University: lead
• Occlutech International AB: collaborator

Study Sites (1)

Columbia University Irving Medical Center - NewYork Presbyterian Hospital (CUIMC/NYP)

New York, New York, 10032, United States

Location

Related Publications (24)

• Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet. 2000 Nov 11;356(9242):1648-51. doi: 10.1016/s0140-6736(00)03160-3.

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• Schwerzmann M, Wiher S, Nedeltchev K, Mattle HP, Wahl A, Seiler C, Meier B, Windecker S. Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology. 2004 Apr 27;62(8):1399-401. doi: 10.1212/01.wnl.0000120677.64217.a9.

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• Giardini A, Donti A, Formigari R, Salomone L, Palareti G, Guidetti D, Picchio FM. Long-term efficacy of transcatheter patent foramen ovale closure on migraine headache with aura and recurrent stroke. Catheter Cardiovasc Interv. 2006 Apr;67(4):625-9. doi: 10.1002/ccd.20699.

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• Reisman M, Christofferson RD, Jesurum J, Olsen JV, Spencer MP, Krabill KA, Diehl L, Aurora S, Gray WA. Migraine headache relief after transcatheter closure of patent foramen ovale. J Am Coll Cardiol. 2005 Feb 15;45(4):493-5. doi: 10.1016/j.jacc.2004.10.055.

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• Slavin L, Tobis JM, Rangarajan K, Dao C, Krivokapich J, Liebeskind DS. Five-year experience with percutaneous closure of patent foramen ovale. Am J Cardiol. 2007 May 1;99(9):1316-20. doi: 10.1016/j.amjcard.2006.12.054. Epub 2007 Mar 20.

  PMID: 17478165 BACKGROUND

• Kimmelstiel C, Gange C, Thaler D. Is patent foramen ovale closure effective in reducing migraine symptoms? A controlled study. Catheter Cardiovasc Interv. 2007 Apr 1;69(5):740-6. doi: 10.1002/ccd.21025.

  PMID: 17295330 BACKGROUND

• Wahl A, Praz F, Tai T, Findling O, Walpoth N, Nedeltchev K, Schwerzmann M, Windecker S, Mattle HP, Meier B. Improvement of migraine headaches after percutaneous closure of patent foramen ovale for secondary prevention of paradoxical embolism. Heart. 2010 Jun;96(12):967-73. doi: 10.1136/hrt.2009.181156.

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• Dowson A, Mullen MJ, Peatfield R, Muir K, Khan AA, Wells C, Lipscombe SL, Rees T, De Giovanni JV, Morrison WL, Hildick-Smith D, Elrington G, Hillis WS, Malik IS, Rickards A. Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation. 2008 Mar 18;117(11):1397-404. doi: 10.1161/CIRCULATIONAHA.107.727271. Epub 2008 Mar 3.

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• Mattle HP, Evers S, Hildick-Smith D, Becker WJ, Baumgartner H, Chataway J, Gawel M, Gobel H, Heinze A, Horlick E, Malik I, Ray S, Zermansky A, Findling O, Windecker S, Meier B. Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial. Eur Heart J. 2016 Jul 7;37(26):2029-36. doi: 10.1093/eurheartj/ehw027. Epub 2016 Feb 22.

  PMID: 26908949 BACKGROUND

• Tobis JM, Charles A, Silberstein SD, Sorensen S, Maini B, Horwitz PA, Gurley JC. Percutaneous Closure of Patent Foramen Ovale in Patients With Migraine: The PREMIUM Trial. J Am Coll Cardiol. 2017 Dec 5;70(22):2766-2774. doi: 10.1016/j.jacc.2017.09.1105.

  PMID: 29191325 BACKGROUND

• 11. The ESCAPE Migraine Trial: https://clinicaltrials.gov/study/NCT00267371?cond=Migraine%20Headache&intr=PFO%20Closure&page=2&rank=15

  BACKGROUND

• Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks DS, Tirschwell DL; RESPECT Investigators. Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke. N Engl J Med. 2017 Sep 14;377(11):1022-1032. doi: 10.1056/NEJMoa1610057.

  PMID: 28902590 BACKGROUND

• Sondergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, Settergren M, Sjostrand C, Roine RO, Hildick-Smith D, Spence JD, Thomassen L; Gore REDUCE Clinical Study Investigators. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med. 2017 Sep 14;377(11):1033-1042. doi: 10.1056/NEJMoa1707404.

  PMID: 28902580 BACKGROUND

• Kent DM, Thaler DE; RoPE Study Investigators. The Risk of Paradoxical Embolism (RoPE) Study: developing risk models for application to ongoing randomized trials of percutaneous patent foramen ovale closure for cryptogenic stroke. Trials. 2011 Jul 27;12:185. doi: 10.1186/1745-6215-12-185.

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• Kent DM, Saver JL, Kasner SE, Nelson J, Carroll JD, Chatellier G, Derumeaux G, Furlan AJ, Herrmann HC, Juni P, Kim JS, Koethe B, Lee PH, Lefebvre B, Mattle HP, Meier B, Reisman M, Smalling RW, Soendergaard L, Song JK, Mas JL, Thaler DE. Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke. JAMA. 2021 Dec 14;326(22):2277-2286. doi: 10.1001/jama.2021.20956.

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• Rodes-Cabau J, Horlick E, Ibrahim R, Cheema AN, Labinaz M, Nadeem N, Osten M, Cote M, Marsal JR, Rivest D, Marrero A, Houde C. Effect of Clopidogrel and Aspirin vs Aspirin Alone on Migraine Headaches After Transcatheter Atrial Septal Defect Closure: The CANOA Randomized Clinical Trial. JAMA. 2015 Nov 24;314(20):2147-54. doi: 10.1001/jama.2015.13919.

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• Reisman AM, Robbins BT, Chou DE, Yugrakh MS, Gross GJ, Privitera L, Nazif T, Sommer RJ. Ticagrelor for Refractory Migraine/Patent Foramen Ovale (TRACTOR): An open-label pilot study. Neurology. 2018 Nov 27;91(22):1010-1017. doi: 10.1212/WNL.0000000000006573.

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• Sommer RJ, Robbins BT. Migraine Headache and Patent Foramen Ovale: Observational Studies, the Randomized Clinical Trials, and the GORE RELIEF Clinical Study. Cardiol Clin. 2024 Nov;42(4):497-507. doi: 10.1016/j.ccl.2024.01.007. Epub 2024 Feb 29.

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• Sommer RJ, Nazif T, Privitera L, Robbins BT. Retrospective review of thienopyridine therapy in migraineurs with patent foramen ovale. Neurology. 2018 Nov 27;91(22):1002-1009. doi: 10.1212/WNL.0000000000006572.

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MeSH Terms

Conditions

Foramen Ovale, Patent; Migraine Disorders

Interventions

Prasugrel Hydrochloride

Condition Hierarchy (Ancestors)

Heart Septal Defects, Atrial; Heart Septal Defects; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Jessica Ailani, MD

  MedStar Georgetown University Hospital

  PRINCIPAL INVESTIGATOR

• Robert J Sommer, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Robert J Sommer, MD

CONTACT

212-342-0886; rs2463@cumc.columbia.edu

Barbara T Robbins, FNP-BC

CONTACT

212-342-0886; bs2575@cumc.columbia.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine; Director of Invasive Adult Congenital Heart Disease

Model Details: The COMFORT-PFO Study is a single-site, prospective, randomized, clinical investigation designed to evaluate the persistence of migraine reduction in a selected thienopyridine-responsive population. The study compares the durability of treatment effect following treatment with either continued prasugrel therapy or transcatheter PFO closure (both with adjunctive prasugrel therapy), with efficacy assessed after subsequent treatment withdrawal. A total of 32 migraine patients with a confirmed PFO who demonstrate thienopyridine responsiveness during prasugrel testing will be randomized in a 1:1 ratio to one of two treatment groups. Group A will continue prasugrel therapy for an additional 24 weeks. Group B will undergo transcatheter PFO closure and continue prasugrel therapy for 24 weeks. In both groups, efficacy endpoints will be assessed following discontinuation of prasugrel.

Study Record Dates

• First Submitted: May 22, 2026
• First Posted: June 5, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): March 1, 2028
• Last Updated: July 29, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• 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).
• 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.

Locations

US (1)