PV-Isolation With the Cryoballoon Versus RF:a Randomized Controlled Prospective Non-inferiority Trial (FreezeAF)
PV-Isolation With the Cryoballoon Versus RF:a Randomized Controlled Prospective Non-inferiority Trial (FreezeAF)
This study is designed as a randomized, controlled, prospective, non-inferiority clinical
 trial, where the efficacy and safety of the cryoballoon ablation system (CE certificated)
 will be compared to the standard ablation technique (segmental isolation of the pulmonary
 veins) with radiofrequency energy. The primary study aim is to investigate whether the new
 cryoballoon ablation catheter system (Arctic Front CryoAblation Catheters, FlexCath Steerable
 Sheath, CryoCath Technologies Inc., Montreal, Canada) is at least as effective as
 radiofrequency (RF) segmental isolation in electrically disconnecting the pulmonary veins
 (PV) for the treatment of paroxysmal atrial fibrillation (AF) with respect to the absence of
 atrial arrhythmias without persistent complications after six and twelve months. Furthermore,
 the differences in terms of procedural complications such as pulmonary vein stenosis, phrenic
 nerve injuries, cerebrovascular accidents (CVA), pericardial tamponade, pain scores during
 the procedure, levels of cardiac inflammatory markers are compared between the treatment
 groups. The short and long-term clinical success as well as the costs of both systems will
 also be evaluated.
Study objectives:

 This study is designed as a randomized, controlled, prospective, non-inferiority clinical
 trial, where the efficacy and safety of the cryoballoon ablation system (CE certificated)
 will be compared to the standard ablation technique (segmental isolation of the pulmonary
 veins) with radiofrequency energy. The primary study aim is to investigate whether the new
 cryoballoon ablation catheter system (Arctic Front CryoAblation Catheters, FlexCath Steerable
 Sheath, CryoCath Technologies Inc., Montreal, Canada) is at least as effective as
 radiofrequency (RF) segmental isolation in electrically disconnecting the pulmonary veins
 (PV) for the treatment of paroxysmal atrial fibrillation (AF) with respect to the absence of
 atrial arrhythmias without persistent complications after six and twelve months. Furthermore,
 the differences in terms of procedural complications such as pulmonary vein stenosis, phrenic
 nerve injuries, cerebrovascular accidents (CVA), pericardial tamponade, pain scores during
 the procedure, levels of cardiac inflammatory markers are compared between the treatment
 groups. The short and long-term clinical success as well as the costs of both systems will
 also be evaluated.

 Brief description of the cryoablation:

 This catheter system uses nitrous oxide as refrigerant to cool the inside of the catheter tip
 or the balloon down to -30 to -70 degree in a closed system. Delivering the freezing energy
 on human cells for several minutes leads to their destruction. The destructed cells cannot
 conduct anymore. For PV isolation the cryoballoon can be placed at the orifice of the
 pulmonary veins to ablate the muscle connections between the PV- and left atrium (LA).

 Study background:

 AF is a common and disabling cardiac arrhythmia, affecting 600.000-700.000 persons in
 Germany. In addition to hemodynamic compromise and higher mortality rates, AF causes an
 increased risk of systemic emboli arising from the LA. The risk of stroke inpatients with
 nonvalvular AF is 5 to 7 times greater than in comparable patients without AF; overall, 20 -
 25% of ischemic strokes are due to cardiac emboli, of which half arise in patients with
 nonvalvular AF. In addition to such proven mortality and morbidity risks, AF is associated
 with a substantial burden of symptoms, stemming from the arrhythmia itself, exacerbation of
 comorbid conditions such as congestive heart failure, associated anxiety over possible
 sequelae as well as the substantial burden of side effects from antiarrhythmic drugs (AAD).
 Currently available treatments are unsatisfactory for many reasons. AAD treatment has a
 relatively low efficacy even in patients suffering from paroxysmal AF, with frequent
 recurrences and a high incidence of intolerable drug side effects. Isolation of PVs using RF
 energy has shown considerable clinical success in the treatment of paroxysmal AF, but has
 been associated with serious complications, including PV stenosis, thromboembolic
 complications, cardiac perforation, phrenic nerve palsies, esophageal fistulae and
 pericardial tamponade. Furthermore, RF can be painful where as freezing with cryotherapy may
 be pain free.

 CryoCath Technologies has developed and tested the Arctic Front™ Cardiac CryoAblation
 Catheter System (with the FlexCath™ Steerable Sheath) to allow the rapid formation of
 continuous cryoablation lesions at the PV ostia. Pre-clinical data have demonstrated
 long-term effectiveness of balloon cryoablation for permanent electrical isolation of the PVs
 with no risk of PV stenosis. Results from these pre-clinical studies suggest that no
 pulmonary venous stenosis and no thromboembolic incidents have occurred even with multiple 4
 or 8-minute cryoenergy deliveries. However, achieving an adequate therapeutic effect using
 focal or linear cryolesions often required multiple applications and lengthy procedure times.
 Balloon cryoablation of subjects with PAF has been studied in PS-011, a feasibility study of
 the Arctic Front™ Balloon Cardiac CryoAblation Catheter System, in conjunction with the
 Freezor® MAX and Xtra and the Arctic Circler Linear™ Cardiac CryoAblation Catheter. Twenty
 (20) subjects were enrolled at two European centers using the 23 mm Arctic Front™ Balloon,
 and an additional 7 subjects were enrolled using 28 mm Arctic Front™ Balloon. Acute
 procedural success was 100%, and long term follow-up reveals a high rate of freedom from
 recurrent AF. A low incidence of adverse events was noted, with two patients experiencing
 reversible loss of phrenic nerve capture during the procedure. Both patients recovered fully.
 Of the original 20 subjects treated with the 23 mm balloon, 16 / 20 (80%) were AF-free
 between the 6 and 12 month follow-up visits. Of the additional 7 subjects treated with the 28
 mm balloon, 5 / 6 (83%) were AF free through 6 months. Another non-randomized feasibility
 study of the Arctic Front™ 23 mm Balloon Cardiac CryoAblation Catheter System under protocol
 PS-012 has completed enrollment at four centers in the United States. Based on incompletely
 monitored data, as of July 12th, 2006, 31 patients have undergone a successful cryoablation
 procedure with Acute Procedural Success (isolation of ≥ 3 PVs) in 100% (31 / 31 subjects).
 Electrical isolation was achieved in 129 / 130 PVs (99.3%). A total of 67 adverse events (AE)
 have been reported, and no deaths. Nine (9) serious AEs have been reported. Four device
 related serious AEs involved changes in phrenic nerve conduction: 3 patients had cryoablation
 discontinued immediately and nerve function recovered completely by 1 month, and the fourth
 subject had transient loss of capture during the procedure, followed at the 1 month visit by
 shortness of breath, a viral infection and slight paralysis of a hemidiaphragm. Two other
 device related serious AEs were a pericardial tamponade requiring pericardiocentesis and
 hospitalization, and a right groin hematoma. Three additional non-device related serious AEs
 included one episode of chest pain, one instance of right neck bleeding after vascular access
 and one instance of left groin site bleeding after vascular access. Long term follow-up for
 PS-012 is incomplete, but 17 subjects have reached 3 months, and 14 / 17 (82%) are free from
 recurrent AF. Only one of these 14 subjects was on a previously failed AF drug, giving a 76%
 (13 / 17) rate of freedom from recurrent AF off drugs.

 Additional data from another non-randomized clinical study are now available (Neumann et al.
 Circumferential pulmonary vein isolation with the cryoballoon technique. JACC 2008, Vol
 52(4); 273-8). 346 patients consecutive patients in three German centers have undergone a
 successful cryoablation therapy. The study population consisted of 293 patients with
 paroxysmal and 53 patients with persistent atrial fibrillation. Isolation of the pulmonary
 veins was achieved in 97% where as freedom from documented paroxysmal atrial fibrillation was
 achieved in 74% after a median follow-up of 12 month. No death and no PV narrowing occurred.
 In 26 patients (7,5%) a phrenic nerve palsy could be observed. The majority of the patients
 recovered within 6 month, all patients recovered within 12 month.

 Based on these encouraging results this randomized clinical study has been designed to
 provide valid scientific evidence of the safety and effectiveness of the Arctic Front™
 Cardiac CryoAblation Catheter System (with a FlexCath™ Steerable Sheath) to electrically
 isolate PVs in patients with PAF by comparing it with segmental isolation with RF-energy,
 which represents the most widely accepted and used energy form in AF-ablation procedures.
 Compared to the RF ablation procedures PV isolation with the Cryo Balloon technique is easier
 and faster to perform and there is no need for expensive additional mapping systems to avoid
 current dreaded complications such as PV-stenosis or esophageal fistula.

 Eligibility criteria:

 Inclusion criteria:

 -  Documented paroxysmal PAF: PAF diagnosis, 2 episodes of PAF within the last 3 months, at
 least 1 episode of PAF must be documented.

 -  Age 18-75

 -  Documented effectiveness failure of at least 1 AAD including beta-blockers

 Exclusion criteria:

 -  AAD usage < 3 half life periods (except beta-blocker)

 -  LA size > 55 mm

 -  LA thrombus

 -  Previous LA ablation/surgery, structural heart disease, heart failure class III-IV

 -  Hypertrophic cardiomyopathy

 -  Mitral prosthesis

 -  Unstable angina

 -  Uncontrolled hyperthyroidism

 -  Stroke or TIA within 6 months

 -  Myocardial infarction within 2 months

 -  Cardiac surgery within 3 months

 -  Thrombocytosis, thrombocytopenia

 -  Any condition contraindicating chronic anticoagulation

 -  EF <40%

 -  Pregnancy

 -  Life expectancy <1year

 Preprocedural investigations:

 -  Transesophageal echocardiography to exclude LA thrombus in each patient before each
 ablation

 -  CT or MRT of the LA (optional)

 Ablation procedure:

 After venous and arterial access a single or double transseptal puncture is performed. In
 both groups a pulmonary vein angiography must be performed before and after PV - isolation
 for all of the PVs. PV - potentials must be recorded before and after PV - isolation with a
 circular mapping catheter. In group 1, the RF - ablation procedure is performed using an open
 4 mm irrigated tip catheter in combination with a 3D - navigation system. It is recommended,
 that the 3D - navigation system should be able to display all mapping and ablation catheters.
 An antral PV - isolation will be performed. In group 2 a cryoablation of the PV - ostia using
 either the 28 mm or the 23 mm cryo-balloon will be attempted. At least two cryoenergy
 applications of 300 - 360 sec must be performed in each PV. Additional cryoenergy
 applications can be delivered if necessary to achieve complete isolation. The 28 mm
 cryoballoon should be used preferentially for all veins. If a complete isolation could not be
 achieved with the 28 mm cryoballoon ablation, a switch over to the 23 mm balloon is possible;
 otherwise touch-ups with a conventional cryocatheter (Freezor® Max, CryoCath) will be
 performed.

 In both groups the aim is to completely isolate the PVs. The upper limit of RF - or cryo -
 applications is dependent on the procedure duration and the clinical condition at the time of
 the procedure and left to the physician´s decision. After the ablation all the pulmonary
 veins should be assessed with angiography to detect an ablation mediated PV - stenosis.

 Anticoagulation: All patients should be anticoagulated four weeks before and at least six
 months after the index procedure. During the procedure the activated clotting time (ACT) must
 be kept between 250-350 sec by i.v. heparin administration.

 AAD: All AAD should be discontinued 4 to 5 half-life periods before the procedure. No AAD
 will be prescribed (except betablocker) after the procedure.

 Follow-up:

 All patients will be monitored during the hospital stay after the procedure (the first
 24-48h). Additional clinical visits will be performed at three, six, nine and twelve months
 after the last procedure. Another MRI or CT scan should be performed at the third month to
 re-evaluate the PVs and at least one 24h holter ECG recording to screen for symptomatic or
 asymptomatic atrial arrhythmias (AF, AT) has to be done. An event recorder or holter ECG to
 reveal the long-term recurrences will be given at the six and twelve month follow-up (for
 minimum of seven days, preferably 14 days) 22. In case of a recurrence a second procedure can
 be performed six months after the index procedure. The procedure of choice for the
 recurrences will be the same modality to which the patient originally had been randomized

 Endpoints:

 Primary endpoints:

 Combined endpoint out of:

 Absence of atrial arrhythmias and absence of persistent complications six and twelve months
 after the procedure .

 Secondary endpoints:

 Short- and mid-term clinical success Long-term clinical success Total radiation exposure
 Total procedure duration Pain sensation during the procedure Quality of life Changes in
 cardiac markers (CK, troponin, CRP) Bleedings Costs

 Biometrical concept:

 Randomization The randomization numbers will be allocated to the two groups in balanced
 permuted blocks using the random number generator of the validated software SAS®. To avoid
 any potential of predicting the group allocation of future patients, the block length is
 fixed in a separate document that is withheld from the study site. Sealed envelopes are
 produced labeled with the randomization number. Inside of the sealed envelope, a data sheet
 defines the group allocation of the patient with the respective randomization number. On
 enrollment in the study, each patient receives the randomization envelope in consecutive
 order of inclusion in the study. Basic characteristics of the patient and day of
 randomization are documented on the data sheet in order to allow a check whether the
 randomization scheme was observed strictly.

 Statistical considerations:

 Test problem and analysis of primary endpoint The primary objective of this trial is to
 demonstrate non-inferiority of isolating PVs procedure with the cryoballoon catheter (CC) as
 compared to radiofrequency isolation (RF) with respect to the primary endpoints "absence of
 atrial arrhythmias and absence of persistent complications six and twelve months after the
 procedure", respectively. For this purpose, the following test problems will be assessed:
 Null hypothesis H0: pCC (rate of absence of atrial arrhythmias and absence of persistent
 complications twelve months after the procedure with CC) - pRF (rate of absence of atrial
 arrhythmias and absence of persistent complications twelve months after the procedure with
 RF) -d versus alternative hypothesis H1: pCC - pRF > -d, where d = 0.15 defines the
 non-inferiority margin that is deemed to be acceptable in view of the advantages of CC with
 respect to aspects other than the primary endpoint. The analogous test problem is formulated
 for the endpoint after six months follow up. These test problems will be analyzed applying
 the non-inferiority test for rates according to Farrington and Manning17 at a one-sided
 significance level of a = 2.5%. The following multiple test procedure for hierarchically
 ordered hypotheses is applied to account for the multiplicity in primary endpoints: The null
 hypothesis formulated for the six months outcome is only tested if the null hypothesis for
 the twelve months outcome can be rejected; otherwise both null hypotheses are accepted. If
 both null hypotheses can be rejected, the null hypotheses H0g are tested at one-sided level a
 = 2.5% for margins g < d as long as H0g has to be accepted for a value gSTOP. Then,
 non-inferiority of CC as compared to RF has been shown for all non-inferiority margins g <
 gSTOP. This multiple test procedure controls the overall type I error rate a18, 19.

 Confirmatory analysis will be primarily based on the FAS which is consistent with the
 intention-to-treat (ITT) principle by including all patients who were randomized to the two
 groups. This approach reflects the idea that the study should match as close as possible to
 the conditions in clinical practice. However, the PP analysis plays an important role
 particularly in non-inferiority studies, and therefore the results of the PP analysis set are
 to be interpreted and discussed with special attention in parallel to the ITT analysis.

 Determination of the sample size Sample size calculation is based on the following
 considerations. In view of the advantages of CC as compared to RF in dimensions other than
 the primary endpoints, an inferiority by a difference in rates of 0.15 for CC as compared to
 RF with respect to the two primary outcomes is deemed to be acceptable. Therefore, the
 non-inferiority range was set equal to d = 0.15. On the basis of previous studies and
 experiences with the procedures16, equal rates of pCC = pRF = 0.78 are assumed for sample
 size calculation. Under these assumptions, the sample size required to achieve a power of 1 -
 b = 80% for the one-sided Farrington-Manning test at level a = 2.5% amounts to 2 x 122 = 244
 patients17. In order to cope with the uncertainty about the assumed overall rate of 0.78, a
 sample size review is performed after 150 patients are randomized or the outcome of the
 primary variable is available for 100 patients, respectively, depending on which of the
 events occurs first. No significance test is performed then and hence there is no option for
 early stopping with rejection of the null hypothesis. Instead, the overall rate for the
 primary variable is estimated based on the available data and the sample size is recalculated
 employing the obtained value in the sample size formula (i.e. pCC = pRF = estimated overall
 rate) and leaving the values for a, 1-b, and d as above. It was shown that this procedure
 does not affect the type I error rate of the analysis20.

 Each patient's allocation to the different analysis populations (full analysis set (FAS)
 according to the intention-to-treat (ITT) principle, per protocol (PP) analysis set, safety
 analysis set) will be defined prior to the analysis. The allocation will be documented in the
 statistical analysis plan.

 During the data review before start of any analysis, deviations from the protocol will be
 assessed as "minor" or "major". Major deviations from the protocol will lead to the exclusion
 of a patient from the PP analysis set. If a patient discontinues from the study prematurely,
 missing data with respect to the primary outcome variable will be replaced by ICA-r method19.

 Analysis of secondary endpoints The secondary variables will be analyzed descriptively by
 tabulation of the measures of the empirical distributions. According to the scale level of
 the variables, means, standard deviations, median, 1st and 3rd quartiles as well as minimum
 and maximum or absolute and relative frequencies, respectively, will be reported. Logistic
 regression models will be applied to assess the effects of potential risk factors on primary
 and secondary efficacy variables. Additionally, for variables with longitudinal measurements
 the time courses of individual patients and summarized by treatment groups will be compared.
 Descriptive p-values of the corresponding statistical tests comparing the treatment groups
 and associated 95% confidence intervals will be given.

 The safety analysis will be based on the set of all patients for which one of the procedures
 was applied. Adverse and serious adverse events as well as complications will be tabulated,
 absolute and relative frequencies; the severity and the relationship to the procedure will be
 given and compared between the groups. Cardiac markers will be described and interpreted with
 respect to the reference values, and the measures describing the empirical distributions of
 the changes are calculated. Additionally, for each cardiac marker, shift tables presenting
 changes between the categories "normal" and "abnormal" will be given per treatment group.

 Definitions:

 Acute procedural success: Successfully isolation of all the pulmonary veins

 Clinical success:

 Absence of any atrial arrhythmias sustaining longer than 30 seconds evaluated either by
 telemetric monitoring, 24 hour ECG recordings or event recorder Short-term clinical success:
 from the procedure until hospital discharge Mid term clinical success: up to three months
 after the procedure Long-term clinical success: up to six months after the procedure

 Procedure related complications: Any new PV-stenosis, phrenic nerve palsy, CVA, bleedings or
 vascular complications which occurs during and/or within 48 hours after the procedure.

 Persistent complications:

 Any procedure related complication lasting longer than 6 months after the procedure and
 either classified as major complication or still symptomatic.

 PV-stenosis:

 Angiographic late lumen loss of any PV in comparison to the pre-procedural data Minor:
 asymptomatic or stenosis less than 50%; Major: symptomatic or stenosis greater than 50%. 3
 months after the procedure either a computer tomography, magnet resonance tomography or a
 echocardiography will be performed to re-evaluate the severity grade of the stenosis. If a
 stenosis is detected a repeat diagnosis will be performed at 6 month.

 Phrenic nerve palsy:

 Radiological restricted movement of the diaphragm Minor: asymptomatic or less than 50%
 restriction Major: symptomatic or more than 50% restriction In cases of persistent symptoms
 due to phrenic nerve palsy at least one fluoroscopy will be performed up to the 6 months
 follow-up to verify the restriction of the diaphragm.

 Bleedings and vascular complications:

 Minor: Any bleeding or vascular complication (hematoma, pseudoaneurysm, atriovenous fistula)
 requiring prolonged hospitalization but could be managed conservatively Major: Any bleeding
 or vascular complication requiring additional therapy (i.e. surgery, transfusion therapy)

 CVA: Every new TIA or stroke after the procedure.

 Quality of life:

 Before and at every clinical visit patients will be ask to complete a standardized
 questionnaire to evaluate the symptomatic and life restrictiveness originating from the
 arrhythmia.

 Pain After venous and arterial puncture and after the complete procedure the patients will be
 asked to grade their sensation of pain (range 1-10)

 Costs Standard prices for consumable material such as catheters, electrodes, refrigerant per
 EP study will be evaluated. Purchase or leasing prices i.e. for a mapping system or the cryo
 console will not be considered.

 Abbreviations:

 AAD: Antiarrhythmic drugs AE: Adverse events AF: Atrial fibrillation AT: Atrial tachycardia
 CVA: Cerebrovascular accident EF: Ejection fraction LA: Left atrium PAF: Paroxysmal atrial
 fibrillation PNP: Phrenic nerve palsy PV: Pulmonary vein RF: Radiofrequency energy TIA:
 Transient ischemic attack
Inclusion Criteria:

 -  Documented paroxysmal PAF: PAF diagnosis, 2 episodes of PAF within the last 3 months,
 at least 1 episode of PAF must be documented.

 -  Age 18-75

 -  Documented effectiveness failure of at least 1 AAD including beta-blockers

 Exclusion Criteria:

 -  AAD usage < 3 half life periods (except beta-blocker)

 -  LA size > 55 mm

 -  LA thrombus

 -  Previous LA ablation/surgery, structural heart disease, heart failure class III-IV

 -  Hypertrophic cardiomyopathy

 -  Mitral prosthesis

 -  Unstable angina

 -  Uncontrolled hyperthyroidism

 -  Stroke or TIA within 6 months

 -  Myocardial infarction within 2 months

 -  Cardiac surgery within 3 months

 -  Thrombocytosis, thrombocytopenia

 -  Any condition contraindicating chronic anticoagulation

 -  EF < 40%

 -  Pregnancy

 -  Life expectancy < 1 year