Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05717725 |
| Other study ID # |
PFA SHAM |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 27, 2023 |
| Est. completion date |
December 30, 2024 |
Study information
| Verified date |
March 2024 |
| Source |
Charles University, Czech Republic |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The study is planned as a single-blind, multicenter, prospective, randomized study. Sixty
sbjects will be randomized 1:1 to either: (i) EP study + PFA, or (ii) EP study + Sham
ablation control.
After informed consent is obtained, an implantable loop recorder (ILR) will be implanted
within seven days, and an EP study will be scheduled for 30±5 days after ILR implantation.
Patients in both groups will first undergo an EP study to rule out a concealed AV bypass
tract and supraventricular tachycardia (SVT). Patients will not be randomized if SVT or
concealed AV bypass tract is found during the EP study. Once an SVT or bypass tract is
excluded, randomization will be performed. Patients randomized to Ablation will undergo PVI
using the commercially-available pentaspline PFA catheter (Farawave, Farapulse-BSCI Inc).
Patients randomized to the Sham-ablation Control group will simply undergo approximately
20-30 min of anesthesia with propofol and benzodiazepines in a similar manner as patients in
the ablation arm.
Primary endpoints will be assessed six months after the procedure.
ECGs will be monitored using implantable ECG monitors (ILR) in all patients. There will be
two co-primary endpoints (assessed at six months or at cross-over if Early Exit):
1. Freedom from recurrent AF/AT/AFL (post 2-month blanking), assessed as time-to first
recurrence;
2. Quality of life according to Atrial Fibrillation Effect on QualiTy of life (AFEQT) score
at 6 months (or at cross-over if Early Exit).
Description:
INTRODUCTION The performance of a sham trial for AF ablation has previously been problematic
on ethical grounds. The landscape has changed because (i) CABANA, the only RCT on catheter
ablation inAF, did not demonstrate an improvement in "hard outcomes" in the
intention-to-treat analysis, and (ii) other sham-controlled studies in the cardiovascular
field such as the ORBITA trial of angina relief from percutaneous coronary intervention and
the Symplicity-3 trial of renal sympathetic denervation for hypertension have failed to show
positive outcomes. Thus, only performing sham control studies enabled to document the real
effect of this method in hypertension treatment. Together, this has prompted a renewed call
for a sham-controlled trial of AF ablation to assess the efficacy in arrhythmia freedom and
symptom improvement. Indeed, some cardiologists and general internists have questioned if AF
ablation has any utility in the absence of a sham trial.
Furthermore, the advent of new, faster technology for PVI requiring angiosedation makes the
study more feasible. The speed and safety of pulsed-field ablation to treat AF and the need
for deep sedation have further changed the ethical and practical considerations for a
sham-controlled AF ablation trial. Using the pentaspline PFA catheter (Farawave;
Farapulse-BSCI Inc), PVI can reliably be performed in < 30-60 min at experienced centers. For
all these purposes, the investigators plan to conduct a prospective, multicenter,
single-blinded, randomized trial comparing catheter-based pulsed-field ablation to a
sham-control procedure for paroxysmal or persistent AF.
The purpose of PFA-Sham is to determine the relative efficacy of catheter ablation for
symptomatic paroxysmal/persistent AF, when compared against a sham-ablation control
procedure. This is a prospective, multi-center, single-blind, randomized trial.
There are two co-primary hypotheses. First, we hypothesize that patients in the catheter
ablation group will experience greater freedom from recurrent AF/AT/AFL at 6 months
post-procedure. There will be a two-month post-procedure blanking period in both groups.
Freedom from AF/AT/AFL will be assessed as time to first recurrence (or to cross-over if
earlier).
Second, compared with those in the sham-ablation control group, patients in the catheter
ablation group will report higher quality of life as measured by the Atrial Fibrillation
Effect on QualiTy of life (AFEQT) score, at 6 months post-procedure (or at cross-over if
Early Exit).
METHODS The study will be a single-blind, multicenter, prospective, randomized study.
Subjects will be randomized 1:1 to either: (i) EP study + PFA, or (ii) EP study + Sham
ablation control.
After informed consent is obtained, an implantable loop recorder (ILR) will be implanted
within seven days, and an EP study will be scheduled for 30±5 days after ILR implantation.
Patients in both groups will first undergo an EP study to rule out a concealed AV bypass
tract and supraventricular tachycardia (SVT), and catheter ablation of this substrate if
present. Patients will not be randomized if SVT or concealed AV bypass tract is found during
the EP study.
Once an SVT or bypass tract is excluded, randomization will be performed. Patients randomized
to Ablation will undergo PVI using the commercially-available pentaspline PFA catheter
(Farawave, Farapulse-BSCI Inc). Patients randomized to the Sham-ablation Control group will
undergo approximately 20-30 min of anesthesia with propofol and benzodiazepines in a similar
manner as patients in the ablation arm.
INCLUSION CRITERIA
1. Age >18 years
2. Paroxysmal or Persistent Atrial Fibrillation (but not long-standing Persistent AF)
3. Screening (qualifying) AFEQT score ≤ 50
Patients with symptomatic paroxysmal or persistent AF will be included. Symptoms will be
assessed using the AFEQT questionnaire during screening; the presence of significant symptoms
at screening (AFEQT ≤ 50) is a critical component since it will be vital to ensure a
sufficiently symptomatic population to avoid a Type 2 error. Patients with long-standing AF
or AF-induced cardiomyopathy or LV dysfunction will be also excluded. Patients can have SR or
AF on the day of the screening and signed informed consent, but long-standing persistent AF
has to be excluded based on patient history.
EXCLUSION CRITERIA
1. Any prior AF ablation procedure (or left atrial ablation procedure)
2. Untreated other arrhythmias (e.g. atrial flutter, SVT, VT, frequent PVCs);
3. Long-standing Persistent AF episodes (any continuous episodes lasting > 1 year);
4. Permanent AF;
5. No ECG evidence of AF episode >30 seconds in the 6 months prior to randomization;
6. LA size > 55 mm;
7. Hypertrophic cardiomyopathy;
8. Valve disease (any aortic stenosis, moderate or severe mitral regurgitation);
9. Left ventricular ejection fraction ≤ 35% according to echocardiogram within 6 months of
randomization;
10. Moderate or severe pulmonary hypertension
11. History of tachycardia-induced cardiomyopathy;
12. Symptomatic coronary artery disease;
13. Pregnancy;
14. Presence of an artificial valve;
15. Life expectancy less than two years;
16. Known medical condition or contraindication causing potential complications for
interventional procedures or follow up
ENROLLMENT AND ILR IMPLANT
Data will be gathered including the following:
- Demographics including gender, height and weight
- Pertinent medical and cardiovascular history, CHA2DS2-VASc
- AAD and anticoagulation medication history
- 12-lead ECG
- TTE within 6 months
- The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life
assessment at enrollment AFEQT will be used during enrollment to ensure the symptoms of
patients, and presents one of the qualifying (inclusion) criterion. AEFQT is a 20-item
questionnaire, and provides a 4-item Symptoms score, an 8-item Daily Activities score, a
6-item Treatment Concerns score, and a 2-item Treatment Satisfaction scale. Overall and
subscale scores range from 0 to 100. A score of 0 corresponds to complete disability,
while a score of 100 describes the highest level of QOL.In the study, screening
(qualifying) AFEQT score has to be less than 50.
EP STUDY, AFEQT and HADS Before randomization, all patients will undergo an electrophysiology
(EP) study. An EP study will be scheduled at 30 days after ILR implantation. Within 1 day of
the procedure, all patients will have assessment of the baseline AFEQT and Hospital Anxiety
and Depression Scale (HADS), and atrial arrhythmia burden by interrogation of their ILR. (The
HADS scale is a 14-item instrument that evaluates symptoms of anxiety and depression in
medical populations, on a 4-point scale from 0 to 3. A combined HADS score ≥ 7 indicates the
presence of psychological distress and a score ≥ 15 indicates severe psychological distress.
These data (baseline AFEQT, baseline HADS, and ILR interogation) will constitute baseline
measurements for the purpose of endpoint estimation.
The EP study will be done using standard techniques; two EP catheters will be inserted via
one femoral vein (right or left, right preferred). Femoral access should be performed with
ultrasound guidance. One catheter will be inserted in the coronary sinus, the other at the
His bundle area (to record atrial His and ventricular activity). SVT and concealed accessory
pathway (AP) will be excluded using standard EP protocols: retrograde ventricular pacing to
exclude left and right concealed AP, programmed atrial stimulation to exclude dual AV node
physiology, and AV nodal reentry initiation. If concealed AP or inducible AVNRT is present,
the arrhythmia will be targeted, but the patient cannot be randomized. These patients will be
further monitored in the outpatient clinic as NON-randomized patients. These patients that
sign consent but undergo SVT ablation do not count to the 60-patient enrollment goal.
If SVT or concealed AP are excluded, patients will be randomized to the catheter ablation
group (CA) or Control Sham group) in a 1:1 ratio.
Group 1: catheter ablation; or Group 2: sham ablation (control group).
RANDOMIZATION will be done using web-based randomization software at the end of the EP
procedure. The software will be designed to account for gender and the type of AF
(paroxysmal/non-paroxysmal), with the goal of having comparable groups regarding the type of
AF. The randomization process will be done outside all participating centers using an
electronic web-based CRF; therefore, it will be independent of study subjects and site
personnel. No physicia at later out-patient controls will have information on the arm in
which the patient was randomized.
TREATMENTS Ablation Arm: after the EP study, patients will undergo pulmonary vein isolation
(PVI) using a PFA catheter. The same vascular (venous) access used in the EP study will be
used for catheter insertion. An ICE catheter will be positioned in the right atrium, and a
transseptal puncture will be carried out under ICE navigation. In all patients, atropine (1
mg) may be given to avoid a vagal reaction. The ablation will be done using a pentaspline PFA
catheter (Farawave; Farapulse-BSCI Inc.); PFA energy will be applied 4 times in the basket
and 4 in the flower configuration for each pulmonary vein, plus additional lesions as needed.
In patients with persistent AF, an additional posterior wall ablation can be done using a
flower configuration of the catheter. At the end of the procedure, a single figure-of-eight
suture can be placed to achieve hemostasis. The whole procedure will be done under
analgosedation (propofol, benzodiazepines, ketamine, opioids) and with the guidance of an
anesthesiologist, or as per the center standard of care.
Control arm: after the EP study, patients should undergo approximately 20-30 min of
anesthesia with propofol and benzodiazepines in a similar manner as patients in the ablation
arm. An anesthesiologist will guide the analgosedation, or as per the center standard of
care. At the end of the procedure, a figure-of-eight suture will be placed.
After the procedure, patients will be monitored in the hospital, followed by a TTE to rule
out a pericardial effusion. Patients will be discharged the day after the procedure.
Before hospital discharge (ideally the day after the procedure), patients will complete the
baseline Blinding Questionnaire.
In-person assessments at months 2, 3, 6 and 12 months post-procedure
- ECG
- Adverse events
- AAD and anticoagulation medication use
- Recurrent arrhythmia, cardioversions, ablations, hospital admissions
- AF/AT/AFL burden assessment at 6 months and 12 months only (ILR interrogation to core
lab)
- The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life
assessment
- Hospital Anxiety and Depression Scale (HADS) score (at 2 and 6 months only)
- Blinding Questionnaire (at 2 and 6 months only)
Assessments at months 1, 4, 5, 9 post-procedure
These will be performed by phone, and will include the following elements:
- Adverse events
- AAD and anticoagulation medication use
- Recurrent arrhythmia, cardioversions, ablations, hospital admissions
- The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life
assessment AAD use: Class I/III AAD use will be permitted during the first two months
post-ablation, during the post-procedure blanking period. After the 2-month blanking
period, AAD use will represent a treatment failure.
Cardioversions: Electrical/chemical cardioversions may be performed during the 2 month
blanking period. If a subject is in AF near the completion of the blanking period at 2
months, a DCCV should be performed so that the patient "exits" the Blanking period in sinus
rhythm. After the 2-month blanking period, cardioversion will represent a treatment failure.
Early Exit: Any subject may cross over at 6 months. Since the study is open to symptomatic AF
patients, early patient cross-over is only allowed in cases of persistent severe symptoms.
Early cross-over is allowed only in subjects with documented recurrence of AF/AT/AFL, plus
one of the following:
1. AFEQT score at or below their baseline score for 3 consecutive months post-randomization
may cross over, or
2. Subjects who have a drop in the AFEQT score of 10 or more points may cross over after 1
month For early cross-over to occur, the treating cardiologist in follow-up, who is
blinded to treatment assignment, will assess the persistence/worsening of symptoms and
contact the core lab to confirm that AF/AT/AFL has recurred. After this confirmation,
ablation will then be scheduled. The reason for the interaction between the follow-up
physician and the core lab is to access the ILR interrogations (which would not
otherwise be available to the follow-up physician) and to confirm that symptoms are not
the result of an unrelated arrhythmia. Of note, since the treating Cardiologist is
blinded to the treatment assignment, from their perspective, this could be an actual
cross-over or a redo ablation procedure. They will remain blinded to this until after
the 6 month timepoint.
At the point of decision to cross-over / redo ablation, the patient will again take the
AFEQT, HADS and Blinding questionnaire (this will serve in lieu of the 6 month assessments).
Cross-over patients will be scheduled for PVI using pulsed-field ablation technology in the
same manner as in the active ablation group. Beta-blockers and Ca-channel blockers will be
preferentially used for symptom relief until the procedure.
Blinding
- Investigators: The operating physicians (electrophysiologists and anesthetists) will not
be blinded to treatment assignment. As much as possible, site based study personnel who
perform follow-up evaluations will remain blinded to subject treatment assignment.
- Subjects: Study personnel will be trained to avoid disclosing treatment status to study
subjects. Study subjects will sign an informed consent that states that they will not be
informed of their treatment status until the conclusion of their participation in the
study.
- Core lab: The core lab, which will analyze ILR data, will remain blinded as much as
possible consistent with accurate adjudication.
- Data and Safety Monitoring Board (DSMB): In general, the DSMB will review unblinded
results in order to perform their function of protecting the integrity of the study and
the rights, safety and welfare of study subjects.
Subjects will undergo a blinding assessment on day 1 post procedure, and at the 2 and 6 month
visits. They will be asked whether they think they were assigned to the ablation group, the
control group, or if they do not know. They will be asked to rate their degree of confidence
in their answer on a scale of 1 to 5, with 5 pertaining to certainty.
ENDPOINTS
There will be two co-primary endpoints (assessed at six months):
1. Freedom from recurrent AF/AT/AFL (post two month blanking period): assessed as time to
first recurrence (or to cross-over for Early Exits);
2. Quality of life according to the Atrial Fibrillation Effect on QualiTy of life (AFEQT)
score at six months post ablation (or at cross-over for Early Exits).
Secondary endpoints
1. 6-month differences in AF/AT/AFL burden;
2. 6-month difference in HADS scores;
3. 12-month Freedom from recurrent AF/AT/AFL (post two month blanking period);
4. 12-month AFEQT scores (between treatment and control groups);
5. Correlation of AFEQT score with AF recurrence/burden data;
6. Unplanned Cardiovascular Hospitalization;
7. Procedure-related Major Complications;
8. Time to exit from assigned treatment. AF/AFL/AT: episode of the corresponding arrhythmia
that is recorded for review, where the recording contains at least 30 seconds of
continuous interpretable signal. An exception is a 12-lead ECG where the arrhythmia
occurs during the entire tracing and the continuous interpretable signal is 10 seconds
or longer.
ADVERSE EVENTS This study will utilize a core lab for the review and adjudication of AEs. All
safety analyses will utilize the adjudicated rather than site determination of an AE's
characteristics in those instances where the CEC has adjudicated that characteristic to be
different than the site's determination.
In both the control and treatment groups, the risks of sheath insertion in the femoral vein
include access site complications (e.g., hematoma, fistula, pseudo-aneurysm, laceration,
bleeding) potentially requiring surgical intervention. Risks of anesthesia in both groups
include aspiration pneumonia, allergic reaction to medication, and cardiac arrhythmia.
In the treatment group, risks of catheter ablation include the following:
- Air embolism
- Anemia
- Cardiac tamponade or perforation
- Cardiac arrest or cardiac failure
- Cardiogenic shock
- Catheter entrapment potentially requiring endovascular or surgical intervention
- Conduction system injury, either transient or permanent, potentially requiring pacemaker
insertion
- Coronary artery or vein injury
- Death
- Esophageal injury, ulcer or fistula
- Hemopericardium
- Hemoperitoneum
- Hemothorax
- Myocardial infarction / ischemia
- Nerve damage
- Pericardial effusion
- Pericarditis w
- Phrenic nerve injury with potential paralysis of the diaphragm and breathing impairment
- Pneumothorax
- PV injury, perforation or stenosis
- Stroke / transient ischemic attack
STATISTICAL RATIONALE In previously published clinical studies on catheter ablation, the
effect of the ablation on AF-freedom was dependent on 1) ablation technology and 2) the
sensitivity of the ECG monitoring.
Regarding ablation technology, pulsed field ablation seems to be the most effective
technology for the achievement of durable pulmonary vein isolation. Although the number of
operators in these studies have been small, the >90% durability of pulmonary vein isolation
that has been described with PFA is above the best radiofrequency tools including ablation
index etc. Regarding ECG monitoring, it is known that less frequent monitoring (single
intermittent 24-Holter recording) is able to record substantially fewer AF recurrences than
daily trans-telephonic recording or permanent ILR monitoring.
In the recently published EARLY-AF trial comparing cryoablation vs AADs, in which the effect
of ablation was monitored using ILRs, one-year AF-freedom was present in 57.1% of ablated
patients. In a recent study on PFA, one-year AF freedom (monitored using 24-hours Holter
monitoring and weekly ECG transmissions) was achieved in 87.4%. In eight studies comparing
AADs with placebo using mixed monitoring methods (but no study used ILRs) with 655 patients,
the success in placebo arms was 24.9% (95% CI 15-34). However, as noted, no study used ILR
for monitoring, but no study experienced sham-procedure placebo that could be more effective
than pharmacological placebo.
For the QOL Primary Endpoint, means are compared in independent samples, with the test of
equality of means carried out at a 2-sided 0.05 level of significance, with a probability of
90% of rejecting the null hypothesis of equal proportions if the alternative holds. Assuming
an AFEQT score of 50 in the Control group (with a S.D. of 20), and improvement to 70 in the
Ablation group, a total of 25 patients are required in each group, or 50 patients total.
Assuming a 10% crossover (outside the protocol), 55 patients would be required. And finally,
assuming minimal loss to follow-up, a total of 60 patients (30 per arm) will be enrolled.
For the AF Recurrence Primary Endpoint, in the sham-procedure arm, a maximum of 30% freedom
from AF should be expected. In the active-PFA treatment arm, 70% AF freedom is a very
conservative expectation. With β=80% and α=0.025, a total of 25 patients are required in each
group, or 50 patients total. Assuming a 10% crossover (outside the protocol), 55 patients
would be required. And again, assuming minimal loss to follow-up, a total of 60 patients (30
per arm) will be enrolled.
Secondary Endpoint of Psychological Distress: As a secondary endpoint, we have planned for
sufficient sample size to assess differences in psychological distress at 6 months between
groups (using the Hospital Anxiety and Depression score, HADS). Based on the
recently-published REMEDIAL study, where the mean baseline HADS score was approximately 12.3,
we expect a mean baseline HADS score of 13 in our study since we are enriching for a more
symptomatic cohort. We expect a mean HADS score at 6 months post-procedure to be 13 (with
S.D. of 6; consistent with that observed in the REMEDIAL study) in the control group and 8 in
the treatment group (an improvement by 5 points was observed with ablation in the REMEDIAL
study). With β=80% and α=0.025, a total of 28 patients are required in each group, or 56
patients total.
