Clinical trial NCT03494933: Re-evaluation of Optimal Re-synchronisation Therapy in Patients With Chronic Heart Failure
Official title: Re-evaluation of Optimal Re-synchronisation Therapy in Patients With Chronic Heart Failure - An Investigator-initiated, Event-driven, Prospective, Parallel-group, Randomised, Open, Blinded Outcome Assessment (PROBE), Multi-centre Trial Without Investigational Medical Products (Proof of Strategy Trial)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Chronic Heart Failure
Lead sponsor: Helios Health Institute GmbH
Sponsor class: OTHER
Collaborators: name: Heart Center Leipzig - University Hospital
First posted: 2018-04-11
Enrollment: 959
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of the study is to demonstrate that in patients with chronic heart failure who receive optimal medical treatment for this condition and have indication for Cardiac Resynchronisation Therapy, the implantation of a pacemaker (index group) is not inferior to defibrillator (control group) with respect to all-cause mortality.

Detailed description: Heart failure is a leading cause of death, hospitalisation, impaired quality of life and health expenditure. Symptoms and survival can be significantly improved by implantation of a device for Cardiac Resynchronisation Therapy (CRT). CRT devices are available as biventricular pacemakers (CRT-P) or as significantly more complex and cost-intensive biventricular defibrillators (CRT-D).

In patients who have previously experienced a life-threatening arrhythmia, the choice of the CRT-D (and not the CRT-P) is imperative but these are a small minority of patients. For the vast majority of patients receiving CRT therapy, there is currently considerable uncertainty as to whether the defibrillator function is needed and whether its benefits outweigh its risks. The defibrillator function may protect patients from sudden cardiac death. On the other hand, device-associated complications such as device infections appear to be increased; furthermore the defibrillator comes along with specific adverse events, particularly inappropriate shocks. These shocks are common and not only traumatic to patients (potentially leading to post-traumatic stress syndrome, anxiety disorders and depression), they also are negatively associated with overall survival.

The objective of the trial is to demonstrate that in patients with chronic heart failure who receive optimal medical treatment for this condition and have indication for CRT, the implantation of a CRT-P (index group) is not inferior to CRT-D (control group) with respect to all-cause mortality. Patients with an indication for CRT will be randomised to CRT-P or CRT-D.

RESET-CRT is an event-driven trial with a planned number of randomised and treated patients of at least n=1,356 (maximum of 2,004) and of 361 primary endpoints within an estimated median follow-up period of about 29 to 40 months.

No investigational medical product is defined to be used within RESET-CRT since only the therapeutic strategy (CRT-D versus CRT-P) is a pre-defined study treatment and allocated by random group (Proof of Strategy Trial). The devices to be implanted will be decided by the treating physician on the basis of the situation of the individual study patient and in line with local policies in routine clinical care.

Duration of study period:

Enrolment of 1,356 patients is expected to be completed within 52 months after inclusion of the first patient, i.e., by 31 December 2022. With an overall annual event rate between 9.0% and 12.5%, 361 primary endpoints will have occurred within 9 to 20 months of randomisation of the last patient (between 30 September 2023 and 31 August 2024). Under these circumstances, the total study duration will be between 62 and 73 months.

The Steering Committee of the study might prolong the recruitment period, for instance by 12 months, in the event of an unexpected slower recruitment rate or an overall event rate \< 9.0% for the primary endpoint.

For individual patients, the expected median follow-up time is between 29 and 40 months, with a minimum between 9 and 20 months and a maximum between 61 and 72 months. Follow-up may be prolonged by 12 months in the event of a prolonged recruitment period.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years.
* Symptomatic chronic heart failure due to ischemic or non-ischemic cardiomyopathy with NYHA class II, III or ambulatory IV.
* Reduced left ventricular ejection fraction ≤35% in transthoracic echocardiography (TTE) or cardiac magnetic resonance imaging (MRI) assessed verifiably within 4 weeks prior to or on the day of enrolment.
* On Optimal Medical Therapy (OMT) for at least 3 months prior to enrolment.
* Class I or IIa indication for implantation of a device for cardiac resynchronisation therapy (according to 2016 Guidelines of the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure).
* Signed informed consent.

Exclusion criteria:

* Class I or IIa indication for implantation of an ICD for secondary prevention of sudden cardiac death and ventricular tachycardia (according to the 2015 Guidelines of the European Society of Cardiology for the management of patients with ven-tricular arrhythmias and the prevention of sudden cardiac death).
* Violation of Instruction For Use of the selected device by at least one of the random group treatments.
* Ventricular tachycardia induced in an electrophysiological study.
* Carrying any implanted cardiac pacemaker, defibrillator or CRT device.
* Unexplained syncope.
* Hospitalised with unstable heart failure with NYHA class IV within 1 month prior to enrolment.
* Acute coronary syndrome or cardiac revascularization therapy by coronary angioplasty or coronary artery bypass grafting within 6 weeks prior to enrolment.
* Cardiac valve surgery or percutaneous cardiac valvular intervention such as transcatheter aortic valve replacement or transcatheter mitral valve repair performed within 3 months prior to enrolment.
* Reversible non-ischemic cardiomyopathy such as acute viral myocarditis or discontinuation of alcohol in alcohol-induced heart disease.
* On the waiting list for heart transplant.
* Any disease that limits life expectancy to less than 2 years.
* Severe chronic renal disease (GFR\<15 ml/min and/or the need for dialysis)
* Participation in another clinical trial, either within the past 3 months or still ongoing (participation in sub-studies connected to this trial and participation in observational studies permitted).
* Previous participation in RESET-CRT.
* Pregnant women or women of childbearing potential not on adequate birth control.
* Drug abuse or clinically manifest alcohol abuse.

Primary outcomes:
measure: Time from randomisation to the occurrence of all-cause death
timeFrame: Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in)
Secondary outcomes:
measure: Time from randomisation to death from cardiac causes
timeFrame: Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in)
measure: Time from randomisation to sudden cardiac death
timeFrame: Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in)
measure: Time from randomisation to life-threatening arrhythmias
timeFrame: Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in)
measure: Time from randomisation to first composite of Major Adverse Cardiac Event (MACE)
timeFrame: Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in)
measure: Time from randomisation to first hospitalisation for cardiovascular reasons
timeFrame: Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in)
measure: Nights spent in hospital for cardiovascular reasons per year of follow-up
timeFrame: Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in)
measure: Number of hospital readmissions for cardiovascular reasons after randomisation
timeFrame: Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in)
measure: Changes in quality of life (EQ-5D) comparing inclusion/enrolment with 12 and 24 months
timeFrame: at baseline, 12 and 24 months after randomisation
measure: Total cost of treatment as compound endpoint of MACEs, number of hospital days for cardiovascular reasons and ambulatory visits for cardiovascular reasons
timeFrame: Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in)
Other outcomes:
Locations:
city: Aue
country: Germany
facility: Helios Klinikum Aue
city: Bad Berka
country: Germany
facility: Zentralklinik Bad Berka
city: Bad Krozingen
country: Germany
facility: Universitäts-Herzzentrum
city: Bad Neuenahr-Ahrweiler
country: Germany
facility: Marienhaus Klinikum im Kreis Ahrweiler
city: Bad Neustadt a.d. Saale
country: Germany
facility: RHÖN-KLINIKUM Campus Bad Neustadt
city: Bad Oeynhausen
country: Germany
facility: Herz- und Diabeteszentrum NRW - Universitätsklinik der Ruhr-Universität Bochum
city: Bad Segeberg
country: Germany
facility: Segeberger Kliniken
city: Bergheim
country: Germany
facility: Maria-Hilf-Krankenhaus Bergheim
city: Berlin
country: Germany
facility: Sana Klinikum Lichtenberg
city: Berlin
country: Germany
facility: Unfallkrankenhaus Berlin
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Berlin
country: Germany
facility: Jüdisches Krankenhaus Berlin
city: Berlin
country: Germany
facility: Charité Campus Virchow-Klinikum
city: Berlin
country: Germany
facility: Vivantes Klinikum Spandau
city: Berlin
country: Germany
facility: Helios Klinikum Emil von Behring
city: Bernau bei Berlin
country: Germany
facility: Immanuel Klinikum Bernau - Herzzentrum Brandenburg
city: Bielefeld
country: Germany
facility: Klinikum Bielefeld
city: Bochum
country: Germany
facility: Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil
city: Bochum
country: Germany
facility: Augusta Kliniken Bochum
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Bottrop
country: Germany
facility: Knappschaftskrankenhaus Bottrop
city: Coburg
country: Germany
facility: REGIOMED-KLINIKEN Klinikum Coburg
city: Cottbus
country: Germany
facility: Carl-Thiem-Klinikum
city: Dachau
country: Germany
facility: Helios Amper-Klinikum Dachau
city: Detmold
country: Germany
facility: Klinikum Lippe Detmold
city: Dortmund
country: Germany
facility: St.-Johannes-Hospital Dortmund
city: Dortmund
country: Germany
facility: Herz Zentrum Westfalen - Knappschaftskrankenhaus Dortmund
city: Dresden
country: Germany
facility: Praxisklinik Herz und Gefäße
city: Dresden
country: Germany
facility: Herzzentrum Dresden Universitätsklinik
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
city: Erkelenz
country: Germany
facility: Hermann-Josef-Krankenhaus Erkelenz
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Essen
country: Germany
facility: Contilia Herz- und Gefäßzentrum
city: Flensburg
country: Germany
facility: Ev.-Luth. Diakonissenanstalt zu Flensburg
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt
city: Freiberg
country: Germany
facility: Kreiskrankenhaus Freiberg
city: Fulda
country: Germany
facility: Klinikum Fulda
city: Gießen
country: Germany
facility: UKGM - Universitätsklinikum Gießen
city: Goslar
country: Germany
facility: Asklepios Harzklinik Goslar
city: Gotha
country: Germany
facility: Helios Klinikum Gotha
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Gütersloh
country: Germany
facility: Klinikum Gütersloh gGmbH
city: Hagen
country: Germany
facility: Evangelisches Krankenhaus Hagen-Haspe
city: Halle (Saale)
country: Germany
facility: Krankenhaus Martha-Maria Halle-Dölau
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle (Saale)
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf (UKE)
city: Hamburg
country: Germany
facility: Asklepios Kliniken Hamburg GmbH - Asklepios Klinikum Harburg
city: Hamburg
country: Germany
facility: Asklepios Kliniken Hamburg GmbH
city: Hamburg
country: Germany
facility: Albertinen Herz- und Gefäßzentrum - Albertinen Krankenhaus
city: Hamm
country: Germany
facility: St. Marien-Hospital Hamm
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover (MHH)
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Helmstedt
country: Germany
facility: Helios St. Marienberg Klinik Helmstedt
city: Hennigsdorf
country: Germany
facility: Oberhavel Kliniken
city: Hildesheim
country: Germany
facility: Helios Klinikum Hildesheim
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Ingolstadt
country: Germany
facility: Klinikum Ingolstadt
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Kassel
country: Germany
facility: B. Braun Ambulantes Herzzentrum Kassel
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Campus Kiel
city: Kiel
country: Germany
facility: Städtisches Krankenhaus Kiel
city: Koblenz
country: Germany
facility: Katholisches Klinikum Koblenz - Montabaur
city: Krefeld
country: Germany
facility: Helios Klinikum Krefeld
city: Köln
country: Germany
facility: St. Vinzenz-Hospital
city: Köln
country: Germany
facility: Herzzentrum Uniklinik Köln
city: Köln
country: Germany
facility: Krankenhaus Porz am Rhein
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Leipzig
country: Germany
facility: Herzzentrum Leipzig
city: Leverkusen
country: Germany
facility: Klinikum Leverkusen
city: Ludwigsburg
country: Germany
facility: Cardio Centrum Ludwigburg
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Lüdenscheid
country: Germany
facility: Klinikum Lüdenscheid
city: Lünen
country: Germany
facility: St.-Marien-Hospital Lünen
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: Mönchengladbach
country: Germany
facility: Ev. Krankenhaus Bethesda Mönchengladbach
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf
city: Mönchengladbach
country: Germany
facility: Städtische Kliniken Mönchengladbach - Elisabeth-Krankenhaus Rheydt
city: München
country: Germany
facility: Klinik Augustinum
city: München
country: Germany
facility: LMU Klinikum
city: München
country: Germany
facility: Technische Universität München
city: München
country: Germany
facility: München Klinik Neuperlach
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Nauen
country: Germany
facility: Havelland Kliniken
city: Neuwied
country: Germany
facility: Marienhaus Klinikum St. Elisabeth Neuwied
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg Süd
city: Paderborn
country: Germany
facility: St. Vincenz-Krankenhaus
city: Plauen
country: Germany
facility: Helios Vogtland-Klinikum Plauen
city: Quedlinburg
country: Germany
facility: Harzklinikum Dorothea Christiane Erxleben Klinikum Quedlinburg
city: Riesa
country: Germany
facility: Elblandklinikum Riesa
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock
city: Schwedt/Oder
country: Germany
facility: Asklepios Klinikum Uckermark
city: Schwerin
country: Germany
facility: Helios Kliniken Schwerin
city: Siegburg
country: Germany
facility: Helios Klinikum Siegburg
city: Siegen
country: Germany
facility: Marien Kliniken
city: Siegen
country: Germany
facility: Diakonie Klinikum Jung-Stilling
city: Stadtlohn
country: Germany
facility: Krankenhaus Maria-Hilf Stadtlohn Klinikum Westmünsterland
city: Stendal
country: Germany
facility: Johanniter-Krankenhaus Genthin-Stendal
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder Trier
city: Tuttlingen
country: Germany
facility: Klinikum Landkreis Tuttlingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Verden
country: Germany
facility: Aller-Weser-Klinik - Krankenhaus Verden
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar Klinikum
city: Warburg
country: Germany
facility: Helios Klinikum Warburg GmbH
city: Weimar
country: Germany
facility: Sophien- und Hufeland-Klinikum
city: Winnenden
country: Germany
facility: Rems-Murr-Klinikum Winnenden
city: Wuppertal
country: Germany
facility: Helios Universitätsklinikum Wuppertal
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Zwickau
country: Germany
facility: Heinrich-Braun-Klinikum
Study officials:
affiliation: Heart Center Leipzig - University Hospital
name: Gerhard Hindricks, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chatterjee NA, Poole JE. Cardiac Resynchronization Therapy in Nonischemic Cardiomyopathy: To D or P? JACC Heart Fail. 2021 Jun;9(6):450-452. doi: 10.1016/j.jchf.2021.04.001. Epub 2021 May 12. No abstract available.