Methodology Study of Novel Outcome Measures to Assess Progression of ALS

Methodology Study of Novel Electrophysiological, Physical, and Imaging Outcome Measures to Assess the Progression of Amyotrophic Lateral Sclerosis

The primary objectives of the study are to estimate and rank-order the longitudinal standardized mean changes over 6 months and over 12 months, for a set of outcome measures administered to participants with amyotrophic lateral sclerosis (ALS), in order to identify measures that are more sensitive to disease progression than Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). The secondary objectives of this study are: To evaluate the test-retest reproducibility of each outcome measure; To determine correlations between 6 and 12-month changes in all exploratory measures with 18 and 24-month changes in ALSFRS-R and survival; To assess correlations between/among the various measures; To obtain biological samples in order to identify molecular correlates to the clinical measures and to further characterize previously identified and novel molecular biomarkers of disease progression for incorporation into future clinical studies.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis

• Study Type: Observational
• Enrollment (Actual): 138

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Montréal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute Clinical Research Unit
• France
  • Hérault
    • Montpellier, Hérault, France, 34295
      • Hopital Gui de Chauliac, Service de Neurologie
  • Paris
    • Paris cedex 13, Paris, France, 75013
      • Groupe Hospitalier Pitie-Salpetriere
• Germany
  • Berlin, Germany, 13125
    • Charite - Campus Virchow-Klinikum
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Jena, Germany, 07743
    • Universitaetsklinikum Jena
  • Ulm, Germany, 89081
    • Universitaetsklinikum Ulm
• Ireland
  • Dublin, Ireland, Dublin 9
    • Beaumont Hospital
• Netherlands
  • CX
    • Utrecht, CX, Netherlands, 3584
      • UMC Utrecht
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Kantonsspital St. Gallen
• United Kingdom
  • West Midlands
    • Sheffield, West Midlands, United Kingdom, S102JF
      • Royal Hallamshire Hospital
• United States
  • California
    • San Diego, California, United States, 92103
      • University of California San Diego Medical Center
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Florida
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory Clinic
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Charlestown, Massachusetts, United States, 2129
      • Massachusetts General Hospital, MA
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Pennsylvania
    • Hershey, Pennsylvania, United States, EC037
      • Penn State Milton S. Hershey Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 85 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Participants suffering from ALS are recruited by participating physicians in a standard clinical practice setting.

Description

Key Inclusion Criteria:

• A diagnosis of sporadic or familial ALS
• ALS onset within ≤5 years
• Must be 16 to 85 years of age, inclusive, for sites in the United States and 18 to 85 years of age, inclusive, for all sites outside of the United States

Key Exclusion Criteria:

• History of or positive test result at Screening for human immunodeficiency virus (HIV)
• History of or positive test result at Screening for hepatitis C virus (HCV) antibody or hepatitis B virus (HBV)
• Possibility of neuromuscular weakness other than ALS
• Unspecified reasons that, in the opinion of the site Investigator, make the subject unsuitable for enrollment or unlikely to be able to complete, at a minimum, the Month 6 Visit

NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Longitudinal standardized mean change in electrophysiological measures as assessed by electrical impedance myography (EIM)	EIM is an electrophysiological technique in which current is applied to a muscle of interest and resultant voltage and impedance are measured. These measured parameters reflect the conductivity of underlying tissue and presumably the pathologic state of denervated muscle in an ALS participant	Baseline to Month 6 and Baseline to Month 12
Longitudinal standardized mean change in electrophysiological measures as assessed by compound muscle action potential (CMAP)	CMAP is a standard electrophysiological measure generated by maximally stimulating a nerve such that all muscle fibers innervated by the respective nerve are depolarized. Reduction of CMAP amplitude reflects loss of motor axons and, therefore, is directly relevant to ALS.	Baseline to Month 6 and Baseline to Month 12
Longitudinal standardized mean change in electrophysiological measures as assessed by motor unit number estimation (MUNE)	Optional, to be administered at each site's Investigator's discretion. MUNE is used to estimate the number of functioning motor units.	Baseline to Month 6 and Baseline to Month 12
Longitudinal standardized mean change in electrophysiological measures as assessed by motor unit number index (MUNIX)	MUNIX estimates functioning motor units within a muscle. CMAP and surface electromyography potentials (surface interference patterns) are obtained at various levels of voluntary effort, and MUNIX is estimated using power and area of CMAP and surface interference patterns.	Baseline to Month 6 and Baseline to Month 12
Longitudinal standardized mean change in muscle strength measures as assessed by hand-held dynamometry (HHD)	HHD tests isometric strength of multiple muscles using standard participant positioning. Approximately 10 muscle groups will be examined (per each side) in both upper and lower extremities.	Baseline to Month 6 and Baseline to Month 12
Longitudinal standardized mean change in respiratory measures as assessed by slow vital capacity (SVC)	Vital capacity will be measured by means of an SVC test, administered in the upright position. Upright SVC will be determined by performing 3 to 5 measures, in accordance with criteria established by the American Thoracic Society and the European Respiratory Society.	Baseline to Month 6 and Baseline to Month 12
Longitudinal standardized mean change in functional measures as assessed by Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)	The ALSFRS-R has been demonstrated to predict survival. The ALSFRS-R measures 4 functional domains, including respiratory, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48 [Cedarbaum 1999], with higher scores representing better function.	Baseline to Month 6 and Baseline to Month 12

Secondary Outcome Measures

Outcome Measure	Time Frame
Within-participant test-retest reliability between the 2 repeated measurements occurring on Day 1 and Day 7 for EIM	Day 1 and Day 7
Within-participant test-retest reliability between the 2 repeated measurements for CMAP	Day 1 and Day 7
Within-participant test-retest reliability between the 2 repeated measurements for MUNE	Day 1 and Day 7
Within-participant test-retest reliability between the 2 repeated measurements for MUNIX	Day 1 and Day 7
Within-participant test-retest reliability between the 2 repeated measurements for HHD	Day 1 and Day 7
Within-participant test-retest reliability between the 2 repeated measurements for SVC	Day 1 and Day 7
Within-participant test-retest reliability between the 2 repeated measurements for ALSFRS-R	Day 1 and Day 7
Comparison between 6 and 12-month changes in exploratory measures with 18 and 24-month changes in ALSFRS-R and survival	Baseline to Month 24
Comparison between 6-month changes for muscle electrophysiological measures	Baseline to Month 12
Comparison between 6-month changes for muscle strength measures	Baseline to Month 12
Comparison between 6-month changes for functional measures	Baseline to Month 12
Comparison of molecular biomarkers with disease progression	Baseline to Month 12

Collaborators and Investigators

• Sponsor: Biogen

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2016
• Primary Completion (Actual): July 27, 2018
• Study Completion (Actual): August 1, 2019

Study Registration Dates

• First Submitted: October 8, 2015
• First Submitted That Met QC Criteria: November 19, 2015
• First Posted (Estimate): November 23, 2015

Study Record Updates

• Last Update Posted (Actual): October 24, 2019
• Last Update Submitted That Met QC Criteria: October 23, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: 999AS003