Foramen Ovale, PatentINSPIRENCT04713683
Investigation of Nickel Sensitization After Percutaneous Implantation of Patent Foramen Ovale Occluder
A study testing Percutaneous Patent Foramen Ovale Closure in people with Foramen Ovale, Patent and Nickel Sensitivity, run by National and Kapodistrian University of Athens at 1 site in Greece.
Trial summary
Percutaneous PFO closure has been established as a first-line therapy for preventing recurrent strokes in selected patients. The devices used for the specific purpose contain and release nickel, which is considered as the most allergen metal in nature. Read more about this study
- Who is it for?
- Ages 14 years and older
- Conditions the study is for
- Foramen Ovale, Patent, Nickel Sensitivity, Dermatitis Contact Irritant
- What is being tested?
- Percutaneous Patent Foramen Ovale Closure
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 96 participants
- Where
- 1 siteGreece
- Study dates
- 10 Dec 2020to 1 Dec 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 14 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Age: at least 14 years old
- Well-documented indication for percutaneous PFO closure
Who cannot join
- Corticosteroid treatment
- Patient's refusal to participation
Trial locations and contacts
1 site in 1 country.
Greece1 site
First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens
Athens, Attica, 115 28
About this study
Official title: Investigation of Nickel Sensitization After Percutaneous Implantation of Patent Foramen Ovale Occluder; a RandomizEd Trial.
Percutaneous PFO closure has been established as a first-line therapy for preventing recurrent strokes in selected patients. The devices used for the specific purpose contain and release nickel, which is considered as the most allergen metal in nature. Skin patch tests are considered as gold-standard for documenting nickel allergy. While the allergic contact dermatitis induced by nickel is well described, literature is inadequate on explaining the effect of nickel release on the clinical manifestations of patients implanted with such devices.
Our prospective, randomized, blinded trial will try to investigate the above by performing nickel skin patch tests to all patients, 14 days before and 90 days after the implantation. During follow-up, clinical manifestations and transthoracic echocardiographic findings will be evaluated and associated with patch skin tests.
Read the detailed description
Percutaneous PFO closure has been established as a first-line therapy for preventing recurrent strokes, after embolic stroke of unknown source (ESUS) and a patent foramen ovale. The PFO closure is achieved by the implantation of suitable devices, which occlude the shunt between the two atria and prevent the creation and detachment of thrombi. Until today, there are two devices approved by FDA for the specific purpose; Amplatzer PFO Occluder and Gore Cardioform Septal Occluder. Despite the architectonic differences between these devices, the main material of both is nitinol, an alloy of nickel and titanium. While titanium is an extremely rare allergen, nickel is considered as one of the most common allergens and the most frequent metal allergen in nature, with a prevalence about 20%. The main clinical expression of nickel hypersensitivity is allergic contact dermatitis, but cases with systemic allergic reaction have been described as well. It has been observed that nickel is released by the implanted devices and circulates through bloodstream, having the potential to cause systemic clinical picture. Device syndrome includes signs and symptoms (i.e. palpitations, dyspnea, chest pain, rash, etc.), which are appeared after the device placement and are associated with hypersensitivity reaction. The existing literature is considered as inadequate for explaining the effect of nickel release in the patients implanted with an occluder.
The aim of our study is to evaluate whether patients with nickel hypersensitivity have an increased risk of adverse events following PFO closure, to assess the potential influence of device selection, and to evaluate potential sensitization or desensitization in patients without or with pre-existing nickel allergy, respectively.
Nickel hypersensitivity was assessed using skin patch testing prior to the procedure. The primary endpoint was device syndrome, a composite of patient-reported symptoms (chest pain, palpitations, migraines, dyspnea, and rash). Secondary endpoints included arrhythmias, bleeding, stroke, and all-cause mortality.
- Being tested
- Percutaneous Patent Foramen Ovale Closure
- Keywords
- patent foramen ovale, percutaneous pfo closure, Nickel Hypersensitivity, Nickel Sensitisation, device syndrome, skin patch tests
- Medical subject headings
- Foramen Ovale, Patent, Dermatitis, Irritant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Percutaneous Patent Foramen Ovale ClosureDevice
Also called Transcatheter PFO occlusion
Patients with well-documented embolic stroke of unknown source (ESUS) and a patent foramen ovale (PFO) are indicated for percutaneous closure of PFO. The intervention is performed through the right femoral vein. The interventional cardiologist introduces the sheath and advances the device via inferior vena cava to right atrium. Then, the catheter is passed through the PFO, the device is deployed and the occlusion is achieved. The procedure is performed under fluoroscopy guidance with or without transesophageal echocardiography guidance.
| Study group | Role | What they receive |
|---|---|---|
| Amplatzer PFO Occluder | Active comparator | Patients randomized in this arm will be implanted with Amplatzer PFO Occluder. Receives: Device: Percutaneous Patent Foramen Ovale Closure |
| Gore Cardioform Septal | Active comparator | Patients randomized in this arm will be implanted with Gore Cardioform Septal Occluder. Receives: Device: Percutaneous Patent Foramen Ovale Closure |
What is being measured
The primary outcome is the main question the study is designed to answer.
Device syndrome, a composite endpoint consisting of patient-reported new-onset chest pain, palpitations, new-onset or worsening migraines, dyspnea, and rash
Clinical signs and symptoms during the first 90 days after the procedure will be evaluated through a questionnaire.
Measured: The first 90 days after the procedure
Secondary outcomes (10)
The nickel patch tests' results change after Amplatzer Device implantation
Investigating the number of patients received Amplatzer device, who developed nickel sensitization.
Measured: The first 90 days after the procedure
The nickel patch tests' results change after Gore Device implantation
Investigating the number of patients received Gore device, who developed nickel sensitization.
Measured: The first 90 days after the procedure
Residual interatrial leakage
Evaluation of residual interatrial leakage, by performing transthoracic echocardiography
Measured: 90 days after the procedure
Rest allergens skin patch test results' change
The possible change (either as continuous or dichotomous outcome) of rest allergen skin patch test, after the device implantation
Measured: 90 days after the procedure
Nickel patch test results' change
The possible change (either as continuous or dichotomous outcome) of nickel skin patch test, after the device implantation
Measured: 90 days after the procedure
patient-reported new-onset chest pain
patient-reported new-onset chest pain
Measured: 90 days after the procedure
palpitations
as described by the patients
Measured: 90 days after the procedure
new-onset or worsening migraines
as described by the patients
Measured: 90 days after the procedure
dyspnea
as described by the patients
Measured: 90 days after the procedure
Atrial arrhythmias
as described by the patients
Measured: 90 days after the procedure
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jan 2021
- Study start10 Dec 2020
- Primary completion1 Dec 2024
- Study completion1 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Foramen Ovale, PatentStudies of the same condition, open and under way.
- More trials run by National and Kapodistrian University of AthensThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Investigator, Outcomes assessor
- Enrolment
- 96 participants (actual)
Sponsor and investigators
- Lead sponsor
- National and Kapodistrian University of Athens
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Konstantinos Toutouzas, National and Kapodistrian University of Athens
- Investigators
- Konstantinos Toutouzas, MD,PhD, Study chair, First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital of AthensAnastasios Apostolos, MD, Principal investigator, First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital of AthensStamatios Gregoriou, MD, PhD, Study director, First Department of Dermatology-Venereolgy, National and Kapodistrian University of Athens, Andreas Syggros Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04713683
- Sponsor's protocol ID
- NICKEL-PFO TRIAL
- Acronym
- INSPIRE
- Status last verified
- Feb 2025
- First submitted
- 11 Jan 2021
- Last updated
- 6 Feb 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- Undecided
Publications
Apostolos A, Drakopoulou M, Toutouzas K. New migraines after atrial septal defect occlusion. Is the nickel hypersensitivity the start of everything? Med Hypotheses. 2021 Jan;146:110442. doi: 10.1016/j.mehy.2020.110442. Epub 2020 Nov 30. No abstract available.
PubMed 33303305Ahlstrom MG, Thyssen JP, Wennervaldt M, Menne T, Johansen JD. Nickel allergy and allergic contact dermatitis: A clinical review of immunology, epidemiology, exposure, and treatment. Contact Dermatitis. 2019 Oct;81(4):227-241. doi: 10.1111/cod.13327. Epub 2019 Jul 9.
PubMed 31140194Schalock PC, Crawford G, Nedorost S, Scheinman PL, Atwater AR, Mowad C, Brod B, Ehrlich A, Watsky KL, Sasseville D, Silvestri D, Worobec SM, Elliott JF, Honari G, Powell DL, Taylor J, DeKoven J. Patch Testing for Evaluation of Hypersensitivity to Implanted Metal Devices: A Perspective From the American Contact Dermatitis Society. Dermatitis. 2016 Sep-Oct;27(5):241-7. doi: 10.1097/DER.0000000000000210.
PubMed 27649347Prestipino F, Pragliola C, Lusini M, Chello M. Nickel allergy induced systemic reaction to an intracardiac amplatzer device. J Card Surg. 2014 May;29(3):349-50. doi: 10.1111/jocs.12331.
PubMed 24762035Apostolos A, Gregoriou S, Drakopoulou M, Trantalis G, Tsiogka A, Ktenopoulos N, Aggeli K, Stratigos A, Tsioufis K, Toutouzas K. Patent Foramen Ovale Closure in Patients With and Without Nickel Hypersensitivity: A Randomized Trial. Circ Cardiovasc Interv. 2025 Apr;18(4):e015228. doi: 10.1161/CIRCINTERVENTIONS.125.015228. Epub 2025 Mar 9.
PubMed 40057986
Study at a glance
From the registry record, last updated by the sponsor on 6 Feb 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigation of Nickel Sensitization After Percutaneous Implantation of Patent Foramen Ovale Occluder; a RandomizEd Trial.
- ClinicalTrials.gov ID
- NCT04713683
- Acronym / sponsor ID
- INSPIRE / NICKEL-PFO TRIAL
- Keywords
- patent foramen ovale, percutaneous pfo closure, Nickel Hypersensitivity, Nickel Sensitisation, device syndrome, skin patch tests
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 96 participants (actual)
- Lead sponsor
- National and Kapodistrian University of AthensUniversity, hospital or other
- Study start
- 10 Dec 2020 (actual)
- Primary completion
- 1 Dec 2024 (actual)
- Study completion
- 1 Dec 2024 (actual)
- First posted
- 19 Jan 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Percutaneous PFO closure has been established as a first-line therapy for preventing recurrent strokes in selected patients. The devices used for the specific purpose contain and release nickel, which is considered as the most allergen metal in nature. Skin patch tests are considered as gold-standard for documenting nickel allergy. While the allergic contact dermatitis induced by nickel is well described, literature is inadequate on explaining the effect of nickel release on the clinical manifestations of patients implanted with such devices.
Our prospective, randomized, blinded trial will try to investigate the above by performing nickel skin patch tests to all patients, 14 days before and 90 days after the implantation. During follow-up, clinical manifestations and transthoracic echocardiographic findings will be evaluated and associated with patch skin tests.
Detailed description
Percutaneous PFO closure has been established as a first-line therapy for preventing recurrent strokes, after embolic stroke of unknown source (ESUS) and a patent foramen ovale. The PFO closure is achieved by the implantation of suitable devices, which occlude the shunt between the two atria and prevent the creation and detachment of thrombi. Until today, there are two devices approved by FDA for the specific purpose; Amplatzer PFO Occluder and Gore Cardioform Septal Occluder. Despite the architectonic differences between these devices, the main material of both is nitinol, an alloy of nickel and titanium. While titanium is an extremely rare allergen, nickel is considered as one of the most common allergens and the most frequent metal allergen in nature, with a prevalence about 20%. The main clinical expression of nickel hypersensitivity is allergic contact dermatitis, but cases with systemic allergic reaction have been described as well. It has been observed that nickel is released by the implanted devices and circulates through bloodstream, having the potential to cause systemic clinical picture. Device syndrome includes signs and symptoms (i.e. palpitations, dyspnea, chest pain, rash, etc.), which are appeared after the device placement and are associated with hypersensitivity reaction. The existing literature is considered as inadequate for explaining the effect of nickel release in the patients implanted with an occluder.
The aim of our study is to evaluate whether patients with nickel hypersensitivity have an increased risk of adverse events following PFO closure, to assess the potential influence of device selection, and to evaluate potential sensitization or desensitization in patients without or with pre-existing nickel allergy, respectively.
Nickel hypersensitivity was assessed using skin patch testing prior to the procedure. The primary endpoint was device syndrome, a composite of patient-reported symptoms (chest pain, palpitations, migraines, dyspnea, and rash). Secondary endpoints included arrhythmias, bleeding, stroke, and all-cause mortality.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Amplatzer PFO Occluder | Active comparator | Device: Percutaneous Patent Foramen Ovale ClosurePatients randomized in this arm will be implanted with Amplatzer PFO Occluder. |
| Gore Cardioform Septal | Active comparator | Device: Percutaneous Patent Foramen Ovale ClosurePatients randomized in this arm will be implanted with Gore Cardioform Septal Occluder. |
Who may qualify
- Ages
- 14 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- Age: at least 14 years old
- Well-documented indication for percutaneous PFO closure
Key exclusion criteria (2 listed)
- Corticosteroid treatment
- Patient's refusal to participation
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Percutaneous Patent Foramen Ovale ClosureAlso: Transcatheter PFO occlusionPatients with well-documented embolic stroke of unknown source (ESUS) and a patent foramen ovale (PFO) are indicated for percutaneous closure of PFO. The intervention is performed through the right femoral vein. The interventional cardiologist introduces the sheath and advances the device via inferior vena cava to right atrium. Then, the catheter is passed through the PFO, the device is deployed and the occlusion is achieved. The procedure is performed under fluoroscopy guidance with or without transesophageal echocardiography guidance. | Device | Amplatzer PFO Occluder, Gore Cardioform Septal |
Primary outcome
Device syndrome, a composite endpoint consisting of patient-reported new-onset chest pain, palpitations, new-onset or worsening migraines, dyspnea, and rash
Time frame: The first 90 days after the procedure
Clinical signs and symptoms during the first 90 days after the procedure will be evaluated through a questionnaire.
10 secondary outcomes
The nickel patch tests' results change after Amplatzer Device implantation
Time frame: The first 90 days after the procedure
The nickel patch tests' results change after Gore Device implantation
Time frame: The first 90 days after the procedure
Residual interatrial leakage
Time frame: 90 days after the procedure
Rest allergens skin patch test results' change
Time frame: 90 days after the procedure
Nickel patch test results' change
Time frame: 90 days after the procedure
patient-reported new-onset chest pain
Time frame: 90 days after the procedure
palpitations
Time frame: 90 days after the procedure
new-onset or worsening migraines
Time frame: 90 days after the procedure
dyspnea
Time frame: 90 days after the procedure
Atrial arrhythmias
Time frame: 90 days after the procedure
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Feb 2025.
- Results publication: PubMed 33303305Apostolos A, Drakopoulou M, Toutouzas K. New migraines after atrial septal defect occlusion. Is the nickel hypersensitivity the start of everything? Med Hypotheses. 2021 Jan;146:110442. doi: 10.1016/j.mehy.2020.110442. Epub 2020 Nov 30. No abstract available.
- Results publication: PubMed 31140194Ahlstrom MG, Thyssen JP, Wennervaldt M, Menne T, Johansen JD. Nickel allergy and allergic contact dermatitis: A clinical review of immunology, epidemiology, exposure, and treatment. Contact Dermatitis. 2019 Oct;81(4):227-241. doi: 10.1111/cod.13327. Epub 2019 Jul 9.
- Results publication: PubMed 27649347Schalock PC, Crawford G, Nedorost S, Scheinman PL, Atwater AR, Mowad C, Brod B, Ehrlich A, Watsky KL, Sasseville D, Silvestri D, Worobec SM, Elliott JF, Honari G, Powell DL, Taylor J, DeKoven J. Patch Testing for Evaluation of Hypersensitivity to Implanted Metal Devices: A Perspective From the American Contact Dermatitis Society. Dermatitis. 2016 Sep-Oct;27(5):241-7. doi: 10.1097/DER.0000000000000210.
- Results publication: PubMed 24762035Prestipino F, Pragliola C, Lusini M, Chello M. Nickel allergy induced systemic reaction to an intracardiac amplatzer device. J Card Surg. 2014 May;29(3):349-50. doi: 10.1111/jocs.12331.
- Derived from this study: PubMed 40057986Apostolos A, Gregoriou S, Drakopoulou M, Trantalis G, Tsiogka A, Ktenopoulos N, Aggeli K, Stratigos A, Tsioufis K, Toutouzas K. Patent Foramen Ovale Closure in Patients With and Without Nickel Hypersensitivity: A Randomized Trial. Circ Cardiovasc Interv. 2025 Apr;18(4):e015228. doi: 10.1161/CIRCINTERVENTIONS.125.015228. Epub 2025 Mar 9.
- Individual participant dataSharing planned: Undecided
Related trials for Foramen Ovale, Patent
Not yet recruitingObservational study
Hummingbird ICE Study
ATRIAL APPENDAGE CLOSURE for ATRIAL FIBRILLATION, Atrial Fibrillation (AF)
Recruiting
Discontinuation of Antithrombotic Treatment Following Patent Foramen Ovale Closure in Young Patients With Cryptogenic Stroke
Patent Foramen Ovale, Ischemic Stroke
Active, not recruiting
Comparing PFO Outcomes of the Occlutech Flex II PFO Occluder to Standard of Care PFO Occlusion
Stroke, Patent Foramen Ovale
RecruitingPhase 3
Migraine Headaches Elimination With Patent Foramen Ovale-Directed Therapy
Migraine Disease, Patent Foramen Ovale
Recruiting
Comparing Two PFO Closure Devices in Adults With Previous Stroke or TIA
Patent Foramen Ovale, Stroke
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Konstantinos Toutouzas, MD,PhD study chair
First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens
Anastasios Apostolos, MD principal investigator
First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens
Stamatios Gregoriou, MD, PhD study director
First Department of Dermatology-Venereolgy, National and Kapodistrian University of Athens, Andreas Syggros Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Percutaneous Patent Foramen Ovale Closure in people with Foramen Ovale, Patent and Nickel Sensitivity, run by National and Kapodistrian University of Athens at 1 site in Greece.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Device syndrome, a composite endpoint consisting of patient-reported new-onset chest pain, palpitations, new-onset or worsening migraines, dyspnea, and rash (time frame: The first 90 days after the procedure). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04713683, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2025.