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Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT04139460
Other study ID # University Hospital Olomouc
Secondary ID
Status Not yet recruiting
Phase N/A
First received
Last updated
Start date June 2020
Est. completion date January 2026

Study information

Verified date March 2020
Source University Hospital Olomouc
Contact Tomas Skala, MD, PhD
Phone +420 588 44 3212
Email tomasskala@gmail.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The ICD-Reality study is a non-commercial, investigator-led, multicenter, prospective, randomized, controlled trial. We aim to determine the effect of CRT-D or CRT-P implantation in non-ischemic cardiomyopathy and heart failure patients.

The reason why we initiated this trial is the lack of evidence-based treatment for the significant number of these patients. In these patients, 5-year mortality remains as high as 20% despite recent therapeutic advances. Based on currently available evidence, because of a significant decrease in mortality due to modern pharmacotherapy, it is not certain which of these patients should receive a CRT-P and who should receive a CRT-D. No dedicated and adequately powered trial has addressed this important question.

We hypothesize that patients with symptomatic HF, LVEF ≤35%, without left ventricular mid-wall fibrosis on LGE-CMR, will not benefit from CRT-D implantation compared with CRT-P only implantation.

If our hypothesis is confirmed, this could provide evidence for the management of these patients with a significant impact on common daily praxis and health care expenditures.

We aim to enroll 600 patients in the trial. 924 patients are needed to be screened for these 600 patients to be randomized.

Patients with non-ischemic HF visiting an out-patient department and possibly eligible for the trial will have their pharmacotherapy optimized.

Patients with a significant amount of fibrosis will be excluded from the study and treated according to local practice with an emphasis on ICD implantation to prevent SCD.

After fulfilling all eligibility criteria, including maximally tolerated pharmacotherapy, subjects will be randomized by the physicians who enrolled them in a 1:1 ratio to receive CRT-D or CRT-P implantation.

All patients will be followed-up for at least 3 years after the implantation.


Description:

The trial goals The ICD-Reality study is an investigator-led, multicenter, prospective, randomized, controlled trial. We aim to determine the effect of CRT-D or CRT-P implantation in non-ischemic cardiomyopathy and heart failure patients. The reason why we initiated this trial is the lack of evidence-based treatment for the significant number of these patients. In these patients, 5-year mortality remains as high as 20% despite recent therapeutic advances. Based on currently available evidence, because of a significant decrease in mortality due to modern pharmacotherapy, it is not certain which of these patients should receive an ICD. We hypothesize that patients with symptomatic HF, LVEF ≤35%, without left ventricular mid-wall fibrosis on LGE-CMR, will not benefit from CRT-D implantation compared with CRT-P only implantation. If our hypothesis is confirmed, this could provide evidence for the management of these patients with a significant impact on common daily praxis and health care expenditures.

Clinical hypothesis:

Patients with symptomatic HF, with LVEF ≤35% and without LV mid-wall fibrosis on late gadolinium enhancement cardiovascular magnetic resonance imaging (CMR), will not benefit from CRT-D implantation compared with CRT-P only implantation.

Estimated number of patients needed to be screened and randomized:

600 patients are needed to be randomized according to the study power analysis. Since 35 % of patients are estimated to be LG-E positive and thus excluded from randomization, 924 patients are needed to be screened.

Pre-screening:

Patients with non-ischemic HF visiting an out-patient department and possibly eligible for the trial will have their pharmacotherapy optimized. A screening visit in an out-patient department will be scheduled in 1-2 months after pharmacotherapy optimization since the qualifying LVEF and NT-proBNP level has to be measured after a maximal tolerated pharmacotherapy of heart failure has been achieved.

Screening:

After the signing of informed consent, screening examination will be performed. The informed consent will be obtained by attending physician in every center and a signed original will be stored in each individual center for the whole duration of the study. The screening examination will include medical history, documentation of underlying cardiac disease. The following co-morbidities will be specifically documented: peripheral arterial disease, cerebral vascular disease, pulmonary disease, diabetes mellitus, hypertension, sleep apnea, tobacco use, and any malignant disease within the last 5 years. Physical exam with vital signs, NYHA functional class, pulse rate, resting blood pressure will be performed. Cardiovascular pharmacological treatment will be documented. Standard laboratory parameters are recorded, including creatinine, estimated glomerular filtration rate, liver tests, TSH, NT-proBNP. Transthoracic echocardiography will be done to confirm LVEF ≤35% using biplane Simpson's method. Documented will be LV end-systolic and end-diastolic diameters and volumes, thickness of ventricular septum and LV posterior wall, stroke volume, cardiac output, indexed left atrial volume, presence and grade of valvular heart disease, right ventricle diameter, TAPSE, presence and grade of pulmonary hypertension. Selective coronarography will be performed if it was not done before to exclude patients with a severe coronary heart disease. LGE-CMR imaging will be performed by an operator blinded to all other clinical data to evaluate left ventricular mid-wall fibrosis.

Patients with a significant amount of fibrosis will be excluded from the study and treated according to local practice with an emphasis on ICD implantation to prevent SCD.

Randomization:

After fulfilling all eligibility criteria, including maximally tolerated pharmacotherapy, subjects will be randomized by the physicians who enrolled them in a 1:1 ratio to receive CRT-D or CRT-P implantation. Randomization will be carried out by physicians enrolling patients through a stand-alone web-based CRF managed by an independent biomedicine and statistics center, independent on all randomizing personnel. The web-CRF-based allocation sequence will be based on computer-generated random numbers and will be concealed until the type of intervention is assigned.

Treatment:

After randomization, devices will be implanted as soon as possible (within 2 weeks). The ICD will be programmed with anti-tachycardia pacing and shock therapy as per common praxis.

Follow-up:

All patients will be followed-up for at least 3 years after the implantation. After the implantation, all patients will be examined every 6 months in an out-patient department with the assessment of medical history, vital signs, physical exam, and NT-proBNP as in the screening visit. A device control will be performed every 6 months.

After device implantation the concomitant care and all possible concomitant interventions will be carried out as per common praxis.

Patients will be evaluated for possible end-points. Deaths and hospitalizations for heart failure, stroke or arrhythmias will be recorded throughout the study duration.

Quality of life (QoL) is assessed at baseline and annually during follow-up. Patients will fill out the SF-36 Questionnaire for general QoL, the MacNew Questionnaire for disease specific QoL.

An Endpoint Classification Committee will adjudicate hospitalizations and deaths for causality. An independent Data Monitoring Committee will periodically review mortality data throughout the study.

For safety reasons, all patients will be followed using a daily ECG monitoring and analysis. ECG from the Home-monitoring units will be evaluated in a dedicated center. This center will evaluate the ECGs sent from the Home-monitoring units with respect to patient safety and the study end-points. If the Home-monitoring unit reveals any rhythm disturbance they will contact the patient's physician and make a record in the CRF. If a sustained ventricular tachyarrhythmia is documented on a Home-monitoring in a CRT-P patient, a decision will be made and documented about a possible crossover to CRT-D as soon as possible.

Patients who will deviate from intervention protocols (e.g. crossover to CRT-D implantation) will continue to be followed-up.

Blinding:

Trial participants will be blinded to the device type for the whole duration of the trial.

The randomizing and implanting physicians will not be blinded to the type of the device. These physicians will not take care in the subsequent patients' follow-up and sign a declaration of confidentiality.

The same will be true for the physicians / technicians attending to the device interrogation during follow-up visits. The device type will be hidden and physicians will sign a declaration of confidentiality. The patients' documentation will not reveal the device type.

A maximum effort will be done to hide the type of the implanted device. The implantation will be intramuscular and the device interrogation follow-up visits will not reveal the device type.

The physicians attending the follow-up visits and entering all patients' data into web-based CRF will be blinded to the implanted device type.

In case of an emergency with a need to reveal the type of the device, i.e. lead fracture, infection in the place of implantation, ventricular tachycardia, the site principal investigator will decide to unblind the patient. This will be documented in the CRF.


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 924
Est. completion date January 2026
Est. primary completion date January 2026
Accepts healthy volunteers No
Gender All
Age group 18 Years to 99 Years
Eligibility Inclusion Criteria:

- = 18 years of age at the time of screening

- Documented non-ischemic HF with an LVEF = 35

- QRS=130ms; NYHA class II-IV

- Signed written informed consent

- NT-proBNP above 200 pg/ml

Exclusion Criteria:

- Uncorrected congenital heart disease or valve obstruction

- obstructive cardiomyopathy

- active myocarditis

- constrictive pericarditis

- untreated hypothyroidism or hyperthyroidism

- adrenal insufficiency

- active vasculitis due to collagen vascular disease

- Presence on the urgent waiting list for a heart transplant (UNOS category 1A or 1B, or equivalent)

- Patients on the non-urgent waiting list for a heart transplant (UNOS category 2 or 7, or equivalent) are eligible for inclusion in the study

- Recipient of any major organ transplant (e.g., lung, liver, heart)

- Receiving or has received cytotoxic or cytostatic chemotherapy and/or radiation therapy for treatment of a malignancy within 6 month before randomization or clinical evidence of current malignancy, with the following exceptions: basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, prostate cancer (if stable localized disease, with a life expectancy of > 2.5 years in the opinion of the investigator)

- Known to be human immunodeficiency virus positive with an expected survival of less than 5 years due to HIV

- Chronic kidney disease with glomerular filtration rate <30 ml/min

- Chronic dialysis treatment

- Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on self-report

- Any condition (e.g., psychiatric illness) or situation that, in the investigator's opinion, could put the subject at significant risk, confound the study results, or interfere significantly with the subject's participation in the study

- Unwilling to participate

Additional information related to inclusion and exclusion criteria:

- The qualifying LVEF and NT-proBNP level has to be measured after a maximal tolerated pharmacotherapy of heart failure has been achieved.

- A non-ischemic cause of HF has to be determined by coronary angiography. Patients could be included even if they will have one or two coronary arteries with stenosis, if the extent of coronary artery disease will not be considered to be sufficient to account for the reduced LVEF. Patients with a significant coronary heart disease (CAD) will be excluded.

- Patients with an existing conventional pacemaker could be included if they will be willing to have the device changed or upgraded.

- Patients with any form of atrial fibrillation will not be excluded.

Study Design


Intervention

Device:
CRT-D
After randomization, devices will be implanted as soon as possible (within 2 weeks). The ICD will be programmed with anti-tachycardia pacing and shock therapy as per common praxis.
CRT-P
After randomization, devices will be implanted as soon as possible (within 2 weeks).

Locations

Country Name City State
Czechia University hospital Olomouc Olomouc Ceská Republika

Sponsors (1)

Lead Sponsor Collaborator
University Hospital Olomouc

Country where clinical trial is conducted

Czechia, 

References & Publications (23)

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Barra S, Providência R, Boveda S, Duehmke R, Narayanan K, Chow AW, Piot O, Klug D, Defaye P, Gras D, Deharo JC, Milliez P, Da Costa A, Mondoly P, Gonzalez-Panizo J, Leclercq C, Heck P, Virdee M, Sadoul N, Le Heuzey JY, Marijon E. Device complications with addition of defibrillation to cardiac resynchronisation therapy for primary prevention. Heart. 2018 Sep;104(18):1529-1535. doi: 10.1136/heartjnl-2017-312546. Epub 2018 Mar 14. — View Citation

Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004 May 20;350(21):2140-50. — View Citation

Dichtl W, Wolber T, Paoli U, Brüllmann S, Stühlinger M, Berger T, Spuller K, Strasak A, Pachinger O, Haegeli LM, Duru F, Hintringer F. Appropriate therapy but not inappropriate shocks predict survival in implantable cardioverter defibrillator patients. Clin Cardiol. 2011 Jul;34(7):433-6. doi: 10.1002/clc.20910. Epub 2011 Jun 15. — View Citation

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Dixon T, Lim LL, Oldridge NB. The MacNew heart disease health-related quality of life instrument: reference data for users. Qual Life Res. 2002 Mar;11(2):173-83. — View Citation

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Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000 Apr 13;342(15):1077-84. — View Citation

Gart JJ, Nam J. Approximate interval estimation of the ratio of binomial parameters: a review and corrections for skewness. Biometrics. 1988 Jun;44(2):323-38. Review. — View Citation

Gart JJ, Nam JM. Approximate interval estimation of the difference in binomial parameters: correction for skewness and extension to multiple tables. Biometrics. 1990 Sep;46(3):637-43. Erratum in: Biometrics 1992 Sep;48(3):979. — View Citation

Gulati A, Jabbour A, Ismail TF, Guha K, Khwaja J, Raza S, Morarji K, Brown TD, Ismail NA, Dweck MR, Di Pietro E, Roughton M, Wage R, Daryani Y, O'Hanlon R, Sheppard MN, Alpendurada F, Lyon AR, Cook SA, Cowie MR, Assomull RG, Pennell DJ, Prasad SK. Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA. 2013 Mar 6;309(9):896-908. doi: 10.1001/jama.2013.1363. Erratum in: JAMA. 2013 Jul 3;310(1):99. — View Citation

Haugaa KH, Tilz R, Boveda S, Dobreanu D, Sciaraffia E, Mansourati J, Papiashvili G, Dagres N. Implantable cardioverter defibrillator use for primary prevention in ischaemic and non-ischaemic heart disease-indications in the post-DANISH trial era: results of the European Heart Rhythm Association survey. Europace. 2017 Apr 1;19(4):660-664. doi: 10.1093/europace/eux089. — View Citation

Hawkins NM, Grubisic M, Andrade JG, Huang F, Ding L, Gao M, Bashir J. Long-term complications, reoperations and survival following cardioverter-defibrillator implant. Heart. 2018 Feb;104(3):237-243. doi: 10.1136/heartjnl-2017-311638. Epub 2017 Jul 26. — View Citation

Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A, Levine JH; Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004 May 20;350(21):2151-8. — View Citation

Køber L, Thune JJ, Nielsen JC, Haarbo J, Videbæk L, Korup E, Jensen G, Hildebrandt P, Steffensen FH, Bruun NE, Eiskjær H, Brandes A, Thøgersen AM, Gustafsson F, Egstrup K, Videbæk R, Hassager C, Svendsen JH, Høfsten DE, Torp-Pedersen C, Pehrson S; DANISH Investigators. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med. 2016 Sep 29;375(13):1221-30. doi: 10.1056/NEJMoa1608029. Epub 2016 Aug 27. — View Citation

Kutyifa V, Geller L, Bogyi P, Zima E, Aktas MK, Ozcan EE, Becker D, Nagy VK, Kosztin A, Szilagyi S, Merkely B. Effect of cardiac resynchronization therapy with implantable cardioverter defibrillator versus cardiac resynchronization therapy with pacemaker on mortality in heart failure patients: results of a high-volume, single-centre experience. Eur J Heart Fail. 2014 Dec;16(12):1323-30. doi: 10.1002/ejhf.185. Epub 2014 Nov 7. — View Citation

Petrie MC, Connelly DT, Gardner RS. Who needs an implantable cardioverter-defibrillator? Controversies and opportunities after DANISH. Eur J Heart Fail. 2018 Mar;20(3):413-416. doi: 10.1002/ejhf.1135. Epub 2018 Jan 12. — View Citation

Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members; Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016 Aug;18(8):891-975. doi: 10.1002/ejhf.592. Epub 2016 May 20. — View Citation

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* Note: There are 23 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Re-hospitalization for heart failure Event rate 0-3 years after device implantation
Primary Ventricular tachycardia Event rate, sustained ventricular tachycardia documentation during follow-up 0-3 years after device implantation
Primary Major adverse cardiac events (MACE) Event rate of MACE, defined as a composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death 0-3 years after device implantation
Secondary Sudden cardiac death Event rate of sudden cardiac death 0-3 years after device implantation
Secondary Cardiovascular death Event rate of cardiovascular death 0-3 years after device implantation
Secondary Resuscitated cardiac arrest or sustained ventricular tachycardia Event rate of resuscitated cardiac arrest or sustained ventricular tachycardia 0-3 years after device implantation
Secondary Device-related complications Event rate of any complication requiring hospitalization 0-3 years after device implantation
Secondary The impact in terms of overall quality of life by the SF-36 Questionnaire The SF-36 measures eight scales: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100. The lower the score the more disability. The higher the score the less disability. 3 years after device implantation
Secondary The impact in terms of overall quality of life by the MacNew Questionnaire The MacNew consists of 27 items which fall into three domains: 13-item physical limitations domain scale, 14-item emotional function domain scale, 13-item social function domain scale. The maximum possible score in any domain is 7 (high QoL). The minimum is 1 (low QoL). Missing responses do not contribute to the score. 3 years after device implantation