Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis.
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.


CONCLUSIONS
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.
Piepers
Sanne
S
Department of Neurology, Rudolf Magnus Institute of Neuroscience University Medical Centre Utrecht, Utrecht, The Netherlands.
Veldink
Jan H
JH
de Jong
Sonja W
SW
van der Tweel
Ingeborg
I
van der Pol
W-Ludo
WL
Uijtendaal
Esther V
EV
Schelhaas
H Jurgen
HJ
Scheffer
Hans
H
de Visser
Marianne
M
de Jong
J M B Vianney
JM
Wokke
John H J
JH
Groeneveld
Geert Jan
GJ
van den Berg
Leonard H
LH
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D018450:Disease Progression; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000502:physiology; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014635:Valproic Acid