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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03588286




Registration number
NCT03588286
Ethics application status
Date submitted
4/07/2018
Date registered
17/07/2018
Date last updated
2/10/2019

Titles & IDs
Public title
Programmed Ventricular Stimulation to Risk Stratify for Early Cardioverter-Defibrillator (ICD) Implantation to Prevent Tachyarrhythmias Following Acute Myocardial Infarction (PROTECT-ICD)
Scientific title
Programmed Ventricular Stimulation to Risk Stratify for Early Cardioverter-Defibrillator (ICD) Implantation to Prevent Tachyarrhythmias Following Acute Myocardial Infarction (PROTECT-ICD)
Secondary ID [1] 0 0
PROTECT-ICD, Version 4
Universal Trial Number (UTN)
Trial acronym
PROTECT-ICD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sudden Cardiac Death 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases
Cardiovascular 0 0 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Surgery - Electrophysiology study (EPS)
Other interventions - Standard Care
Treatment: Surgery - Cardiac Magnetic Resonance (CMR)

Experimental: Intervention Arm (Early EPS) - The intervention group all undergo electrophysiologic study early after myocardial infarction (within 40 days of MI).
If the study is positive (inducible monomorphic ventricular tachycardia of cycle length greater than or equal to 200ms) participants have an ICD implanted. Participants with a negative study (no inducible arrhythmia or induced ventricular fibrillation/ ventricular flutter cycle length <200ms) are discharged without an ICD.
A proportion of trial patients from both the intervention and control arms at >48 hours following revascularisation for STEMI will undergo CMR to enable correlation with (1) inducible VT at EPS and (2) SCD and non-fatal arrhythmia on follow up. CMR will simultaneously assess left ventricular function, ventricular strain, myocardial infarction size, and peri-infarction injury.

Active Comparator: Control Arm (Standard Care) - The control group receive ongoing standard care according to the practise of their institution. This includes discharge from hospital as per their treating physician and follow up as usual in the community. Participants in this group would be eligible to receive an ICD according to the standard practise of their cardiologist (guideline recommendations are after 40 days following myocardial infarction or 90 days following revascularisation only in patients with left ventricular ejection fraction less than or equal to 30% or less than or equal to 35% in the presence of heart failure).
A proportion of trial patients from both the intervention and control arms at >48 hours following revascularisation for STEMI will undergo CMR to enable correlation with (1) inducible VT at EPS and (2) SCD and non-fatal arrhythmia on follow up. CMR will simultaneously assess left ventricular function, ventricular strain, myocardial infarction size, and peri-infarction injury.


Treatment: Surgery: Electrophysiology study (EPS)
EPS will be performed in all patients in the intervention arm with programmed ventricular stimulation with a drive train of 8 beats at 400 ms with up to 4 extrastimuli and stimulation from the right ventricular apex with current delivered at twice pacing threshold. The end point for stimulation will be sustained monomorphic ventricular tachycardia (VT) lasting > 10 seconds. If sustained monomorphic VT with cycle length (CL) =200ms is induced by =4 extra stimuli the EPS result will be considered positive for inducible VT.30 Ventricular fibrillation or flutter with CL<200ms will be considered a negative result. The Programmed Ventricular Stimulation (PVS) induction will be repeated a second time if the initial induction was negative for VT.

Other interventions: Standard Care
The control group receive ongoing standard care according to the practise of their institution. This includes discharge from hospital as per their treating physician and follow up as usual in the community. Participants in this group would be eligible to receive an ICD according to the standard practise of their cardiologist (guideline recommendations are after 40 days following myocardial infarction or 90 days following revascularisation only in patients with left ventricular ejection fraction less than or equal to 30% or less than or equal to 35% in the presence of heart failure).

Treatment: Surgery: Cardiac Magnetic Resonance (CMR)
CMR will be performed on either a 1.5-T or 3-T scanner. Gadolinium contrast (Gd-BOPTA, MultihanceTM) will be administered for quantification myocardial perfusion imaging with subsequent late gadolinium enhanced imaging after a total dose of 0.1mmol/kg. Exclusion criteria specific for CMR will include pregnancy, renal insufficiency defined as glomerular filtration rate (GFR) <30 mL/min, contraindication to MRI (including non-MRI compatible pacemaker/ICD or metal implants, non-MR safe prosthetic heart valves), claustrophobia which cannot be controlled via standard methods (benzodiazepines and/or sedative antihistamine administration) and prior allergic reaction to gadolinium-based contrast agent.

Intervention code [1] 0 0
Treatment: Surgery
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Sudden cardiac death - Cause of death will be determined based on information obtained from witnesses, family members, death certificates, hospital records and autopsy or coroner reports. Sudden cardiac death will be explicitly defined as death that occurs "suddenly and unexpectedly" in a patient in otherwise stable condition and includes witnessed instantaneous deaths (with or without documentation of arrhythmia), unwitnessed deaths if the patient had been seen within 24 hours before death (in the absence of another clear cause of death), deaths caused by incessant ventricular tachyarrhythmia, deaths considered a sequel of cardiac arrest and deaths resulting from pro-arrhythmia of anti-arrhythmic drugs.31 The remainder of deaths will be classified as either non-sudden cardiovascular death, or non-cardiovascular death. Operative deaths associated with the implantation of an ICD will be counted as non-sudden cardiovascular death.
Timepoint [1] 0 0
2 years after randomisation
Primary outcome [2] 0 0
Non-fatal arrhythmia - Non-fatal arrhythmia includes resuscitated cardiac arrest, sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) in participants without an ICD. Resuscitated cardiac arrest is defined as a sudden circulatory arrest requiring cardiopulmonary resuscitation (CPR) (with or without documented arrhythmia) from which the patient regains consciousness. VT and VF are defined as ECG or telemetry-documented ventricular tachycardia or ventricular fibrillation. Only sustained ventricular tachycardia will be included (greater than 30 seconds of VT) or if the VT required emergency treatment with anti-arrhythmic medications or electrical cardioversion.
Timepoint [2] 0 0
2 years after randomisation
Secondary outcome [1] 0 0
All-cause mortality - All deaths.
Timepoint [1] 0 0
2 years after randomisation
Secondary outcome [2] 0 0
Non-sudden cardiovascular death - Non-sudden cardiovascular deaths will be classified as death due to myocardial infarction, heart failure or another cardiovascular cause including cerebrovascular or peripheral vascular causes.
Timepoint [2] 0 0
2 years after randomisation
Secondary outcome [3] 0 0
Non-fatal repeat MI - Non-fatal repeat MI requires the presence of two of the following three: symptoms of myocardial ischaemia, a characteristic rise and fall in cardiac markers and a typical ECG pattern involving the development of Q waves or persistent T wave changes.
Timepoint [3] 0 0
2 years after randomisation
Secondary outcome [4] 0 0
Heart failure - Heart failure is defined as symptoms or signs consistent with congestive heart failure with use of intravenous decongestive therapy greater than 2 hours (IV diuretics, IV nesiritide, IV inotropes) in a patient not requiring hospital admission, or, augmented heart failure regimen with oral or intravenous medications in patients requiring hospital admission.
Timepoint [4] 0 0
2 years after randomisation
Secondary outcome [5] 0 0
Inappropriate ICD denial - Inappropriate ICD denial will be defined as patients who did not receive an ICD based on their intervention allocation, who went on to have documented non-fatal arrhythmia or sudden cardiac death.
Timepoint [5] 0 0
2 years after randomisation
Secondary outcome [6] 0 0
Appropriate ICD activations (in patients with ICD) - Appropriate ICD activation will be defined as ventricular tachyarrhythmia due to VT which meets the treatment criteria defined above or VF.
Timepoint [6] 0 0
2 years after randomisation
Secondary outcome [7] 0 0
Inappropriate ICD activations (in patients with ICD) - Inappropriate ICD activations will include supra-ventricular tachycardia, atrial fibrillation/flutter, T wave over-sensing, sinus tachycardia and noise from lead complications or extraneous noise.
Timepoint [7] 0 0
2 years after randomisation
Secondary outcome [8] 0 0
Complications or re-hospitalisation associated with ICD implantation (in patients with ICD) - Complications or re-hospitalisation associated with ICD implantation (in patients with ICD)
Timepoint [8] 0 0
2 years after randomisation

Eligibility
Key inclusion criteria
- 2-40 days (inclusive) following a myocardial infarct

- Impaired left ventricular systolic function (LVEF=40% or at least moderately impaired)
Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age <18 or >85;

2. Pregnancy;

3. Nursing home resident dependent on one or more activities of daily living;

4. Significant non-cardiac co-morbidity with high likelihood of death within 1 year (this
would include any metastatic malignancy, or other terminal disease);

5. Significant psychiatric illnesses that may be aggravated by device implantation or
that may preclude regular follow up;

6. Intravenous drug abuse (ongoing);

7. Unresolved infection associated with risk for hematogenous seeding;

8. Pre-existing implantable cardioverter-defibrillator (ICD);

9. Secondary prevention indication for an ICD (i.e. sustained ventricular arrhythmias
occurring more than 48 hours after qualifying myocardial infarction (patients with
ventricular arrhythmias occurring =48 hours of myocardial infarction, or with
non-sustained ventricular tachycardia at any time, are not excluded));

10. On the heart transplant list;

11. Recurrent unstable angina despite revascularisation (defined as ongoing chest pain or
ischemic symptoms at rest or with minimal exertion despite adequate treatment with
anti-anginal medications);**

12. Congestive heart failure New York Heart Association class IV, defined as shortness of
breath at rest, which is refractory to medical treatment (not responding to
treatment)** **NOTE: patients who meet exclusion based on (11) or (12) can be reviewed
again in 2-3 days and if symptoms have resolved or treatment performed can be
re-considered for inclusion.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,VIC
Recruitment hospital [1] 0 0
Canberra Hospital - Garran
Recruitment hospital [2] 0 0
Nepean Hospital - Kingswood
Recruitment hospital [3] 0 0
John Hunter Hospital - New Lambton Heights
Recruitment hospital [4] 0 0
Prince of Wales Hospital - Randwick
Recruitment hospital [5] 0 0
Royal North Shore Hospital - Saint Leonards
Recruitment hospital [6] 0 0
Westmead Hospital - Westmead
Recruitment hospital [7] 0 0
Wollongong Hospital - Wollongong
Recruitment hospital [8] 0 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [9] 0 0
Carins Hospital - Cairns
Recruitment hospital [10] 0 0
The Prince Charles Hospital - Chermside
Recruitment hospital [11] 0 0
The Townsville Hospital - Douglas
Recruitment hospital [12] 0 0
Royal Brisbane and Women's Hospital - Herston
Recruitment hospital [13] 0 0
Gold Coast University Hospital - Southport
Recruitment hospital [14] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [15] 0 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [16] 0 0
MonashHeart - Clayton
Recruitment hospital [17] 0 0
Northern Hospital - Epping
Recruitment hospital [18] 0 0
Footscray Hospital - Footscray
Recruitment hospital [19] 0 0
Austin Hospital - Heidelberg
Recruitment hospital [20] 0 0
Sunshine Hospital - Saint Albans
Recruitment postcode(s) [1] 0 0
2605 - Garran
Recruitment postcode(s) [2] 0 0
2747 - Kingswood
Recruitment postcode(s) [3] 0 0
2305 - New Lambton Heights
Recruitment postcode(s) [4] 0 0
2031 - Randwick
Recruitment postcode(s) [5] 0 0
2065 - Saint Leonards
Recruitment postcode(s) [6] 0 0
2145 - Westmead
Recruitment postcode(s) [7] 0 0
2500 - Wollongong
Recruitment postcode(s) [8] 0 0
4575 - Birtinya
Recruitment postcode(s) [9] 0 0
4870 - Cairns
Recruitment postcode(s) [10] 0 0
4032 - Chermside
Recruitment postcode(s) [11] 0 0
4814 - Douglas
Recruitment postcode(s) [12] 0 0
4029 - Herston
Recruitment postcode(s) [13] 0 0
4215 - Southport
Recruitment postcode(s) [14] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [15] 0 0
5112 - Elizabeth Vale
Recruitment postcode(s) [16] 0 0
3168 - Clayton
Recruitment postcode(s) [17] 0 0
3076 - Epping
Recruitment postcode(s) [18] 0 0
3011 - Footscray
Recruitment postcode(s) [19] 0 0
3084 - Heidelberg
Recruitment postcode(s) [20] 0 0
3021 - Saint Albans
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Massachusetts
Country [2] 0 0
Czechia
State/province [2] 0 0
Prague
Country [3] 0 0
Germany
State/province [3] 0 0
Bad Neustadt An Der Saale
Country [4] 0 0
Germany
State/province [4] 0 0
Brandenburg
Country [5] 0 0
Germany
State/province [5] 0 0
Leipzig
Country [6] 0 0
Hungary
State/province [6] 0 0
Budapest
Country [7] 0 0
Latvia
State/province [7] 0 0
Riga
Country [8] 0 0
Malaysia
State/province [8] 0 0
Kuala Lumpur
Country [9] 0 0
New Zealand
State/province [9] 0 0
Auckland
Country [10] 0 0
New Zealand
State/province [10] 0 0
Hamilton
Country [11] 0 0
New Zealand
State/province [11] 0 0
Wellington
Country [12] 0 0
Poland
State/province [12] 0 0
Lódz
Country [13] 0 0
Russian Federation
State/province [13] 0 0
Saint Petersburg
Country [14] 0 0
Russian Federation
State/province [14] 0 0
Samara
Country [15] 0 0
Singapore
State/province [15] 0 0
Singapore
Country [16] 0 0
Slovakia
State/province [16] 0 0
Bratislava
Country [17] 0 0
Switzerland
State/province [17] 0 0
Basel
Country [18] 0 0
Switzerland
State/province [18] 0 0
Bern
Country [19] 0 0
Switzerland
State/province [19] 0 0
Lausanne

Funding & Sponsors
Primary sponsor type
Other
Name
Western Sydney Local Health District
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The PROTECT-ICD trial is a physician-led, multi-centre randomised controlled trial targeting
prevention of sudden cardiac death in patients who have poor cardiac function following a
myocardial infarct (MI). The trial aims to assess the role of electrophysiology study (EPS)
in guiding implantable cardioverter-defibrillator (ICD) implantation, in patients early
following MI (first 40 days). The secondary aim is to assess the utility of cardiac MRI (CMR)
in analysing cardiac function and viability as well as predicting inducible and spontaneous
ventricular tachyarrhythmia when performed early post MI.

Following a MI patients are at high risk of sudden cardiac death (SCD). The risk is highest
in the first 40 days; however, current guidelines exclude patients from receiving an ICD
during this time. This limitation is based largely on a single study, The Defibrillator in
Acute Myocardial Infarction Trial (DINAMIT), which failed to demonstrate a benefit of early
ICD implantation. However, this study was underpowered and used non-invasive tests to
identify patients at high risk. EPS identifies patients with the substrate for re-entrant
tachyarrhythmia, and has been found in multiple studies to predict patients at risk of SCD.
Contrast-enhanced CMR is a non-invasive test without radiation exposure which can be used to
assess left ventricular function. In addition, it provides information on myocardial
viability, scar size and tissue heterogeneity. It has an emerging role as a predictor of
mortality and spontaneous ventricular arrhythmia in patients with a previous MI.

A total of 1,058 patients who are at high risk of SCD based on poor cardiac function (left
ventricular ejection fraction (LVEF) =40%) following a ST-elevation or non-STE myocardial
infarct will be enrolled in the trial. Patients will be randomised 1:1 to either the
intervention or control arm.

In the intervention arm all patients undergo early EPS. Patients with a positive study
(inducible ventricular tachycardia cycle length =200ms) receive an ICD, while patients with a
negative study (inducible ventricular fibrillation or no inducible VT) are discharged without
an ICD, regardless of the LVEF.

In the control arm patients are treated according to standard local practice. This involves
early discharge and repeat assessment of cardiac function after 40 days or after 90 days
following revascularisation (PCI or CABG). ICD implantation after 40 days according to
current guidelines (LVEF=30%, or =35% with New York Heart Association (NYHA) class II/III
symptoms) could be considered, if part of local standard practice, however the ICD is not
funded by the trial.

A proportion of trial patients from both the intervention and control arms at >48 hours
following MI will undergo CMR to enable correlation with (1) inducible VT at EPS and (2) SCD
and non-fatal arrhythmia on follow up. It will be used to simultaneously assess left
ventricular function, ventricular strain, myocardial infarction size, and peri-infarction
injury. The size of the infarct core, infarct gray zone (as a measure of tissue
heterogeneity) and total infarct size will be quantified for each patient.

All patients will be followed for 2 years with a combined primary endpoint of non-fatal
arrhythmia and SCD. Non-fatal arrhythmia includes resuscitated cardiac arrest, sustained
ventricular tachycardia (VT) and ventricular fibrillation (VF) in participants without an
ICD. Secondary endpoints will include all-cause mortality, non-sudden cardiovascular death,
non-fatal repeat MI, heart failure and inappropriate ICD denial. Secondary endpoints for CMR
correlation will include (1) the presence or absence of inducible VT at EP study, and (2)
combined endpoint of appropriate ICD activation or SCD at follow up.

It is anticipated that the intervention arm will reduce the primary endpoint as a result of
prevention of a) early sudden cardiac deaths/cardiac arrest, and b) sudden cardiac
death/cardiac arrest in patients with a LVEF of 31-40%. It is expected that the 2-year
primary endpoint rate will be reduced from 6.7% in the control arm to 2.8% in the
intervention arm with a relative risk reduction (RRR) of 68%. A two-group chi-squared test
with a 0.05 two-sided significance level will have 80% power to detect the difference between
a Group 1 proportion of 0.028 experiencing the primary endpoint and a Group 2 proportion of
0.067 experiencing the primary endpoint when the sample size in each group is 470. Assuming
1% crossover and 10% loss to follow up the required sample size is 1,058 (n=529 patients per
arm). To test the hypothesis that tissue heterogeneity at CMR predicts both inducible and
spontaneous ventricular tachyarrhythmias will require a sample size of 400 patients to
undergo CMR.

It is anticipated that the use of EPS will select a group of patients who will benefit from
an ICD soon after a MI. This has the potential to change clinical guidelines and save a large
number of lives.
Trial website
https://clinicaltrials.gov/show/NCT03588286
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Study Principal Investigator Study Principal Investigator
Address 0 0
Western Sydney Local Health District
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Pramesh Kovoor
Address 0 0
Country 0 0
Phone 0 0
+61 2 8890 6030
Fax 0 0
Email 0 0
pramesh.kovoor@sydney.edu.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03588286