Levetiracetam for Cramps, Spasticity and Neuroprotection in Motor Neuron Disease

A Pilot Trial of Levetiracetam for Cramps, Spasticity and Neuroprotection in Motor Neuron Disease

Levetiracetam (Keppra) is used to treat partial onset seizures. Its biological effects suggest it might also be useful in treating 3 aspects of human motor neuron diseases (MNDs) for which no effective therapy exists: cramps, spasticity, and disease progression.

Study Overview

• Status: Completed
• Conditions: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Primary Lateral Sclerosis; Progressive Muscular Atrophy
• Intervention / Treatment: Biological: Levetiracetam

Detailed Description

Cramps in MNDs are believed to occur as a result of high-frequency burst firing of alpha motor neurons. Levetiracetam inhibits burst firing in epileptic rat hippocampus. Levetiracetam has never been tested against cramps in humans; however, it has helped another condition believed to result from burst firing of a motor nerve: hemi-facial spasm.

The mechanisms underlying spasticity in MNDs likely involve imbalance between excitatory and inhibitory influences on the alpha motor neurons. Levetiracetam may modulate these influences in a number of ways, including reducing the effects of zinc and beta-carbolines in GABA and glycine receptors. Levetiracetam reduces phasic (but not tonic) spasticity in patients with multiple-sclerosis.

Levetiracetam may have neuroprotective properties. In a model of cerebral ischemia induced by occlusion of the rat internal carotid artery, pre-treatment with levetiracetam reduced infarct size in a dose-dependent manner. In rats injected with kainic acid to induce calcium overload, oxidative stress and neurotoxicity, pretreatment with levetiracetam offset kainic acid's effects. The mechanisms for these effects may relate to levetiracetam's ability to influence calcium currents, or its ability to increase the release of growth factors from astrocytes, mechanisms that would be relevant in MNDs. Levetiracetam's ability to inhibit histone deacetylase may also help slow MNDs progression.

OBJECTIVES: 1. Assess the safety and tolerability of levetiracetam over 9 months in patients with MNDs. 2. Determine whether treatment with levetiracetam is associated with a reduction in cramps, spasticity or motor neuron disease progression.

METHODS:Open-label, Phase 2 trial of 20 adult patients with MNDs (ALS, PLS or PMA) at Duke University ALS Clinic. Eligible patients have cramps with average severity 50/100 points, are able to provide informed consent, have normal renal functions and are on a stable riluzole dose. Exclusions include pregnancy, unstable mental illness, dementia, drug abuse or non-compliance. The first 3 months of the study are a baseline period. Over the remaining 9 months, patients take levetiracetam at increasing doses up to 3000mg per day. Outcome measures include adverse events, tolerability,cramp-pain-severity score, cramp-frequency score, modified Ashworth Spasticity Score, Penn Spasm Score, FVC, ALSFRS-R and MMT.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University ALS Clinic - 932 Morreene Road

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients with MNDs (ALS, PLS or PMA)who have cramps with average severity 50/100 points, are able to provide informed consent, have normal renal function and are on a stable riluzole dose.

Exclusion Criteria:

• Pregnancy; unstable medical illness, dementia; drug abuse or non-compliance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability at 9 months of treatment.	9 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Cramps scores, spasticity scores, FVC, ALSFRS, MMT	9 months

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: UCB Pharma
• Investigators: Principal Investigator: Richard S Bedlack, MD, PhD, Duke University

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): December 1, 2007
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: May 9, 2006
• First Submitted That Met QC Criteria: May 9, 2006
• First Posted (Estimate): May 11, 2006

Study Record Updates

• Last Update Posted (Estimate): June 19, 2013
• Last Update Submitted That Met QC Criteria: June 17, 2013
• Last Verified: January 1, 2009

More Information

Terms related to this study

• Keywords: spasticity; motor neuron disease; amyotrophic lateral sclerosis primary lateral; sclerosis; progressive muscular atrophy; cramps
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Muscle Hypertonia; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Muscular Atrophy; Atrophy; Muscle Spasticity; Muscular Atrophy, Spinal; Anticonvulsants; Nootropic Agents; Levetiracetam
• Other Study ID Numbers: Pro00005846; 8380-06-3R0 (Other Identifier: DUMC)