Statistical considerations for MARS

For patients that had a history of previous ablation (original MARS trial sample size calculations) the pilot data showed that among 169 patients we observed a response rate of p₁=42% for repeat PVAI and p₂=76% for 32 patients undergoing VOM-PV.

Group sequential two proportions power analysis using simulation was performed using PASS V12 (Kaysville, UT). The following assumptions were made:

Response rate in PV-VOM: p₁=0.76

Response rate in PVAI: p₂= 0.42

Hypotheses: H0: p₁= p₂; H1: p₁ ≠ p₂

Test Statistic: Z-Test (Unpooled)

Zero Adjustment Method: None

Alpha-Spending Function: O’Brien-Fleming Analog

Beta-Spending Function: None

Futility Boundary Type: None

Number of Looks: 3

Simulations: 100000

Group sequential trials with sample sizes of 33 and 33 at the final look achieve 81% power to detect a difference of 0.34 between a treatment group proportion of 0.76 and a control group proportion of 0.42 at the 0.05 significance level (alpha) using a two-sided Z-Test (Unpooled).

We propose to monitor efficacy at two interim time points and one final time period (i.e., three “looks”) when primary outcome data (12 month follow-up) are available for 1/3, 2/3 and 3/3 of the total sample size of MARS subjects. During the interim analysis, estimations of conditional power and futility will be performed, to provide information for clinical trial continuation decisions. The sample size will not be subject to any changes.

A study-specific data safety monitoring board (DSMB) has been established by the NHLBI (National Heart, Lung, and Blood Institute) which is funding this clinical trial (R01 HL115003). The DSMB will review safety events, efficacy interim analyses, monitored study conduct and will review and approve protocol modifications. None of the members of the DSMB are listed on the protocol as sub-investigators or have conflicting interests in the trial results. The DSMB is made up of electrophysiology consultants familiar with ablation procedures that will have insights into the specific clinical scenarios that can occur in AF ablation. Additionally, the DSMB will have a dedicated statistician and bioethicist, an expert in clinical trials, and an NIH official. A steering committee is responsible for study design and conduct. A data coordinating center has been constituted at the Dan L. Duncan Institute for Clinical & Translational Research of Baylor College of Medicine. Independent study monitoring of data integrity will be conducted at all sites. The study is also overseen by the FDA (IND# 115,060). and registered as {"type":"clinical-trial","attrs":{"text":"NCT 01898221","term_id":"NCT01898221"}}NCT 01898221 at www.clinicaltrials.gov. Adverse events will be monitored by an investigator non involved in the procedure or patient follow-up, and blinded to the randomization outcome (NSK).

The primary endpoint will be determined by clinical follow-ups and by 1-month continuous monitoring performed at 6- and 12-months post-randomization. External event monitors will be provided by MediLynx (Plano, TX). Data from implanted devices (pacemaker, defibrillators, or implantable loop recorders) able to provide 1-month AF burden will be acceptable substitutes. Data will be verified by a core laboratory led by an investigator non involved in the procedure or patient follow-up, and blinded to the randomization outcome (ASD).

Indices of left atrial function will be assessed at 12 months post-randomization by the core echocardiography laboratory led by an investigator blinded to the randomization outcome (SN).

An independent monitor will assess data accuracy and integrity in all sites after site activation and continue periodically based on enrollment until all subjects have completed trial visits or the trial has been terminated. Monitoring visits will include review of informed consent process, eligibility, adherence to the clinical protocol, and adverse events. Safety issues and/or trends in data errors or deviations will be managed by the administrative study team (principal investigator, trial manager).

Each site’s first 3 enrolled patients will be monitored at 100% of data items and thereafter, every 10^th patient will be monitored. Exclusion/inclusion criteria and adverse events will be monitored in every patient.

The initial sites include Houston Methodist DeBakey Heart Center, Houston DeBakey VA Medical Center, both in Houston, and Texas Cardiac Arrhythmia Institute in St Davids’s Medical Center in Austin, Texas. The trial will open at additional sites, including Arizona Heart Rhythm Center, University of Southern California, Virginia Commonwealth University, and others. Given the VOM ethanol procedural complexity, operators will undergo dedicated training prior to site qualification, including formal review of procedural steps and pre-recorded video, as well as on-site proctoring during site-initiation visit.