Randomized Open-label Single-center Trial on Remote Assistance Implementing Certified Specialized Engineers During Interventional Cardiology Procedures
Phase: NA
Conditions: Telemedicine, Heart Failure, Defibrillators
Sponsor: University of Calabria

Study Protocol and Statistical Analysis 
Plan 
 
Official Study Title: 
Electronic Device Implantation Through Remote Guidance 
Unique Protocol ID:  
#224 
NCT Number:  
NCT06404021 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Document Date:  
17 June 2021 
Version: 1.0 
 
 
 
 
 
 
 
 
 
 
 

Table of Contents 
1. Introduction 
2. Background and Rationale 
3. Objectives 
4. Study Design 
5. Study Population 
6. Inclusion and Exclusion Criteria 
   6.1 Inclusion Criteria 
   6.2 Exclusion Criteria 
7. Intervention and Procedures 
   7.1 Standard Procedure Description 
   7.2 Remote Support Technical Setup 
   7.3 Real-time Interaction and Safety Measures 
8. Data Collection and Management 
   8.1 Case Report Form (CRF) Elements 
   8.2 Data Privacy and Storage 
9. Outcome Measures 
   9.1 Primary Endpoint Definition and Description 
10. Statistical Analysis Plan 
   10.1 Descriptive and Inferential Analysis 
   10.2 Longitudinal Parameter Evaluation 
   10.3 Missing Data and Sensitivity Analysis 
11. Ethical and Regulatory Considerations 
12. Risk Management 
13. Dissemination Plan 
 
 
 
 

List of Abbreviations 
 
- CRP: C-reactive protein 
- CRT-D: Cardiac Resynchronization Therapy with Defibrillator 
- CT: Computed Tomography 
- ECG: Electrocardiogram 
- EP: Electrophysiology 
- EU: European Union 
- FCS: Field Clinical Specialist 
- HF: Heart Failure 
- ICD: Implantable Cardioverter-Defibrillator 
- IQR: Interquartile Range 
- INR: International Normalized Ratio 
- LVEF: Left Ventricular Ejection Fraction 
- NYHA: New York Heart Association 
- RM: Remote Monitoring 
- SCD: Sudden Cardiac Death 
- SD: Standard Deviation 
- S-ICD: Subcutaneous Implantable Cardioverter-Defibrillator 
- TV-ICD: Transvenous ICD 
 
 
 
 
 
 
 
 
 
 
 

1. Introduction  
Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, 
with sudden cardiac death (SCD) and heart failure (HF) representing major clinical and 
economic burdens. Implantable Cardioverter Defibrillators (ICDs) and Cardiac 
Resynchronization Therapy with Defibrillator (CRT-D) devices are evidence-based 
therapies that have significantly improved survival in patients with systolic dysfunction and 
electrical dyssynchrony. 
The standard practice of device implantation relies heavily on the presence of a Field 
Clinical Specialist (FCS), a biomedical engineer who provides intraoperative technical 
support. However, the physical presence of FCS personnel is not always feasible, especially 
in rural areas or during public health emergencies such as the COVID-19 pandemic. In this 
context, telemedicine represents a potentially transformative approach to decentralize 
technical expertise and make advanced cardiac care more accessible. 
This protocol describes a structured, stepwise investigation to assess whether remote FCS 
guidance can safely and effectively substitute the in-person presence during ICD and CRT-D 
implantation procedures. 
2. Background and Rationale  
The implantation of ICD and CRT-D devices involves complex decision-making and precise 
programming of leads and generators, for which collaboration between electrophysiologists 
and FCS personnel is considered standard of care. Remote monitoring (RM) of implanted 
devices has already demonstrated safety, efficiency, and improved clinical outcomes post-
discharge. However, little is known about the application of telemedicine during the 
implantation phase. 
This knowledge gap is particularly significant in healthcare systems with limited resources 
or geographic barriers, where the availability of expert personnel cannot be always 
guaranteed. Telemedicine systems that enable real-time audiovisual communication, device 
programming, and procedural support may offer a safe, cost-effective alternative, but 
require formal validation. 
In this study, we propose a three-phase approach, including preclinical simulation, phantom 
testing, and randomized controlled patient enrollment, to evaluate the feasibility and safety 
of remotely guided ICD/CRT-D implantation. 
3. Objectives 
• 
To evaluate the feasibility and procedural success rate of ICD and CRT-D 
implantations performed under real-time remote guidance by a FCS. 
o 
To assess differences in total EP lab occupancy time (minutes). 
o 
To compare fluoroscopy time (minutes) as a marker of radiation exposure. 

o 
To evaluate the technical stability of implanted device parameters (voltage, 
impedance, amplitude). 
o 
To document any procedural complications or need for reintervention. 
4. Study Design  
This is a prospective, randomized, controlled pilot study with a 2:1 allocation ratio. After 
initial validation phases (simulator and phantom), thirty patients will be randomized to: 
• 
Control group: Standard implantation with FCS physically present in the EP lab. 
• 
Intervention group: Implantation conducted with the FCS providing remote 
audiovisual guidance. 
Randomization will be stratified by device type (ICD, CRT-D, S-ICD) to ensure balance 
between groups. 
5. Study Population  
Patients scheduled for ICD or CRT-D implantation at the Cardiology Units of the Academic 
Hospital “Annunziata” in Cosenza and Academic Hospital “Renato-Dulbecco” in Catanzaro 
will be screened. All participants will be asked to sign informed consent prior to inclusion. 
6. Inclusion and Exclusion Criteria  
Inclusion Criteria: 
• 
Age: 18–85 years. 
• 
Indication for de novo ICD or CRT-D implantation according to ESC Guidelines. 
o 
Primary prevention of SCD with LVEF ≤ 35% (measured by 
echocardiography, Simpson biplane method) and NYHA class II or III, on 
optimal medical therapy for at least 3 months. 
o 
Secondary prevention in survivors of cardiac arrest due to ventricular 
fibrillation or sustained ventricular tachycardia. 
o 
Indication for CRT-D: LVEF ≤ 35%, QRS duration ≥ 130 ms, preferably with 
left bundle branch block morphology, and NYHA II–IV symptoms. 
• 
Written informed consent signed. 
Exclusion Criteria: 
• 
Permanent pacemaker dependency requiring tailored programming strategies. 
• 
Previous device implant with generator replacement only. 

• 
Active infection or systemic inflammation defined by the presence of at least one of 
the following: 
o 
C-reactive protein (CRP) >10 mg/L 
o 
Body temperature >37.5°C 
o 
Clinical signs of systemic inflammation (e.g., leukocytosis >12,000/mm³ or 
leukopenia <4,000/mm³) 
o 
Suspected or confirmed sepsis as per Sepsis-3 criteria: an increase in SOFA 
score ≥2 points from baseline and confirmed or suspected infection, 
supported by imaging (e.g., pulmonary infiltrates on chest X-ray, abscess on 
ultrasound/CT) or microbiological tests. 
• 
Participation in other investigational studies that may interfere with this protocol. 
• 
Pregnancy or lactation. 
• 
Cognitive or psychiatric impairment interfering with consent or adherence. 
• 
Severe coagulopathy (INR >2.5 without correctable cause). 
7. Intervention and Procedures  
Each procedure will follow the standard protocol for device implantation. In the control 
arm, the FCS will operate in person, while in the intervention arm, the FCS will be connected 
through a secured video/audio system using high-definition PTZ cameras, screen sharing 
from the programmer, and real-time communication. 
Procedural steps include: 
• 
Venous access (usually via left or right subclavian or cephalic vein). 
• 
Lead positioning under fluoroscopic guidance. 
• 
Intraoperative testing: pacing threshold (V), sensing amplitude (mV), impedance 
(Ohm). 
• 
Generator placement and programming. 
• 
Wound closure and sterile dressing. 
Total EP lab occupancy time and skin-to-skin procedural duration will be recorded. 
8. Data Collection and Management  
A case report form (CRF) will be compiled for each participant. Collected data include: 
• 
Demographics, clinical history, and indication for implantation. 

• 
Intraoperative data: lead model, positioning, parameter values (e.g., ventricular 
threshold in V, impedance in Ohm). 
• 
Adverse events and complications. 
• 
Remote monitoring reports at 1 and 6 months. 
Data will be pseudonymized and stored in a secure, password-protected database. Data 
protection will comply with GDPR and institutional guidelines. 
9. Outcome Measures: 
• 
Procedural success: defined as completion of the device implantation with 
acceptable electrical parameters: 
o 
Atrial threshold <1.0 V at 0.5 ms pulse width 
o 
Right ventricular threshold <1.0 V at 0.5 ms 
o 
Atrial sensing >1.0 mV; ventricular sensing >5.0 mV 
o 
Lead impedance 300–1500 Ohm 
o 
LV threshold (for CRT-D) <2.5 V at 0.5 ms with confirmed biventricular 
pacing on ECG 
• 
EP lab occupancy time: measured in minutes from patient entry to exit. 
• 
Fluoroscopy time: total duration in minutes of x-ray exposure during the 
implantation. 
• 
Procedural complications: 
o 
Lead dislodgement confirmed by chest x-ray or electrical changes 
o 
Pocket hematoma requiring intervention 
o 
Infection requiring antibiotic therapy or reintervention 
o 
Generator malfunction 
• 
Parameter stability at follow-up: 
o 
Variation in pacing thresholds, impedance, and sensing values over time 
o 
Defined as Δ parameter < ±20% from baseline 
• 
Remote monitoring performance: 
o 
Number of successful data transmissions 

o 
Device alerts and clinical actions triggered 
10. Statistical Analysis Plan  
The statistical analysis of this pilot study is designed to explore the feasibility and 
preliminary outcomes associated with remote versus standard FCS-guided ICD/CRT-D 
implantation. All data will be analyzed using IBM SPSS Statistics version 23.0. 
Descriptive statistics will be used to summarize the overall sample characteristics. 
Continuous variables (e.g., fluoroscopy time, procedural duration, electrical parameters) 
will be described using means and standard deviations (SD) if normally distributed, or 
medians and interquartile ranges (IQR) otherwise. Categorical variables (e.g., procedural 
success, complications) will be reported as absolute frequencies and percentages. 
Normality of continuous variables will be assessed with the Shapiro–Wilk test. 
Homogeneity of variances will be verified using Levene’s test. 
For group comparisons: 
• 
Unpaired Student’s t-test will be used for continuous variables with normal 
distribution. 
• 
Mann–Whitney U test will be used for non-normally distributed continuous 
variables. 
• 
Chi-square test or Fisher’s exact test will be applied for categorical variables, 
depending on expected frequencies. 
In addition, longitudinal evaluation of device parameters (e.g., thresholds and impedances) 
from baseline to follow-up (1 and 6 months) will be analyzed using repeated measures 
ANOVA for normally distributed variables or the Friedman test for non-parametric 
distributions. 
To enhance the robustness of findings, particularly given the limited sample size, bootstrap 
resampling with 5,000 iterations will be used to generate empirical confidence intervals 
(95% CI) around key estimates. 
A two-sided p-value <0.05 will be considered statistically significant. Effect sizes (e.g., 
Cohen’s d or rank biserial correlation) will be reported where appropriate to aid 
interpretation. 
Missing data will be handled through complete-case analysis. If the rate of missingness 
exceeds 5% for any primary variable, a sensitivity analysis will be performed using multiple 
imputation to explore the potential impact on results. 
All analyses will be exploratory in nature given the pilot status of the trial, and the results 
will be used to inform sample size calculations for future larger-scale studies. 

11. Ethical and Regulatory Considerations  
The protocol has been reviewed and approved by the institutional ethics board. All 
participants will sign an informed consent form. The study adheres to the Declaration of 
Helsinki and Regulation EU 679/2016. 
12. Risk Management  
The technical risk is minimized by preclinical testing and in-hospital presence of the FCS, 
even in remote procedures. All personnel are trained. Backup systems (local programmers, 
redundant connections) are in place. Defibrillation testing will only occur in patients where 
clinically indicated and with on-site FCS. 
13. Dissemination Plan  
Results will be submitted to peer-reviewed journals. Participants will be offered a summary 
of the findings on request.