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Migraine With Aura and Patent Foramen Ovale: Identification of Biomarkers to Select Patients In Whom Intervention Would Be Beneficial (MANET) (MANET)

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ClinicalTrials.gov Identifier: NCT06046508
Recruitment Status : Recruiting
First Posted : September 21, 2023
Last Update Posted : February 8, 2024
Sponsor:
Collaborators:
IRCCS Policlinico S. Donato
Università di Cagliari
Federico II University
Information provided by (Responsible Party):
Centro Cardiologico Monzino

Study Description
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Brief Summary:
This is a multicenter prospective observational study aimed to asses whether a specific prothrombotic platelet phenotype can discern migraine patients with PFO (patent forame ovale) - related symptoms from patients with incidental PFO. The study will also explore additional distinguishing features of causal and incidental PFO using a metabolomics approach. It involves the enrollment of well-characterized patient cohorts and an ex vivo approach using comparative cell biology models that reproduce the most critical aspects of the clinical scenario.

Condition or disease Intervention/treatment
Migraine Headache PFO - Patent Foramen Ovale Other: blood samples collection

Detailed Description:

Patients with PFO, who meet all the inclusion and none of the exclusion criteria, will be enrolled in the study. Patients will undergo percutaneous correction of PFO and the following evaluations as clinical practice:

  • thrombophilic screening (factor V and II and MTHFR gene mutation); sampling for homocysteine, Protein C (Prot C), Protein S (Prot S) and antithrombin III assay;
  • anatomic evaluation of the SIA (Saccular intracranial aneurysm) by color-doppler TT echocardiogram and intracardiac ultrasound for definition of the anatomy of the fossa ovalis: tunneled appearance; absence of SIA aneurysm; bulging of the SIA; convex right/left SIA aneurysm;
  • quantification of right-left intracardiac shunt by CT doppler;
  • classification of migraine according to Anzola scale at baseline visit, post PFO correction, at follow-up at 6 and 12 months.

For the purpose of the study, blood sampling will be performed for evaluation of platelet reactivity; oxidative stress, aggregability, and deformability of red blood cells; and isolation of Endothelial Colony Forming Cells (ECFCs) for analysis of endothelial function. The latter in particular will be evaluated in comparison with the endothelial function of 30 subjects without known disease with age > 18 years, enrolled as a control group.

All analyses will be performed before PFO correction and 180 days after surgery.

Study Design
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Study Type : Observational
Estimated Enrollment : 120 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Migraine With Aura and Causal or Incidental Patent Foramen Ovale (PFO): Identification of Biomarker(s) to Select Patients Who Would Most Benefit From PFO Closure. The MANET Study
Actual Study Start Date : May 18, 2023
Estimated Primary Completion Date : April 2025
Estimated Study Completion Date : April 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Migraine
MedlinePlus related topics: Migraine

Groups and Cohorts
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Group/Cohort Intervention/treatment
Sigle arm study
Patients with migraine headache with aura (MHA), patent foramen ovale (PFO) and previous neurological event (transient ischemic attack -TIA- or stroke) with clinical indication for percutaneous correction of the defect according to guidelines will be enrolled
 Other: blood samples collection
patients, who meet all the inclusion criteria and none of the exclusion criteria, will be enrolled and they will perform a blood withdrawal before PFO correction and 180 days after the intervention


Outcome Measures
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Primary Outcome Measures :
  1. Number of migraineurs patients with Platelet activation [ Time Frame: through study completion, an average of 2 years ]
    Fresh whole blood will be stained for tissue factor (TF) expression, platelet activation markers [P-selectin and activated glycoprotein IIbIIIa] and annexinV binding to phosphatidylserine (PS). Flow cytometry analysis will be performed on fixed samples. Platelet procoagulant potential will be assessed by thrombin generation assay. The CAT assay (Chloramphenico Acetyltransferase) lwill be performed in the presence of a neutralizing anti-Tisse Factor (aTF) antibody (Ab) to assess the contribution of TF, and by adding an excess of exogenous phospholipids.

  2. Number of migraineurs patients with high Thrombin generation levels [ Time Frame: through study completion, an average of 2 years ]
    Flow cytometry MV characterization will be performed on stored patients' plasma samples. On the same plasma samples, MV procoagulant potential will be assessed by thrombin generation assay.

  3. levels of the oxidative status in PFO patients [ Time Frame: through study completion, an average of 2 years ]
    RBC (red blood cells) deformability and aggregability, generation of oxygen radicals in RBC and platelets of the overall enrolled population will be analyzed at T0 and at T1. Systemic redox status will be quantified by evaluating concentrations of both reduced glutathione (GSH) and its oxidized form GSSG (oxidized glutathione) on stored samples.

  4. Number of migraineurs patients with Untargeted metabolomics [ Time Frame: through study completion, an average of 2 years ]
    The metabolomic patterns of plasma, urine and platelets/ECFC (endothelial-colony forming cells) of the enrolled population will be investigated by a combined use of spectroscopy and multivariate and univariate statistical tools in order to identify the molecular fingerprint that could build a score able to identify patients with incidental PFO.


Secondary Outcome Measures :
  1. Elucidate whether mechanical stress related to the right-to-left shunt may influence Erythrocyte behavior affecting in turn oxidative stress status [ Time Frame: through study completion, an average of 2 years ]
    This will be accomplished ex vivo by using a microfluidic platform that recapitulates the specific shear stress profiles to which blood is exposed as it flows through the PFO

  2. Assess whether a unique endothelial dysfunction profile identifies migraineurs with incidental PFO [ Time Frame: through study completition, an average of 2 years ]
    Functional profiling will be carried out, by measuring proliferation, migration and in vitro angiogenesis. The pro-inflammatory and pro-thrombotic phenotype of the cells will be assessed using a panel of molecular markers. Platelet adhesion will be determined on resting and activated ECFC under flow conditions; thrombin generation will be measured using a cell-based assay.


Biospecimen Retention:   Samples Without DNA
blood samples will be used for platelet and erythrocyte function analysis and assessment of endothelial function

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Patients with MHA, PFO and previous neurological event (TIA or stroke) with clinical indication for percutaneous correction of the defect according to guidelines.

As a control group, 30 subjects without known disease with age > 18 years will be enrolled.

Criteria

Inclusion Criteria:

  • presence of PFO with right-left shunt at baseline > 10 MES and during Valsalva > 20 MES
  • previous Stroke or TIA
  • positive MRI for ischemic outcomes
  • SIA aneurysm or residual Chiari/Eustachian valve network
  • thrombophilic screening positivity (MTHFR/prot C/prot S)
  • cability to sign informed consent for study participation and adherence to planned clinical follow-ups

Exclusion Criteria:

  • paroxysmal/refractory atrial fibrillation
  • TSA vasculopathy
  • left ventricular ejection fraction <30%
  • moderate/severe mitral valve regurgitation
  • need for long-term anticoagulant therapy
  • allergy or intolerance to antiplatelet therapy
  • nickel allergy
  • severe chronic kidney disease (GFR < 30 mL/min)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06046508


Contacts
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Contact: Daniela Trabattoni, MD 0285800 ext 2780 daniela.trabattoni@cardiologicomonzino.it
Contact: Marina Camera, PhD 025800 ext 2255 marina.camera@cardiologicomonzino.it

Locations
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Italy
IRCCS Policlinico San Donato Recruiting
San Donato Milanese, Milan, Italy, 20097
Contact: Massimo Chessa, MD, PhD    0252774846    Massimo.chessa@grupposandonato.it   
Università di Cagliari Active, not recruiting
Cagliari, Italy, 09124
Azienda Ospedaliera Universitaria "Federico II" Not yet recruiting
Napoli, Italy, 80131
Contact: Giuseppe Gargiulo, MD, PhD       giuseppe.gargiulo1@unina.it   
Sponsors and Collaborators
Centro Cardiologico Monzino
IRCCS Policlinico S. Donato
Università di Cagliari
Federico II University
Investigators
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Principal Investigator: Daniela Trabattoni, MD IRCCS Centro Cardiologico Monzino
More Information
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Responsible Party: Centro Cardiologico Monzino
ClinicalTrials.gov Identifier: NCT06046508    
Other Study ID Numbers: CCM 1934
First Posted: September 21, 2023    Key Record Dates
Last Update Posted: February 8, 2024
Last Verified: September 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centro Cardiologico Monzino:
platelets
prothrombotic platelets phenotype
metabolomics
Additional relevant MeSH terms:
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Migraine Disorders
Migraine with Aura
Foramen Ovale, Patent
Headache
Headache Disorders, Primary
Headache Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
 Pain
Neurologic Manifestations
Heart Septal Defects, Atrial
Heart Septal Defects
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities