Use Instructions

48
APPENDIX VII
Current Clinical Summary: FIX-HF-5C
Study Design
FIX-HF-5C was a prospective, randomized, third-party blinded, multicenter study
involving 160 patients. Key inclusion criteria included EF ≥ 25% and ≤ 45%, normal sinus
rhythm, QRS duration <130 ms and NYHA Class III or ambulatory IV heart failure despite
GDMT (including ICD when indicated). Main exclusion criteria included baseline peak
VO
2
< 9 or > 20 mL/min/kg, hospitalization for heart failure 30 days before enrollment,
clinically significant ambient ectopy (> 8,900 premature ventricular contractions [PVCs] /
24 hours), PR interval > 375 ms, and chronic atrial fibrillation or atrial flutter within 30
days of enrollment.
A device implant date was scheduled for all eligible patients, which served as the study
start date (SSD) for all patients. Patients were then randomized 1:1 to either continued
OMT alone (control group) or OMT plus CCM (CCM group). Patients randomized to the
CCM group were implanted with the device and the implant date was canceled for
patients randomized to the control group. Patients returned to the clinic for evaluation at 2
weeks, 12 weeks, and 24 weeks. Follow-up visits included 2 CPX tests, a blinded NYHA
assessment, MLWHFQ quality of life assessment, and an assessment of adverse events
(AEs).
Blinding of NYHA and CPX
NYHA was assessed by a blinded on-site clinician according to their standard clinical
practice.
CPX tests were assessed by an independent core laboratory blinded to the
randomization assignment of individual patients.
Primary Effectiveness Endpoint
The primary effectiveness endpoint was defined as the change in peak VO
2
from
baseline at 24-weeks between the control and CCM groups as evaluated by the blinded
core laboratory. The primary effectiveness analysis employed a Bayesian repeated
measures linear model to estimate group differences in mean peak VO
2
at 24 weeks from
baseline, with fixed 30% borrowing of information (70% down-weighting) from the
corresponding treatment group difference observed in the FIX-HF-5 study subgroup
defined as EF ≥ 25%.
Secondary Effectiveness Endpoints
Because there were multiple secondary hypotheses being tested, the method of alpha
control was the closed form hierarchical method. For these analyses, if the one-sided p-
value for the secondary endpoint was ≤ 0.025, the null hypothesis was rejected, and the
next secondary endpoint was tested. The hierarchy for testing the secondary endpoints is
the following:
• Minnesota Living with Heart Failure Questionnaire
• NYHA classification
• Peak VO2 with a peak respiratory equivalent ratio (RER) ≥ 1.05
Safety Endpoints
The primary safety endpoint was the proportion of patients experiencing an OPTIMIZER
device- or procedure-related complication through the 24-week follow up period as
determined by the events adjudication committee (EAC). The primary safety endpoint
was evaluated against a prespecified performance goal of 70% which was derived from
several prior studies involving CRT (PMAs P010012: Contak CD CRT D, P030005:
Contak Renewal TR, P030035: St. Jude Frontier, and P010012/S37: Contak Renewal
3AVT; Van Rees, 2011).