A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation in Patients With Moderately Reduced Left Ventricular Ejection Fraction and a Narrow QRS Duration: Study Rationale and Design

• An earlier randomized study of cardiac contractility modulation met its safety end point, a noninferiority analysis of all-cause mortality and hospitalization.
• The study missed its primary efficacy end point, anaerobic ventilatory threshold based on a responders' analysis and multiple imputation to account for missing data.
• Subgroup analysis showed that patients with ejection fraction ≥25% exhibited a significant response in the primary and secondary efficacy end points.
• A new study with statistical analysis based on a generalized linear mixed-effects regression model and bayesian statistics and using peak VO2 as the primary efficacy end point has been designed and is described in this paper.

Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the cardiac absolute refractory period that enhance the strength of cardiac muscular contraction. The FIX-HF-5 study was a prospective randomized study comparing CCM plus optimal medical therapy (OMT) to OMT alone that included 428 New York Heart Association (NYHA) functional class III or IV heart failure patients with ejection fraction (EF) ≤45% according to core laboratory assessment. The study met its primary safety end point, but did not reach its primary efficacy end point: a responders analysis of changes in ventilatory anaerobic threshold (VAT). However, in a prespecified subgroup analysis, significant improvements in primary and secondary end points, including the responder VAT end point, were observed in patients with EFs ranging from 25% to 45%, who constituted about one-half of the study subjects. We therefore designed a new study to prospectively confirm the efficacy of CCM in this population. A hierarchic bayesian statistical analysis plan was developed to take advantage of the data already available from the first study. In addition, based on technical difficulties encountered in reliably quantifying VAT and the relatively large amount of nonquantifiable studies, the primary efficacy end point was changed to peak VO2, with significant measures incorporated to minimize the influence of placebo effect. In this paper, we provide the details and rationale of the FIX-HF-5C study design to study CCM plus OMT compared with OMT alone in subjects with normal QRS duration, NYHA functional class III or IV, and EF 25%–45%. This study is registered on www.clinicaltrials.gov with identifier no. NCT01381172.