Cardiac Contractility Modulation Therapy in Amyloid Cardiomyopathy Patients With Heart Failure (AMY-CCM)

Cardiac Contractility Modulation Therapy in Amyloid Cardiomyopathy Patients With Heart Failure With Mid-range Ejection Fraction: a Multicentre Registry

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Amyloidosis Cardiac
• Intervention / Treatment: Device: Cardiac Contractility Modulation (CCM)

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.

• Study Type: Observational
• Enrollment (Anticipated): 25

Contacts and Locations

• Study Contact: Name: Procolo Marchese, MD; Phone Number: +393921133283; Email: procolo.marchese@gmail.com

Study Locations

• Italy
  • Marche (AP)
    • Ascoli Piceno, Marche (AP), Italy, 63100
      • Recruiting
      • Ospedale Mazzoni
      • Contact: Procolo Marchese; Phone Number: +393921133283; Email: procolo.marchese@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cardiac Amyloidosis patients; Patients with 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. Already implanted with ICD or PM if needed, fullfilling the indication for CCM implantation.	Device: Cardiac Contractility Modulation (CCM); Patients will be implanted with CCM device according to indications, to improve Heart Failure symptoms and then enrolled in the Registry if they fullfil Inclusion and Exclusion Criteria (First of all if they are diagnosed with TTR Amyloidosis)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	The occurrence of any of the events mentioned (worsening of heart failure or intravenous intervention) involves reaching the endpoint	12-month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of clinical need to increase oral dose of diuretic drug and/or to add another diuretic drug class	Change from baseline to 2 weeks, 1,3, 6 and 12-month	12-month
Occurrence of oral dose diuretic drug reduction	Change from baseline to 2 weeks, 1,3, 6 and 12-month	12-month
NYHA class	Change from baseline to 2 weeks, 1,3, 6 and 12-month	12-month
Distance walked at the 6-minute walking test	Change from baseline to 2 weeks, 1,3, 6 and 12-month in meters walked during the test	12-month
Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score	Change from baseline to 2 weeks, 1,3, 6 and 12-month in the KCCQ-OS score	12-month
Biomarker (NT-proBNP)	Change from baseline to 2 weeks, 1,3, 6 and 12-month in the biomarker level (pg/ml)	12-month
Biomarker (HS-Troponin)	Change from baseline to 2 weeks, 1,3, 6 and 12-month in the biomarker level (ng/l)	12-month
Echocardiographic parameters (Ejection Fraction)	Change from baseline to 2 weeks, 1,3, 6 and 12-month in EF (%)	12-month
Echocardiographic parameters (End diastolic volume and End systolic volume)	Change from baseline to 2 weeks, 1,3, 6 and 12-month in End diastolic volume and End systolic volume respectively (ml)	12-month

Collaborators and Investigators

• Sponsor: Ospedale C & G Mazzoni
• Investigators: Principal Investigator: Procolo Marchese, MD, Ospedale Mazzoni (Ascoli Piceno)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2021
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: December 7, 2021
• First Submitted That Met QC Criteria: December 21, 2021
• First Posted (Actual): December 22, 2021

Study Record Updates

• Last Update Posted (Actual): December 22, 2021
• Last Update Submitted That Met QC Criteria: December 21, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Heart Failure; Cardiac Contractility Modulation; CCM; Cardiac Amyloidosis
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Proteostasis Deficiencies; Heart Failure; Amyloidosis; Cardiomyopathies
• Other Study ID Numbers: AMYCCM190421

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No