Paroxysmal Atrial Fibrillation
Conditions
Brief summary
The purpose of this study is to assess the safety and effectiveness of the Circular and Crescent Mapping and Ablation catheters and the workflow of the Multi-Electrode Irrigated Pulmonary Vein Isolation System when used for the treatment of drug refractory symptomatic paroxysmal atrial fibrillation (PAF).
Detailed description
The study will include a Workflow Phase to verify consistent workflow of all study device components and evaluate acute safety. Upon meeting the defined criteria, the Workflow Phase will be closed and further enrollment will be toward the Main Study Phase which includes the roll-in (the first 3 subjects enrolled at each site following the closure of the Workflow Phase) and Subpopulation Neurological Assessments (SNA) substudy subjects. SNA assessment is a prospective, non-randomized, controlled, acute assessment of two ablation devices to determine if intracerebral microemboli are generated during or immediately after radiofrequency ablation therapy for PAF. SNA subjects will remain and complete the Main Study Phase. However, SNA-control subjects will not be considered part of the Main Study Phase. All subjects, including the subjects enrolled under the Workflow Phase will be included in the Safety Cohort (evaluated for Primary Safety endpoint and all Secondary Safety endpoints).
Interventions
DEVICEnMARQ™ System
The nMARQ™ System is indicated for catheter-based electrophysiological mapping for the treatment of drug refractory recurrent symptomatic paroxysmal atrial fibrillatioon.
Sponsors
Biosense Webster, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with symptomatic Paroxysmal Atrial Fibrillation (PAF) who have had at least one documented Atrial Fibrillation (AF) episode in the twelve (12) months prior to enrollment. Documentation may include electrocardiogram (ECG), transtelephonic monitor (TTM), Holter Monitor (HM), or telemetry strip. 2. Failure of at least one antiarrhythmic drug for AF (class I or III, or Atrioventricular (AV) nodal blocking agents such as beta blockers and calcium channel blockers), as evidenced by recurrent symptomatic AF, or intolerable side effects. 3. Age 18 years or older. 4. Able and willing to comply with all pre-, post- and follow-up testing and requirements. 5. Signed Patient Informed Consent Form.
Exclusion criteria
1. AF secondary to electrolyte imbalance, thyroid disease, or reversible or non-cardiac cause. 2. Patients with Persistent or Long-standing AF (AF episode lasting \> 30 days in duration. 3. Diagnosed atrial myxoma. 4. Left atrial size \> 5.5cm. 5. Left Ventricular ejection fraction \< 40%. 6. Contraindication to Computed Axial Tomography/Magnetic Resonance Imaging (CT/MRI) procedures 7. New York Heart Association Class III or IV. 8. Previous ablation for enrolled arrhythmia (AF). 9. Documented left atrial thrombus on imaging (example: transesophageal echocardiography or intracardiac echocardiography). 10. Myocardial Infarction within the previous 60 days (2 months). 11. Any valvular cardiac surgical procedure (that is, valve repair or replacement and presence of a prosthetic valve). 12. Coronary artery bypass graft procedure with the last 180 days 6 months. 13. Cardiac Surgery (that is, ventriculotomy, atriotomy) within the past 60 days (2 months). 14. Awaiting cardiac transplantation or other cardiac surgery within the next 365 days (12 months). 15. History of documented thromboembolic event within the past one (1) year. 16. Significant pulmonary disease, (example: restrictive pulmonary disease, constrictive or chronic obstructive pulmonary disease) or any other disease or malfunctions of the lungs or respiratory system that produces chronic symptoms. 17. Significant congenital anomaly or medical problem that in the opinion of the investigator would preclude enrollment in this study. 18. Active illness or active systemic infection or sepsis. 19. Unstable angina. 20. History of blood clotting or bleeding abnormalities. 21. Contraindication to anticoagulation (that is, Heparin or Warfarin). 22. Life expectancy less than 365 days (12 months) 23. Presence of intramural thrombus, tumor or other abnormality that precludes catheter introduction or manipulation. 24. Women who are pregnant (as evidence by pregnancy test if subject is of child bearing potential) and/or breast feeding. 25. Presence of a condition that precludes vascular access. 26. Enrollment in an investigational study evaluating another device or drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Incidence of Early Onset Primary Adverse Events | Any of above events occurring within 7 days post-procedure (also including the incidence of pulmonary vein stenosis and atrio-esophageal fistula occurring > 7 days and up to one year post-procedure) | The primary safety endpoint is the incidence of early onset primary adverse events within 7 days of the mapping and ablation procedure. Primary adverse events include pericardial effusion requiring intervention, atrial perforation, pericarditis requiring intervention, cardiac tamponade, pneumothorax, death, pulmonary edema, diaphragmatic paralysis, heart block, stroke / cerebrovascular accident (CVA), hospitalization (initial and prolonged), thromboembolism, myocardial infarction (MI), transient ischemic attack (TIA), and vascular access complications. In addition, pulmonary vein stenosis and atrio-esophageal fistula that occurs greater than one week (7 days) post-procedure are deemed primary adverse event. |
| Incidence of Freedom From Documented Symptomatic Atrial Fibrillation | Evaluated from Day 91 to Day 240 | The primary effectiveness endpoint is freedom from documented symptomatic atrial fibrillation based on electrocardiographic data through 8 months post ablation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Completion of Ablation Procedure | From 7 days to 12 months post study procedure | This secondary outcome describes the acute effectiveness, which is defined as pulmonary vein isolation (PVI) documented by confirmed entrance block (with or without the use of a focal catheter). |
| Absence of Documented Symptomatic PAF Through 6 Months and 12 Months Post Procedure | 6 and12 months post study procedure | This endpoint is defined as the absence of documented symptomatic PAF recurrence through 6 months and 12 months post index ablation procedure. |
| Incidence of Non-Primary Serious Adverse Events (SAEs) up to 12 Months | 12 months post study procedure | This secondary safety endpoint includes non-primary serious adverse events within 7 days post-procedure and serious adverse events from 7 days to 12 months post-procedure. |
| Subpopulation Neurological Assessments (SNA) Endpoint 2 - Incidence of New Neurological Findings Post Ablation | 48 hours post-ablation | All SNA subjects were to be evaluated by expert neurologists for existing neurological deficits prior to ablation procedure. After procedure, those subjects were also to be assessed for new neurological deficits. |
| Subpopulation Neurological Assessments (SNA) Endpoint 1 - Incidence of Cerebral Embolic (ACE) Lesions Post Ablation | 48 hours post-ablation | Evaluation of post-ablation generation incidence of asymptomatic cerebral microembolic lesions post ablation, as documented by MRI. All microembolic lesions reported in this study are asymptomatic. |
| Assessment of Pulmonary Vein (PV) Narrowing and Stenosis at 3 Months After Index Ablation | Three months after index ablation | Incidence of narrowing of PV and stenosis at 3 months post ablation, for subjects with available CT/MRA scans at 3 months. PV Stenosis is defined as 70% or more PV diameter reduction. |
Countries
Belgium, Czechia, Denmark, France, Germany, Italy
Participant flow
Recruitment details
A total of 186 eligible subjects enrolled in this study across 8 sites in Europe. The first was enrolled on March 14, 2011 and was treated on March 15, 2011. The last was enrolled on October 16, 2012. The study's last 12 month follow-up visit occurred on September 27, 2013.
Pre-assignment details
The Main Study consisted only of subjects treated with nMARQ ablation system, without a control arm. Later, a Subpopulation Neurological Assessment (SNA) was added to evaluate for potential cerebral micro-emboli and neurological deficits post ablation. The SNA included a comparator control arm of subjects treated with the Navistar® ThermoCool®.
Participants by arm
| Arm | Count |
|---|---|
| nMARQ™ (Main Study- Single Arm) This group of subjects underwent electrophysiological mapping and radiofrequency ablation with the Biosense Webster nMARQ™ system. The Main Study (167 subjects) consists only of subjects treated with the nMARQ catheter. | 163 |
| NAVISTAR® THERMOCOOL® (SNA Subpopulation Only) Version 3.0 of the Clinical Investigation Plan added a Subpopulation Neurological Assessments (SNA) designed to evaluate post-ablation generation of cerebral microemboli and associated neurological deficits.
These assessments were done in a prospective, non-randomized manner, comparing subjects treated with the nMARQ system against control subjects treated with the NAVISTAR® THERMOCOOL® Irrigated Tip Catheter.
Per study design, the data from the NAVISTAR® THERMOCOOL® subpopulation would be used for SNA analysis only. The data in this column are presented for transparency; but cannot be compared statistically against the data from the Main Study group. | 17 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Neurological exam not done | 0 | 1 |
| Overall Study | Never had insertion of study catheter | 4 | 1 |
| Overall Study | Procedure terminated prior to ablation | 3 | 0 |
Baseline characteristics
| Characteristic | NAVISTAR® THERMOCOOL® (SNA Subpopulation Only) | Total | nMARQ™ (Main Study- Single Arm) |
|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 9.86 | 58.49 years STANDARD_DEVIATION 10 | 58.7 years STANDARD_DEVIATION 10.24 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 124 Participants | 110 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 56 Participants | 53 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 56 Participants | 53 Participants |
| Race (NIH/OMB) White | 14 Participants | 124 Participants | 110 Participants |
| Sex: Female, Male Female | 3 Participants | 54 Participants | 51 Participants |
| Sex: Female, Male Male | 14 Participants | 126 Participants | 112 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 163 | 5 / 18 |
| serious Total, serious adverse events | 31 / 163 | 0 / 18 |
Outcome results
Primary
Incidence of Freedom From Documented Symptomatic Atrial Fibrillation
The primary effectiveness endpoint is freedom from documented symptomatic atrial fibrillation based on electrocardiographic data through 8 months post ablation.
Time frame: Evaluated from Day 91 to Day 240
Population: Effectiveness cohort: This population excludes those subjects who never underwent insertion of study catheter, those who terminated procedure prior to ablation, and those who were enrolled during the Workflow phase (20 subjects) and Roll-in phase (22 subjects). This analysis also excludes two subjects who withdrew consent post ablation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| nMARQ™ (Main Study- Single Arm) | Incidence of Freedom From Documented Symptomatic Atrial Fibrillation | 71.6 percentage of participants |
95% CI: [63.3, 79.8]
Primary
The Incidence of Early Onset Primary Adverse Events
The primary safety endpoint is the incidence of early onset primary adverse events within 7 days of the mapping and ablation procedure. Primary adverse events include pericardial effusion requiring intervention, atrial perforation, pericarditis requiring intervention, cardiac tamponade, pneumothorax, death, pulmonary edema, diaphragmatic paralysis, heart block, stroke / cerebrovascular accident (CVA), hospitalization (initial and prolonged), thromboembolism, myocardial infarction (MI), transient ischemic attack (TIA), and vascular access complications. In addition, pulmonary vein stenosis and atrio-esophageal fistula that occurs greater than one week (7 days) post-procedure are deemed primary adverse event.
Time frame: Any of above events occurring within 7 days post-procedure (also including the incidence of pulmonary vein stenosis and atrio-esophageal fistula occurring > 7 days and up to one year post-procedure)
Population: Safety Population as defined above
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| nMARQ™ (Main Study- Single Arm) | The Incidence of Early Onset Primary Adverse Events | 5.5 percentage of participants |
Secondary
Absence of Documented Symptomatic PAF Through 6 Months and 12 Months Post Procedure
This endpoint is defined as the absence of documented symptomatic PAF recurrence through 6 months and 12 months post index ablation procedure.
Time frame: 6 and12 months post study procedure
Population: This analysis population is the effectiveness cohort, excluding 2 subjects who withdrew consent prior to Day 91. The effectiveness cohort includes those who received treatment with the investigational device; but does not include 20 workflow and 22 roll-in subjects.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| nMARQ™ (Main Study- Single Arm) | Absence of Documented Symptomatic PAF Through 6 Months and 12 Months Post Procedure | 6 months post ablation | 73.3 percentage of participants |
| nMARQ™ (Main Study- Single Arm) | Absence of Documented Symptomatic PAF Through 6 Months and 12 Months Post Procedure | 12 months post ablation | 60.3 percentage of participants |
Secondary
Assessment of Pulmonary Vein (PV) Narrowing and Stenosis at 3 Months After Index Ablation
Incidence of narrowing of PV and stenosis at 3 months post ablation, for subjects with available CT/MRA scans at 3 months. PV Stenosis is defined as 70% or more PV diameter reduction.
Time frame: Three months after index ablation
Population: Subjects in safety analysis group who also had CT/MRI PV scan available at the 3-month post-ablation interval (144 of 160 subjects)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| nMARQ™ (Main Study- Single Arm) | Assessment of Pulmonary Vein (PV) Narrowing and Stenosis at 3 Months After Index Ablation | 0-20% Reduction of PV Diameter | 47.2 percentage of participants with CT/MRI |
| nMARQ™ (Main Study- Single Arm) | Assessment of Pulmonary Vein (PV) Narrowing and Stenosis at 3 Months After Index Ablation | 21- 50% Reduction of PV Diameter (Mild) | 51.4 percentage of participants with CT/MRI |
| nMARQ™ (Main Study- Single Arm) | Assessment of Pulmonary Vein (PV) Narrowing and Stenosis at 3 Months After Index Ablation | 51-70% Reduction of PV Diameter (Moderate) | 1.4 percentage of participants with CT/MRI |
| nMARQ™ (Main Study- Single Arm) | Assessment of Pulmonary Vein (PV) Narrowing and Stenosis at 3 Months After Index Ablation | > 70% Reduction of PV Diameter (Severe) | 0.0 percentage of participants with CT/MRI |
Secondary
Incidence of Completion of Ablation Procedure
This secondary outcome describes the acute effectiveness, which is defined as pulmonary vein isolation (PVI) documented by confirmed entrance block (with or without the use of a focal catheter).
Time frame: From 7 days to 12 months post study procedure
Population: Safety population excluding one subject without source document at site
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| nMARQ™ (Main Study- Single Arm) | Incidence of Completion of Ablation Procedure | 100 percentage of participants |
Secondary
Incidence of Non-Primary Serious Adverse Events (SAEs) up to 12 Months
This secondary safety endpoint includes non-primary serious adverse events within 7 days post-procedure and serious adverse events from 7 days to 12 months post-procedure.
Time frame: 12 months post study procedure
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| nMARQ™ (Main Study- Single Arm) | Incidence of Non-Primary Serious Adverse Events (SAEs) up to 12 Months | Non-primary serious AEs within 7 days | 0.6 percentage of participants |
| nMARQ™ (Main Study- Single Arm) | Incidence of Non-Primary Serious Adverse Events (SAEs) up to 12 Months | Serious adverse events from 7 days to 12 months | 15.3 percentage of participants |
Secondary
Subpopulation Neurological Assessments (SNA) Endpoint 1 - Incidence of Cerebral Embolic (ACE) Lesions Post Ablation
Evaluation of post-ablation generation incidence of asymptomatic cerebral microembolic lesions post ablation, as documented by MRI. All microembolic lesions reported in this study are asymptomatic.
Time frame: 48 hours post-ablation
Population: Neurological assessment subpopulation. This population includes 19 subjects from the nMARQ main study and 17 subjects from the Thermocool control group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| nMARQ™ (Main Study- Single Arm) | Subpopulation Neurological Assessments (SNA) Endpoint 1 - Incidence of Cerebral Embolic (ACE) Lesions Post Ablation | 21.1 percentage of subjects with ACE Lesion |
| NAVISTAR® THERMOCOOL® (SNA Subpopulation Only) | Subpopulation Neurological Assessments (SNA) Endpoint 1 - Incidence of Cerebral Embolic (ACE) Lesions Post Ablation | 5.9 percentage of subjects with ACE Lesion |
Secondary
Subpopulation Neurological Assessments (SNA) Endpoint 2 - Incidence of New Neurological Findings Post Ablation
All SNA subjects were to be evaluated by expert neurologists for existing neurological deficits prior to ablation procedure. After procedure, those subjects were also to be assessed for new neurological deficits.
Time frame: 48 hours post-ablation
Population: Neurological assessment subpopulation. This population includes 19 subjects from the nMARQ main study and 17 subjects from the Thermocool control group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| nMARQ™ (Main Study- Single Arm) | Subpopulation Neurological Assessments (SNA) Endpoint 2 - Incidence of New Neurological Findings Post Ablation | 0 percentage of participants |
| NAVISTAR® THERMOCOOL® (SNA Subpopulation Only) | Subpopulation Neurological Assessments (SNA) Endpoint 2 - Incidence of New Neurological Findings Post Ablation | 0 percentage of participants |