Migraine DiseasePhase 3COMFORT-PFONCT07629635
Migraine Headaches Elimination With Patent Foramen Ovale-Directed Therapy
A Phase 3 study testing Prasugrel 5mg and Transcatheter Closure of Patent Foramen Ovale in people with Migraine Disease and Patent Foramen Ovale, run by Columbia University at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Migraine Disease, Patent Foramen Ovale
- What is being tested?
- Prasugrel 5mg and Transcatheter Closure of Patent Foramen Ovale
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Oct 2026to Mar 2028
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
None listed.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Columbia University Irving Medical Center - NewYork Presbyterian Hospital (CUIMC/NYP)
New York, New York, 10032
Robert J Sommer, MD, 2123420886, rs2463@cumc.columbia.edu
Barbara T Robbins, FNP-BC, 2123420886, bs2575@cumc.columbia.edu
About this study
Official title: 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.
Read more
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?
Read the 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.
- Conditions
- Migraine Disease, Patent Foramen Ovale
- Being tested
- Prasugrel 5mg, Transcatheter Closure of Patent Foramen Ovale
- Keywords
- Migraine Headaches, Patent Foramen Ovale, Thienopyridine, COMFORT-PFO, Prasugrel
- Medical subject headings
- Foramen Ovale, Patent, Migraine Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Prasugrel 5mgDrug
Also called Prasugrel Hydrochloride
Six months of daily prasugrel therapy following randomization.
Transcatheter Closure of Patent Foramen OvaleDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Prasugrel 5mg; Device: Transcatheter Closure of Patent Foramen Ovale |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: upon completion of the 56-day Post-Therapy monitoring session
Secondary outcomes (6)
Effect Persistence (EP)
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.
Measured: upon completion of the 56-day Post-Therapy monitoring session
Responder-based Endpoints
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.
Measured: upon completion of the 56-day Post-Therapy monitoring session
Absolute reduction in MMD from Baseline to Post-Therapy
This measure will calculate the absolute difference in MMD between the Baseline monitoring session and the Post-Therapy monitoring session.
Measured: upon completion of the 56-day Post-Therapy monitoring session
Percent reduction in MMD from Baseline to Post-Therapy
This measure will assess the percentage difference in MMD between the Baseline monitoring session and the Post-Therapy session.
Measured: upon completion of the 56-day Post-Therapy monitoring session
Change in MSQ 2.1 Score (Baseline Score - Post-thienopyridine Score)
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.
Measured: Baseline and upon completion of the 56-day Post-Therapy monitoring session
Change in HIT-6 Score (Baseline Score - Post-thienopyridine Score)
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.
Measured: Baseline and upon completion of the 56-day Post-Therapy monitoring session
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jun 2026
- Study start15 Oct 2026 (estimated)
- Primary completion31 Dec 2027 (estimated)
- Study completionMar 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for Migraine DiseaseStudies of the same condition, open and under way.
- More trials run by Columbia UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 32 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Columbia University
- Sponsor type
- University, hospital or other
- Collaborators
- Occlutech International AB, W.L.Gore & Associates
- Responsible party
- Principal investigator, Robert Sommer, Columbia University
- Investigators
- Jessica Ailani, MD, Principal investigator, MedStar Georgetown University HospitalRobert J Sommer, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07629635
- Sponsor's protocol ID
- ACYY2573
- Acronym
- COMFORT-PFO
- Status last verified
- Oct 2026
- First submitted
- 22 May 2026
- Last updated
- 8 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- Yes
- Individual data sharing
- Yes: 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.
Publications
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.
PubMed 11089825Schwerzmann 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.
PubMed 15111681Giardini 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.
PubMed 16548006Reisman 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.
PubMed 15708692Slavin 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.
PubMed 17478165Kimmelstiel 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.
PubMed 17295330Wahl 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.
PubMed 20538672Dowson 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.
PubMed 18316488Mattle 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.
PubMed 26908949Tobis 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.
PubMed 2919132511. The ESCAPE Migraine Trial: https://clinicaltrials.gov/study/NCT00267371?cond=Migraine%20Headache&intr=PFO%20Closure&page=2&rank=15
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.
PubMed 28902590Sondergaard 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.
PubMed 28902580Kent 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.
PubMed 21794121Kent 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.
PubMed 34905030