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Migraine is a common, chronic neurovascular disorder characterized by attacks of severe headache, autonomic nervous system dysfunction and, in some patients, aura, and disabling neurological symptoms. Worldwide, migraine prevalence is as high as 18% in the general population. Increased frequency of patent foramen ovale (PFO) in migraineurs was first reported in 1998 in a case-control study. Since then, others have described a 60% prevalence of PFO in patients suffering from migraine with aura. The presence of a right-to-left shunt (RLS) is thought to be a potent trigger of migraine attacks, although the mechanism is unknown. Moreover, PFO closure has correlated with improved migraine symptoms in several retrospective uncontrolled studies. The aim of this single-center, prospective study is to assess the impact of PFO closure on migraine attacks over time together with evaluation of potential predictive risk factors.
The Study will evaluate the results of approximately 100 subjects from a single center study registered in this trial. Subjects who experienced transient ischemic attack (TIA) or stroke with a clinical indication to PFO closure and symptomatic for migraine with/o aura are considered for a migraine score analysis at baseline before PFO closure and during the subsequent follow-up (FU) at 6 and 12-months, together with lab evaluation for platelet reactivity tests (P selectin, Thromboxane B2), Prostaglandin E1 and 2 (PGE1, PGE2), serotonin, cytokines and prostaglandin PGE1 urinary metabolite run under aspirin therapy.
The research questions are as follows:
Does the presence of a large PFO have any impact on migraine with aura?
Do migraineurs with aura and PFO have higher biomarkers of platelet activation than control patients? and are they at higher risk of stroke and TIA recurrences based on high on clopidogrel platelet reactivity?
What is the effect of PFO severity on monthly migraine frequency and aura frequency?
What is the result of PFO closure in migraineur patients with PFO? Do Migraine with aura patients with large PFO have higher platelet activation and better migraine resolution after PFO closure?
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Migraine evaluation in PFO patients | Experimental | Patients symptomatic for migraine with/o aura and addressed to patent foramen ovale closure (Occlutech Figulla Flex II PFO occluder device) for a previous ischemic event, will receive dual antiplatelet therapy (DAPT) for 2 months after procedure and aspirin alone subsequently. Patients will undergo evaluation of platelet reactivity, serotonin and cytokines before PFO closure with a dedicated device and at 6 months follow-up and these results compared to those of a control, group of healthy subjects treated with aspirin alone |
|
| healthy subjects on aspirin treatment | No Intervention | 12 healthy subjects on 100 mg aspirin daily will be compared to PFO patients in terms of platelet reactivity, serotonin and cytokines |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| patent foramen ovale closure | Device | Pts undergoing PFO closure will receive 2-months of DAPT and 6 months of aspirin after patent foramen ovale (PFO) closure; they will be compared to healthy subjects on aspirin treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Migraine Characteristics | The evaluation in absolute numbers of patients fully responders, non-responders or with a moderate benefit on migraine symptoms after PFO Closure was performed | The outcome data were evaluated at 6-months and 12-months after PFO closure and compared to baseline |
| Migraine Assessment by Anzola's Score | The change in migraine severity, incidence and duration with or without aura as measured by the Anzola's score (The score is the expression of the sum of each corresponding value referring to migraine duration, frequency and the presence or absence of aura). The minimum value was 2 and the maximum 9; the higher the value, worse is the migraine classification. Anzola's score: Duration 0=No pain 1=<6 hours 2=6-12 hours 3=>12 hours Frequency 0=No pain 1=1-4/month 2=5-9/month 3=>10/month Aura 0=No aura 1=Aura in ≥1 attack | Baseline, 6 months and 12-months after PFO closure |
| Measure | Description | Time Frame |
|---|---|---|
| Platelet Activation (I) | Platelet Thrombin generation potential in migraineurs and healthy subjects | baseline and 6 months after PFO closure |
| Platelet Activation (II) | Platelet Thrombin generation Potential in Migraneurs and Healthy subjects |
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Inclusion Criteria:
Exclusion Criteria:
Keywords: PFO, migraine, migraine with aura, aura, platelets
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| Name | Affiliation | Role |
|---|---|---|
| Daniela Trabattoni, MD | Centro Cardiologico Monzino, IRCCS | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centro Cardiologico Monzino, IRCCS | Milan | MI | 20138 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35818509 | Derived | Trabattoni D, Brambilla M, Canzano P, Becchetti A, Teruzzi G, Porro B, Fiorelli S, Muratori M, Tedesco CC, Veglia F, Montorsi P, Bartorelli AL, Tremoli E, Camera M. Migraine in Patients Undergoing PFO Closure: Characterization of a Platelet-Associated Pathophysiological Mechanism: The LEARNER Study. JACC Basic Transl Sci. 2022 Apr 13;7(6):525-540. doi: 10.1016/j.jacbts.2022.02.002. eCollection 2022 Jun. |
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After screening of 93 consecutive PFO patients suffering from migraine 15 were excluded due to unwillingness to sign the informed consent, absence of patent PFO at the invasive evaluation, intolerance to antiplatelet therapy. Finally, 78 pts were enrolled in the study and assigned to the PFO Arm; another arm included 12healthy subjects on Aspirin treatment
Patients were enrolled at Centro Cardiologico Monzino, Milan, Italy between February 2018 and April 2020
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| ID | Title | Description |
|---|---|---|
| FG000 | PFO and Migraine Pts | 93 consecutive patients addressed to PFO closure and suffering from migraine with aura were prospectively screened. 78 patients were enrolled in the study (T0) |
| FG001 | Healthy Subjects on Aspirin | 12 healthy subjects on ASA treatment were the control group for phase 2 study |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Final evaluation was performed on 62 patients. This group was compared to a control group (12 healthy subjects) on aspirin. Comparison was performed before PFO closure (T0) and during follow-up (T1) in terms of serotonin, platelet aggregation and activation markers and cell-associated procoagulant effect
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| ID | Title | Description |
|---|---|---|
| BG000 | PFO Patients Enrolled | We enrolled consecutive patients who met the inclusion criteria, symptomatic for migraine alone and Migraine with aura (MHA) patients. The leading indication to PFO closure was a previous TIA or stroke in 37 patients while an off-label indication was offered to 25 patients. These pts underwent PFO closure with the Occlutech Figulla device and treated with dual antiplatelet therapy (Aspirin 100 mg/day + Clopidogrel 75 mg/day), followed by aspirin 100 mg/day alone. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Migraine Characteristics | The evaluation in absolute numbers of patients fully responders, non-responders or with a moderate benefit on migraine symptoms after PFO Closure was performed | Analysis performed only in PFO Group patients as not applicable to the control Healthy subjects group | Posted | Count of Participants | Participants | The outcome data were evaluated at 6-months and 12-months after PFO closure and compared to baseline |
|
|
in -hospital, 6 months and 1 year
Adverse event definitions were the same adopted by clinicaltrials.gov ; EVENTS WERE COLLECTED during clinical visit in-hospital and at follow-up
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Migraine Evaluation in PFO Patients | Patients symptomatic for migraine with/o aura and addressed to patent foramen ovale closure (Occlutech Figulla Flex II PFO occluder device) for a previous ischemic event, will receive dual antiplatelet therapy (DAPT) for 2 months after procedure and aspirin alone subsequently. Clinical evaluation performed during in-hospital stay, at 6- and 12-months follow-up |
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MHA may have a multifactorial etiology. The role of oxidative stress appears consistent and corroborated by the in vitro data. The effect of serotonin and oxidative stress was tested on platelets from healthy subjects and not from pts because the Sars-Cov-2 pandemic imposed restrictions on pts enrolment. Finally, the thrombin generation capacity of platelets and MVs were included after the study started to support the pro-coagulant phenotype evidenced by ad interim flow cytometry data analysis
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trials' Office Chief | Centro Cardiologico Monzino, IRCCS | +390258002 | 675 | alessandra.terragni@ccfm.it |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 9, 2018 | Jul 27, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| C566800 | Platelet Aggregation, Spontaneous |
| D020325 | Migraine with Aura |
| D054092 | Foramen Ovale, Patent |
| D008881 | Migraine Disorders |
| D004827 | Epilepsy |
| ID | Term |
|---|---|
| D051270 | Headache Disorders, Primary |
| D020773 | Headache Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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Group 1: patients treated with PFO closure Group 2: Healthy subjects on Aspirin therapy
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|
| Baseline and 6 months after PFO closure |
| Platelet Activation (III) | Platelets' endogenous thrombin generation potential in Migraneurs and Healthy subjects | baseline and six months after PFO closure |
| Platelet Activation (IV) | Platelets' functional activity measured as the amount of thrombin generation | Baseline and six-months after PFO closure |
| Platelet Aggregation (I) | Platelet aggregation was measured on PAP-8 aggregometer (BioData). Briefly, PRP aliquots (250µL) were pipetted into a siliconized glass cuvette, stirred at 1200 rpm at 37°C and stimulated with arachidonic acid (1mM), collagen (2µg/ml), ADP (5µM), TRAP-6 (5µM). Light transmission was recorded for 5 min after stimuli addition and platelet aggregation was reported as maximal percentage of light transmission. Aspirin-treated patients were considered drug responders when platelet aggregation was less than 20% after arachidonic acid (1mM) stimulation. | baseline and 6 months after PFO Closure |
| Clinical Outcomes | Absence of TIA and stroke recurrences after PFO closure and during the follow-up | In hospital, six and 12 months follow-up |
| BG001 | Healthy Subjects | Healthy subjects on aspirin treatment by at least 15 days were the comparative group for platelet aggregation markers and activation markers, platelet procoagulant, circulating serotonin and cell-associated procoagulant potential |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants | No |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Migraine | number of participants sffering from Migraine alone (MA) | Number | Migraine |
|
| Migraine with aura (MHA) | Number of patients suffering from Migraine with aura (MHA) | Number | Migraine with aura |
|
| Patients finally evaluated | 8 patients refused to continue the study ; 8 patients were not compliant to aspirin treatment, therefore final analysis was performed on 62 patients | Number | participants |
|
| Participants |
|
|
| Primary | Migraine Assessment by Anzola's Score | The change in migraine severity, incidence and duration with or without aura as measured by the Anzola's score (The score is the expression of the sum of each corresponding value referring to migraine duration, frequency and the presence or absence of aura). The minimum value was 2 and the maximum 9; the higher the value, worse is the migraine classification. Anzola's score: Duration 0=No pain 1=<6 hours 2=6-12 hours 3=>12 hours Frequency 0=No pain 1=1-4/month 2=5-9/month 3=>10/month Aura 0=No aura 1=Aura in ≥1 attack | Analysis performed only in PFO Group patients as not applicable to the control Healthy subjects group | Posted | Mean | Standard Deviation | score on a scale | Baseline, 6 months and 12-months after PFO closure |
|
|
|
| Secondary | Platelet Activation (I) | Platelet Thrombin generation potential in migraineurs and healthy subjects | Posted | Mean | Standard Deviation | min | baseline and 6 months after PFO closure |
|
|
|
| Secondary | Platelet Activation (II) | Platelet Thrombin generation Potential in Migraneurs and Healthy subjects | Analysis of platelets' intrinsic characteristics including thrombin-formation capacity, the amount of thrombin and the kinetic rate (peak velocity) | Posted | Mean | Standard Deviation | nMol/L/min | Baseline and 6 months after PFO closure |
|
|
|
| Secondary | Platelet Activation (III) | Platelets' endogenous thrombin generation potential in Migraneurs and Healthy subjects | Posted | Mean | Standard Deviation | nmol/L x min | baseline and six months after PFO closure |
|
|
|
| Secondary | Platelet Activation (IV) | Platelets' functional activity measured as the amount of thrombin generation | Posted | Mean | Standard Deviation | nmol/L | Baseline and six-months after PFO closure |
|
|
|
| Secondary | Platelet Aggregation (I) | Platelet aggregation was measured on PAP-8 aggregometer (BioData). Briefly, PRP aliquots (250µL) were pipetted into a siliconized glass cuvette, stirred at 1200 rpm at 37°C and stimulated with arachidonic acid (1mM), collagen (2µg/ml), ADP (5µM), TRAP-6 (5µM). Light transmission was recorded for 5 min after stimuli addition and platelet aggregation was reported as maximal percentage of light transmission. Aspirin-treated patients were considered drug responders when platelet aggregation was less than 20% after arachidonic acid (1mM) stimulation. | Patients were analysed at baseline before PFO closure, six months after procedure and compared to healthy subjects | Posted | Median | Inter-Quartile Range | AUC (AU x min) | baseline and 6 months after PFO Closure |
|
|
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| Secondary | Clinical Outcomes | Absence of TIA and stroke recurrences after PFO closure and during the follow-up | Clinical evaluation of neurologic recurrences or death was performed during in-hospital stay and subsequent follow-up; Analysis performed only in PFO Group patients as not applicable to the control Healthy subjects group | Posted | Count of Participants | Participants | In hospital, six and 12 months follow-up |
|
|
|
| 0 |
| 62 |
| 0 |
| 62 |
| 0 |
| 62 |
| EG001 | Healthy Subjects | control Healthy subjects group | 0 | 12 | 0 | 12 | 0 | 12 |
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| D009422 | Nervous System Diseases |
| D006344 | Heart Septal Defects, Atrial |
| D006343 | Heart Septal Defects |
| D006330 | Heart Defects, Congenital |
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Collagen (2µg/ml) |
|
| Title | Measurements |
|---|---|
|
| TIA/stroke post PFO Closure |
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| Recurrent TIAs /stroke @6 months FU |
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| Recurrent TIAs /stroke @12 months FU |
|