Migraine Headaches Elimination With Patent Foramen Ovale-Directed Therapy

Official title

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

Overview

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?

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.

Interventions

• Drug Prasugrel 5mg
  Six months of daily prasugrel therapy following randomization.
• 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.

Primary outcome measures

• Reduction in Monthly Migraine Days (MMD) [Time frame: upon completion of the 56-day Post-Therapy monitoring session]

Secondary outcome measures (6)

• Effect Persistence (EP) [Time frame: 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]
• Absolute reduction in MMD from Baseline to Post-Therapy [Time frame: 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]
• 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]
• Change in HIT-6 Score (Baseline Score - Post-thienopyridine Score) [Time frame: Baseline and upon completion of the 56-day Post-Therapy monitoring session]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

United States · 1 center

• Columbia University Irving Medical Center - NewYork Presbyterian Hospital (CUIMC/NYP) — New York

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. PMID 11089825
• 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. PMID 15111681
• 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. PMID 16548006
• 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. PMID 15708692
• 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
• 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
• 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. PMID 20538672
• 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 PMID 18316488

Identifiers

NCT: NCT07629635 · ACYY2573

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗