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Trial record 17 of 9014 for:    Genetic Diseases, Inborn AND genetic disorder

Evaluate the Effort Test as a Therapeutic Monitoring Tool in Acute Rhabdomyolyses (EFFORHAB)

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ClinicalTrials.gov Identifier: NCT03802279
Recruitment Status : Not yet recruiting
First Posted : January 14, 2019
Last Update Posted : January 14, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

The prognosis of rhabdomyolyses related to hereditary diseases of metabolism is poor and treatments are only symptomatic. Rhabdomyolysis outbreaks are frequently precipitated by fever and fasting. They are unpredictable. In spite of the care of patient in an intensive care unit, the occurrence of renal failure and heart rhythm disorders explains a significant acute-phase mortality rate. There is an urgent need to understand the pathophysiological mechanisms of rhabdomyolyses related to hereditary diseases of metabolism, in order to identify specific treatments.

Patients with rhabdomyolyses have few clinical signs outside of access. So there is a methodological difficulty in following a treatment test. There is an urgency to identify follow-up parameters in anticipation of new therapies.

The objective of this study is to validate the hypothesis that effort test and cardiac function parameters are usable in the treatment monitoring for patients with acute rhabdomyolysis linked to a hereditary disease of metabolism and thus propose the effort test as an assessment tool for future clinical trials. In order to do so, the correlation between the results of the effort tests, performed to each patient with rhabdomyolysis related to a hereditary disease of metabolism, with the severity of the disease will be evaluated. This study is original because it opens up innovative prospects for monitoring in the field of hereditary diseases of metabolism, with the identification of new monitoring tools.


Condition or disease Intervention/treatment
Rhabdomyolysis Linked to a Hereditary Disease of Metabolism Other: Effort test Other: Functional tests on fibroblasts

  Show Detailed Description

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Study Type : Observational
Estimated Enrollment : 56 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Study of the Correlation Between the Effort Test, With the Assessment of Peripheral Oxygen Consumption and Cardiac Output in Patients With Acute Rhabdomyolysis Related to a Hereditary Disease of Metabolism, and the Biochemical Flux on Myoblasts: Evaluate the Effort Test as a Therapeutic Monitoring Tool in Acute Rhabdomyolyses
Estimated Study Start Date : January 2019
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : March 2021

Group/Cohort Intervention/treatment
Rhabdomyolysis with myoblasts back up

Patients with a rhabdomyolysis linked to a hereditary disease of metabolism who have benefited from a diagnostically muscle biopsy and whose myoblasts are available.

Patients benefit from an effort test as part of their care.

Other: Effort test

Cardiac function:

Echocardiography: left ventricular ejection fraction and global longitudinal strain will be measured.

Cardiopulmonary exercise test (CPET): left ventricular stroke volume was assessed noninvasively using a thoracic bioelectrical impedance device : maximal stroke volume at the peak of effort will be considered.

Peripheral muscle function:

  • CPET: Oxygen uptake (VO2) (and carbon dioxide) output are measured. The slope of the relationship (dQ/dVO2) will be calculated between cardiac output (Q) and VO2 using measurements of Q (using measure of the stroke volume by thoracic bioelectrical impedance device) and VO2 at rest as well as during submaximal and maximal exercise
  • Muscle oxygenation is measured using a near-infrared spectroscopy device.
  • VO2 et Q will be measured : dQ/dVO2 is high in case of oxydation defect; If Q is low because of a concommittant cardiac impairement, the DAV = VO2/Q, and DO = (Q x DAV) / (200 - DAV) will be calculated.

Other: Functional tests on fibroblasts
Functional tests performed on fibroblasts in primary culture, using as tracers of stable isotope-labeled substrates. The metabolites of interest are assayed in mass spectrometry.

Rhabdomyolysis

Patients with a rhabdomyolysis linked to a hereditary disease of metabolism who have benefited or not from a diagnostically muscle biopsy but whose myoblasts are not available.

Patients benefit from an effort test as part of their care.

Other: Effort test

Cardiac function:

Echocardiography: left ventricular ejection fraction and global longitudinal strain will be measured.

Cardiopulmonary exercise test (CPET): left ventricular stroke volume was assessed noninvasively using a thoracic bioelectrical impedance device : maximal stroke volume at the peak of effort will be considered.

Peripheral muscle function:

  • CPET: Oxygen uptake (VO2) (and carbon dioxide) output are measured. The slope of the relationship (dQ/dVO2) will be calculated between cardiac output (Q) and VO2 using measurements of Q (using measure of the stroke volume by thoracic bioelectrical impedance device) and VO2 at rest as well as during submaximal and maximal exercise
  • Muscle oxygenation is measured using a near-infrared spectroscopy device.
  • VO2 et Q will be measured : dQ/dVO2 is high in case of oxydation defect; If Q is low because of a concommittant cardiac impairement, the DAV = VO2/Q, and DO = (Q x DAV) / (200 - DAV) will be calculated.

Witness patients : effort test
10 patient-matched healthy controls for age and sex having performed an effort test and cardiac exploration as part of their care.
Other: Effort test

Cardiac function:

Echocardiography: left ventricular ejection fraction and global longitudinal strain will be measured.

Cardiopulmonary exercise test (CPET): left ventricular stroke volume was assessed noninvasively using a thoracic bioelectrical impedance device : maximal stroke volume at the peak of effort will be considered.

Peripheral muscle function:

  • CPET: Oxygen uptake (VO2) (and carbon dioxide) output are measured. The slope of the relationship (dQ/dVO2) will be calculated between cardiac output (Q) and VO2 using measurements of Q (using measure of the stroke volume by thoracic bioelectrical impedance device) and VO2 at rest as well as during submaximal and maximal exercise
  • Muscle oxygenation is measured using a near-infrared spectroscopy device.
  • VO2 et Q will be measured : dQ/dVO2 is high in case of oxydation defect; If Q is low because of a concommittant cardiac impairement, the DAV = VO2/Q, and DO = (Q x DAV) / (200 - DAV) will be calculated.

Witness patients : myoblasts
6 healthy controls matched by age and sex having performed a muscle biopsy as part of their care and whose myoblasts are kept.
Other: Functional tests on fibroblasts
Functional tests performed on fibroblasts in primary culture, using as tracers of stable isotope-labeled substrates. The metabolites of interest are assayed in mass spectrometry.




Primary Outcome Measures :
  1. Measurement of cardiac output (Q) [ Time Frame: Day 0 ]
    Effort test

  2. Measurement of oxygen consumption (VO2) [ Time Frame: Day 0 ]
    Effort test

  3. Calculation of the slope of the relationship heart rate-oxygen consumed (dQ/dVO2) [ Time Frame: Day 0 ]
    Effort test

  4. Calculation of the maximum arteriovenous difference (DAV) : DAV=VO2/Q [ Time Frame: Day 0 ]
    Effort test

  5. Calculation of maximum muscle diffusion (DM) using the equation of Fick: DM = (Q x DAV)/(200-DAV) [ Time Frame: Day 0 ]
    Effort test

  6. Peripheral muscular oxygenation [ Time Frame: Day 0 ]
    Measurement of peripheral muscular oxygenation during the effort test.

  7. Systolic ejection volume at the peak of the effort during the effort test [ Time Frame: Day 0 ]

    Evaluation of cardiac performance by the value of the systolic ejection volume at the peak of the effort.

    The systolic ejection volume is measured beat per beat during the effort test.


  8. Ejection fraction of the left ventricle [ Time Frame: Day 0 ]
    Measurement of the ejection fraction of the left ventricle in Simpson biplane and the longitudinal strain of the left ventricle in echocardiography.

  9. Metabolic pathways of myoblasts [ Time Frame: From study start until 26 months ]
    Myoblasts will be incubated in the presence of stable isotope-labeled tracers. The natural metabolites labelled with stable isotopes will be dosed. The acylcarnitines will be dosed on a mass spectrometer. The Krebs cycle intermediates will be measured in gas chromatography coupled with mass spectrometry.


Secondary Outcome Measures :
  1. Presence of cardiomyopathy [ Time Frame: Day 0 ]
    Clinical severity of rhabdomyolysis linked to a hereditary disease of metabolism.

  2. Age of onset of disease (neonatal, < 2 years, 2 - 10 years, > 10 years) [ Time Frame: Day 0 ]
    Clinical severity of rhabdomyolysis linked to a hereditary disease of metabolism.

  3. Number of acute episodes of rhabdomyolyses [ Time Frame: Day 0 ]
    Clinical severity of rhabdomyolysis linked to a hereditary disease of metabolism.

  4. Character of mutations nonsense or missense of the hereditary disease of metabolism [ Time Frame: Day 0 ]

    Genotypic severity of rhabdomyolysis linked to a hereditary disease of metabolism.

    Information available in the patient medical record.




Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The population to be studied consists of 40 patients with metabolic rhabdomyolyses followed by the centre of reference for metabolic diseases of the child and adult of the Necker Hospital.
Criteria

subjects with metabolic rhabdomyolysis related to a hereditary metabolic disease :

Inclusion Criteria:

  • pathology characterized on the biochemical and molecular level
  • patients who can make an effort test
  • patients who benefited from a diagnostically targeted muscle biopsy with backup of myoblasts (group 1)
  • patients who have benefited from a diagnostically targeted muscle biopsy but whose myoblasts are not available (group 2) Exclusion Criteria
  • inability or refusal of compliance to the requirements of the research
  • patients with contraindications for the effort test in particular heart failure and acute rhabdomyolysis
  • Patients without biochemical and/or molecular diagnosis

Criteria for inclusion of witness patients :

  • holders of parental authority and/or patients not opposed to the use of their cardio-respiratory analysis results for this study or to the use of their myoblasts for this study
  • normal cardio-respiratory analysis results
  • normal myoblasts (group 4).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03802279


Contacts
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Contact: Pascale de Lonlay, Professor +33 1 44 49 48 52 pascale.delonlay@aphp.fr
Contact: Hélène Morel +33 1 44 38 16 53 helene.morel@aphp.fr

Locations
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France
Hôpital Necker-Enfants Malades Not yet recruiting
Paris, France, 75015
Contact: Pascale de Lonlay, Professor    +33 1 44 49 48 52    pascale.delonlay@aphp.fr   
Contact: Hélène Morel    +33 1 71 19 63 46    helene.morel@aphp.fr   
Sub-Investigator: Jean-Baptiste Arnoux, MD, PhD         
Sub-Investigator: Antoine Legendre, MD, PhD         
Sub-Investigator: Diala Khraiche, MD, PhD         
Sub-Investigator: Florence Habarou, MD, PhD         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Pascale de Lonlay Assistance Publique - Hôpitaux de Paris
Study Chair: Antoine Legendre, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Chair: Florence Habarou, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Chair: Caroline Tuchmann-Durand, MD, PhD Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03802279     History of Changes
Other Study ID Numbers: APHP 180 009
2018-A01771-54 ( Registry Identifier: ID-RCB )
First Posted: January 14, 2019    Key Record Dates
Last Update Posted: January 14, 2019
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Rhabdomyolysis linked to a hereditary disease of metabolism
Correlation between the effort test and the severity of the disease and biochemical flux on myoblasts
Additional relevant MeSH terms:
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Rhabdomyolysis
Genetic Diseases, Inborn
Muscular Diseases
Musculoskeletal Diseases