Study of Predictive Factors of Progression of Motor Neurone Disease (PULSE)

Study of Predictive Factors of Progression of Motor Neurone Disease Prognosis and Endophenotype Biomarkers French Database Set up

Amyotrophic lateral sclerosis (ALS) is a complex polymorph and devastating neurodegenerative disease. Although the pathophysiological mechanisms underlying the development of ALS remain to be fully elucidated, there have been significant advances in the understanding of ALS pathogenesis, with evidence emerging of a complex interaction between genetic factors and dysfunction of vital molecular pathways. However, the numerous randomized clinical trials (RCT) for ALS have failed to generate improved drug treatments. Biomarkers able to bring prognostic value and to distinguish the different endophenotypes of this polymorphic disease could help to better select clusters of patients in order to improve the RCT outcomes. However, little progress has been made in the development of viable diagnostic, prognostic and monitoring markers. This could be explained by common shortcomings, such as relatively small sample sizes, statistically underpowered study designs, lack of disease controls and poorly characterized patient cohorts. It is yet crucial that the investigators further develop and validate ALS biomarkers and incorporate these biomarkers into the drug development pipeline for ALS.

The aim of the present study is therefore to determine the clinical, biological, imaging, and electrophysiological biomarkers of prognosis of survival without events (i.e. severe comorbidity, 24 hours of non invasive ventilation, tracheotomy). This is a prospective observational multicentric French study of a cohort of 1000 ALS patients.

This large multimodal database will be open for international fruitful scientific collaborations.

Study Overview

• Status: Recruiting
• Conditions: Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Other: biomarkers (composite analysis)

Detailed Description

This is a prospective observational multicentric French study of a cohort of 1000 ALS patients, 100 neurological controls and 200 healthy controls followed from the first signs to the end of the disease.

The aim of the present study is therefore to determine the clinical, biological, imaging, and electrophysiological biomarkers of prognosis of survival without events (i.e. severe comorbidity, 24 hours of non invasive ventilation, tracheotomy).

Secondary objectives will notably include i) the biomarkers of disease progression ii) biomarkers of diagnosis as compared with controls iii) the determination of the different endophenotypes according to the prognosis, the genetic profiles and the initial clinical presentations. Criteria of assessment will notably include detailed medical history, habitus, past and present treatments, vascular risk factors, ALSFRS-R, muscular testing, respiratory parameters including early nocturnal saturation and apneal profile, the detailed and predetermined clinical presentations, extensive cognitive and behavioral examination, extensive blood, cerebrospinal fluid, urines biological tests, genetic analyses, multiple brain and spinal MRI sequences, and electrophysiological tests (i.e. electromyogram, MUNIX, triple stimulation). Invasive tests will be optional (i.e. lumbar puncture, skin biopsies, muscular biopsies).

The large number of patients will allow in depth statistical analyses, notably to establish decisional trees (CHAID).

• Study Type: Observational
• Enrollment (Anticipated): 1000

Contacts and Locations

• Study Contact: Name: David Devos, MD, PhD; Email: david.devos@chru-lille.fr

Study Locations

• France
  • Angers, France
    • Recruiting
    • CHU Pontchaillou
    • Principal Investigator: Dominique Maugin, MD,PhD
  • Caen, France
    • Recruiting
    • CHU Côte de Nacre
    • Principal Investigator: Fausto Viader, MD
  • Clermont-Ferrand, France
    • Recruiting
    • CHU Gabriel Montpied
    • Principal Investigator: Nathalie Guy, MD
  • Lille, France
    • Recruiting
    • CHRU, Hôpital Salengro
    • Contact: David Devos, MD, PhD; Email: david.devos@chru-lille.fr
    • Principal Investigator: David Devos, MD, PhD
  • Limoges, France
    • Recruiting
    • Hopital Dupuytren
    • Principal Investigator: Philippe Couratier, MD
  • Lyon, France
    • Recruiting
    • Hôpital Neurologique Pierre Wertheimer
    • Principal Investigator: Emilien Bernard, MD,PhD
  • Marseille, France
    • Recruiting
    • AP-HM,Hôpital de la Timone
    • Principal Investigator: Attarian Shahram, MD,PhD
  • Montpellier, France
    • Recruiting
    • Hopital Gui de Chauliac
    • Principal Investigator: William Camu, MD
  • Nice, France
    • Recruiting
    • Hôpital de l'Archet 1, CHU
  • Paris, France
    • Recruiting
    • Hôpital La Pitié (AP-HP)
    • Principal Investigator: François Salachas, MD
  • Saint Brieuc, France
    • Recruiting
    • Centre Hospitalier
    • Principal Investigator: Yvan Kolev, MD
  • Saint Etienne, France
    • Recruiting
    • Hôpital Nord
    • Principal Investigator: Jean-Christophe Antoine, MD,PhD
  • Tours, France
    • Recruiting
    • CHU Bretonneau
    • Principal Investigator: Philippe Corcia, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Multicentric French cohort of 1000 ALS patients, 100 neurological controls and 200 healthy controls

Description

Inclusion Criteria for ALS patients:

• Patients with suspicion of Amyotrophic lateral sclerosis
• Since the first signs (cramps fasciculation) or first deficit at the diagnosis work up
• Patient older than 18 years
• Patient able to provide informed consent

Inclusion Criteria for healthy controls:

• Subjects older than 18 years (matched population for age and sex with ALS)
• Neurological testing and examination showing no neurological disorders.
• Not having severe disease or life- functional prognosis

Inclusion Criteria for neurological controls:

• Patients having a typical neurodegenerative diseases other than ALS (Parkinson's disease, Alzheimer's disease)
• Not having severe disease or life- functional prognosis
• Patient older than 18 years (matched population for age and sex with ALS)
• Patient able to provide informed consent

Exclusion Criteria:

• Subjects younger than 18 years
• Patient unable to provide informed consent
• Having severe disease or life- functional prognosis
• Contraindications MRI

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
patients; follow up of patients with amyotrophic lateral sclerosis from the first signs to the end of the disease	Other: biomarkers (composite analysis); biological, imaging, electrophysiological and anatomopathological examinations
neurological controls; patients with other neurological disease	Other: biomarkers (composite analysis); biological, imaging, electrophysiological and anatomopathological examinations
healthy controls; age matched healthy controls	Other: biomarkers (composite analysis); biological, imaging, electrophysiological and anatomopathological examinations

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of biomarkers of survival	The predictive value of the clinical, biological, imaging, and electrophysiological biomarkers of survival will be analyzed according to the life duration (months) without events (i.e. severe comorbidity, 24 hours of non invasive ventilation, tracheotomy)	From date of randomization until the date of first documented progression , assessed up to 100 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of biomarkers of disease progression	The predictive value of the clinical, biological, imaging, and electrophysiological biomarkers of prognosis will be analyzed according to the rate of progression of the ALSFRS-R score	baseline, 3 months, 6 months, 9 months, 12 months, 15 months, 24 months, 36 months, 48 months (average)
Clinical endophenotypes according to the survival duration	The determination of the different clinical, biological, radiological and electrophysiological endophenotypes (clusters of the same characteristics) according to the survival duration	From date of randomization until the date of death related with ALS or tracheotomy or continuous non invasive ventilation (24 hours a day), whichever came first, assessed up to 100 months
Genetic endophenotypes	the determination of the different clinical, biological, radiological and electrophysiological endophenotypes (clusters of the same characteristics) according to the according to the genetic forms (SOD1, TDP43, FUS, C9orf72,...)	the date of death related with ALS or tracheotomy or continuous non invasive ventilation (24 hours a day), whichever came first, assessed up to 100 months

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Investigators: Study Chair: David DEVOS, MD, PhD, University Hospital, Lille

Publications and helpful links

General Publications

• Le Gall L, Duddy WJ, Martinat C, Mariot V, Connolly O, Milla V, Anakor E, Ouandaogo ZG, Millecamps S, Laine J, Vijayakumar UG, Knoblach S, Raoul C, Lucas O, Loeffler JP, Bede P, Behin A, Blasco H, Bruneteau G, Del Mar Amador M, Devos D, Henriques A, Hesters A, Lacomblez L, Laforet P, Langlet T, Leblanc P, Le Forestier N, Maisonobe T, Meininger V, Robelin L, Salachas F, Stojkovic T, Querin G, Dumonceaux J, Butler Browne G, Gonzalez De Aguilar JL, Duguez S, Pradat PF. Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles. J Cachexia Sarcopenia Muscle. 2022 Apr;13(2):1385-1402. doi: 10.1002/jcsm.12945. Epub 2022 Feb 22.
• Grolez G, Kyheng M, Lopes R, Moreau C, Timmerman K, Auger F, Kuchcinski G, Duhamel A, Jissendi-Tchofo P, Besson P, Laloux C, Petrault M, Devedjian JC, Perez T, Pradat PF, Defebvre L, Bordet R, Danel-Brunaud V, Devos D. MRI of the cervical spinal cord predicts respiratory dysfunction in ALS. Sci Rep. 2018 Jan 29;8(1):1828. doi: 10.1038/s41598-018-19938-2.

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2015
• Primary Completion (Anticipated): January 1, 2026
• Study Completion (Anticipated): January 1, 2026

Study Registration Dates

• First Submitted: January 7, 2015
• First Submitted That Met QC Criteria: February 10, 2015
• First Posted (Estimate): February 11, 2015

Study Record Updates

• Last Update Posted (Actual): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: prognosis; multimodal biomarkers; endophenotypes
• Additional Relevant MeSH Terms: Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: 2012-50 (Other Identifier: CCRRC); 2013-A00969-36 (Other Identifier: ID RCB number, ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No