Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis

A Randomized, Double-Blind, Placebo-Controlled Sequential Clinical Trial of Sodium Valproate in ALS

The purpose of this study is to determine whether the use of sodium valproate is effective in slowing the disease progression in Amyotrophic Lateral Sclerosis.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Sodium Valproate

Detailed Description

Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by progressive degeneration of motor neurons leading to muscle weakness.

The pathogenesis of ALS is unknown, but there is convincing evidence that several molecular mechanisms play a role. Previous studies investigated the role of the Survival Motor Neuron (SMN) gene in ALS. Recent data suggest that SMN genotypes producing less SMN protein increase susceptibility and severity of ALS. This leads to the hypothesis that the clinical expression of ALS is influenced by the total SMN protein level in affected patients. In a population of ALS patients in the Netherlands we found that SMN genotypes producing less SMN protein appear to increase susceptibility and severity of ALS. It was shown that the HDAC inhibitor sodium valproate (SVP) increases levels of SMN protein in vitro. From these results and from data suggesting neuroprotective properties of SVP, it is hypothesised that SVP could extend survival of patients with ALS. In addition, sodium valproate significantly prolonged the disease duration in the animal model for ALS, the SOD1 transgenic mouse. Given that SVP is a FDA-approved compound with well-known pharmacokinetic and toxicity profiles, it is an attractive candidate for a clinical trial in ALS patients.

• Study Type: Interventional
• Enrollment (Actual): 165
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • UMC Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Definite, probable, or probable-laboratory supported ALS according to the revised El Escorial World Federation of Neurology criteria.
• Intake of riluzole 50 mg twice a day (bid)
• A disease duration at inclusion of more than 6 months and less than 36 months [inclusive] (disease onset is defined as the date of first symptoms excluding muscle cramps and fasciculations)
• Vital capacity (VC%) ≥ 70% of normal value (slow expiration, best of a minimum of three and a maximum of five measurements, with a respiratory function validly assessable and a spontaneous, non-assisted ventilation)
• Ages 18 - 85 years (inclusive)
• Capable of thoroughly understanding the trial information given; has signed the informed consent.

Exclusion Criteria:

• Tracheostomy, tracheostomal ventilation of any type, non-invasive ventilation more than 16 hours/ day, or supplemental oxygen during the last three months prior to inclusion.
• Any medical condition or intoxication known to have an association with motor neuron dysfunction, which might confound or obscure the diagnosis of ALS.
• Presence of any concomitant life-threatening disease or any disease or impairment likely to interfere with functional assessment.
• Confirmed hepatic insufficiency or abnormal liver function (ASAT, ALAT greater than twice the upper limit of normal range).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Survival

Secondary Outcome Measures

Outcome Measure
The rate of decline of daily functioning

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: Princess Beatrix Muscle Foundation
• Investigators: Study Chair: Leonard H Van den Berg, MD, PhD, UMC Utrecht; Principal Investigator: Sanne Piepers, MD, UMC Utrecht; Principal Investigator: Sonja W De Jong, MD, UMC Utrecht

Publications and helpful links

General Publications

• Piepers S, Veldink JH, de Jong SW, van der Tweel I, van der Pol WL, Uijtendaal EV, Schelhaas HJ, Scheffer H, de Visser M, de Jong JM, Wokke JH, Groeneveld GJ, van den Berg LH. Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis. Ann Neurol. 2009 Aug;66(2):227-34. doi: 10.1002/ana.21620.

Study record dates

Study Major Dates

• Study Start: April 1, 2005
• Study Completion (Actual): February 1, 2007

Study Registration Dates

• First Submitted: August 24, 2005
• First Submitted That Met QC Criteria: August 24, 2005
• First Posted (Estimate): August 26, 2005

Study Record Updates

• Last Update Posted (Estimate): May 1, 2007
• Last Update Submitted That Met QC Criteria: April 30, 2007
• Last Verified: April 1, 2007

More Information

Terms related to this study

• Keywords: ALS; Amyotrophic Lateral Sclerosis (ALS); randomised trial; Sodium Valproate
• 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; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: 04/182-0