Reinnervation and Neuromuscular Transmission in ALS (RANTAL)

• ClinicalTrials.gov Identifier: NCT06219759
• Recruitment Status: Recruiting
• First Posted: January 23, 2024
• Last Update Posted: May 8, 2024
• Sponsor: University of Aarhus
• Collaborator: Aarhus University Hospital
• Information provided by (Responsible Party): University of Aarhus

Tracking Information

• First Submitted Date: January 2, 2024
• First Posted Date: January 23, 2024
• Last Update Posted Date: May 8, 2024
• Estimated Study Start Date: May 2024
• Estimated Primary Completion Date: December 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 12, 2024)

• Reinnervation [ Time Frame: From baseline and 8 months ]
  Difference between fast and slow progressing patients in change in mean amplitude size of motor units as estimated by MScanFit motor unit number estimation.
• Blood biomarkers [ Time Frame: Baseline ]
  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.
• Fatigue and decrement [ Time Frame: Baseline ]
  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.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: January 12, 2024)

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

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Reinnervation and Neuromuscular Transmission in ALS
• Official Title: Reinnervation and Neuromuscular Transmission in Patients With Amyotrophic Lateral Sclerosis

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Blood samples stored for batch analysis.

• Sampling Method: Non-Probability Sample
• Study Population: Patients refered for neurophysiological examination or patients followed at out-patient clinics.
• Condition: Amyotrophic Lateral Sclerosis

Intervention

Other: Observational study

Observational study.

Study Groups/Cohorts

• 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.

  Intervention: Other: 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.
  Intervention: Other: Observational study
• Healthy controls
  Healthy controls.
  Intervention: Other: Observational study
• Disease controls
  Patients with another motor neuron disease than ALS with slow progression.
  Intervention: Other: Observational study

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 12, 2024): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2026
• Estimated Primary Completion Date: December 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Jesper Storgaard, MD; 004520231903; jesstg@rm.dk

• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT06219759
• Other Study ID Numbers: 8340; 1-10-72-153-23 ( Other Identifier: Regional Research Ethics Committee Region Midtjylland )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Aarhus
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Aarhus
• Original Study Sponsor: Same as current
• Collaborators: Aarhus University Hospital

Investigators

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

• PRS Account: University of Aarhus
• Verification Date: January 2024