Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis

Ann Neurol. 2009 Aug;66(2):227-34. doi: 10.1002/ana.21620.


Objective: To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design.

Methods: Between April 2005 and January 2007, 163 ALS patients received VPA 1,500mg or placebo daily. Primary end point was survival. Secondary outcome measure was decline of functional status measured by the revised ALS Functional Rating Scale. Analysis was by intention to treat and according to a sequential trial design. This trial was registered with ClinicalTrials.gov (number NCT00136110).

Results: VPA did not affect survival (cumulative survival probability of 0.72 in the VPA group [standard error (SE), 0.06] vs 0.88 in the placebo group [SE, 0.04] at 12 months, and 0.59 in the VPA group [SE, 0.07] vs 0.68 in the placebo group [SE, 0.08] at 16 months) or the rate of decline of functional status. VPA intake did not cause serious adverse reactions.

Interpretation: Our finding that VPA, at a dose used in epilepsy, does not show a beneficial effect on survival or disease progression in patients with ALS has implications for future trials with histone deacetylase inhibitors in ALS and other neurodegenerative diseases. The use of a sequential trial design allowed inclusion of only half the number of patients required for a classic trial design and prevented patients from unnecessarily continuing potentially harmful study medication.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / mortality
  • Disease Progression
  • Double-Blind Method
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Genotype
  • Histone Deacetylase Inhibitors
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Motor Neurons / physiology
  • Sequence Analysis, DNA
  • Severity of Illness Index
  • Survival of Motor Neuron 1 Protein / genetics
  • Survival of Motor Neuron 2 Protein / genetics
  • Treatment Outcome
  • Valproic Acid / administration & dosage
  • Valproic Acid / adverse effects
  • Valproic Acid / therapeutic use*


  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • SMN1 protein, human
  • SMN2 protein, human
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Valproic Acid

Associated data

  • ClinicalTrials.gov/NCT00136110