Advanced Heart Failure: The Predictive Value of Dobutamine Echo-stress in the Clinical Response to Cardiac Contractility Modulation Therapy (CCM)
Conditions: Symptomatic Congestive Heart Failure
Sponsor: Quovadis Associazione

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q.U.O.V.A.D.I.S. Associazione Riconosciuta “No-Profit” 
Galleria Ezzelino, 5 - 35139 Padova (I) 
e-mail: info@quovadis-ass.it ; PEC: quovadis-ass@pec.it 
 
 
PREDICT-CCM Study 
ADVANCED HEART FAILURE: THE PREDICTIVE VALUE OF 
DOBUTAMINE ECHO-STRESS IN THE CLINICAL RESPONSE TO 
CARDIAC CONTRACTILITY MODULATION THERAPY (CCM) 
v.1.2 
Principal Investigator:  
Dr. Francesco Zanon, 
 
 
 
 
 
 
UO Cardiologia,  
 
 
 
 
 
 
Santa Maria della Misericordia H. 
 
 
 
 
 
 
ULSS5 Polesana - Rovigo (Italy) 
 
Promoter:  
QUOVADIS no-profit Association, Padua (I) 

PREDICT-CCM Study - Protocol v.1.2; 06-03-2025  
 
 
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Study Coordinator: Dr. Francesco Zanon  
 
Study Title: PREDICT-CCM Study 
ADVANCED HEART FAILURE: THE PREDICTIVE VALUE OF DOBUTAMINE ECHO-STRESS IN THE 
CLINICAL RESPONSE TO CARDIAC CONTRACTILITY MODULATION THERAPY (CCM) 
 
 
I have read the protocol and accept participating in the study and fulfilling its requirements. 
 
Principal Investigator: 
Name _____Francesco_____________________ 
Surname ___Zanon_________ 
Signature ______________________________ 
Date __________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________________________________ 
List of variations v.1.0 → v.1.1 
• In the objectives, replace "adequate medical therapy" with "medical and 
interventional therapy"; 
• In the inclusion criteria, eliminate “QRS < 130 ms”; 
• In the inclusion criteria, correct "F.E." with "E.F." 
 
 
 

PREDICT-CCM Study - Protocol v.1.2; 06-03-2025  
 
 
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TABLE OF CONTENTS 
 
ABBREVIATIONS  
 
 
 
 
 
 
  4 
INTRODUCTION AND STUDY RATIONAL 
 
 
 
 
  5 
OBJECTIVE 
 
 
 
 
 
 
 
  9 
Primary End-Point 
 
 
 
 
 
  9 
Secondary End-Points 
 
 
 
 
 
  9 
STUDY POPULATION 
 
 
 
 
 
 
10 
Inclusion Criteria  
 
 
 
 
 
10 
Exclusion Criteria  
 
 
 
 
 
10 
STUDY DESIGN 
 
 
 
 
 
 
 
11 
MEDICAL DEVICES 
 
 
 
 
 
 
11 
Possible Complications of Device Implantation 
 
 
12 
Potential Adverse Effects  
 
 
 
 
13 
Risks Associated With Participation In The Clinical Study 
 
14 
The Risk To Benefit Rationale 
 
 
 
 
14 
FLOW CHART 
 
 
 
 
 
 
 
15 
STUDY PROCEDURES 
 
 
 
 
 
 
16 
Enrollment Visit  
 
 
 
 
 
16 
Installing And Programming the Optimizer Smart Mini Device   
19 
Follow-Up 
 
 
 
 
 
 
19 
Unscheduled Visits 
 
 
 
 
 
20 
End Of Study 
 
 
 
 
 
 
20 
Premature Suspension 
 
 
 
 
 
20 
ADVERSE EVENTS  
 
 
 
 
 
 
20 
Adverse Events, Definitions 
 
 
 
 
20 
Serious Adverse Device Effects 
 
 
 
 
21 
Unanticipated Serious Adverse Device Effects 
 
 
21 
Device Specific Events 
 
 
 
 
 
21 
Collection, Evaluation, And Recording Of A.E. 
 
 
22 
Safety Reporting  
 
 
 
 
 
25 
DATA COLLECTION 
 
 
 
 
 
 
26 
Source Document 
 
 
 
 
 
26 
Document Retention 
 
 
 
 
 
26 
Electronic Data Collection  
 
 
 
 
26 
Data Protection  
 
 
 
 
 
27 
STATISTICAL ANALYSIS 
 
 
 
 
 
 
27 
General Statistical Methods 
 
 
 
 
27 
Hypotheses 
 
 
 
 
 
 
28 
Sample Size Estimation 
 
 
 
 
 
28 
Primary End-Point 
 
 
 
 
 
30 
Secondary End-Points 
 
 
 
 
 
31 
ETHICAL AND Regulatory Considerations 
 
 
 
 
31 
BIBLIOGRAFY 
 
 
 
 
 
 
 
33 
 
 

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ABBREVIATIONS 
ADR 
 
Adverse drug reaction  
A.E. 
 
Adverse event  
ASADE  
Anticipated serious adverse device effect  
AT 
 
Atrial tachycardia  
AV                 
Atrioventricular 
CCM 
 
Cardiac Contractility Modulation 
C.E. 
 
European Community 
CIP 
 
Clinical investigational plain 
CRF 
 
Clinical Report Form 
CRT 
 
Cardiac Resynchronization Therapy 
CTCAE  
Common Terminology Criteria for Adverse Events 
DFU 
 
Direction for use 
D.D.                Device Deficiencies 
EDC 
 
Electronic data collection 
ECG 
 
Electro cardio gramma 
EHRA  
European Heart Rhythm Association 
EMA 
 
European Medicine Agency 
ESC 
 
European Society of Cardiology 
GCP 
 
Good Clinical Practice 
GDPR  
General Data Protection Regulation (E.U.) 
H.F. 
 
Heart Failure 
I.B. 
 
Investigator brochure 
ICH 
 
International Conference on Harmonisation 
IFU 
 
Instruction for use 
ITT 
 
Intention-to-treat 
LDDSE  
Low-Dose Dobutamine Stress Echocardiography 
LVESV  
Left Ventricular End-Systolic Volume 
LV                 
Left ventricle 
LVAT            
Left ventricular activation time 
LVEF 
 
Left ventricle ejection fraction 
NYHA  
New York Health Association 
OMT  
Optimal medical therapy 
PM                
Pacemaker 
PR                 
Interval between P wave to R wave (ECG measurement) 
RCT              
Randomized controlled trial 
REDCap 
Research Electronic Data Capture 
R.V.                 Right ventricular 
SADE  
Serious adverse device effect  
SAE 
 
Serious adverse event  
SND              
Sinus node disease 
UO 
 
Unità Operativa 
USADE  
Unanticipated Serious Adverse Device Effect 
 
 

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Introduction 
Heart failure (H.F.) has a very poor prognosis in terms of mortality, quality of life, and 
functional capacity. It is one of the most important cardiovascular diseases in terms of global 
prevalence and healthcare costs. Despite appropriate medical care, many patients experience 
frequent hospitalizations and limitations in daily activities1.  
The prevalence of heart failure ranges between 1% and 3% in the general adult population in 
industrialized countries. It is expected to increase substantially due to the availability of better 
diagnostic tools and medical treatments that prolong life after diagnosis of HF2. 
The latest international guidelines on the management of reduced ejection fraction H.F. 
recommend a timely approach with the simultaneous introduction of the four main categories 
of drugs (ACE inhibitors or ARNIs, beta-blockers, mineralocorticoid receptor antagonists 
(MRAs), and SGLT2 inhibitors). If drug therapy alone is not sufficient or not well tolerated by 
the subject, or if there is a disorder in the conduction of the electrical impulse (in particular, a 
left bundle branch block), it is possible to associate it with electrical therapy, which consists of 
the implantation of biventricular cardiac devices (pacemakers or defibrillators) that 
resynchronize cardiac contraction (cardiac resynchronization therapy, CRT). These devices 
work in close synergy with anti-decompensation drugs to curb the progression of heart failure 
and, in some cases, restore normal cardiac contractility. Cardiac resynchronization therapy, 
combined with drug therapy, has been shown to improve survival and quality of life by 
reducing the symptoms of heart failure, increasing exercise capacity, and enabling subjects to 
resume many of their daily activities.  
 
Cardiac Contractility Modulation (CCM) 
CRT is indicated for patients with a large QRS (>130 ms and evidence of left bundle branch 
block)3; however, the percentage of individuals who do not respond to CRT varies between 
studies, usually between 25% and 33%4. Randomized clinical trials have shown that Cardiac 
Contractility Modulation (CCM) is a treatment option5 for patients with symptomatic heart 
failure despite optimized medical therapy and not eligible for CRT. CCM therapy has also been 
evaluated in patients who have not responded to CRT6 therapy. 
The implanted device for CCM consists of an implantable pulse generator (like a pacemaker) 
equipped with a transcutaneously rechargeable battery connected to two ventricular leads 
that transmit high-energy electrical impulses within the absolute refractory period of the 
myocardial action potential. The device has no pacing or antiarrhythmic functions and is 
designed to work even in patients already implanted with pacemakers or defibrillators. 
 
The FIX-HF-47, FIX-HF-58,9, and FIX-HF-5C10 trials demonstrated the safety and efficacy of the 
CCM device concerning the following end-points: 
• NYHA classroom improvement. 
• Improvement in the quality of life (according to the Minnesota Living with Heart 
Failure Questionnaire – MLHFQ). 
• Improvement in functional capacity at the 6-minute walk test (6MWT). 

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• Increased peak oxygen consumption (VO2). 
• Reduction of cardiovascular death and hospitalizations for heart failure. 
 
The CCM has been shown to improve myocardial contractility11 by improving cardiomyocyte 
management of intracellular calcium. It exerts short- and long-term effects and positively 
modulates cardiac cell gene expression. 
 
The Optimizer Smart system has been approved in countries where the C.E. mark applies 
since October 3, 2016.  
The OPTIMIZER Smart System is indicated for use in patients over 18 who have symptomatic 
heart failure due to systolic left ventricular dysfunction despite medical and interventional 
therapy. CCM therapy delivered by the OPTIMIZER system has been shown to improve the 
clinical status, functional capacity, and quality of life and prevent hospital admissions in 
symptomatic patients with left heart failure who are carefully selected and followed by 
cardiologists experienced in the treatment of heart failure12. 
 
The Optimizer Smart device was FDA-approved on March 21, 2019, for delivering Cardiac 
Contractility Modulation (CCM) therapy. This approval is unique in that it is the first device to 
be granted "Breakthrough Device" status by the FDA and to have been included in the FDA's 
review panel for cardiovascular devices – where it received a unanimous recommendation for 
approval due to its favorable benefit/risk ratio and then obtained PMA approval by the FDA12. 
 
In the 2021 ESC guidelines for diagnosing and treating acute and chronic heart failure13, CCM 
is an "under evaluation" therapy in NYHA class III/IV patients, with LVEF between 25% and 
45% and QRS duration <130 ms. 
 
In the consensus paper published in 2024 by the Heart Failure Association (HFA) and the 
European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC)14, 
CCM is suggested as a therapy that experienced operators who cooperate in a 
multidisciplinary team for heart failure should consider if symptoms persist. 
 
It has been evaluated that, for heart failure patients with reduced ejection fraction, the 
addition of CCM therapy could be more convenient than OMT alone (i.e., the combined use 
of five classes of drugs that, individually, have already been shown to improve the prognosis 
of infarcted patients: acetylsalicylic acid, beta-blockers, statins, antagonists of the renin-
angiotensin system, and thienopyridines), if we consider a time horizon of the whole life15, 16. 
In selected cases, and when no other therapeutic options are available, CCM can be adjunct 
in patients who do not respond to CRT29.  
In a recent study30, CCM significantly improved H.F. in patients with reduced ejection fraction 
(HFrEF), NYHA class III, and moderately prolonged QRS of 120-149 ms. 
 

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Pharmacological stress echocardiography 
Pharmacological stress echocardiography is indicated for the diagnosis and treatment of 
suspected ischemic heart disease or left ventricular dysfunction of suspected ischemic origin. 
The examination consists of performing an echocardiogram during the infusion of increasing 
drug doses that stimulate the sympathetic nervous system, stimulating the heart with an 
effect similar to physical exertion. The heart reacts with increased contraction force and 
frequency; sometimes, blood pressure can also increase. The examination helps to recognize 
the possible presence of stress-induced myocardial ischemia. 
Other indications of stress echocardiography include quantifying contractile reserve in 
cardiomyopathies, evaluating cardiac valvulopathy and congenital heart disease, and 
evaluating diastolic function and pulmonary hypertension. The main advantages of stress 
echocardiography are its simplicity, low cost, wide availability, and absence of radiation17, 18. 
 
The most used drugs in this procedure are Dobutamine or dipyridamole. 
Dobutamine is a synthetic catecholamine that primarily stimulates β1 adrenergic receptors 
and, to a lesser extent, α1 and β2 receptors.  
The protocol for standard dobutamine examination was defined in the American Society of 
Echocardiography (ASE) guidelines of 200719. A graduated dobutamine infusion is usually 
administered at a 5 μg/kg starting dose per minute. The dobutamine infusion aims to achieve 
a heart rate of 85% of the maximum heart rate predicted for the person's age. The dose of 
Dobutamine is increased every 3-5 minutes to 10, 20, 30, and finally to 40 μg/kg per minute20.  
 
On the other hand, the "low-dose" dobutamine stress echocardiography (LDDSE) test is 
optimal for detecting ischemia and assessing viability by searching for the "biphasic response." 
A myocardial area increases its contraction at a low dose of inotropic but later becomes 
hypokinetic or akinetic at higher doses of dobutamine20. 
During the low-dose dobutamine stress echocardiography, the subject is stressed with 
Dobutamine by standardized incremental infusions of 5, 10, and 20 μg/kg/min. Each infusion 
dose is administered for a maximum of five minutes18, 20, 21, 22. 
 
As assessed by low-dose dobutamine stress echo, left ventricular contractile reserve is a 
helpful marker for predicting functional improvement of the left ventricle and determining 
long-term prognosis in patients with dilated heart disease23. 
Low-dose dobutamine stress echocardiography has proven to be a simple and effective 
procedure for selecting patients who are candidates for CRT, having demonstrated the 
correlation between contractile reserve and response to subsequent resynchronization 
therapy24. The assay was also used to quantify the degree of remodeling after CRT25 therapy. 
Many CRT studies have evaluated left ventricular reverse remodeling by echocardiographic 
testing with low-dose Dobutamine. A positive response criterion is a reduction of left 
ventricular end-systolic volume (LVESV) greater than or equal to 15% 26, 27, 28. 
 

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Introductory summary 
When no other therapeutic options are available, CCM can be a helpful complement to 
treating heart failure, improving quality of life, and prolonging survival. Still, the high cost and 
availability of implantations in qualified centers limit its use.  
Then, searching for indicators that maximize the benefit/risk ratio is appropriate. According to 
the study's proponents, the contractile reserve of the left ventricle assessed by stress echo to 
low-dose Dobutamine may be among the most promising indicators for this purpose. 
 
 
 

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Objective of the study 
The objective of the study is to evaluate the long-term clinical and instrumental response of 
CCM treatment in adult subjects suffering from symptomatic heart failure due to systolic left 
ventricular dysfunction despite adequate medical therapy. 
 
End-point assessment will be performed in the entire cohort of enrolled subjects and two sub-
cohorts, divided according to the response to stress echocardiography with preimplantation 
low-dose Dobutamine:  
- "DeltaESV>=15%" sub-cohort, with a decrease in LVESV greater than or equal to 15%  
- "DeltaESV<15%" sub-cohort, with a decrease in LVESV of less than 15%. 
 
Primary End-point  
• The proportion of subjects with clinical response to CCM therapy at 12 months (NYHA 
reduction ≥ 1 class), 
 
Secondary Clinical End-points 
1. Reduction in the number of hospitalizations, visits to the Emergency Department, or 
access to day hospital facilities for more than 4 hours (e.g., by intravenous infusion of 
cardiac inotropic drugs) compared to the year before the study. 
2. Change in the quality-of-life score estimated with the "Quality of Life Questionnaire 
with Heart Failure – Minnesota" (MLHFQ) between baseline and end of follow-up, 
3. Change in walk distance between baseline and end of follow-up in the walk test 
(6MWT) (optional), 
4. Change in NT-proBNP level between baseline and end of follow-up. 
 
Secondary Echocardiographic End-points 
1. The proportion of subjects with LVESV decreased by ≥ 15% on echocardiography at 
end-of-follow-up compared to preimplantation, 
2. The proportion of subjects with increased integral velocity time (VTI) ≥ 20% between 
preimplantation and end-of-follow-up echocardiography, 
3. The proportion of subjects with a 20% increase in ejection fraction (LVEF) between 
preimplantation and end-of-follow-up echocardiography, 
4. The proportion of subjects with progression or, conversely, improvement in Mitral 
Regurgitation (M.R.; classified as mild, moderate, or severe). 
 
Secondary Security End-points 
1. The proportion of subjects who, during follow-up, will be evolved to cardiac 
resynchronization system (CRT) implantation, 
2. The proportion of subjects who, during follow-up, will be evolved to left ventricular 
assist device (LVAD) implantation, 

PREDICT-CCM Study - Protocol v.1.2; 06-03-2025  
 
 
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3. The proportion of subjects who will have received a cardiac transplant during follow-
up, 
4. The proportion of subjects who will die from H.F. during follow-up (it is also compared 
to the predicted mortality by the "MAGGIC" score33).  
5. Assessment of the arrhythmic burden (in the case of a patient with an ICD: number of 
episodes of ventricular tachycardia treated with ATP/shock; in the case of a patient 
with a Pacemaker/ICD/Loop recorder: percentage of time spent in atrial fibrillation). 
6. Rate of all procedure-related adverse events.  
7. Potentially harmful factors like the procedure time and fluoroscopy time.  
8. Rate of re-operations (lead revision/replacement/infection). 
 
 
Study population 
 
Inclusion Criteria 
• Subject of both sexes with age ≥ 18 years,  
• Ability to understand and sign informed consent to participate in the study and 
consent to process sensitive personal data. 
• Carrier of symptomatic heart failure, despite optimal medical therapy (OMT),  
• Reduced left ventricular systolic function (E.F. <50%), 
• It was positively evaluated for implanting a system for cardiac contractility modulation 
(CCM) (according to the European Society of Cardiology 2021 Guidelines on heart 
failure and the provisions of the C.E. mark approval)13.  
• Have presented at least one hospitalization, access to the Emergency Department, or 
access to day hospital facilities for more than 4 hours (e.g., by intravenous infusion of 
cardiac inotropic drugs) in the year before implantation. 
 
Exclusion Criteria 
• Life expectancy < 1 year due to non-cardiac comorbidities that reduce prognosis,  
• Presence of contraindications to the CCM implantation procedure (absence of vascular 
access usable for CCM implantation, active infectious processes, active severe 
coagulopathies, presence of mechanical tricuspid valve)31, 
• Contraindications to the performance of the echocardiographic test under 
pharmacological stress (heart failure in progress, myocardial infarction in the acute 
phase, acute inflammatory processes of the heart muscle and/or pericardium, critical 
aortic valve stenosis and severe obstructions to left ventricular outflow, dissecting 
aneurysm of the aorta, severe arrhythmias not controlled by therapy, known 
hypersensitivity to the drug, intraventricular thrombi)21. 
 
 
 

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Study design 
The "Predict-CCM" is an observational cohort, retrospective and prospective, multicenter, 
independent, non-profit study.  
 
The Promoter is the recognized non-profit association Q.U.O.V.A.D.I.S. of Padua (I). 
 
Dr. Francesco Zanon of UO Cardiologia, S. Maria della Misericordia Hospital, ULSS5 Polesana, 
Rovigo (I), coordinates the study. 
 
The participating clinical centers are experts in assisting individuals with severe heart failure 
and implanting cardiac contractility modulation (CCM) systems. 
 
Enrollable subjects who, in the participating Clinical Centers, received a CCM implant from July 
1, 2024, to the start of the study will be part of the retrospective cohort, while subsequent 
subjects of the prospective cohort. 
Enrollment in the study will continue for 2 years.  
The follow-up period for each subject will be 12 months after implantation.  
 
The study involves clinical-instrumental controls and data collection in eCRF at the time of 
enrollment, at implantation, at least once between 1 and 6 months of follow-up and twelfth 
months after CCM implantation.   
 
 
Medical Device  
 
Subjects participating in the study carry or will carry the CE-certified medical device 
"OPTIMIZER Smart Mini" by Impulse Dynamics (USA). The assignment of a patient involved in 
the study to CCM through the “OPTIMIZER Smart Mini" system will be determined 
independently of the patient's participation in the study, and the treatment is part of the 
routine clinical practice at each involved center. This device delivers Cardiac Contractility 
Modulation (CCM) therapy. It is indicated for use in patients over 18 years of age with 
symptomatic heart failure due to systolic left ventricular dysfunction despite appropriate 
medical treatment.31 
The OPTIMIZER Smart Mini Implantable Pulse Generator is a programmable device with an 
internal battery and telemetry functions. The system is suitable for treating heart failure, a 
condition in which the heart muscle does not pump blood as it should, resulting in reduced 
cardiac output. 
The OPTIMIZER Smart Mini monitors the heart's intrinsic activity. It sends CCM signals to the 
heart tissue during the ventricular absolute refractory period, when the heart tissue cannot 
activate, thus making the CCM signal non-excitatory. The CCM signal is sent in sync with the 

PREDICT-CCM Study - Protocol v.1.2; 06-03-2025  
 
 
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local electrical activity detected. It can achieve the desired effect on the tissue, i.e., treating 
heart failure by increasing cardiac output or heart muscle contractility. 
 
The OPTIMIZER Smart Mini is connected to two or three implantable leads, two of which are 
implanted in the right ventricle and one, optionally, in the right atrium. 
 
The battery inside the IPG OPTIMIZER Smart Mini is rechargeable via the Vesta35 charging 
system. 
The Vesta charger is powered by a rechargeable battery and is used by the patient to charge 
their transcutaneously implanted IPG OPTIMIZER Smart Mini using inductive energy transfer. 
It incorporates a graphical display that shows a different screen for each operating status, 
alert, and other information it receives through daily communications with the IPG OPTIMIZER 
Smart Mini. 
 
The Intelio programmer uses telemetry to query and program the IPG OPTIMIZER Smart Mini. 
With the Intelio programmer, the clinician can obtain diagnostic data from the IPG OPTIMIZER 
Smart Mini and customize the operating parameters of the IPG OPTIMIZER Smart Mini to meet 
the specific needs of each patient35. 
 
 
 
    
  
OPTIMIZER Smart Mini 
 
Caricatore Vesta 
 
   Programmatore Intelio 
 
 
Possible complications of device implantation31 
Like any surgical procedure, implanting an IPG OPTIMIZER Smart Mini has some risks.  
 
Complications of device implantation reported in the literature include, but are not limited to: 
•Infection 
• Skin necrosis 
• Device migration 
• Hematoma formation 
• Seroma formation 

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• Histotoxic reactions (see also: Potential adverse effects, Section 7) 
 
Acute and chronic complications reported in the literature include, but are not limited to: 
• Lead fracture 
• Lead displacement 
• Atrial or ventricular perforation 
• Rare cases of pericardial tamponade 
 
In sporadic cases (<1%), transvenous lead placement may cause venous thrombosis and 
subsequent SVC syndrome. 
 
Potential adverse effects31 
Examples of adverse effects that may occur following the surgical procedure are listed below 
in order of clinical severity: 
1. Death 
2. Arrhythmias (brady- or tachyarrhythmias including fibrillation) 
3. Stroke or TIA ("transient ischemic attack") 
4. Formation of blood clots 
5. Respiratory/ventilatory failure 
6. AD/VD drilling 
7. Hemorrhage 
8. Infection 
9. Pericardial or pleural effusion 
10. Pneumothorax 
11. Injury to the heart or blood vessels 
12. Heart muscle damage 
13. Damage to the tricuspid valve, potentially resulting in regurgitation of the tricuspid 
valve 
14. Damage to the specialized tissue in the heart responsible for initiating each 
heartbeat (i.e., the heart's conduction system) 
15. Pain at the incision site 
 
Examples of additional adverse effects that may occur because of the delivery of MCC therapy 
are listed below in order of clinical severity: 
1. Abnormal heart function 
2. Atrial and ventricular tachyarrhythmias 
3. Atrial and ventricular bradyarrhythmias 
4. Worsening heart failure 
5. Damage to myocardial tissue 
6. Lead Shift 
7. Chest pain 

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8. Chest wall sensations 
9. Inappropriate ICD behavior because of interaction with an implanted IPG OPTIMIZER 
Smart Mini 
 
Risks associated with Participation in the Clinical Study   
All procedures and tests planned for the follow-up period are standard of care. This study is 
observational, therefore, the risks associated with the implant procedure are to be 
considered independent of participation in the study..  
 
Additional minimum risks may be linked to the procedure and follow-up testing, which are 
unforeseen now.  
 
Possible Interactions with Concomitant Medical Treatments   
There is no risk of interactions between medical therapies and the study procedures.   
 
Risk Minimization Actions   
Additional risks may exist. Risks can be minimized by performing procedures in the 
appropriate hospital environment, adhering to subject selection criteria, and monitoring the 
subject's physiological status during research procedures and/or follow-ups.  
 
Anticipated Benefits   
The enrolled subject will receive effective and safe treatment for his health problem, 
potentially improving the disease's symptoms. Furthermore, medical science and future 
patients may benefit from this study's results.   
 
The Risk to Benefit Rationale   
The devices used in the study are CE-marked and have been proven suitable for their 
intended purpose. There are no unacceptable residual or intolerable risks, and all applicable 
risks have been addressed by providing appropriate Device Instructions for Use. Evaluating 
the risks and benefits expected to be associated with using these devices demonstrates that 
when used under the intended conditions, the benefits associated with their use should 
outweigh the risks. 
 
 

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Flow chart 
                        Visit 
 
Data to be  
collected 
Enrollment 
Procedure 
(CCM) 
between 1 
and 6 
months of 
follow-up 
12-mo 
control 
end-of-
study 
In-office visit 
X 
 
X  
X 
Informed content 
X 
 
 
 
Physical 
examination 
X 
 
X 
X 
Medical history 
X 
 
 
 
Cardiovascular drug 
therapy 
X 
 
X 
X 
Echocardiographic 
data 
X 
 
 
X 
LDDSE (LVESV) 
X 
 
 
 
Procedural data 
 
X 
 
 
NYHA score 
assessment 
X 
 
X 
X 
NT-proBNP 
X 
 
 
X 
6MWT assessment 
(optional) 
X 
 
 
X 
MLHFQ QoL 
assessment 
X 
 
X 
X 
Complications  
(Adverse Events) 
 
X 
X 
X 
Electrocardiographic 
data (12-lead) 
X 
X 
X 
X 
 
 
 

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Study Procedures 
 
Enrollment visit 
 
Collection of written informed consent 
Patients will be given informed consent, which the Ethics Committee approves. Each study 
procedure will occur after the patient has agreed to participate by signing and dating the 
informed consent only. 
While asking for informed consent, the Investigator will inform the interested party that 
Participation in the study is voluntary and that refusal will not lead to the loss of any benefit 
or affect the doctor's relationship. Also, it will be disclosed that withdrawal from the study is 
possible at any time without providing a specific reason. Before enrolling in the study, each 
subject will receive a full explanation of the nature and purpose of the study from the 
Investigator, along with a description of the benefits and risks associated with Participation. 
A transparent information sheet covering all crucial aspects of the study will be delivered to 
the subject. Once read, the subject will have the opportunity to ask questions. Sufficient time 
will be given to consider the various aspects presented before being asked to sign and date 
the informed consent form. The original copy of the signed and dated Investigator will keep 
the informed consent form in the study file held in the Center. The subject will receive a copy 
of the signed and dated informed consent form for future reference. 
 
The consent forms may be signed for retrospective subjects at the first contact following the 
CCM implantation. 
 
Screening Visit 
After obtaining written informed consent, all potentially considered subjects will complete 
the screening visit. 
The visit includes the collection of the following information: 
• Demographic data, including age and gender, 
• Cardiovascular history,  
• Including any cardiac surgery,  
• Risk factors, and comorbidity, 
• Number of hospitalizations, visits to the Emergency Department, or visits to day 
hospital facilities for more than 4 hours (e.g., for intravenous infusion of cardiac 
inotropic drugs), 
• Echocardiographic (2D and 3D), 
• Electrocardiographic data, 
• Low-dose Dobutamine stress echocardiographic examination.  
 

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The echocardiographic (2D and 3D) and Low-dose Dobutamine stress echocardiographic 
examination is the most commonly available imaging technique for evaluating the above 
factors and the appropriate treatment approach. 
A physical examination will also collect body weight, height, and blood pressure data.  
 
The criteria for inclusion and exclusion regarding the subject's eligibility for the study will then 
be verified. 
 
A patient is considered enrolled in the clinical investigation from the moment the patient 
provides written informed consent, has been confirmed to meet all inclusion criteria and none 
of the exclusion criteria, and has had the CCM leads inserted into the subject's vasculature. 
 
Low-dose dobutamine echo-stress  
During the low-dose Dobutamine (LDDSE) stress echocardiography procedure, the subject is 
stressed with Dobutamine by standardized incremental infusions of 5, 10, and 20 μg/kg/min. 
Each infusion dose is administered for a maximum duration of five minutes. 
The LDDSE protocol is considered completed if there is a 10% increase in heart rate.18, 20, 21, 22  
 
Blood pressure and ECG are traced at rest, and the end of each LDDSE protocol phase is 
monitored during the investigation. The infusion is discontinued if any of the following events 
occur: arrhythmia, angina, hemodynamic decompensation, ECG, or left ventricular wall 
movement abnormalities in at least two segments. 
 
This study uses two-dimensional echocardiography to evaluate reverse remodeling of the left 
ventricle during dobutamine echo-stress. The echocardiographic response to the dobutamine 
stress test is considered positive (presence of contractile reserve) if the reduction in left 
ventricular end-systolic volume (LVESV) is at least 15% compared to baseline27. 
 
The parameters to be measured at baseline and each LDDSE protocol phase are as follows:  
• End-systolic volume (ml) in biplane, 
• End-diastolic volume (ml) in biplane, 
• Left ventricular ejection fraction (%) in biplane, 
• Degree of mitral regurgitation (mild, moderate, severe), 
• Stroke volume (ml) with continuity equation, 
• PAPs (mmHg), 
• Degree of diastolic dysfunction (first, second, third, fourth degree). 
 
In the case of contraindications to echo-stress with Dobutamine, the subject should not be 
tested. It cannot be enrolled in the study as reported in the paragraph of "exclusion criteria." 
 

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The contraindications to the execution of the echocardiographic test under pharmacological 
stress are21:  
• heart failure in progress,  
• myocardial infarction in the acute phase,  
• acute inflammatory processes of the heart muscle and/or pericardium,  
• critical aortic valve stenosis and/or severe obstructions to left ventricular outflow,  
• aortic dissecting aneurysm,  
• severe arrhythmias not controlled by therapy,  
• known hypersensitivity to the drug,  
• intraventricular thrombi.  
 
As in current clinical practice, if the subject's home drug therapy involves taking beta-blockers, 
it must be suspended the day before and on the morning of the LDDSE examination, while if 
the subject has an implantable cardiac device (pacemaker, defibrillator), it is not indicated to 
reprogram the pacing mode or the base frequency. 

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Implanting and programming the Optimizer Smart Mini device  
The Optimizer Smart device will be installed according to the instructions given in the user 
manual.31  
Two actively fixated leads (conventionally called R.V. and L.S.) are placed in the right 
ventricle, one preferably in the anterior septum and the other in the posterior septum, 
about halfway between the base and the apex. An acceptable alternative is to place both 
leads in an anterior or posterior septal position, provided they are at least 2 cm apart. In 
patients who have an implantable ICD, ensure that there is adequate separation between 
the implanted CCM leads and those of the ICD.31  
 
In patients who have an implantable ICD, evaluate with a cross-talk test the maximum 
amount of delay of the CCM series allowed before the ICD begins to perceive CCM therapy 
impulses as R waves inappropriately.35 
Technical implant data, including, but not limited to, lead positions, venous access, pacing 
thresholds, and EGM signals, are reported in the CRF sheets.  
Any complications associated with the implant (failure to place the electrode due to 
inadequate pacing and sensing parameters or repeated electrode dislocation, pericardial 
effusion, pneumothorax, hemothorax, hematoma of the generator pocket, electrode 
dislocation) are also collected in the same form.  
Optimizer Smart device parameters will be programmed to ensure smooth therapy delivery 
and maximize therapy percentage according to the directions in the device user manual 31 
and programming system.35  
Under standard conditions, the device is programmed to deliver CCM therapy for seven 1-
hour periods distributed equally over the 24 hours of the day. 
 
Follow-up 
The first control between 1 and 6 months of follow-up, and the second one at 12 months (± 1 
month). 
 The following data collections are required:  
• Physical examination, 
• Symptoms, Adverse Events, 
• NYHA class variation and Quality-of-life assessment by Minnesota Living with Heart 
Failure Questionnaire (MLHFQ), 
• Cardiovascular drug therapy revision, 
• A 12-lead electrocardiogram,  
• CCM examination, 
 
Further echocardiographic examinations are required at a 12-month (± 1 month) follow-up 
visit. 
 

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Reintervention for lead revision/replacement 
After successful implantation, a Patient needing reintervention for lead revision/replacement 
will undergo the procedure according to standard clinical practice and the relative information 
data collected. 
 
Unscheduled visit 
An unscheduled visit is an additional visit to those foreseen by the study. The following clinical 
practice will handle unscheduled visits, and critical clinical data will be collected. 
 
End of Study 
The study will end when the last enrolled subject performs the scheduled visit 12 months 
after enrollment, and the related data will be stored in the CRF. 
The Sponsor may terminate this study prematurely, in its entirety, or at any study site, for 
reasonable and documented reasons, provided that written notice is submitted before the 
scheduled termination. The Investigator may also stop the study at his site for understandable 
reasons upon written notification to the Sponsor before the expected end. Either party does 
not require notice if the study is interrupted due to security reasons. If the Sponsor finishes 
the trial for security reasons, he must immediately notify the investigators by telephone and 
provide written instructions for closing the study. The reasons for the Sponsor or 
Investigator's early termination of a participating site may include but are not limited to the 
Investigator's failure to proceed following the protocol, with local health authority 
requirements or with Sponsor procedures, or due to inadequate patient recruitment. 
 
Premature suspension 
Enrolled subjects will permanently leave the study when any of the following events occur: 
• the occurrence of one of the exclusion criteria, 
• a severe adverse event (SAE) that achieves one of the exclusion criteria, 
• withdrawal of consent to participate in the study at any time and for any reason, 
• if the Investigator deems it necessary in the interest of the patient or if it is no longer 
compliant with the study procedures (e.g., unavailability for the planned check-ups) 
or in the case of a female patient who develops a pregnancy, 
 
Prematurely suspended subjects will not be replaced. 
 
 
Adverse Events 
 
Adverse events, definitions 
"Adverse event (A.E.)" is any harmful clinical event that occurs in a subject enrolled in a clinical 
trial and does not necessarily have a causal relationship with the treatment. 
 

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Therefore, an adverse event can be a harmful and unwanted sign (e.g., tachycardia, edema, 
including an abnormal result of laboratory tests), a symptom (e.g., dyspnea, chest pain), or a 
disease, regardless of the relationship judgment causal with study treatment. Pre-existing 
conditions for entering the patient in the study are excluded from the concept of A.E. 
 
"Adverse reaction (ADR)": any A.E. that is believed to be related to study treatment. The 
definition implies the reasonable possibility of a causal relationship between the adverse 
event and the study treatment. 
The Investigator will assess the causality relationship dichotomously (at least possible 
relationship/relationship excluded). The ADR definition also includes the study treatment 
administration's errors, which is different from what the protocol describes. 
 
"Serious adverse event (SAE)": any adverse event (A.E.) that meets one or more of the 
following criteria: 
o 
It has a fatal outcome 
o 
Immediately endangers the life of the subject 
o 
Requires hospitalization or prolonged ongoing hospitalization * 
o 
It involves a persistent or significant disability or incapacity 
o 
It determines a congenital anomaly or a congenital disability 
o 
It is considered an important medical event in the Investigator's judgment (e.g., 
an event that requires active intervention to prevent one of the characteristics 
/consequences mentioned above). 
* An A.E. is not considered an SAE if hospitalization was scheduled before the subject 
was enrolled or did not entail the night's stay. 
 
Serious Adverse Device Effects  
A serious adverse device effect (SADE) is an adverse device effect that has resulted in any of 
the consequences characteristic of a serious adverse event.  
 
Unanticipated Serious Adverse Device Effects  
An unanticipated serious adverse device effect (USADE) is one whose incidence, severity, or 
outcome has not been identified in the current risk analysis report.  
NOTE: Anticipated serious adverse device effect (ASADE) is an effect whose nature, 
incidence, severity, or outcome has been identified in the risk analysis report.  
 
Device-Specific Events  
Device deficiency is the inadequacy of a medical device concerning its identity, quality, 
durability, reliability, safety, or performance.  
NOTE: Device deficiencies include malfunctions, use errors, and inadequacy in the 
information supplied by the manufacturer.  
 

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Device malfunction means a medical device's failure to perform under its intended purpose 
when used per the IFU/DFU, I.B., or Clinical Investigational Plan.  
 
Device Deficiencies (D.D.) and other device issues should not be reported as A.E.s. Instead, 
they should be reported on the appropriate CRF. If an A.E. results from a device deficiency or 
other device issue, the A.E. should be reported on the appropriate CRF.  
Device malfunctions, failures, or deficiencies may or may not cause the subject to 
experience the harmful effect. By definition, all AE/SAE associated with a device failure is 
device-related.  
 
Collection, evaluation, and recording of adverse events (A.E.) 
At each visit provided by the protocol, the patient will be asked to report any signs or 
symptoms that arose after the previous visit. The patient will also receive instructions to 
promptly contact the Center if new signs or symptoms occur between visits. The Investigator 
must ensure the collection of all the A.E.s occurring in the patient during his stay in the office, 
not only of the events observed/reported on the occasion of the scheduled views. 
 
The Investigator will evaluate whether a particular medical condition observed in the subject 
or reported by him can be considered an A.E. based on the interview with the patient, on the 
physical examination, and, if necessary, on laboratory tests and instrumental examinations of 
the case. 
 
When the Investigator has identified an A.E., he will register it in the outpatient medical record 
and the appropriate section of the Electronic Data Capture (EDC) platform. In this section, the 
Investigator will describe the A.E. both freely ("verbatim") and code it according to standard 
medical terminology (CTCAE v5.0). 
 
Besides, the Investigator for each A.E. will define Severity by the Grading Scale: 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; no intervention indicated 
Grade 2 
Moderate 
Minimal, local, or noninvasive intervention indicated, limiting 
age-appropriate instrumental activities of daily living 
 (ADL) 
Grade 3 
Severe  
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL 
Grade 4 
Life-threatening 
Life-threatening consequences: urgent intervention indicated 
Grade 5 
Death 
Death related to A.E. 
Reference: Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
 

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The period for collecting and recording adverse events (A.E.) 
The Investigator will collect and record each A.E. arising from signing the informed consent 
form until the end of the clinical trial's follow-up period. 
The Investigator will follow all the A.E.s registered until their resolution or until, in his opinion, 
it will no longer be possible to have further information on the event and the outcome. 
After the clinical trial closes, the Investigator will communicate to the Promoter any new 
information about previously registered A.E.s that he should become aware of. 
 
Pre-existing clinical conditions 
The clinical conditions present when the informed consent form is signed will be registered as 
"pre-existing" in the appropriate section of the EDC platform. 
Any new clinical condition or worsening of a pre-existing clinical condition that arises after 
signing the informed consent form will be recorded as A.E., except for the clinical events 
identified in this protocol as an end-point. 
 
Abnormal laboratory values 
Abnormalities of laboratory values that require clinical intervention (e.g., therapeutic 
measures), further investigations (other than simple repetition of the test), or that are 
considered clinically significant by the Investigator will be recorded as A.E. 
 
Pregnancies 
Should pregnancy occur, the patient will early terminate her Participation in the trial. 
Pregnancy per se is not considered an A.E. unless there is a suspicion that experimental 
treatment has interfered with contraceptive systems' effectiveness. 
In any case, the pregnancy must be registered and followed until its conclusion. 
 
Efficacy end-point 
Clinical events identified in this protocol as an efficacy end-point will not be recorded as A.E. 
Reporting of adverse events 
 
Serious adverse events (SAE) and serious adverse device effect (SADE) 
The Investigator is required to register each SAE and SADE on the EDC platform within three 
calendar days of its knowledge. 
The EDC platform automatically sends an alert email to the Study Coordinator for each 
registered SAE and SADE. 
If there is a lack of information on the SAE and SADE, the Study Coordinator will contact the 
Investigator to obtain an update. 
If the SAE and SADE are fatal or have endangered the patient's life, the Study Coordinator will 
contact the Investigator to obtain a detailed clinical report on the event. 
 
Non-serious adverse events 

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The Investigator must also record all non-serious adverse events during the clinical trial 
(including the follow-up period) in the appropriate section of the EDC. 
 
Pregnancies 
Any pregnancy cases and new information on pregnancies reported must be registered and 
transmitted to the Study Coordinator within 48 hours of learning them. 
 
Relationship to the device or procedure 
The Investigator will use the following definitions to assess the relationship to the device or 
procedure:  
Not Related: Relationship to the device or procedure can be excluded when:  
• the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures;  
• the event has no temporal relationship with the use of the device or the procedure;  
• the event does not follow a known response pattern to the medical device (if the response 
pattern is previously known) and is biologically implausible;  
• the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase 
of the level of activation/exposure) do not impact the event;  
• the event involves a body site or an organ not expected to be affected by the device or 
procedure; the event can be attributed to another cause (e.g., an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment, or other risk 
factors);  
• the event does not depend on a false result given by the device used for diagnosis, when 
applicable; harms to the subject are not clear due to use error;  
• To establish the non-relatedness, not all the criteria listed above might be met 
simultaneously, depending on the type of device/procedures and the event.  
Unlikely Related: The relationship with the use of the device or procedure seems 
irrelevant, and/or another cause can reasonably explain the event, but additional 
information may be obtained.  
Possibly Related: The relationship with using the device or procedure is weak but cannot 
be completely ruled out. Alternative causes are also possible (e.g., an underlying or 
concurrent illness or clinical condition or an effect of another device, drug, or treatment). 
Cases where relatedness cannot be assessed or no information is obtained should also be 
classified as possibly related.  
Probably Related: The relationship with the device or procedure's use seems relevant, 
and/or another cause cannot reasonably explain the event, but additional information may 
be obtained.  
Causal Relationship: The event is associated with the device or with procedure beyond 
reasonable doubt when:  
• the event is a known side effect of the product category the device belongs to or of 

PREDICT-CCM Study - Protocol v.1.2; 06-03-2025  
 
 
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similar devices and procedures;  
• the event has a temporal relationship with device use/application or procedure;  
• the event involves a body site or organ that a device or procedure is applied to and/or 
affects;  
• the event follows a known response pattern to the medical device (if the response 
pattern is previously known);  
• the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the event (when clinically feasible);  
• other possible causes (e.g., an underlying or concurrent illness/clinical condition 
or/and an effect of another device, drug, or treatment) have been adequately ruled 
out;  
• harm to the subject is due to error in use;  
• the event depends on a false result given by the device used for diagnosis, when 
applicable;  
• Only some of the criteria mentioned above might be met simultaneously to establish 
their relatedness. 
If the relationship between any adverse event and the device's use is considered unlikely, 
possibly, or probably related, that event will be classified as an ADE or SADE.  
 
Safety Reporting 
Safety surveillance within this study and safety reporting performed by the Investigator and 
Sponsor starts as soon as the subject is enrolled. Safety surveillance and reporting will 
continue until the last investigational visit has been performed, the subject is deceased, 
concludes their Participation in the clinical investigation, or the subject withdraws from the 
clinical investigation. All adverse event data, including deaths, will be collected throughout 
the abovementioned period and reported to the Study Sponsor through the EDC platform. 
Additional information on an adverse event should be updated within the appropriate case 
report form. Unchanged, chronic, non-worsening, or pre-existing conditions are not A.E.s and 
should not be reported.  
For this clinical study, the following events will be reported:  
• Serious adverse events 
• Adverse events that are considered related to either the leads or the MCC 
implantation procedure by the Investigator 
Non-cardiac-related abnormal laboratory values will not be regarded as A.E.s unless:  
• The Investigator determined that the value is clinically significant,  
• The abnormal lab value required intervention, or  
• The abnormal lab value required the subject to terminate the study. 
The Investigator will further report the SAE to the local E.C. according to the institution's 
E.C. reporting requirements. 
 

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Data Collection 
 
Source Data 
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are in source documents (original records or certified 
copies). Any data recorded directly on the CRFs (i.e., no prior written or electronic record of 
data) is considered source data. 
 
Source Documents 
Original documents, data, and records (e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; subjects' diaries or evaluation checklists; pharmacy 
dispensing records; recorded data from automated instruments; copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, or records kept at the pharmacy, at the 
laboratories, and medico-technical departments involved in the clinical trial). 
All parameters asked for in the case report form (CRF) should be documented in the source 
documents. 
 
Document retention 
The Study sponsor and the Principal Investigators will maintain the clinical investigation 
documents as required. Measures will be taken to prevent accidental or premature 
destruction of these documents. 
These documents must be retained for 10 years after the clinical investigation concludes and 
made available for monitoring or auditing by the Sponsor's representative or representatives 
of the applicable regulatory agencies. 
All source documents must be stored for the maximum time required by the hospital's 
regulations, research institute, or practice. 
 
Electronic Data Collection 
An "Electronic Data Capture" (EDC) system based on the "Research Electronic Data Capture" 
platform (REDCap, produced and distributed by Vanderbilt University and "REDCap 
Consortium") will be used for the collection of data in the various participating Centers. 
The eCRF (clinical data collection forms) can be consulted as an accompanying document to 
the protocol. 
 
Data protection 
The personal data of the enrolled subjects will be treated with the utmost confidentiality 
under the provisions of Italian Legislative Decree 211/2003, subsequent amendments and 
additions, and E.U. Regulation 2016/679 ("GDPR"). In particular, the subject's personal data 

PREDICT-CCM Study - Protocol v.1.2; 06-03-2025  
 
 
27 
will be known only to the Investigator and his collaborators who follow the patient and collect 
their consent for the treatment. A unique numerical identification number will be used to 
identify each enrolled subject. 
 
An administrator guarantees the use and maintenance of the REDCap platform by managing 
users with a flexible and granular authorization system. REDCap applies the permissions 
granted to each user who connects to it through a web browser and the protocol with SSL 
encryption (using a personal "username" and "password"), activating certain functions, tabs, 
links, and buttons according to the privileges granted and the group/center of belonging. 
REDCap allows a complete "audit" of user procedures, recording all data operations, including 
viewing and exporting. The operational control log stores the date, time, and user who 
operates, allowing a complete review and remote monitoring of the clinical study if necessary. 
All users who have access to the EDC platform, investigators, staff members, and data 
managers must have attended a training event to increase the reliability, quality, and 
integrity of the data recorded on the platform. 
 
REDCap implementations allow compliance with the most common industry standards and 
EMA requirements (GCP, Privacy-IT: DL 211/2003 and subsequent amendments and 
additions; E.U. Regulation 2016/679 "GDPR") and FDA (21-CFR2-Part 11). 
 
Every effort is made to ensure compliance with the "GCDMP" guidelines (Good Clinical Data 
Management Practice, published by the Society for Clinical Data Management, 2013), in 
particular for the reliability, quality, integrity, and security of data registered on the EDC 
platform, both from a procedural and I.T. point of view with the use of "state of the art" 
solutions. 
 
STATISTICAL ANALYSIS  
 
General Statistical Methods  
All variables will be analyzed descriptively with the appropriate statistical methods: for 
categorical variables using frequency tables and continuous variables with sample statistics 
(e.g., average, median, standard deviation, minimum and maximum value, 25 ° and 75 ° 
quartile). 
The selected baseline covariates may be compared for 'like-to-like' in the two sub-cohorts of 
subjects with appropriate statistical tests for discrete and continuous variables.  
Unless otherwise specified, all statistical tests will be 2-tailed and at a significance level of 5%. 
All primary and secondary analyses will be performed on the modified intention-to-treat (ITT) 
population, which includes all enrolled subjects who have undergone CCM implantation. 
Subjects who will be enrolled but withdraw consent before undergoing the CCM implant 
procedure can be replaced, even if they do not lose their unique identification code. 

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Subjects who leave the observation without presenting the end-point will be considered 
censored and considered to have participated in the risk during the observation period. 
For those not present for the clinical evaluations at the control between the 1st to 6th month 
and 12th month of observation, every effort will be made to determine a possible outcome of 
interest for the study and make them assessable as end-points. 
 
The overall sample size is justified by hypothesis parameters and driven by the primary end-
point to preserve its adequate statistical power.  
The primary end-point: Proportion of subjects with clinical response to CCM therapy at 12 
months (NYHA reduction ≥ 1 class). 
 
Hypotheses 
Based on the analysis of the on-topic (poor) scientific literature and our experience in the 
field, we can hypothesize that:  
1. In all subjects, the proportion of subjects with clinical response to CCM therapy at 12 
months (NYHA reduction ≥ 1 class) of follow-up will be near 70%, 
2. The proportion of subjects who will have a positive response to LDDSE before CCM 
implantation (i.e., with a decrease in LVESV greater than or equal to 15%) will be 80%.  
 
Sample size estimation 
When the proportion of subjects with clinical response to CCM therapy at 12 months is 70%, 
a sample size of 120 will produce an acceptable two-sided 95% confidence interval with a 
width equal to 17%. 
As Figure 1 shows, this sample size will allow us to be adequately confident even in modest 
variations in the expected proportion. 
 

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 Figure 1 
Legend: 
P: clinical response proportion in the comprehensive cohort, 
N: sample size 
C.I. Width: width of 95% Confidence Limits 
 
Under Hypotheses 2, the two sub-cohorts will be composed of: 
80 subjects in the "DeltaESV>=15%", where we assume a clinical response to CCM therapy at 
12 months around 80%, and 
40 subjects in the "DeltaESV<15%", where we assume a clinical response to CCM therapy at 
12 months around 40%, 
 
We should have adequate power to evaluate the prognostic contribution of a positive LDDSE 
test, even in the presence of minor variations in the observed responses compared to the 
expected ones (Figure 2). 
 

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 Figure 2 
Legend: 
P2: clinical response proportion in sub-cohort "DeltaESV<15%", 
OR1: Odds Ratio ("DeltaESV>=15%" versus "DeltaESV<15%") 
 
The power was estimated by PASS v.11 (NCSS Inc., Kaysville, Utah, USA). 
 
Statistical analysis specifications 
The purpose of the study is predominantly descriptive. 
 
Primary End-point 
The proportion of subjects with clinical response to CCM therapy at 12 months (NYHA 
reduction ≥ 1 class) will be estimated with its 95% C.L. for the entire cohort and the two sub-
cohorts. In this case, the crude O.R. for clinical response between the sub-cohorts 
("DeltaESV>=15%" versus "DeltaESV<15%") will be estimated with his 95% C.L., and the Fisher 
Exact test will evaluate the association between the two factors. 
 
A multivariable logistic regression will test the likely presence of risk factors for the primary 
efficacy end-points and provide the correct O.R. estimation for any other clinical or 
instrumental descriptors that characterize the enrolled subjects. Those descriptors 
significantly associated (p<0.10) with the clinical response in the univariate analysis will be 
introduced into the multivariable regression and further selected using the Forward Stepwise 
Wald method. 
 

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Secondary End-points 
All continuous secondary end-points will be summarized with the number of non-missing 
data, mean ± standard deviation, median, and range (minimum-maximum). All categorical 
secondary end-points will be tabulated with the occurrence and proportion with its 95% CI. A 
paired t-test will be used for the comparison within the group, and the equivalent non-
parametric test, such as the signed-rank test or sign test, will be used if the assumption for 
the paired t-test is violated. Comparison between groups will be performed using a t-test or 
equivalent non-parametric tests, such as the Wilcoxon rank-sum test or Kolmogorov-Smirnov 
test, when the assumption for the t-test is violated. 
All categorical secondary end-points will be tabulated by occurrence and percentage. Then, 
Fisher's exact test will be used to compare the groups.  
 
All statistical analyses will be performed using SPSS Statistics, version 26 or later (IBM Corp. 
Armonk, NY), and STATISTICA v12 (StatSoft, Tulsa, OK). 
 
Final report and publication of the results 
The study results will be reported in a final integrated, statistical, and clinical report compliant 
with the GCP-ICH-E6, STROBE, and TRIPOD guidelines. The report's content will be approved 
jointly by the Clinical Coordinator of the study and the Promoter. 
The same joint approval will apply to the contents of the first publication and the first public 
presentation of the study results, which the Promoter undertakes to carry out even if there is 
negative evidence of them. Any secondary publications or presentations will be subject to 
prior notification by the Coordinator to the Promoter or vice versa, with the recipient's 
capacity to comment. 
 
 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
This clinical trial will follow the principles laid down by the 18th World Medical Assembly 
(Helsinki, 1964) and all applicable amendments established by the World Medical 
Assemblies (the latest revisions of the WHO Declaration of Helsinki, 2024), the Declaration 
of Oviedo, and the ICH guidelines for Good Clinical Practice (ICH-E6-R2).  
This clinical trial will comply with all international laws and regulations, the national laws 
and regulations of the country where it is performed, and any other applicable guidelines. 
 
Responsibilities of the Investigator(s) 
The Investigator (s) undertake(s) the responsibility to perform the study following this 
Protocol, Good Clinical Practice, and the applicable regulatory requirements. The 
Investigator must ensure compliance with the investigational product schedule, visits 
schedule, and procedures required by the protocol. The Investigator agrees to provide all 
information requested in the Case Report Form (CRF) accurately and legibly. The Investigator 

PREDICT-CCM Study - Protocol v.1.2; 06-03-2025  
 
 
32 
may implement a deviation from or a change of the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior E.C. approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it, and, if appropriate, the proposed 
protocol amendment(s) should be submitted. The Investigator must have an adequate 
number of qualified staff and adequate facilities for the foreseen duration of the trial to 
conduct the trial properly and safely. 
 
Participant subjects 
Each subject may be enrolled after reviewing the relevant information and signing the 
informed consent forms for participation in the study and consent to process sensitive 
personal data. 
For retrospective subjects, the consent forms may be signed at the first contact following the 
installation of the CCM. 
 
 
Ethics Committee (E.C.) Approvals  
This clinical trial protocol, as well as the informed consent, are to be submitted to the 
appropriate Ethics Committee, and it is mandatory to obtain the written and dated approval, 
signed by the chairman with Ethics Committee(s) composition. 
The clinical trial, the documents reviewed, the list of voting members and their 
qualifications, and the review date should be clearly stated on the written Ethics Committee 
approval. 
 
 

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Bibliografia 
1 Levy D, Kenchaiah S, Glarson M, et al. Long-term trends in the incidence of and survival with 
heart failure. N Engl J Med 2002;347:1397-402. 
 
2 Savarese G, Becher P, Lund L, et al. Global burden of heart failure: a comprehensive and 
updated review of epidemiology, Cardiov Res, 2022; Vol 118, Issue 17: 3272–3287. 
 
3 Cleland JG, Daubert JC, Erdmann E, et al.; Cardiac Resynchronization-Heart Failure (CARE-
HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in 
heart failure. N Engl J Med 2005;352:1539-49. 
 
4 M. Glikson, J.C. Nielsen, M.B. Kronborg, et al. 2021 ESC Guidelines on cardiac pacing and 
cardiac resynchronization therapy. Eur Heart J, 42 (2021), pp. 3427-3520 
 
5 Campbell CM, Kahwash R, Abraham WT. Optimizer Smart in the treatment of moderate-to-
severe chronic heart failure. Future Cardiol 2020;16:13-25. 
 
6 Nägele H, Behrens S, et al. Cardiac contractility modulation in non-responders to cardiac 
resynchronization therapy. Europace. 2008 Dec;10(12):1375-80.  
 
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