Clinical trial NCT05167799: Cardiac Contractility Modulation Therapy in Amyloid Cardiomyopathy Patients With Heart Failure
Official title: Cardiac Contractility Modulation Therapy in Amyloid Cardiomyopathy Patients With Heart Failure With Mid-range Ejection Fraction: a Multicentre Registry
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Amyloidosis Cardiac
Heart Failure
Keywords: Cardiac Amyloidosis
Heart Failure
Cardiac Contractility Modulation
CCM
Lead sponsor: Ospedale C & G Mazzoni
Sponsor class: OTHER
First posted: 2021-12-22
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: This Registry includes patients with chronic, symptomatic heart failure with moderately-to-severely reduced left ventricular systolic function despite optimal pharmacological and electrical therapy, who have been diagnosed with TTR Cardiac Amyloidosis. The clinical trial study (prospective registry) will be conducted in accordance with the protocol, with the Helsinki Declaration and with the favorable opinion of the local Ethics Committee of the participating Centers.

Brief summary: The primary aim of this observational registry is to evaluate the efficacy of CCM in patients with heart failure with mid-range or reduced EF and diagnosis of TTR amyloidosis. The efficacy will be evaluated in terms of composite of occurrence of heart failure-related hospitalizations and/or acute intravenous interventions (IVI) at 12-month follow up compared to those reported 12 months before CCM implantation. Among the secondary endpoints, clinical functional status, quality of life, drug changes and Echocardiographic parameters will be evaluated and compared from baseline to follow up.

Detailed description: Amyloidosis represents a group of human degenerative diseases characterized by the deposition of aggregates of abnormally folded proteins in single or multi-organs. Cardiac amyloidosis is primarily associated with the systemic production and release of a number of amyloidogenic proteins, notably immunoglobulin light chain proteins (also known as amyloid light chain or AL) or transthyretin proteins (TTR). Notably, although myocardial dysfunction is generally understood as a result of infiltration by extracellular amyloid deposits, there is experimental evidence of direct cytotoxic effect, possibly due to oxidative stress.

Since neither HF optimal medical therapy nor HF devices seems to have a clear benefit in amyloid cardiomyopathy, this clinical setting needs to test other therapeutic options.

Randomized clinical trials have shown that Cardiac contractility modulation (CCM) may be considered as a concrete therapeutic option in patients with symptomatic Heart Failure (HF) despite optimal medical therapy (OMT), with Left Ventricular Ejection Fraction (LVEF) between 25% and 45%, with narrow QRS complex (\<130ms).

CCM signal treatment reverses the cardiac maladaptive fetal gene program and normalizes expression of key sarcoplasmic reticulum Ca2+ cycling and stretch response genes. Specifically, 3-month on CCM therapy resulted in decreased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase (MAPK) and p21 Ras and increased expression of α-MHC, SERCA-2a, phospholamban, and ryanodine receptors. Notably, pre-clinical data suggest that triggering p38α MAPK autophosphorylation plays a crucial role in amyloidogenic light-chain mediated cellular oxidative stress, dysfunction and ultimately cell death in cardiomyocytes. Therefore CCM mechanism of action could be beneficial in cardiac amyloidosis but there are no data in this specific clinical setting.

Eligibility criteria: Inclusion Criteria:

* Age 18 years or older
* Male or a nonpregnant female
* All of the following: Established diagnosis of amyloid TTR Cardiomyopathy; baseline ejection fraction ≥25% and ≤45%; at least one hospitalization due to worsening heart failure over the year before entry into the registry.
* ICD if indicated
* PM if indicated
* Willing and able to return for all follow-up visits

Exclusion Criteria:

* AL amyloid cardiomyopathy
* Subjects who have a potentially correctible cause of heart failure (eg, Ischemic or valvular or congenital heart disease).
* Scheduled for CABG or PCI or has undergone a CABG within 90 d or PCI within 30 d.
* Myocardial infarction within 90 days
* Mechanical tricuspid valve
* Prior heart transplant
* Chronic haemodialysis
* Familial TTR amyloidotic cardiomyopathy with significant polyneuropathy potentially eligible for Patirisan or Inotersen17
* Unable to provide informed consent

Primary outcomes:
measure: Composite of occurrence of hospitalizations due to worsening of heart failure and/or acute intravenous administrations of diuretics or inotropic drugs over the 12 months after entry into the registry.
timeFrame: 12-month
Secondary outcomes:
measure: Occurrence of clinical need to increase oral dose of diuretic drug and/or to add another diuretic drug class
timeFrame: 12-month
measure: Occurrence of oral dose diuretic drug reduction
timeFrame: 12-month
measure: NYHA class
timeFrame: 12-month
measure: Distance walked at the 6-minute walking test
timeFrame: 12-month
measure: Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score
timeFrame: 12-month
measure: Biomarker (NT-proBNP)
timeFrame: 12-month
measure: Biomarker (HS-Troponin)
timeFrame: 12-month
measure: Echocardiographic parameters (Ejection Fraction)
timeFrame: 12-month
measure: Echocardiographic parameters (End diastolic volume and End systolic volume)
timeFrame: 12-month
Other outcomes:
Locations:
city: Ascoli Piceno
country: Italy
facility: Ospedale Mazzoni
state: Marche (AP)
Study officials:
affiliation: Ospedale Mazzoni (Ascoli Piceno)
name: Procolo Marchese, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shi J, Guan J, Jiang B, Brenner DA, Del Monte F, Ward JE, Connors LH, Sawyer DB, Semigran MJ, Macgillivray TE, Seldin DC, Falk R, Liao R. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4188-93. doi: 10.1073/pnas.0912263107. Epub 2010 Feb 11.
citation: Brenner DA, Jain M, Pimentel DR, Wang B, Connors LH, Skinner M, Apstein CS, Liao R. Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress. Circ Res. 2004 Apr 30;94(8):1008-10. doi: 10.1161/01.RES.0000126569.75419.74. Epub 2004 Mar 25.
citation: Kristen AV, Dengler TJ, Hegenbart U, Schonland SO, Goldschmidt H, Sack FU, Voss F, Becker R, Katus HA, Bauer A. Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death. Heart Rhythm. 2008 Feb;5(2):235-40. doi: 10.1016/j.hrthm.2007.10.016. Epub 2007 Oct 9.
citation: Abraham WT, Kuck KH, Goldsmith RL, Lindenfeld J, Reddy VY, Carson PE, Mann DL, Saville B, Parise H, Chan R, Wiegn P, Hastings JL, Kaplan AJ, Edelmann F, Luthje L, Kahwash R, Tomassoni GF, Gutterman DD, Stagg A, Burkhoff D, Hasenfuss G. A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation. JACC Heart Fail. 2018 Oct;6(10):874-883. doi: 10.1016/j.jchf.2018.04.010. Epub 2018 May 10.
citation: Anker SD, Borggrefe M, Neuser H, Ohlow MA, Roger S, Goette A, Remppis BA, Kuck KH, Najarian KB, Gutterman DD, Rousso B, Burkhoff D, Hasenfuss G. Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction. Eur J Heart Fail. 2019 Sep;21(9):1103-1113. doi: 10.1002/ejhf.1374. Epub 2019 Jan 16.