Moderate Intensity Training in Patients With Truncating Genetic Variants in TTN.

November 21, 2022 updated by: Ida Finsen Flensted, Rigshospitalet, Denmark

A Clinical Trial, Investigating the Effect of a Home-based Moderate Intensity Training Program on Oxidative Capacity and Hemodynamics in Patients With Truncating Genetic Variants in TTN.

The aim is to investigate the effect of an 8-week moderate-intensity exercise program on aerobic fitness and cardiac contractility in patients with truncations of the sarcomeric protein titin.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Mutations leading to truncations of the large sarcomeric protein titin was discovered in 2012 as the most prevalent genetic cause of familial dilated cardiomyopathy, affecting approximately 25% of all cases of familial dilated cardiomyopathy. The dilated cardiomyopathy phenotype associated with truncating titin variants (TTNtv) is associated with a high prevalence of arrhythmias but is generally thought to represent a relatively mild DCM phenotype, which often responds well to medical therapy.

In vitro experiments on human induced pluripotent stem cells show that TTNtv leads to sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Experiments in animal models suggest patients with TTNtv are intolerant to long-lasting hemodynamic stress. This finding is supported by clinical studies in which a significant proportion of patients with peripartum cardiomyopathy, alcoholic cardiomyopathy and chemotherapy-induced cardiomyopathy were found to carry TTNtv.

So far, no interventional studies have been carried out specifically in patients with TTNtv. In an older study putative variants in TTN have been suggested to be associated with cardiac adaptations to endurance training, namely the rate of change in stroke volume during submaximal exercise.

Previous interventional exercise-studies in patients with a range of mutations in genes encoding proteins of the cytoskeleton, sarcomere, ion-channels and enzymes of the mitochondrial respiratory chain, safely improves oxidative fitness. Studies carried out on patients with heart failure of mixed etiologies and in patients with hypertrophic cardiomyopathy reveals similar beneficial effects of exercise. These studies reject the idea that training "diseased" muscle tissue leads to further muscle damage or is ineffective.

Many patients with cardiomyopathy often lead a sedentary life but aspire to live a physically active lifestyle and take advantage of the many documented health benefits of exercise. However, recommendations for engaging in physical activity in patients with heart failure and cardiomyopathies are vague since proper evidence does not exist for each genetic disorder.

In large-scale, prospective studies, it has been shown that physical fitness level and all-cause mortality are inversely related, even when corrected for other known risk factors. VO2peak reflects the physiological correlate of oxidative capacity in the muscular and cardiovascular systems. Low VO2peak is linked with an increased risk of ischemic heart disease, cancer and metabolic syndrome.

As a result, increasing VO2peak in patients with cardiomyopathy, who often have low baseline values of VO2peak, could lead to substantial long-term health benefits.

The study is an open label, non-randomized clinical crossover trial, investigating the effect of an 8-week exercise program in patients with pathogenic TTN variants that dispose or has resulted in cardiomyopathy.

The crossover trial has a two-period design. In the first study period, participants will not be exposed to any intervention and will be advised to not start any new medications, diets or participate in any activities which could influence their health. In the second period, participants will perform regular moderate-intensity exercise 3 times/week. Both study periods will last 8 weeks.

Based on results from prior trials we estimated that training would improve VO2peak by 10% (an estimated absolute increase of 2.5 ml O2/kg/min) with a standard deviation of 8.5%. Accordingly, we estimated that inclusion of 10 subjects would provide a power of 91% to detect this difference at a significance level of 0.05, using a paired t-test. Assuming a drop-out-rate of 20% a total of 14 patients should as a minimum be enrolled in the study. As a result, we aimed for the inclusion of a minimum of 14 trial participants, but up to 27 (if practically feasible) to make the evaluation of underlying physiological mechanisms leading to improved fitness possible.

Our hypothesis is that moderate-intensity exercise training safely improves oxidative capacity and that beneficial effects are partly caused by improvements in cardiac contractility.

Study Type

Interventional

Enrollment (Actual)

14

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Copenhagen, Denmark, 2100
        • Copenhagen Neuromuscular Center, Rigshospitalet

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Age ≥ 18 years
  2. Mutations in the TTN gene leading to truncating variants in cardiac expressed exons of titin.
  3. A clinical diagnosis of dilated cardiomyopathy or fulfulling criteria for the diagnosis of heart failure or hypokinetic non-dilated cardiomyopathy.

Exclusion Criteria:

  1. New York Heart Association functional class IV.
  2. Patients with a left ventricular assist device or who have had a heart transplant.
  3. Change in heart failure medications within the last month.
  4. CRT implantation within the last 6 months.
  5. Inability to perform exercise due to orthopedic or other non-cardiovascular limitations.
  6. Clinical history of exercise-induced syncope likely caused by ventricular tachyarrhythmias.
  7. Current participation in moderate or high intensity exercise exceeding 2.5 hours/per week.
  8. Inability to give informed consent.
  9. Pregnant women.
  10. Severe vascular disease (IE claudicatio intermittens).
  11. Severe valvular disease (moderate aortic stenosis/regurgitation or severe mitral regurgitation/stenosis).
  12. Life expectancy less than 12 months.
  13. Expected reduced compliance.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Placebo periode
In the first study period, participants will not be exposed to any intervention and will be advised to not start any new medications, diets or participate in any activities which could influence their health.
Experimental: Exercise periode
In the second period, participants will perform regular moderate-intensity exercise 3 times/week.
Behavioral: Training
In the 8-week training period, participants will have three training sessions with a duration of 30 minutes at 70% of VO2peak per week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Difference in change in peak oxygen uptake (VO2peak) as measured in an incremental cycle-ergometer exercise test to exhaustion, in the placebo vs intervention period
Time Frame: 8 weeks
The VO2peak will be defined as the 20 consecutive seconds with the highest average VO2 during the incremental cycle-ergometer exercise test to exhaustion.
8 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Difference in change in left ventricular stroke volume at approximately 50% of maximal exertion in the placebo vs intervention period.
Time Frame: 8 weeks
Left ventricular stroke volume will be measured at the same load after the intervention periode and the placebo periode.
8 weeks
Change in blood volume with training.
Time Frame: 8 weeks
8 weeks
Change in hemoglobin mass with training.
Time Frame: 8 weeks
8 weeks
Difference in change in cardiac output at approximately 50% of maximal exertion in the placebo vs intervention period.
Time Frame: 8 weeks
Cardiac output will be measured at the same load after the intervention periode and the placebo periode.
8 weeks
Difference in change in cardiac output at 100% of VO2peak, in the placebo vs intervention period.
Time Frame: 8 weeks
The VO2peak will be defined as the 20 consecutive seconds with the highest average
8 weeks
Difference in change in left ventricular stroke volume at 100% of VO2peak, in the placebo vs intervention period.
Time Frame: 8 weeks
The VO2peak will be defined as the 20 consecutive seconds with the highest average
8 weeks
Difference in change in cardiac index at rest and during exercise
Time Frame: 8 weeks
8 weeks
Global longitudinal strain as measured by echocardiography
Time Frame: 8 weeks
8 weeks
Left ventricular volumetric measures from 3D echocardiography
Time Frame: 8 weeks
8 weeks
Change in systemic blood pressure
Time Frame: 8 weeks
8 weeks
Maximal workload in the maximal exercise test
Time Frame: 8 weeks
8 weeks
Performance in a 6-minute walk test
Time Frame: 8 weeks
8 weeks
Quality of life indicators as measured in the Short Form Health Survey (SF-36)
Time Frame: 8 weeks
8 weeks
Changes in cardiac and skeletomuscular biomarkers (CKMB, CK, NT proBNP, myoglobin, TnT, TnI)
Time Frame: 8 weeks
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rigshospitalet, Denmark

Investigators

  • Principal Investigator: John Vissing, MD PhD, Rigshospitalet, Denmark

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 14, 2022

Primary Completion (Actual)

September 21, 2022

Study Completion (Actual)

September 21, 2022

Study Registration Dates

First Submitted

December 17, 2021

First Submitted That Met QC Criteria

December 17, 2021

First Posted (Actual)

January 6, 2022

Study Record Updates

Last Update Posted (Actual)

November 22, 2022

Last Update Submitted That Met QC Criteria

November 21, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 75682

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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