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

Sponsor

Ospedale C & G Mazzoni (Other)

Overall Status

Recruiting

CT.gov ID

NCT05167799

Collaborator

(none)

Enrollment

Location

36.6

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Amyloidosis Cardiac Heart Failure	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 Design

Study Type:

Observational

Anticipated Enrollment :

25 participants

Observational Model:

Case-Only

Time Perspective:

Prospective

Official Title:

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

Actual Study Start Date :

May 13, 2021

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

Arm	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)

Arm

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)

Outcome Measures

Primary Outcome Measures

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. [12-month]
The occurrence of any of the events mentioned (worsening of heart failure or intravenous intervention) involves reaching the endpoint

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 100 Years

Sexes Eligible for Study:

All

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