Geert Jan Groeneveld

Publications (3)14.18 Total impact

• Article: Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis.

  Sanne Piepers, Jan H Veldink, Sonja W de Jong, Ingeborg van der Tweel, W-Ludo van der Pol, Esther V Uijtendaal, H Jurgen Schelhaas, Hans Scheffer, Marianne de Visser, J M B Vianney de Jong, John H J Wokke, Geert Jan Groeneveld, Leonard H van den Berg
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  ABSTRACT: 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. 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). 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. 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.
  Annals of Neurology 04/2009; 66(2):227-34. · 11.09 Impact Factor
• Article: Alternative trial design in amyotrophic lateral sclerosis saves time and patients.

  Geert Jan Groeneveld, Michael Graf, Ingeborg van der Tweel, Leonard H van den Berg, Albert C Ludolph
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  ABSTRACT: A sequential trial design is an alternative for the classical trial design with a fixed sample size, that permits stopping a trial as soon as enough evidence for a treatment effect, or a lack thereof, is obtained. This study aimed to determine the difference in efficiency of time and patient number between a classical trial design and a sequential trial design. In this study we re-analysed a previously published classically designed clinical trial according to a sequential trial design. We subsequently determined the difference in total running time and patient number. We found that the sequential analysis offered a gain in time of 38%. We conclude that the sequential trial design may in certain situations be superior to the classical design.
  Amyotrophic lateral sclerosis: official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 11/2007; 8(5):266-9. · 3.09 Impact Factor
• Article: Sequential designs for clinical trials in amyotrophic lateral sclerosis.

  Geert Jan Groeneveld, Ingeborg van der Tweel, John H J Wokke, Leonard H van den Berg
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  ABSTRACT: The objective of this paper is to discuss the sequential trial design and its advantages in clinical trials for ALS. The sequential trial design is an alternative to the classical trial design, which permits stopping a study as soon as a treatment effect can be significantly demonstrated or denied. As an example of a sequential survival analysis, a recently completed clinical trial is described. A secondary outcome measure used in the same trial, the decline of the vital lung capacity, was re-analyzed sequentially, in order to illustrate the use of the sequential method for a non-survival variable. To compare the classical with the sequential trial design, the number of patients needed in trials aiming at survival effects ranging from 10% to 20% with a power of 80% or 90% was calculated for both designs. In the given examples the time needed to prove the null hypothesis in the survival analysis, and the number of patients needed to prove the null hypothesis in the analysis of the vital capacity is lower than would have been the case in a classical analysis. In 18 of 24 different situations, the chance is at least 90% that with a sequential trial design fewer patients are needed. We argue that, particularly for ALS trials, a sequential design may be superior to a classical trial design, as it most often requires fewer patients than classically designed trials of equal power, and more importantly may avoid unnecessary continuation.
  Amyotrophic Lateral Sclerosis 01/2005; 5(4):202-7.