LEARNER: pLatelEts And MigRaine iN patEnt foRamen Ovale

• Sponsor: Centro Cardiologico Monzino (Other)
• Overall Status: Completed
• CT.gov ID: NCT03521193
• Collaborator: (none)
• Enrollment: 90
• Location: 1
• Arms: 2
• Actual Duration (Months): 32.5
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Platelet Aggregation, Spontaneous; Migraine With Aura; Patent Foramen Ovale	Device: patent foramen ovale closure	N/A

Detailed Description

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?

Study Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Group 1: patients treated with PFO closure Group 2: Healthy subjects on Aspirin therapyGroup 1: patients treated with PFO closure Group 2: Healthy subjects on Aspirin therapy
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Migraine in Patients Undergoing PFO (Patent Foramen Ovale) Closure: Evaluation of a Platelet-associated Pathophysiologic Linking Mechanism
• Actual Study Start Date: Feb 15, 2018
• Actual Primary Completion Date: Oct 31, 2020
• Actual Study Completion Date: Oct 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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. 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	Device: patent foramen ovale closure; 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; Other Names: Occlutech Figulla Flex II PFO device; aspirin
No Intervention: healthy subjects on aspirin treatment 12 healthy subjects on 100 mg aspirin daily will be compared to PFO patients in terms of platelet reactivity, serotonin and cytokines

Outcome Measures

Primary Outcome Measures

1. Change in Migraine Characteristics [The outcome data were evaluated at 6-months and 12-months after PFO closure and compared to baseline]

   The evaluation in absolute numbers of patients fully responders, non-responders or with a moderate benefit on migraine symptoms after PFO Closure was performed

2. Migraine Assessment by Anzola's Score [Baseline, 6 months and 12-months after PFO closure]

   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

Secondary Outcome Measures

1. Platelet Activation [baseline and 6 months]

   Platelet poor plasma levels of P selectin and serum concentration of B2-thromboxane (TXB2). (Plasma levels of P-selectin: ng/ml; Serum TXB2: ng/ml)

2. Platelet Reactivity Tests [baseline and 6 months]

   Verify-now Platelet Reactivity Unit (PRU): measures the P2Y12 platelet receptor blockade and platelet response to aspirin by an arachidonic acid initiated reaction. Verify-Now P2Y12 (PRU): Cut off: 208; -Verify-Now Aspirin (Aspirin Reactivity Unit (ARU): Cut off: 550

3. Clinical Outcomes [In hospital, six and 12 months follow-up]

   Absence of TIA and stroke recurrences after PFO closure and during the follow-up

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients older than 18 years with more than 2 criteria:

• Previous Stroke or TIA (transient ischemic attack)

• positive MRI for ischemic events -

• PFO with a baseline R-L shunt > 10 microembolic signals (MES) and > 20 MES during/after Valsalva Manoeuver

• Atrial septal aneurysm (ASA) or residual Chiari network or Eustachian Valve

• positive Thrombophilic screening (MTHFR/prot C/Prot S)

• Ability to sign the informed consent for the study participation

Exclusion Criteria:

• Patients older than 70 years

• Paroxysmal Atrial fibrillation

• Carotid, vertebral or basilar artery stenosis> 50% on duplex imaging

• Inadequate temporal bone windows (signals) for transcranial Doppler insonation

• medication overuse headache

• history of cognitive dysfunction, epilepsy, brain injury

• use of continuous positive airway pressure (CPAP) within 6 months of study enrollment

• Left Ventricular Ejection Fraction (LVEF) < 30%

• Moderate/severe mitral valve regurgitation

• Known Allergy to aspirin

• Known allergy to nickel

• Severe chronic kidney disease (GFR < 30 ml/min)

• Beck depression inventory score > or= 29

• State-trait anxiety inventory score exceeding cut-off for are and sex

Keywords: PFO, migraine, migraine with aura, aura, platelets

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centro Cardiologico Monzino, IRCCS	Milan	MI	Italy	20138

Sponsors and Collaborators

• Centro Cardiologico Monzino

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 9, 2018

More Information

Publications

None provided.

• Responsible Party: Daniela Trabattoni, MD, FACC, Centro Cardiologico Monzino
• ClinicalTrials.gov Identifier: NCT03521193
• Other Study ID Numbers: CCM769
• First Posted: May 11, 2018
• Last Update Posted: Aug 9, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daniela Trabattoni, MD, FACC, Centro Cardiologico Monzino: Migraine;; PFO; platelet reactivity; aura
• Additional relevant MeSH terms: Migraine Disorders; Migraine with Aura; Foramen Ovale, Patent; Aspirin

Study Results

Participant Flow

Recruitment Details	Patients were enrolled at Centro Cardiologico Monzino, Milan, Italy between February 2018 and April 2020
Pre-assignment Detail	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

Arm/Group Title	PFO and Migraine Pts	Healthy Subjects on Aspirin
Arm/Group Description	93 consecutive patients addressed to PFO closure and suffering from migraine with aura were prospectively screened. 78 patients were enrolled in the study (T0)	12 healthy subjects on ASA treatment were the control group for phase 2 study
Period Title: Overall Study
STARTED	78	12
COMPLETED	62	12
NOT COMPLETED	16	0

Baseline Characteristics

Arm/Group Title	PFO Patients Enrolled	Healthy Subjects	Total
Arm/Group Description	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.	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	Total of all reporting groups
Overall Participants	78	12	90
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.6 (12)	41 (10)	40.8 (10)
Sex: Female, Male (Count of Participants)
Female	63 80.8%	8 66.7%	71 78.9%
Male	15 19.2%	4 33.3%	19 21.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	78 100%	12 100%	90 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Italy	78 100%	12 100%	90 100%
Migraine (Migraine) [Number]
Number [Migraine]	60	0	60
Migraine with aura (MHA) (Migraine with aura) [Number]
Number [Migraine with aura]	18	0	18
Patients finally evaluated (participants) [Number]
Number [participants]	62 79.5%	12 100%	74 82.2%

Outcome Measures

1. Primary Outcome

Title	Change in Migraine Characteristics
Description	The evaluation in absolute numbers of patients fully responders, non-responders or with a moderate benefit on migraine symptoms after PFO Closure was performed
Time Frame	The outcome data were evaluated at 6-months and 12-months after PFO closure and compared to baseline

Outcome Measure Data

Analysis Population Description

Analysis performed only in PFO Group patients as not applicable to the control Healthy subjects group

Arm/Group Title	Migraine Assessment After PFO Closure
Arm/Group Description	Migraine symptoms evaluation after PFO closure
Measure Participants	62
Migraine : Complete Migraine Resolution	43 55.1%
Migraine : Non-responders	2 2.6%
Migraine Symptoms improvement	17 21.8%

2. Primary Outcome

Title	Migraine Assessment by Anzola's Score
Description	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
Time Frame	Baseline, 6 months and 12-months after PFO closure

Outcome Measure Data

Analysis Population Description

Analysis performed only in PFO Group patients as not applicable to the control Healthy subjects group

Arm/Group Title	PFO Patients Enrolled
Arm/Group Description	We enrolled consecutive patients who met the inclusion criteria, symptomatic for migraine alone and Migraine with aura (MHA) patients. Eight patients refused to continue the study and eight were non-compliant to antiplatelet therapy during the follow-up. . 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.
Measure Participants	62
Anzola's score @Baseline	7.2 (1.68)
Anzola's score@6-mos post PFO Closure	1.09 (1.47)
Anzola's score @12-mos post PFO closure	1.1 (1.57)

3. Secondary Outcome

Title	Platelet Activation
Description	Platelet poor plasma levels of P selectin and serum concentration of B2-thromboxane (TXB2). (Plasma levels of P-selectin: ng/ml; Serum TXB2: ng/ml)
Time Frame	baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Platelet Reactivity Tests
Description	Verify-now Platelet Reactivity Unit (PRU): measures the P2Y12 platelet receptor blockade and platelet response to aspirin by an arachidonic acid initiated reaction. Verify-Now P2Y12 (PRU): Cut off: 208; -Verify-Now Aspirin (Aspirin Reactivity Unit (ARU): Cut off: 550
Time Frame	baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Clinical Outcomes
Description	Absence of TIA and stroke recurrences after PFO closure and during the follow-up
Time Frame	In hospital, six and 12 months follow-up

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	PFO Patients Enrolled
Arm/Group Description	We enrolled 62 consecutive PFO patients suffering from migraine, addressed to PFO closure. 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.
Measure Participants	62
In -hospital vascular complications	1 1.3%
device malpositioning/embolization	0 0%
Transient atrial fibrillation	5 6.4%
TIA/stroke post PFO Closure	0 0%
Recurrent TIAs /stroke @6 months FU	0 0%
Recurrent TIAs /stroke @12 months FU	0 0%

Adverse Events

Time Frame	in -hospital, 6 months and 1 year
Adverse Event Reporting Description	Adverse event definitions were the same adopted by clinicaltrials.gov ; EVENTS WERE COLLECTED during clinical visit in-hospital and at follow-up
Arm/Group Title	Migraine Evaluation in PFO Patients		Healthy Subjects
Arm/Group Description	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		control Healthy subjects group
All Cause Mortality
	Migraine Evaluation in PFO Patients		Healthy Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/62 (0%)		0/12 (0%)
Serious Adverse Events
	Migraine Evaluation in PFO Patients		Healthy Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/62 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Migraine Evaluation in PFO Patients		Healthy Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/62 (0%)		0/12 (0%)

Limitations/Caveats

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

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.