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Study of miRNA Expression Pattern as Diagnostic and Prognostic Biomarker in Amyotrophic Lateral Sclerosis (MIRSLA)

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ClinicalTrials.gov Identifier: NCT01992029
Recruitment Status : Terminated
First Posted : November 25, 2013
Last Update Posted : November 5, 2018
Sponsor:
Information provided by (Responsible Party):
University Hospital, Bordeaux

Brief Summary:
The principal goal is to demonstrate that a specific pattern of microRNA (miRNA) expression can be correlated with the definite diagnostic of Amyotrophic Lateral Sclerosis (ALS). The investigators will use biological sample (from muscle biopsy, Cerebrospinal Fluid (CSF) and blood sample) collected in three control populations: definite ALS patients according to El Escorial diagnostic criterion, control patients without any neurological disease having an orthopedic surgery for shoulder disease, and control patient explored for peripheral neuropathy and myopathy. A second goal will correlate the miRNA pattern to the severity and/or progression rate of the motor neurons define as the progression rate of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score/year.

Condition or disease Intervention/treatment
Amyotrophic Lateral Sclerosis ALS Other: Clinical evaluation Procedure: Muscular biopsy Procedure: Lumbar puncture Procedure: Blood sampling Other: Neurological assessments Procedure: Neuro-muscular biopsy and lumbar puncture Procedure: Blood sample Device: Cervical spinal cord and brain MRI

Detailed Description:

Amyotrophic Lateral Sclerosis is an adult-onset neuro degenerative disease leading to muscle wasting, palsy and death due to respiratory failure within 3 to 5 years. The only effective drug (Riluzole) increases the life expectancy for about three months, knowing that on average, the diagnostic is given after a delay of one year in France. The identification of new biomarkers for early diagnostic is therefore of fundamental importance. This could improve the treatment efficacy but also give important clues about the prognostic, the rate of evolution and overall help identify new targets for future therapeutics. The investigators' goals are to find specific miRNA patterns expression associated to ALS in humans and use those patterns as diagnostic and prognostic tools.

miRNA are non-coding small fragments of RNA that binds mRNA and can down regulate their expression. In humans, around 700 miRNA have been so far identified. The role of miRNA in human pathology is well established in various types of cancer, but recent works have emphasize their role in neuro degenerative diseases and their expression profile can considered specific for Alzheimer, Parkinson and Huntington diseases. Very few data are currently available about their expression pattern in ALS. Previous studies have however shown that down regulating of some miRNA in spinal cord Moto neurons can trigger an ALS-like clinical phenotype. A more recent work on transgenic murine model SOD1 G93A has demonstrated the role of the specific miRNA206 in regulating the re-innervation processes at the neuro-muscular junction. Mi206 have the ability to promote the re-innervation process and therefore to slow the disease progression.

This research aimed to study the expression of more than 700 miRNA in four different groups (20 patients per group): ALS patients, normal control having a shoulder surgery during which they will have a muscle (deltoid) biopsy, patients explored for peripheral neuropathy with a blood sample, a lumbar puncture for CSF examination and neuro-muscular biopsy and patient explored for myopathy with a blood sample, a lumbar puncture for CSF examination and a muscular biopsy. The ALS group will be followed up every 4 months with ALSFRS scoring and blood sample and a second CSF sample only at M12. miRNA pattern expression will be compared and considered significant for a 2-fold change.

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Study Type : Observational
Actual Enrollment : 5 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Etude de l'Expression Des Micro-RNA Comme Biomarqueur Diagnostic et Pronostic Dans la Sclérose Latérale Amyotrophique
Actual Study Start Date : June 17, 2014
Actual Primary Completion Date : October 2015
Actual Study Completion Date : October 22, 2015


Group/Cohort Intervention/treatment
ALS Patients Other: Clinical evaluation
Clinical evaluation using MRC scale, Norris bulbar scale, ALSFRS score and respiratory evaluation ( Vital Capacity, PiMax and SNIP) at M0, M4, M8, M12

Procedure: Muscular biopsy
Muscular biopsy at M0

Procedure: Lumbar puncture
Lumbar puncture at M0 and M12

Procedure: Blood sampling
Blood sampling at M0, M4, M4, M8 and M12

Device: Cervical spinal cord and brain MRI
ALS patients : MRI at inclusion and Month 8 Control patients suffering from neuropathy : MRI at inclusion and Month 8 Control patients suffering from myopathy : MRI at inclusion Control subjects : MRI at inclusion

Control patients suffering from neuropathy Other: Neurological assessments
Neurological assessments (MRC score and cognitive scales: MMS and BREF)

Procedure: Neuro-muscular biopsy and lumbar puncture
Neuro-muscular biopsy and lumbar puncture for patients explored for peripheral neuropathy

Procedure: Blood sample
Blood sample for qRT PCR, detection and quantification for miRNA

Device: Cervical spinal cord and brain MRI
ALS patients : MRI at inclusion and Month 8 Control patients suffering from neuropathy : MRI at inclusion and Month 8 Control patients suffering from myopathy : MRI at inclusion Control subjects : MRI at inclusion

Control patients suffering from myopathy Other: Neurological assessments
Neurological assessments (MRC score and cognitive scales: MMS and BREF)

Procedure: Muscular biopsy
Muscular biopsy for patient explored for myopathy

Procedure: Blood sample
Blood sample for qRT PCR, detection and quantification for miRNA

Device: Cervical spinal cord and brain MRI
ALS patients : MRI at inclusion and Month 8 Control patients suffering from neuropathy : MRI at inclusion and Month 8 Control patients suffering from myopathy : MRI at inclusion Control subjects : MRI at inclusion

Control subjects
control patients without any neurological disease having an orthopedic surgery for shoulder disease
Other: Neurological assessments
Neurological assessments (MRC score and cognitive scales: MMS and BREF)

Procedure: Muscular biopsy
Muscular biopsy for patient explored for myopathy

Procedure: Blood sample
Blood sample for qRT PCR, detection and quantification for miRNA

Device: Cervical spinal cord and brain MRI
ALS patients : MRI at inclusion and Month 8 Control patients suffering from neuropathy : MRI at inclusion and Month 8 Control patients suffering from myopathy : MRI at inclusion Control subjects : MRI at inclusion




Primary Outcome Measures :
  1. miRNA expression [ Time Frame: At inclusion (day 0) ]
    miRNA expression pattern in ALS patients compared to control patients.


Secondary Outcome Measures :
  1. miRNA evolution [ Time Frame: 12 months after inclusion ]
    Evolution of miRNA expression level in blood and CSF of ALS patients

  2. miRNA expression pattern in different ALS patients compared to control patients predictive of the clinical phenotype and of the progression of the disease. [ Time Frame: Day 0 (inclusion) ]
  3. Difference in diffusivity parameters of MRI [ Time Frame: At inclusion (Day 0) and 8 month after inclusion ]
    Difference in diffusivity parameters of MRI between ALS subjects and control groups


Biospecimen Retention:   Samples With DNA
Whole blood Cerebrospinal fluid muscle


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Ages Eligible for Study:   45 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Patients suffering from ALS, neuropathy, myopathy or control subjects having a shoulder surgery during which they will have a muscle (deltoid) biopsy
Criteria

Inclusion Criteria:

For ALS patients:

  • Age between 45 and 70 years old
  • Patients with definite criteria of ALS according to revised El Escorial criterion (1998).
  • ALS Patients with a clinical motor impairment of the limbs +/- impairment of the bulbar muscles.
  • Patients with a clinical motor impairment on the deltoid muscle (MRC score<5)

For control patients:

  • Age between 45 and 70 years old
  • Patients having an orthopedic surgery of the shoulder with a normal neurological examination
  • Patients having a peripheral neuropathy with a motor component needing a biological blood sample, a lumbar puncture for CSF examination and a neuro-muscular biopsy for complete diagnostic
  • Patients having a muscular myopathy needing a biological blood sample and a deltoid muscle biopsy for complete diagnostic.
  • Patients affiliated to a governmental health plan
  • Clear and loyal consent form written and signed by the patient and the investigator ( before any exam and at least the day of inclusion)

Exclusion Criteria:

  • Patients not eligible for a muscle biopsy (anti-coagulation, anti aggregation or blood coagulation pathologies)
  • Patients not eligible for lumbar puncture (anti-coagulation, anti aggregation or blood coagulation pathologies, recent spine surgery, acquired or congenital spine malformation, clinical signs of intracranial hypertension, cutaneous infection at the punction site).
  • ALS patient with isolated bulbar symptoms
  • Patients with a clinical syndrome of ALS-plus associating extra-pyramidal symptoms, cerebellar or spino-cerebellar syndromes autonomic disorders or ocular palsy.
  • Patients with marked cognitive impairments (MMS<24/30 or BREF<14/18)
  • Pregnant or breastfeeding women
  • Patients with any neurological or non-neurological disorders interfering with the ALSFRS score
  • Patients who could not express their consent
  • Patients in emergency situation
  • Patients under guardianship or judicial protection
  • Pace maker, cochlear implant
  • Spinal cord compression or trauma
  • Spine surgery
  • Spinal deformity
  • Claustrophobia
  • Metallic foreign body
  • Pregnancy
  • Vital capacity < 50 %

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): NCT01992029


Locations
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France
CHU de Bordeaux
Bordeaux, France, 33000
Sponsors and Collaborators
University Hospital, Bordeaux
Investigators
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Principal Investigator: Anne-Cécile WIELANEK-BACHELET, MD University Hospital, Bordeaux
Study Chair: Rodolphe THIEBAUT, MD, PhD University Hospital, Bordeaux
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Responsible Party: University Hospital, Bordeaux
ClinicalTrials.gov Identifier: NCT01992029    
Other Study ID Numbers: CHUBX 2012/13
First Posted: November 25, 2013    Key Record Dates
Last Update Posted: November 5, 2018
Last Verified: November 2018
Keywords provided by University Hospital, Bordeaux:
ALS
miRNA
biomarker
monocentric observational study
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases