Exercise Training and Rehabilitation In Cardiac Amyloidosis (ERICA)

Exercise Training and Rehabilitation In Cardiac Amyloidosis: ERICA-Study

Notwithstanding the dramatic improvement associated with Tafamidis in Heart Failure (HF) due to wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), remarkable morbidity and mortality still burden this disease. Exercise training (ET) is a first-line recommended treatment for unselected HF patients, whose effects on ATTRwt-CA form remain however unexplored. The investigators hereby present rationale and design of the Exercise training and Rehabilitation in Cardiac Amyloidosis (ERICA) study, whose aim is to determine whether a tailored, supervised ET program might improve exercise capacity in HF due to ATTRwt-CA. This interventional, controlled study will randomize ATTRwt-CA patients into a control group (C) and a primary training group (ET-1). After 12 weeks, patients in group C will be offered to undergo the same ET program (ET-2) for further 12 weeks, considering the last observation as baseline. Primary endpoint will be the distance obtained at the 6-minute walk test (6MWD) performed at baseline and after 12-weeks of treatment in pooled ET-1 and ET-2 groups compared to C. Quality of life, peak oxygen consumption, left and right heart architecture and function, natriuretic peptides will be secondary endpoints. This study will be the first testing the effects of ET in patients with ATTRwt-CA.

Study Overview

• Status: Enrolling by invitation
• Conditions: Cardiac Amyloidosis
• Intervention / Treatment: Other: Exercise training (ET1+ET2); Behavioral: Optimal Medical Therapy (No-ET)

Detailed Description

Among Systemic amyloidosis, the peculiar deposition of beta-amyloid fibrils agglomerates localized in the interstitial space between the cardiomyocytes characterizes the spectrum of cardiac amyloidosis (AC). All AC phenotypes culminate in a progressive deterioration of cardiac compliance up to a true infiltrative cardiomyopathy with restrictive physiology. Clinical presentation may vary from mildly symptomatic Heart Failure (HF), usually labeled, and mistakenly confused as a classic Heart Failure with preserved ejection fraction (HFpEF) up to a severe scenario of severe cardiac decompensation with fluid overload, marked shortness of breath, fatigue and orthostatic hypotension. Syncope may also appear due to infiltration in the conduction system leading to sinoatrial disease and atrioventricular block. To date, more than 30 proteins responsible for the deposition of fibrils have been identified and of these 9 have been identified as responsible for the cardiac involvement of the disease. AC is determined in 98% of cases by the accumulation of monoclonal light chains of immunoglobulins (AL) or transthyretin (ATTR); the latter can occur either in its hereditary form (ATTRv) or in the wild-type variant (ATTRwt). Although AC is perceived as a rare disease, standing a reported prevalence of around 1/100,000 inhabitants, a recent metanalysis reported AC as underlying HF cause in 13.7% of cases, varying from 15.1% of Heart Failure (HF) with preserved ejection fraction (HFpEF) and 11.3% in reduced fraction phenotype (HFrEF). This mismatch begets the hypothesis that AC is often underdiagnosed, probably due to its challenging diagnosis, the diverse spectrum of clinical presentation ranging from severely compromised clinical cases to rather silent manifestations, and the absence of specific therapies for this condition making until a few years ago AC a true orphan disease. This paradigm has been subverted in recent years, by the emergence of tafamidis, a targeted drug from amyloidosis that binds transthyretin, preventing tetramer dissociation and production of amyloid. Tafamidis has been successfully tested for ATTRwt-AC in a relatively large multicenter, international, double-blind, placebo-controlled, phase 3 trial, the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), showing a remarkable improvement of the composite outcome of all-cause mortality and hospitalizations due to cardiovascular causes. Apart from Tafamidis, there are no evidence supporting the use of guideline-directed medical therapy (GDMT) used in classical forms of HF in ATTR-ACT. On top of GDMT, exercise training (ET) remains largely uninvestigated in AC. ET consists of a multidisciplinary approach, including a medical evaluation with modification of cardiovascular risk factors, prescription of a physical exercise program and psychosocial evaluation and is currently recommended with the highest degree of recommendation (in class I, type A level) in current guidelines on HF. To date, there are no data about the efficacy and safety of ET in AC, specifically in the ATTRwt-AC. We hereby present the outlines and the study protocol of the Exercise Rehabilitation and training in Cardiac Amyloidosis (ERICA) study, whose aim is to investigate and analyze the safety and the efficacy of cardiac rehabilitation on patients with AC, specifically those affected by the ATTR-wt form. The present study aims to investigate and analyze, through an interventional longitudinal, controlled, randomized, design, the effects of a structured program of Exercise training in patients with ATTRwt-AC.

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Naples, Italy, 80131
    • Department of Translational Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged 18 or older
• Established ATTRwt diagnosis
• Heart Failure diagnosis
• Informed consent according to Italian regulations

Exclusion Criteria:

• Unstable Angina
• Acutely decompensated Heart Failure within 1 month before enrollment
• Occurrence of complex ventricular arrhythmias
• Presence of intracavitary thrombus
• recent (< 1 year) thrombophlebitis with or without pulmonary embolism
• Severe obstructive cardiomyopathies
• Severe or symptomatic aortic stenosis
• Uncontrolled inflammatory or infectious diseases
• Any musculoskeletal conditions preventing physical exercise

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exercise training; Patients will undergo exercise training, nutritional advice, smoking cessation, lipid profile evaluation, control and management of body weight and abdominal circumference; evaluation of the drug therapy in progress; psycho-social evaluation.	Other: Exercise training (ET1+ET2); Exercise training will consist of continuous aerobic training of moderate intensity on cycle ergometer/treadmill, with a frequency of 2-3 weekly sessions lasting 12 weeks, with exercise intensity of VO2 peak of 40% gradually increasing up to 50-60% of VO2 peak based on individual tolerability and improvement; 55-65% of heart rate at peak; 40-59% of heart rate reserve; 4-6 Metabolic equivalents (METS); the duration of the session will gradually increase from 15-30 min to 45-60 min.
Active Comparator: Controls; control group who won't undergo exercise training and will be managed with optimal medical therapy	Behavioral: Optimal Medical Therapy (No-ET); Patients will be handled according to optimal medical therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
distance obtained at the 6-minute walk test (6MWD)	distance (meters) obtained at the 6-minute walk test (6MWD) performed at baseline and after 12-weeks of treatment treatment in pooled ET-1 and ET-2 groups compared to No-ET.	Baseline and after 12-weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
N terminal pro brain natriuretic peptide (NT-pro BNP) serum levels	serum levels (ng/ml)	Baseline and after 12-weeks of treatment
Troponin serum levels	serum levels (ng/ml)	Baseline and after 12-weeks of treatment
Galectin-3 serum levels	serum levels (ng/ml)	Baseline and after 12-weeks of treatment
Transthyretin serum levels	serum levels (ng/ml)	Baseline and after 12-weeks of treatment
Quality of life assessment	Kansas City Questionnaire (ranges 0 to 100 where 100 is the better quality of life score )	Baseline and after 12-weeks of treatment
Left ventricular ejection fraction (LVEF)	assessed at echocardiography (%)	Baseline and after 12-weeks of treatment
Left atrial (LA,ml) volume	assessed at echocardiography in ml	Baseline and after 12-weeks of treatment
global longitudinal strain (GLS)	assessed at echocardiography in %	Baseline and after 12-weeks of treatment
Tricuspid Annular Plane Systolic Excursion (TAPSE)	assessed at echocardiography in mm	Baseline and after 12-weeks of treatment
estimated systolic Pulmonary arterial pressure	assessed at echocardiography in mmHg	Baseline and after 12-weeks of treatment
Right Ventricular Free-wall Strain (RVFWS)	assessed at echocardiography in %	Baseline and after 12-weeks of treatment
Myocardial work	assessed at echocardiography in mm Hg%	Baseline and after 12-weeks of treatment
Peak oxygen consumption (VO2 peak)	assessed during Cardiopulmonary exercise test in mL/(kg·min)	Baseline and after 12-weeks of treatment
Work (Watt)	assessed during Cardiopulmonary exercise test in watt	Baseline and after 12-weeks of treatment
Respiratory efficiency	minute ventilation (VE)/ carbon dioxide (VCO2) slope assessed during Cardiopulmonary exercise test in watt	Baseline and after 12-weeks of treatment
Adverse Events	Any adverse Event with special focus on Serious Adverse event	Baseline and after 12-weeks of treatment

Collaborators and Investigators

• Sponsor: Federico II University
• Investigators: Principal Investigator: Alberto M. Marrra, Md,PhD, Department of Translational Medical Sciences

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2024
• Primary Completion (Actual): January 30, 2024
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: April 15, 2024
• First Submitted That Met QC Criteria: May 10, 2024
• First Posted (Actual): May 14, 2024

Study Record Updates

• Last Update Posted (Actual): May 14, 2024
• Last Update Submitted That Met QC Criteria: May 10, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Heart Failure; Rehabilitation; Exercise Training; Cardiomyopathies; Cardiac Amyloidosis; wild-type transthyretin
• Additional Relevant MeSH Terms: Metabolic Diseases; Proteostasis Deficiencies; Amyloidosis
• Other Study ID Numbers: ERICA562023CRCA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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