Reinnervation and Neuromuscular Transmission in ALS (RANTAL)

Reinnervation and Neuromuscular Transmission in Patients With Amyotrophic Lateral Sclerosis

The aim of this study is to describe the changes in the neuromuscular connection in patients with amyotrophic lateral sclerosis (ALS). The study consist of three substudies that have the following main hypothesis:

1. that ALS patients do not demonstrate equal capacity for muscle reinnervation and that reinnervation preserves muscle function and thereby slows down progression.
2. that blood concentrations of c-terminal agrin fragment (bCAF) reflect neuromuscular transmission deficiency and that blood concentration of neural cell adhesion molecule reflects degree of muscle denervation in patients.
3. that ALS patients with decrement when examined with repetitive nerve stimulation have more physical fatigue, slower progression, higher degree of reinnervation and higher bCAF compared to ALS patients without decrement.

There will be 3 inclusion groups.

1. patients referred for neurophysiological examination on suspicion of motor neuron disease.
2. healthy controls
3. disease control: patients with another motor neuron disease with slow progression.

All participants will be invited for at least 1 visit (baseline). If participants in group 1 eventually receive the diagnosis of ALS they will be invited for 2 additional visits 4 og 8 months after baseline visit, respectively.

Examinations will consist of:

• nerve conduction study
• repetitive nerve stimulation (except for healthy controls) to examine impairment of the neuromuscular connection.
• motor unit number estimation with MScanFit to estimate number and size of motor units.
• ultrasound examination of muscles to measure size and condition of muscles.
• questionnaires on fatigue and functional status.
• blood sample for measurement of specialized analysis (c-terminal agrin fragment and neural cell adhesion molecule) and routine analysis (liver and kidney function as well as neurofilament light chain)
• muscle strength assessment manually and by dynamometer to follow progression of muscle weakness
• bioelectrical impedance measurement to follow the overall body composition.

Study Overview

• Status: Recruiting
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Other: Observational study

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Jesper Storgaard, MD; Phone Number: 004520231903; Email: jesstg@rm.dk

Study Locations

• Denmark
  • Region Midtjylland
    • Aarhus, Region Midtjylland, Denmark, 8200
      • Recruiting
      • Department of Neurology, Aarhus University Hospital
      • Contact: Jesper H Storgaard, MD; Phone Number: 004520231903; Email: jesstg@rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients refered for neurophysiological examination or patients followed at out-patient clinics.

Description

Inclusion Criteria:

• Referred to clinical neurophysiological examination on suspicion of motor neuron disease or diagnosed with ALS according to Gold Coast criteria within the last 3 months.
• Age ≥18 years old
• Able and willing to provide informed consent

Exclusion Criteria:

• Former central or peripheral nervous system disease
• Diabetes
• Electrophysiological signs of polyneuropathy at baseline visit
• Pacemaker
• Pregnancy

For disease controls the exclusion criteria are the same, but the inclusion criteria:

• Diagnosed with disease with slow, progressive loss of motor neurons
• Age ≥18 years old
• Able and willing to provide informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
ALS patients; Patients enrolled prior to determination of diagnosis on referral to neurophysiological examination. When the diagnosis is later established they get categorized as ALS patients. ALS patients with recent diagnosis might also be included directly.	Other: Observational study; Observational study.
ALS mimic disease patients; Patients enrolled prior to determination of diagnosis on referral to neurophysiological examination. When diagnosis is later established and the diagnosis is NOT ALS they get categorized as ALS mimic disease patients.	Other: Observational study; Observational study.
Healthy controls; Healthy controls.	Other: Observational study; Observational study.
Disease controls; Patients with another motor neuron disease than ALS with slow progression.	Other: Observational study; Observational study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reinnervation	Difference between fast and slow progressing patients in change in mean amplitude size of motor units as estimated by MScanFit motor unit number estimation.	From baseline and 8 months
Blood biomarkers	Difference in blood concentration of c-terminal agrin fragment and neural cell adhesion molecule at baseline between ALS patients, healthy controls and ALS mimic disease patients.	Baseline
Fatigue and decrement	Difference in proportion of participants with decrement between ALS patients and ALS mimic disease patients as well as degree of fatigue among ALS patients with and without neuromuscular transmission deficiency.	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in mean amplitude size over time in patients.	Mean amplitude size measured by MScanFit technique.	Baseline, 4 months and 8 months.
Difference in motor unit number estimation over time in patients.	Motor unit number estimation measured by MScanFit technique.	Baseline, 4 months and 8 months.
Difference in mean amplitude size between patients and control groups	Mean amplitude size measured by MScanFit technique.	Baseline.
Muscle strength assessed with manual muscle strength testing	Difference in measures from manual muscle strength testing.	Baseline, 4 months and 8 months.
Difference in isometric ankle dorsiflexion strength measured on dynamometer.	Measured on dynamometer.	Baseline, 4 months and 8 months.
Difference in handgrip strength measured on dynamometer.	Measured with handgrip dynamometer.	Baseline, 4 months and 8 months.
Correlation between decrement at repetitive nerve stimulation and signs of reinnervation as measured by mean amplitude size.	Decrement measured with repetitive nerve stimulation and mean amplitude size measured with MScanFit technique.	Baseline, 4 months and 8 months.
Blood concentration of c-terminal agrin fragment and neural cell adhesion molecule.	Difference in blood measurements of c-terminal agrin fragment, neural cell adhesion molecule, neurofilament light chain and routine kidney and liver markers.	Baseline, 4 months and 8 months.
Difference in muscle thickness as measured by ultrasound examination of muscles	Measured by ultrasound examination.	Baseline, 4 months and 8 months.
Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised scores	Difference in scores from Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised. Scale 0-48, with 48 being the best.	Baseline, 4 months and 8 months.
Multidimensional Fatigue Inventory scores	Difference in scores from Multidimensional Fatigue Inventory. Scale 4-20, with 20 indicating worst degree of fatigue.	Baseline, 4 months and 8 months.
Fatigue Severity Scale scores	Difference in scores from Fatigue Severity Scale. Scale 9-63, with 63 indicating worst degree of fatigue.	Baseline, 4 months and 8 months.
Difference in free fatt mass as measured by bioelectrical impedance analysis.	Measured by bioelectrical impedance analysis.	Baseline, 4 months and 8 months.

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital
• Investigators: Principal Investigator: Jesper H Storgaard, MD, Aarhus University and Department of Neurology, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: January 2, 2024
• First Submitted That Met QC Criteria: January 12, 2024
• First Posted (Actual): January 23, 2024

Study Record Updates

• Last Update Posted (Actual): August 7, 2024
• Last Update Submitted That Met QC Criteria: August 6, 2024
• Last Verified: January 1, 2024

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: 8340; 1-10-72-153-23 (Other Identifier: Regional Research Ethics Committee Region Midtjylland)

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