Clinical trial NCT03802279: Evaluate the Effort Test as a Therapeutic Monitoring Tool in Acute Rhabdomyolyses
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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Rhabdomyolysis Linked to a Hereditary Disease of Metabolism
Keywords: Rhabdomyolysis linked to a hereditary disease of metabolism
Correlation between the effort test and the severity of the disease and biochemical flux on myoblasts
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2019-01-14
Enrollment: 27
Sex: ALL
Minimum age (years): 6
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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.

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.

Detailed description: Rhabdomyolysis is a poorly known symptom associated with the destruction of skeletal muscle cells. The diagnosis of rhabdomyolyses is carried when the dosage of muscle enzymes, in particular creatine phosphate kinase (KPC), is greater than 1000 U/L (normal \< 160 U/L).

Rhabdomyolyses may be of viral origin, but fever and viruses are also triggers of genetic diseases. Also, the incidence of genetic rhabdomyolyses, representing 10 to 15% of all rhabdomyolyses, is underestimated. Genetic causes are heterogeneous. They are mainly attributed to hereditary diseases of metabolism, in particular fatty acid oxidation defects, Lipin-1 deficiency, muscle glycogenoses, TANGO2 deficiency, mitochondrial cytopathies and calcium channels anomalies of in particular RYR1.

Whatever the cause, traumatic, infectious or genetic, the rhabdomyolyses cause an alteration of the metabolism of adenosine triphosphate and a deregulation of the ionic channels, with the consequences of an intracytoplasmic calcium release and the destruction of muscle cells.

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.

The pathophysiological mechanism of rhabdomyolyses related to Lipin-1 deficiency has been identified. Two patients with Lipin-1 deficiency treated in vivo by Hydroxychloroquine (Plaquenil ®, 6 mg/kg/day by one oral intake) rapidly standardized their serum inflammatory profile and corrected their clinical phenotype: Plasma creatine phosphokinase levels, Amount of mitochondrial DNA in plasma, number of myolyses, muscular pain, quality of life. One of these two patients, suffering from cardiac dysfunction already reported in Lipin-1 deficiency (left ventricular ejection fraction or LVEF 45%), significantly and durably improved cardiac function after one month of treatment (LVEF 62%). In addition, his fatigability and sleep disturbances have dramatically improved.

Disruption of mitophagy and immunity could be a common denominator for rhabdomyolyses linked to hereditary diseases of metabolism, which could, despite their heterogeneity, benefit from a common therapeutic approach, Now non-existent. There could be a role of inflammation in rhabdomyolyses outbreaks of metabolic origin and new therapeutic approaches could be imagined as in the Lipin-1 deficiency.

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.

In the Lipin deficiency, an anomaly of the effort tests with measurement of oxygen consumption and cardiac output was characterized. These effort tests were carried out in the context of care, in order to recognize for a given patient whether the practice of sport is a factor triggering rhabdomyolysis.

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. To date, no tests are available for 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 assessed, including:

1) Metabolic flux on myoblasts, 2) clinical severity (onset of disease, number of rhabdomyolyses, cardiomyopathy), 3) genotype.

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.

Eligibility 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).

Primary outcomes:
measure: Measurement of cardiac output (Q)
timeFrame: Day 0
measure: Measurement of oxygen consumption (VO2)
timeFrame: Day 0
measure: Calculation of the slope of the relationship heart rate-oxygen consumed (dQ/dVO2)
timeFrame: Day 0
measure: Calculation of the maximum arteriovenous difference (DAV) : DAV=VO2/Q
timeFrame: Day 0
measure: Calculation of maximum muscle diffusion (DM) using the equation of Fick: DM = (Q x DAV)/(200-DAV)
timeFrame: Day 0
measure: Peripheral muscular oxygenation
timeFrame: Day 0
measure: Systolic ejection volume at the peak of the effort during the effort test
timeFrame: Day 0
measure: Ejection fraction of the left ventricle
timeFrame: Day 0
measure: Metabolic pathways of myoblasts
timeFrame: From study start until 26 months
Secondary outcomes:
measure: Presence of cardiomyopathy
timeFrame: Day 0
measure: Age of onset of disease (neonatal, < 2 years, 2 - 10 years, > 10 years)
timeFrame: Day 0
measure: Number of acute episodes of rhabdomyolyses
timeFrame: Day 0
measure: Character of mutations nonsense or missense of the hereditary disease of metabolism
timeFrame: Day 0
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Pascale de Lonlay
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Antoine Legendre, MD, PhD
role: STUDY_CHAIR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Florence Habarou, MD, PhD
role: STUDY_CHAIR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Caroline Tuchmann-Durand, Pharm. D, PhD
role: STUDY_CHAIR
References: