EFICAC-TTR Trial: Exercise and Nutritional Supplementation in Transthyretin Cardiac Amyloidosis (EFICAC-TTR)

A Prospective, Randomized, Multicenter Clinical Trial on the Effect of a Home-Based Multicomponent Exercise Program Combined With Nutritional Supplementation in Patients With Transthyretin Cardiac Amyloidosis

Transthyretin cardiac amyloidosis (TTR-CA) is a heart disease that mainly affects older adults and often leads to reduced physical capacity, muscle weakness, frailty, and a decline in quality of life. While current medical treatments can slow disease progression, they do not fully address functional limitations or muscle deterioration.

The EFICAC-TTR study is a prospective, randomized, multicenter clinical trial designed to evaluate whether a combined non-pharmacological intervention can improve physical function in patients aged 70 years or older with confirmed TTR-CA.

A total of 102 participants will be randomly assigned to one of three groups: (1) usual medical care, (2) a home-based multicomponent exercise program combined with fiber supplementation, or (3) the same exercise program combined with creatine monohydrate and β-hydroxy-β-methylbutyrate (HMB) supplementation. The exercise program is adapted to each participant's functional level and is performed at home.

The main outcomes of the study are changes in walking capacity, measured by the 6-minute walk test, and muscle strength, assessed by handgrip strength after 12 weeks. Secondary outcomes include changes in body composition, frailty, quality of life, and clinical events, while mechanistic biomarkers are assessed as exploratory outcomes.

This study aims to determine whether combining exercise with nutritional supplementation can safely improve functional capacity and overall health in older adults with transthyretin cardiac amyloidosis.

Study Overview

• Status: Not yet recruiting
• Conditions: Transthyretin Cardiac Amyloidosis
• Intervention / Treatment: Other: Usual Care; Behavioral: Home-Based Multicomponent Exercise Program; Dietary supplement: Fiber Supplementation (Microcrystalline Cellulose); Dietary supplement: Creatine and HMB Supplementation

• Study Type: Interventional
• Enrollment (Estimated): 102
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Juan Mielgo-Ayuso, PhD; Phone Number: +34 947 25 87 00; Email: jmielgo@ubu.es
• Study Contact Backup: Name: José A Pérez Rivera, PhD, MD; Phone Number: +34 947 28 19 64; Email: jangel.perezrivera@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥70 years.
• Confirmed diagnosis of transthyretin cardiac amyloidosis (TTR-CA) based on positive bone scintigraphy with diphosphonates (Perugini grade 2 or 3) and absence of monoclonal protein.
• Clinical stability during the 4 weeks prior to enrollment.
• Ability to understand the study procedures and provide written informed consent.

Exclusion Criteria:

• Light-chain (AL) amyloidosis or other non-TTR amyloidosis variants.
• Absolute medical contraindication to moderate-intensity exercise.
• Severe comorbid conditions with an estimated life expectancy <6 months.
• Severe cognitive impairment (Mini-Mental State Examination score <20).
• Concurrent participation in another clinical trial or structured exercise program.
• Known allergy or intolerance to creatine, beta-hydroxy-beta-methylbutyrate (HMB), or microcrystalline cellulose.
• Severe renal impairment requiring dialysis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Usual Care; Participants receive usual medical care for transthyretin cardiac amyloidosis, including routine cardiology follow-up and general lifestyle recommendations, without structured exercise or nutritional supplementation.	Other: Usual Care; Standard clinical management for transthyretin cardiac amyloidosis according to routine cardiology practice.
Placebo Comparator: Exercise + Fiber Supplementation (Active Control); Participants perform a home-based multicomponent exercise program and receive daily supplementation with microcrystalline cellulose, used as a nutritionally inert control supplement.	Behavioral: Home-Based Multicomponent Exercise Program; A 12-week home-based multicomponent exercise program adapted from the Vivifrail model, including strength, balance, mobility, and endurance exercises tailored to individual functional capacity.; Dietary supplement: Fiber Supplementation (Microcrystalline Cellulose); Daily oral supplementation with microcrystalline cellulose, used as a nutritionally inert control supplement to match supplementation procedures.
Experimental: Exercise + Creatine and HMB Supplementation; Participants perform a home-based multicomponent exercise program and receive daily supplementation with creatine monohydrate (3 g/day) and β-hydroxy-β-methylbutyrate (HMB, 3 g/day).	Behavioral: Home-Based Multicomponent Exercise Program; A 12-week home-based multicomponent exercise program adapted from the Vivifrail model, including strength, balance, mobility, and endurance exercises tailored to individual functional capacity.; Dietary supplement: Creatine and HMB Supplementation; Daily oral supplementation with creatine monohydrate (3 g/day) and β-hydroxy-β-methylbutyrate (HMB, 3 g/day) for 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Handgrip Strength	Change in maximal isometric handgrip strength measured in kilograms (kg) using a calibrated handheld dynamometer (best of three attempts for the dominant hand), expressed as the difference between baseline and 12 weeks.	Baseline and 12 weeks
Change in 6-Minute Walk Test Distance	Change in walking capacity assessed by the 6-minute walk test, measured as the difference in total distance walked (meters) between baseline and 12 weeks.	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Fat Mass	Change in total body fat mass measured in kilograms (kg) using multifrequency bioelectrical impedance analysis, expressed as the difference between baseline and 12 weeks.	Baseline and 12 weeks
Change in Skeletal Muscle Mass	Change in skeletal muscle mass measured in kilograms (kg) using multifrequency bioelectrical impedance analysis, expressed as the difference between baseline and 12 weeks.	Baseline and 12 weeks
Change in Fat-Free Mass	Change in fat-free mass measured in kilograms (kg) using multifrequency bioelectrical impedance analysis, expressed as the difference between baseline and 12 weeks.	Baseline and 12 weeks
Change in Phase Angle	Change in phase angle measured in degrees (°) using multifrequency bioelectrical impedance analysis, expressed as the difference between baseline and 12 weeks.	Baseline and 12 weeks
Change in Frailty Status Assessed by the FRAIL Scale	Change in frailty status assessed by the FRAIL scale, a 5-item questionnaire with scores ranging from 0 to 5, where higher scores indicate greater frailty, expressed as the difference between baseline and 12 weeks.	Baseline and 12 weeks
All-Cause Mortality	All-cause mortality, defined as death from any cause during the follow-up period.	Up to 6 months
Change in Short Physical Performance Battery (SPPB) Score	Change in Short Physical Performance Battery (SPPB) total score, ranging from 0 to 12 points, where higher scores indicate better physical performance, expressed as the difference between baseline and 12 weeks.	Baseline and 12 weeks
Change in Clinical Frailty Scale (CFS) Score	Change in frailty severity assessed by the Clinical Frailty Scale (CFS), a 9-point ordinal scale ranging from 1 (very fit) to 9 (terminally ill), where higher scores indicate greater frailty.	Baseline and 12 weeks
Change in Barthel Index Score	Change in functional independence assessed by the Barthel Index, scored from 0 to 100, where higher scores indicate greater independence.	Baseline and 12 weeks
Change in SARC-F Score	Change in sarcopenia risk assessed by the SARC-F questionnaire, with scores ranging from 0 to 10, where higher scores indicate greater sarcopenia risk.	Baseline and 12 weeks
Change in Minnesota Living With Heart Failure Questionnaire Score	Change in health-related quality of life assessed by the Minnesota Living With Heart Failure Questionnaire (MLHFQ), with total scores ranging from 0 to 105, where higher scores indicate worse quality of life.	Baseline and 12 weeks
Change in Charlson Comorbidity Index	Change in comorbidity burden assessed using the Charlson Comorbidity Index, a weighted index that accounts for the number and severity of comorbid conditions, where higher scores indicate greater comorbidity burden.	Baseline and 12 weeks
Incidence of Heart Failure Hospitalizations	Number of hospitalizations due to heart failure occurring during the follow-up period.	Up to 6 months
Incidence of Non-Heart Failure Hospitalizations	Hospital admissions due to causes other than heart failure during the follow-up period.	Up to 6 months
Incidence of Emergency Department Visits	Number of emergency department visits during follow-up.	Up to 6 months
Incidence of Intervention-Related Adverse Events	Number and type of adverse events related to exercise and/or supplementation, classified according to severity and relatedness, collected throughout the follow-up period.	Up to 6 months
Rate of Supplement Discontinuation	Proportion of participants who discontinue study supplements.	Up to 6 months
Exercise Program Adherence	Proportion (%) of prescribed exercise sessions completed, with adequate adherence defined as completion of at least 80% of prescribed sessions.	Up to 12 weeks
Supplement Adherence	Proportion (%) of planned supplement doses consumed, with optimal compliance defined as 90-110%.	Up to 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Growth Differentiation Factor 15 (GDF-15)	Change in serum GDF-15 concentration (pg/mL) measured by immunoassay.	Baseline and 12 weeks
Change in Soluble ST2	Change in serum soluble ST2 concentration (ng/mL) measured by immunoassay.	Baseline and 12 weeks
Change in Interleukin-6 (IL-6)	Change in serum interleukin-6 (IL-6) concentration (pg/mL) measured by immunoassay.	Baseline and 12 weeks
Change in C-Reactive Protein (CRP)	Change in serum C-reactive protein (CRP) concentration (mg/L) measured by immunoassay.	Baseline and 12 weeks
Change in circulating miR-21 expression	Change in circulating miR-21 expression measured by quantitative PCR, expressed as relative expression (ΔΔCt).	Baseline and 12 weeks
Change in circulating miR-29 expression	Change in circulating miR-29 expression measured by quantitative PCR, expressed as relative expression (ΔΔCt).	Baseline and 12 weeks
Change in circulating miR-34a expression	Change in circulating miR-34a expression measured by quantitative PCR, expressed as relative expression (ΔΔCt).	Baseline and 12 weeks
Change in circulating miR-155 expression	Change in circulating miR-155 expression measured by quantitative PCR, expressed as relative expression (ΔΔCt).	Baseline and 12 weeks
Change in PBMC Macrophage Polarization (M1/M2) by Flow Cytometry	Change in macrophage polarization profile assessed by flow cytometry immunophenotyping of PBMC-derived macrophages, expressed as M1/M2 ratio.	Baseline and 12 weeks
Change in Pro-inflammatory (M1) Gene Expression Markers	Change in gene expression of predefined pro-inflammatory (M1) markers in PBMC-derived macrophages, measured by quantitative PCR and expressed as relative expression (ΔΔCt).	Baseline and 12 weeks
Change in Anti-inflammatory (M2) Gene Expression Markers	Change in gene expression of predefined anti-inflammatory (M2) markers in PBMC-derived macrophages, measured by quantitative PCR and expressed as relative expression (ΔΔCt).	Baseline and 12 weeks

Collaborators and Investigators

• Sponsor: Universidad de Burgos
• Collaborators: Hospital Universitario de Burgos
• Investigators: Principal Investigator: Juan Mielgo-Ayuso, PhD, Universidad de Burgos; Study Chair: José A Pérez Rivera, PhD, MD, Hospital Universitario de Burgos

Publications and helpful links

General Publications

• Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, Schneider SM, Sieber CC, Topinkova E, Vandewoude M, Visser M, Zamboni M; Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019 Jul 1;48(4):601. doi: 10.1093/ageing/afz046. No abstract available.
• Ramos-Hernandez R, Miguel-Ortega A, Martinez-Ferran M, Fernandez-Lazaro D, Busto N, Mielgo-Ayuso J. Combined creatine and HMB co-supplementation improves functional strength independent of muscle mass in physically active older adults: a randomized crossover trial. Geroscience. 2025 Oct 10. doi: 10.1007/s11357-025-01889-y. Online ahead of print.
• de Souto Barreto P, Rolland Y, Vellas B, Maltais M. Association of Long-term Exercise Training With Risk of Falls, Fractures, Hospitalizations, and Mortality in Older Adults: A Systematic Review and Meta-analysis. JAMA Intern Med. 2019 Mar 1;179(3):394-405. doi: 10.1001/jamainternmed.2018.5406.
• Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, Basso C, Brucato A, Burazor I, Caforio ALP, Damy T, Eriksson U, Fontana M, Gillmore JD, Gonzalez-Lopez E, Grogan M, Heymans S, Imazio M, Kindermann I, Kristen AV, Maurer MS, Merlini G, Pantazis A, Pankuweit S, Rigopoulos AG, Linhart A. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021 Apr 21;42(16):1554-1568. doi: 10.1093/eurheartj/ehab072.
• Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019 Jun 11;73(22):2872-2891. doi: 10.1016/j.jacc.2019.04.003.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: December 17, 2025
• First Submitted That Met QC Criteria: January 7, 2026
• First Posted (Actual): January 15, 2026

Study Record Updates

• Last Update Posted (Actual): February 11, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Exercise Training; Older Adults; Frailty; Creatine; Functional Capacity; Nutritional Supplementation; Cardiac Amyloidosis; Transthyretin Cardiac Amyloidosis; Beta-Hydroxy Beta-Methylbutyrate
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Neuromuscular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Peripheral Nervous System Diseases; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Proteostasis Deficiencies; Amyloid Neuropathies; Amyloidosis, Familial; Amyloidosis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Frailty; Amyloid Neuropathies, Familial; Amino Acids, Peptides, and Proteins; Organic Chemicals; Amino Acids; Guanidines; Amidines; Creatine; microcrystalline cellulose
• Other Study ID Numbers: EFICAC-TTR-UBU-HUBU

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data that underlie the results reported in publications will be made available upon reasonable request.
• IPD Sharing Time Frame: Beginning 6 months after publication and ending 5 years after publication.
• IPD Sharing Access Criteria: Access to de-identified individual participant data will be granted upon reasonable request to the principal investigator. Requests must include a methodologically sound research proposal and will be evaluated for scientific merit and feasibility. Data sharing will require the execution of a data sharing agreement and will comply with applicable data protection and privacy regulations.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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