DOPA-RESPONSIVE DYSTONIC CAMPTOCORMIA

Riluzole is the only approved medication that extends survival for patients with amyotrophic lateral sclerosis (ALS). While other potential neuroprotective agents have been evaluated in randomized clinical trials, none has shown unequivocal success and none has been approved by regulatory agencies. Few symptomatic therapies have been tested in ALS. Effectiveness for drugs with modest benefit can be established only through large phase III randomized clinical trials. With numerous potential agents but limited resources, priority should be given to agents that show promise in phase II trials before proceeding to evaluation in phase III trials. In this article, we review drug development in early phase ALS trials and introduce novel designs. First, to maximize the therapeutic potential of the test medication, we need to identify the highest dose that produces a tolerable level of side effects. Second, candidate treatments should be ranked by conducting randomized selection trials between competing new treatments. The selection paradigm adopts a statistical viewpoint different from the hypothesis testing framework in conventional trials. We exemplify this approach by describing a group-sequential selection design developed for a phase II, randomized, multicenter trial of two combination treatments in patients with ALS, and illustrate the sample size reduction from a conventional trial.

[1]  J. Veldink,et al.  A randomized sequential trial of creatine in amyotrophic lateral sclerosis , 2003, Annals of neurology.

[2]  G. Cutter,et al.  Futility studies , 2006, Neurology.

[3]  J. Cedarbaum,et al.  Performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in multicenter clinical trials , 1997, Journal of the Neurological Sciences.

[4]  G. Parry,et al.  Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis , 1996, Neurology.

[5]  W. Bradley.  A controlled trial of recombinant methionyl human BDNF in ALS , 1999, Neurology.

[6]  J. Cedarbaum,et al.  The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function , 1999, Journal of the Neurological Sciences.

[7]  B E Storer,et al.  Design and analysis of phase I clinical trials. , 1989, Biometrics.

[8]  R. Elble,et al.  A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease , 2006, Neurology.

[9]  S Chevret,et al.  The continual reassessment method in cancer phase I clinical trials: a simulation study. , 1993, Statistics in medicine.

[10]  C. Tanner,et al.  Optimizing the ongoing search for new treatments for Parkinson disease , 2006, Neurology.

[11]  T. Hanafusa,et al.  Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS , 2006, Neurology.

[12]  B. Levin.  The utility of futility. , 2005, Stroke.

[13]  P. Kaufmann,et al.  The ALSFRSr predicts survival time in an ALS clinic population , 2005, Neurology.

[14]  M. Swash,et al.  El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis , 2000, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[15]  Ying Kuen Cheung,et al.  A Simple Technique to Evaluate Model Sensitivity in the Continual Reassessment Method , 2002, Biometrics.

[16]  J O'Quigley,et al.  Continual reassessment method: a practical design for phase 1 clinical trials in cancer. , 1990, Biometrics.

[17]  Yuko Y Palesch,et al.  Applying a Phase II Futility Study Design to Therapeutic Stroke Trials , 2005, Stroke.

[18]  M. Gaweł,et al.  Effect of recombinant human insulin-like growth factor-I on progression of ALS , 1997, Neurology.

[19]  J. Heemskerk.  High throughput drug screening , 2004, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[20]  Ninds Net-Pd Investigators.  A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. , 2006 .

[21]  H. Robbins,et al.  Sequential Tests Involving Two Populations , 1974 .

[22]  G. Parry,et al.  Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis , 2001, Neurology.

[23]  G. Levy,et al.  A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS , 2006, Neurology.

[24]  F. Schick,et al.  New Imaging Techniques of Fat, Muscle and Liver within the Context of Determining Insulin Sensitivity , 2006, Hormone Research in Paediatrics.