## Protocol Section
### Identification Module
**NCT ID:** NCT03802279

**Acronym:** EFFORHAB

**Brief Title:** 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

#### Organization Study ID Info
**ID:** APHP 180 009
#### Organization
**Class:** OTHER
**Full Name:** Assistance Publique - Hôpitaux de Paris
#### Secondary ID Infos
**Domain:** ID-RCB
**ID:** 2018-A01771-54
**Type:** REGISTRY
### Status Module
#### Completion Date
**Date:** 2021-12-31

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2022-10-12

**Type:** ACTUAL

**Last Update Submit Date:** 2022-10-10

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2021-12-31

**Type:** ACTUAL

#### Start Date
**Date:** 2019-10-25

**Type:** ACTUAL

**Status Verified Date:** 2022-10

#### Study First Post Date
**Date:** 2019-01-14
**Type:** ACTUAL
**Study First Submit Date:** 2018-12-06
**Study First Submit QC Date:** 2019-01-10
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Assistance Publique - Hôpitaux de Paris

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**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.

### Conditions Module

**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

### Design Module

#### Design Info

**Observational Model:** CASE_CONTROL

**Time Perspective:** PROSPECTIVE

#### Enrollment Info

**Count:** 27

**Type:** ACTUAL

**Study Type:** OBSERVATIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 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.

**Intervention Names:**

- Other: Effort test

- Other: Functional tests on fibroblasts

**Label:** Rhabdomyolysis with myoblasts back up

#### Arm Group 2

**Description:** 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.

**Intervention Names:**

- Other: Effort test

**Label:** Rhabdomyolysis

#### Arm Group 3

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

**Intervention Names:**

- Other: Effort test

**Label:** Witness patients : effort test

#### Arm Group 4

**Description:** 6 healthy controls matched by age and sex having performed a muscle biopsy as part of their care and whose myoblasts are kept.

**Intervention Names:**

- Other: Functional tests on fibroblasts

**Label:** Witness patients : myoblasts

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Rhabdomyolysis

- Rhabdomyolysis with myoblasts back up

- Witness patients : effort test

**Description:** 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.

**Name:** Effort test

**Type:** OTHER

#### Intervention 2

**Arm Group Labels:**

- Rhabdomyolysis with myoblasts back up

- Witness patients : myoblasts

**Description:** 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.

**Name:** Functional tests on fibroblasts

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** Effort test

**Measure:** Measurement of cardiac output (Q)

**Time Frame:** Day 0

**Description:** Effort test

**Measure:** Measurement of oxygen consumption (VO2)

**Time Frame:** Day 0

**Description:** Effort test

**Measure:** Calculation of the slope of the relationship heart rate-oxygen consumed (dQ/dVO2)

**Time Frame:** Day 0

**Description:** Effort test

**Measure:** Calculation of the maximum arteriovenous difference (DAV) : DAV=VO2/Q

**Time Frame:** Day 0

**Description:** Effort test

**Measure:** Calculation of maximum muscle diffusion (DM) using the equation of Fick: DM = (Q x DAV)/(200-DAV)

**Time Frame:** Day 0

**Description:** Measurement of peripheral muscular oxygenation during the effort test.

**Measure:** Peripheral muscular oxygenation

**Time Frame:** Day 0

**Description:** 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.

**Measure:** Systolic ejection volume at the peak of the effort during the effort test

**Time Frame:** Day 0

**Description:** Measurement of the ejection fraction of the left ventricle in Simpson biplane and the longitudinal strain of the left ventricle in echocardiography.

**Measure:** Ejection fraction of the left ventricle

**Time Frame:** Day 0

**Description:** 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.

**Measure:** Metabolic pathways of myoblasts

**Time Frame:** From study start until 26 months

#### Secondary Outcomes

**Description:** Clinical severity of rhabdomyolysis linked to a hereditary disease of metabolism.

**Measure:** Presence of cardiomyopathy

**Time Frame:** Day 0

**Description:** Clinical severity of rhabdomyolysis linked to a hereditary disease of metabolism.

**Measure:** Age of onset of disease (neonatal, < 2 years, 2 - 10 years, > 10 years)

**Time Frame:** Day 0

**Description:** Clinical severity of rhabdomyolysis linked to a hereditary disease of metabolism.

**Measure:** Number of acute episodes of rhabdomyolyses

**Time Frame:** Day 0

**Description:** Genotypic severity of rhabdomyolysis linked to a hereditary disease of metabolism.

Information available in the patient medical record.

**Measure:** Character of mutations nonsense or missense of the hereditary disease of metabolism

**Time Frame:** Day 0

### Eligibility Module

**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).

**Maximum Age:** 75 Years

**Minimum Age:** 6 Years

**Sampling Method:** NON_PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- CHILD

- ADULT

- OLDER_ADULT

**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.

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Paris

**Country:** France

**Facility:** Hôpital Necker-Enfants Malades

**Zip:** 75015

#### Overall Officials

**Official 1:**

**Affiliation:** Assistance Publique - Hôpitaux de Paris

**Name:** Pascale de Lonlay

**Role:** PRINCIPAL_INVESTIGATOR

**Official 2:**

**Affiliation:** Assistance Publique - Hôpitaux de Paris

**Name:** Antoine Legendre, MD, PhD

**Role:** STUDY_CHAIR

**Official 3:**

**Affiliation:** Assistance Publique - Hôpitaux de Paris

**Name:** Florence Habarou, MD, PhD

**Role:** STUDY_CHAIR

**Official 4:**

**Affiliation:** Assistance Publique - Hôpitaux de Paris

**Name:** Caroline Tuchmann-Durand, Pharm. D, PhD

**Role:** STUDY_CHAIR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009135

- Term: Muscular Diseases

- ID: D000009140

- Term: Musculoskeletal Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC05

- Name: Musculoskeletal Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC16

- Name: Diseases and Abnormalities at or Before Birth

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M15035

- Name: Rhabdomyolysis

- Relevance: HIGH

- As Found: Rhabdomyolysis

- ID: M23686

- Name: Genetic Diseases, Inborn

- Relevance: HIGH

- As Found: Hereditary Diseases

- ID: M12092

- Name: Muscular Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12097

- Name: Musculoskeletal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T170

- Name: Acute Graft Versus Host Disease

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000012206

- Term: Rhabdomyolysis

- ID: D000030342

- Term: Genetic Diseases, Inborn

### Misc Info Module

- Version Holder: 2024-05-24
