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

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

Tracking Information

• First Submitted Date: August 21, 2023
• First Posted Date: September 21, 2023
• Last Update Posted Date: February 8, 2024
• Actual Study Start Date: May 18, 2023
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 6, 2024)

• 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.
• 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.
• 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.
• 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.

Original Primary Outcome Measures (submitted: September 12, 2023)

• 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.
• Thrombin generation [ 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.
• Quantification of the oxidative status [ 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.
• 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.

Current Secondary Outcome Measures (submitted: September 12, 2023)

• 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
• 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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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 Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples Without DNA

Description:

blood samples will be used for platelet and erythrocyte function analysis and assessment of endothelial function

• 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.

Condition

• Migraine Headache
• PFO - Patent Foramen Ovale

Intervention

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

Study Groups/Cohorts

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

Intervention: Other: blood samples collection

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 12, 2023): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 2025
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

Eligibility 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Daniela Trabattoni, MD; 0285800 ext 2780; daniela.trabattoni@cardiologicomonzino.it

Contact: Marina Camera, PhD; 025800 ext 2255; marina.camera@cardiologicomonzino.it

• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT06046508
• Other Study ID Numbers: CCM 1934
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Centro Cardiologico Monzino
• Original Responsible Party: Same as current
• Current Study Sponsor: Centro Cardiologico Monzino
• Original Study Sponsor: Same as current

Collaborators

• IRCCS Policlinico S. Donato
• Università di Cagliari
• Federico II University

Investigators

• Principal Investigator: Daniela Trabattoni, MD; IRCCS Centro Cardiologico Monzino

• PRS Account: Centro Cardiologico Monzino
• Verification Date: September 2023