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

• ClinicalTrials.gov Identifier: NCT02360891
• Recruitment Status: Recruiting
• First Posted: February 11, 2015
• Last Update Posted: November 7, 2022
• Sponsor: University Hospital, Lille
• Information provided by (Responsible Party): University Hospital, Lille

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Amyotrophic Lateral Sclerosis; Motor Neuron Disease	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 Design

• Study Type: Observational [Patient Registry]
• Estimated Enrollment: 1000 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Target Follow-Up Duration: 10 Years
• Official Title: Study of Predictive Factors of Progression of Motor Neurone Disease Prognosis and Endophenotype Biomarkers French Database Set up
• Actual Study Start Date: January 12, 2015
• Estimated Primary Completion Date: January 2026
• Estimated Study Completion Date: January 2026

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

1. Change of biomarkers of survival [ Time Frame: From date of randomization until the date of first documented progression , assessed up to 100 months ]
   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)

Secondary Outcome Measures :

1. Change of biomarkers of disease progression [ Time Frame: baseline, 3 months, 6 months, 9 months, 12 months, 15 months, 24 months, 36 months, 48 months (average) ]
   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
2. Clinical endophenotypes according to the survival duration [ Time Frame: 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 ]
   The determination of the different clinical, biological, radiological and electrophysiological endophenotypes (clusters of the same characteristics) according to the survival duration
3. Genetic endophenotypes [ Time Frame: 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 ]
   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,...)

Biospecimen Retention:   Samples With DNA

whole blood, serum, white cells, platelets, cerebrospinal fluid,skin, muscle, brains

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

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

Criteria

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

Contacts and Locations

Contacts

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

Locations

France

CHU Pontchaillou; Recruiting

Angers, France

Principal Investigator: Dominique Maugin, MD,PhD

CHU Cote de Nacre; Recruiting

Caen, France

Principal Investigator: Fausto Viader, MD

CHU Gabriel Montpied; Recruiting

Clermont-Ferrand, France

Principal Investigator: Nathalie Guy, MD

CHRU, Hôpital Salengro; Recruiting

Lille, France

Contact: David Devos, MD, PhD david.devos@chru-lille.fr

Principal Investigator: David Devos, MD, PhD

Hôpital Dupuytren; Recruiting

Limoges, France

Principal Investigator: Philippe Couratier, MD

Hôpital Neurologique Pierre Wertheimer; Recruiting

Lyon, France

Principal Investigator: Emilien Bernard, MD,PhD

AP-HM,Hôpital de la Timone; Recruiting

Marseille, France

Principal Investigator: Attarian Shahram, MD,PhD

Hôpital Gui de Chauliac; Recruiting

Montpellier, France

Principal Investigator: William Camu, MD

Hôpital de l'Archet 1, CHU; Recruiting

Nice, France

Hôpital La Pitié (AP-HP); Recruiting

Paris, France

Principal Investigator: François Salachas, MD

Centre Hospitalier; Recruiting

Saint Brieuc, France

Principal Investigator: Yvan Kolev, MD

Hôpital Nord; Recruiting

Saint Etienne, France

Principal Investigator: Jean-Christophe Antoine, MD,PhD

CHU Bretonneau; Recruiting

Tours, France

Principal Investigator: Philippe Corcia, MD

Sponsors and Collaborators

University Hospital, Lille

Investigators

• Study Chair: David Devos, MD, PhD; University Hospital, Lille

More Information

Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University Hospital, Lille
• ClinicalTrials.gov Identifier: NCT02360891
• Other Study ID Numbers: 2012-50; 2013-A00969-36 ( Other Identifier: ID RCB number, ANSM )
• First Posted: February 11, 2015
• Last Update Posted: November 7, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Lille:

multimodal biomarkers; prognosis; endophenotypes

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases