CardiomyopathiesNCT05180188
Moderate Intensity Training in Patients With Truncating Genetic Variants in TTN.
A study testing Training in people with Cardiomyopathies and Truncation Mutation, run by Copenhagen University Hospital, Rigshospitalet at 1 site in Denmark.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cardiomyopathies, Truncation Mutation, TTN
- What is being tested?
- Training
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 1 siteDenmark
- Study dates
- 14 Feb 2022to 21 Sep 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Mutations in the TTN gene leading to truncating variants in cardiac expressed exons of titin.
- A clinical diagnosis of dilated cardiomyopathy or fulfulling criteria for the diagnosis of heart failure or hypokinetic non-dilated cardiomyopathy.
Who cannot join
- New York Heart Association functional class IV.
- Patients with a left ventricular assist device or who have had a heart transplant.
- Change in heart failure medications within the last month.
- CRT implantation within the last 6 months.
- Inability to perform exercise due to orthopedic or other non-cardiovascular limitations.
- Clinical history of exercise-induced syncope likely caused by ventricular tachyarrhythmias.
Show all 13Show fewer
- Current participation in moderate or high intensity exercise exceeding 2.5 hours/per week.
- Inability to give informed consent.
- Pregnant women.
- Severe vascular disease (IE claudicatio intermittens).
- Severe valvular disease (moderate aortic stenosis/regurgitation or severe mitral regurgitation/stenosis).
- Life expectancy less than 12 months.
- Expected reduced compliance.
Trial locations and contacts
1 site in 1 country.
Denmark1 site
Copenhagen Neuromuscular Center, Rigshospitalet
Copenhagen, 2100
About this study
Official title: 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.
Read the 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.
- Conditions
- Cardiomyopathies, Truncation Mutation, TTN
- Being tested
- Training
- Keywords
- TTNtv mutation, Intensity training, Exercise, VO2 max, Cardiac output
- Medical subject headings
- Cardiomyopathies, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TrainingBehavioural
In the 8-week training period, participants will have three training sessions with a duration of 30 minutes at 70% of VO2peak per week.
| Study group | Role | What they receive |
|---|---|---|
| Placebo periode | No intervention | 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. |
| Exercise periode | Experimental | In the second period, participants will perform regular moderate-intensity exercise 3 times/week. Receives: Behavioral: Training |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
The VO2peak will be defined as the 20 consecutive seconds with the highest average VO2 during the incremental cycle-ergometer exercise test to exhaustion.
Measured: 8 weeks
Secondary outcomes (14)
Difference in change in left ventricular stroke volume at approximately 50% of maximal exertion in the placebo vs intervention period.
Left ventricular stroke volume will be measured at the same load after the intervention periode and the placebo periode.
Measured: 8 weeks
Change in blood volume with training.
Measured: 8 weeks
Change in hemoglobin mass with training.
Measured: 8 weeks
Difference in change in cardiac output at approximately 50% of maximal exertion in the placebo vs intervention period.
Cardiac output will be measured at the same load after the intervention periode and the placebo periode.
Measured: 8 weeks
Difference in change in cardiac output at 100% of VO2peak, in the placebo vs intervention period.
The VO2peak will be defined as the 20 consecutive seconds with the highest average
Measured: 8 weeks
Difference in change in left ventricular stroke volume at 100% of VO2peak, in the placebo vs intervention period.
The VO2peak will be defined as the 20 consecutive seconds with the highest average
Measured: 8 weeks
Difference in change in cardiac index at rest and during exercise
Measured: 8 weeks
Global longitudinal strain as measured by echocardiography
Measured: 8 weeks
Left ventricular volumetric measures from 3D echocardiography
Measured: 8 weeks
Change in systemic blood pressure
Measured: 8 weeks
Maximal workload in the maximal exercise test
Measured: 8 weeks
Performance in a 6-minute walk test
Measured: 8 weeks
Quality of life indicators as measured in the Short Form Health Survey (SF-36)
Measured: 8 weeks
Changes in cardiac and skeletomuscular biomarkers (CKMB, CK, NT proBNP, myoglobin, TnT, TnI)
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jan 2022
- Study start14 Feb 2022
- Primary completion21 Sep 2022
- Study completion21 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (35)Papers the sponsor has linked to this study.
- Other trials for CardiomyopathiesStudies of the same condition, open and under way.
- More trials run by Copenhagen University Hospital, RigshospitaletThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- Copenhagen University Hospital, Rigshospitalet
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ida Finsen Flensted, Copenhagen University Hospital, Rigshospitalet
- Investigators
- John Vissing, MD PhD, Principal investigator, Copenhagen University Hospital, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05180188
- Sponsor's protocol ID
- 75682
- Status last verified
- Nov 2022
- First submitted
- 17 Dec 2021
- Last updated
- 22 Nov 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. doi: 10.1056/NEJMoa1110186.
PubMed 22335739Tayal U, Prasad S, Cook SA. Genetics and genomics of dilated cardiomyopathy and systolic heart failure. Genome Med. 2017 Feb 22;9(1):20. doi: 10.1186/s13073-017-0410-8.
PubMed 28228157Ahlberg G, Refsgaard L, Lundegaard PR, Andreasen L, Ranthe MF, Linscheid N, Nielsen JB, Melbye M, Haunso S, Sajadieh A, Camp L, Olesen SP, Rasmussen S, Lundby A, Ellinor PT, Holst AG, Svendsen JH, Olesen MS. Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation. Nat Commun. 2018 Oct 17;9(1):4316. doi: 10.1038/s41467-018-06618-y.
PubMed 30333491Corden B, Jarman J, Whiffin N, Tayal U, Buchan R, Sehmi J, Harper A, Midwinter W, Lascelles K, Markides V, Mason M, Baksi J, Pantazis A, Pennell DJ, Barton PJ, Prasad SK, Wong T, Cook SA, Ware JS. Association of Titin-Truncating Genetic Variants With Life-threatening Cardiac Arrhythmias in Patients With Dilated Cardiomyopathy and Implanted Defibrillators. JAMA Netw Open. 2019 Jun 5;2(6):e196520. doi: 10.1001/jamanetworkopen.2019.6520.
PubMed 31251381Tayal U, Newsome S, Buchan R, Whiffin N, Walsh R, Barton PJ, Ware JS, Cook SA, Prasad SK. Truncating Variants in Titin Independently Predict Early Arrhythmias in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol. 2017 May 16;69(19):2466-2468. doi: 10.1016/j.jacc.2017.03.530. No abstract available.
PubMed 28494986Choi SH, Weng LC, Roselli C, Lin H, Haggerty CM, Shoemaker MB, Barnard J, Arking DE, Chasman DI, Albert CM, Chaffin M, Tucker NR, Smith JD, Gupta N, Gabriel S, Margolin L, Shea MA, Shaffer CM, Yoneda ZT, Boerwinkle E, Smith NL, Silverman EK, Redline S, Vasan RS, Burchard EG, Gogarten SM, Laurie C, Blackwell TW, Abecasis G, Carey DJ, Fornwalt BK, Smelser DT, Baras A, Dewey FE, Jaquish CE, Papanicolaou GJ, Sotoodehnia N, Van Wagoner DR, Psaty BM, Kathiresan S, Darbar D, Alonso A, Heckbert SR, Chung MK, Roden DM, Benjamin EJ, Murray MF, Lunetta KL, Lubitz SA, Ellinor PT; DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium. Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation. JAMA. 2018 Dec 11;320(22):2354-2364. doi: 10.1001/jama.2018.18179.
PubMed 30535219Verdonschot JAJ, Hazebroek MR, Derks KWJ, Barandiaran Aizpurua A, Merken JJ, Wang P, Bierau J, van den Wijngaard A, Schalla SM, Abdul Hamid MA, van Bilsen M, van Empel VPM, Knackstedt C, Brunner-La Rocca HP, Brunner HG, Krapels IPC, Heymans SRB. Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias. Eur Heart J. 2018 Mar 7;39(10):864-873. doi: 10.1093/eurheartj/ehx808.
PubMed 29377983Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O'Regan DP, San TR, de Marvao A, Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O'Donnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SA. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015 Jan 14;7(270):270ra6. doi: 10.1126/scitranslmed.3010134.
PubMed 25589632Jansweijer JA, Nieuwhof K, Russo F, Hoorntje ET, Jongbloed JD, Lekanne Deprez RH, Postma AV, Bronk M, van Rijsingen IA, de Haij S, Biagini E, van Haelst PL, van Wijngaarden J, van den Berg MP, Wilde AA, Mannens MM, de Boer RA, van Spaendonck-Zwarts KY, van Tintelen JP, Pinto YM. Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy. Eur J Heart Fail. 2017 Apr;19(4):512-521. doi: 10.1002/ejhf.673. Epub 2016 Nov 3.
PubMed 27813223Jansen M, Baas AF, van Spaendonck-Zwarts KY, Ummels AS, van den Wijngaard A, Jongbloed JDH, van Slegtenhorst MA, Lekanne Deprez RH, Wessels MW, Michels M, Houweling AC, Hoorntje ET, Helderman-van den Enden PJTM, Barge-Schaapveld DQCM, Peter van Tintelen J, van den Berg MP, Wilde AAM, Ploos van Amstel HK, Hennekam EAM, Asselbergs FW, Sijbrands EJG, Dooijes D. Mortality Risk Associated With Truncating Founder Mutations in Titin. Circ Genom Precis Med. 2019 May;12(5):e002436. doi: 10.1161/CIRCGEN.118.002436.
PubMed 31112426Verdonschot JAJ, Hazebroek MR, Wang P, Sanders-van Wijk S, Merken JJ, Adriaansen YA, van den Wijngaard A, Krapels IPC, Brunner-La Rocca HP, Brunner HG, Heymans SRB. Clinical Phenotype and Genotype Associations With Improvement in Left Ventricular Function in Dilated Cardiomyopathy. Circ Heart Fail. 2018 Nov;11(11):e005220. doi: 10.1161/CIRCHEARTFAILURE.118.005220.
PubMed 30571196Felkin LE, Walsh R, Ware JS, Yacoub MH, Birks EJ, Barton PJ, Cook SA. Recovery of Cardiac Function in Cardiomyopathy Caused by Titin Truncation. JAMA Cardiol. 2016 May 1;1(2):234-5. doi: 10.1001/jamacardio.2016.0208. No abstract available.
PubMed 27437901Hinson JT, Chopra A, Nafissi N, Polacheck WJ, Benson CC, Swist S, Gorham J, Yang L, Schafer S, Sheng CC, Haghighi A, Homsy J, Hubner N, Church G, Cook SA, Linke WA, Chen CS, Seidman JG, Seidman CE. HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science. 2015 Aug 28;349(6251):982-6. doi: 10.1126/science.aaa5458.
PubMed 26315439Huttner IG, Wang LW, Santiago CF, Horvat C, Johnson R, Cheng D, von Frieling-Salewsky M, Hillcoat K, Bemand TJ, Trivedi G, Braet F, Hesselson D, Alford K, Hayward CS, Seidman JG, Seidman CE, Feneley MP, Linke WA, Fatkin D. A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance. Circ Genom Precis Med. 2018 Aug;11(8):e002135. doi: 10.1161/CIRCGEN.118.002135.
PubMed 30354343Gramlich M, Michely B, Krohne C, Heuser A, Erdmann B, Klaassen S, Hudson B, Magarin M, Kirchner F, Todiras M, Granzier H, Labeit S, Thierfelder L, Gerull B. Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease. J Mol Cell Cardiol. 2009 Sep;47(3):352-8. doi: 10.1016/j.yjmcc.2009.04.014. Epub 2009 May 4.
PubMed 19406126
Study at a glance
From the registry record, last updated by the sponsor on 22 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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.
- ClinicalTrials.gov ID
- NCT05180188
- Acronym / sponsor ID
- 75682
- Conditions
- Cardiomyopathies, Truncation Mutation, TTN
- Keywords
- TTNtv mutation, Intensity training, Exercise, VO2 max, Cardiac output
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- Copenhagen University Hospital, RigshospitaletUniversity, hospital or other
- Study start
- 14 Feb 2022 (actual)
- Primary completion
- 21 Sep 2022 (actual)
- Study completion
- 21 Sep 2022 (actual)
- First posted
- 6 Jan 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Placebo periode | No intervention | –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. |
| Exercise periode | Experimental | Behavioral: TrainingIn the second period, participants will perform regular moderate-intensity exercise 3 times/week. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Age ≥ 18 years
- Mutations in the TTN gene leading to truncating variants in cardiac expressed exons of titin.
- A clinical diagnosis of dilated cardiomyopathy or fulfulling criteria for the diagnosis of heart failure or hypokinetic non-dilated cardiomyopathy.
Key exclusion criteria (13 listed)
- New York Heart Association functional class IV.
- Patients with a left ventricular assist device or who have had a heart transplant.
- Change in heart failure medications within the last month.
- CRT implantation within the last 6 months.
- Inability to perform exercise due to orthopedic or other non-cardiovascular limitations.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TrainingIn the 8-week training period, participants will have three training sessions with a duration of 30 minutes at 70% of VO2peak per week. | Behavioural | Exercise periode |
Primary outcome
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.
14 secondary outcomes
Difference in change in left ventricular stroke volume at approximately 50% of maximal exertion in the placebo vs intervention period.
Time frame: 8 weeks
Change in blood volume with training.
Time frame: 8 weeks
Change in hemoglobin mass with training.
Time frame: 8 weeks
Difference in change in cardiac output at approximately 50% of maximal exertion in the placebo vs intervention period.
Time frame: 8 weeks
Difference in change in cardiac output at 100% of VO2peak, in the placebo vs intervention period.
Time frame: 8 weeks
Difference in change in left ventricular stroke volume at 100% of VO2peak, in the placebo vs intervention period.
Time frame: 8 weeks
Difference in change in cardiac index at rest and during exercise
Time frame: 8 weeks
Global longitudinal strain as measured by echocardiography
Time frame: 8 weeks
Left ventricular volumetric measures from 3D echocardiography
Time frame: 8 weeks
Change in systemic blood pressure
Time frame: 8 weeks
Maximal workload in the maximal exercise test
Time frame: 8 weeks
Performance in a 6-minute walk test
Time frame: 8 weeks
Quality of life indicators as measured in the Short Form Health Survey (SF-36)
Time frame: 8 weeks
Changes in cardiac and skeletomuscular biomarkers (CKMB, CK, NT proBNP, myoglobin, TnT, TnI)
Time frame: 8 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Nov 2022.
- Background: PubMed 22335739Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. doi: 10.1056/NEJMoa1110186.
- Background: PubMed 28228157Tayal U, Prasad S, Cook SA. Genetics and genomics of dilated cardiomyopathy and systolic heart failure. Genome Med. 2017 Feb 22;9(1):20. doi: 10.1186/s13073-017-0410-8.
- Background: PubMed 30333491Ahlberg G, Refsgaard L, Lundegaard PR, Andreasen L, Ranthe MF, Linscheid N, Nielsen JB, Melbye M, Haunso S, Sajadieh A, Camp L, Olesen SP, Rasmussen S, Lundby A, Ellinor PT, Holst AG, Svendsen JH, Olesen MS. Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation. Nat Commun. 2018 Oct 17;9(1):4316. doi: 10.1038/s41467-018-06618-y.
- Background: PubMed 31251381Corden B, Jarman J, Whiffin N, Tayal U, Buchan R, Sehmi J, Harper A, Midwinter W, Lascelles K, Markides V, Mason M, Baksi J, Pantazis A, Pennell DJ, Barton PJ, Prasad SK, Wong T, Cook SA, Ware JS. Association of Titin-Truncating Genetic Variants With Life-threatening Cardiac Arrhythmias in Patients With Dilated Cardiomyopathy and Implanted Defibrillators. JAMA Netw Open. 2019 Jun 5;2(6):e196520. doi: 10.1001/jamanetworkopen.2019.6520.
- Background: PubMed 28494986Tayal U, Newsome S, Buchan R, Whiffin N, Walsh R, Barton PJ, Ware JS, Cook SA, Prasad SK. Truncating Variants in Titin Independently Predict Early Arrhythmias in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol. 2017 May 16;69(19):2466-2468. doi: 10.1016/j.jacc.2017.03.530. No abstract available.
- Background: PubMed 30535219Choi SH, Weng LC, Roselli C, Lin H, Haggerty CM, Shoemaker MB, Barnard J, Arking DE, Chasman DI, Albert CM, Chaffin M, Tucker NR, Smith JD, Gupta N, Gabriel S, Margolin L, Shea MA, Shaffer CM, Yoneda ZT, Boerwinkle E, Smith NL, Silverman EK, Redline S, Vasan RS, Burchard EG, Gogarten SM, Laurie C, Blackwell TW, Abecasis G, Carey DJ, Fornwalt BK, Smelser DT, Baras A, Dewey FE, Jaquish CE, Papanicolaou GJ, Sotoodehnia N, Van Wagoner DR, Psaty BM, Kathiresan S, Darbar D, Alonso A, Heckbert SR, Chung MK, Roden DM, Benjamin EJ, Murray MF, Lunetta KL, Lubitz SA, Ellinor PT; DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium. Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation. JAMA. 2018 Dec 11;320(22):2354-2364. doi: 10.1001/jama.2018.18179.
- Background: PubMed 29377983Verdonschot JAJ, Hazebroek MR, Derks KWJ, Barandiaran Aizpurua A, Merken JJ, Wang P, Bierau J, van den Wijngaard A, Schalla SM, Abdul Hamid MA, van Bilsen M, van Empel VPM, Knackstedt C, Brunner-La Rocca HP, Brunner HG, Krapels IPC, Heymans SRB. Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias. Eur Heart J. 2018 Mar 7;39(10):864-873. doi: 10.1093/eurheartj/ehx808.
- Background: PubMed 25589632Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O'Regan DP, San TR, de Marvao A, Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O'Donnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SA. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015 Jan 14;7(270):270ra6. doi: 10.1126/scitranslmed.3010134.
- Background: PubMed 27813223Jansweijer JA, Nieuwhof K, Russo F, Hoorntje ET, Jongbloed JD, Lekanne Deprez RH, Postma AV, Bronk M, van Rijsingen IA, de Haij S, Biagini E, van Haelst PL, van Wijngaarden J, van den Berg MP, Wilde AA, Mannens MM, de Boer RA, van Spaendonck-Zwarts KY, van Tintelen JP, Pinto YM. Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy. Eur J Heart Fail. 2017 Apr;19(4):512-521. doi: 10.1002/ejhf.673. Epub 2016 Nov 3.
- Background: PubMed 31112426Jansen M, Baas AF, van Spaendonck-Zwarts KY, Ummels AS, van den Wijngaard A, Jongbloed JDH, van Slegtenhorst MA, Lekanne Deprez RH, Wessels MW, Michels M, Houweling AC, Hoorntje ET, Helderman-van den Enden PJTM, Barge-Schaapveld DQCM, Peter van Tintelen J, van den Berg MP, Wilde AAM, Ploos van Amstel HK, Hennekam EAM, Asselbergs FW, Sijbrands EJG, Dooijes D. Mortality Risk Associated With Truncating Founder Mutations in Titin. Circ Genom Precis Med. 2019 May;12(5):e002436. doi: 10.1161/CIRCGEN.118.002436.
- Background: PubMed 30571196Verdonschot JAJ, Hazebroek MR, Wang P, Sanders-van Wijk S, Merken JJ, Adriaansen YA, van den Wijngaard A, Krapels IPC, Brunner-La Rocca HP, Brunner HG, Heymans SRB. Clinical Phenotype and Genotype Associations With Improvement in Left Ventricular Function in Dilated Cardiomyopathy. Circ Heart Fail. 2018 Nov;11(11):e005220. doi: 10.1161/CIRCHEARTFAILURE.118.005220.
- Background: PubMed 27437901Felkin LE, Walsh R, Ware JS, Yacoub MH, Birks EJ, Barton PJ, Cook SA. Recovery of Cardiac Function in Cardiomyopathy Caused by Titin Truncation. JAMA Cardiol. 2016 May 1;1(2):234-5. doi: 10.1001/jamacardio.2016.0208. No abstract available.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John Vissing, MD PhD principal investigator
Copenhagen University Hospital, Rigshospitalet
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Training in people with Cardiomyopathies and Truncation Mutation, run by Copenhagen University Hospital, Rigshospitalet at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05180188, which also lists 35 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Nov 2022.