Combination Drug Selection Trial Combination Drug Selection Trial The Eleanor and Lou Gehrig MDA/ALS Research Center will coordinate an upcoming multi-center Phase II Selection Trial of Combination Drug Therapy in ALS. The trial is set to begin in March 2006 and will be conducted at 20 ALS Centers across the nation, including Columbia University. The researchers seek 120 people who wish to participate in scientific research. Eligible participants will: • Be between 21 and 85 years of age • Have ALS onset less than 5 years ago • Have a Forced Vital Capacity (FVC) 60% or greater Excess free radicals, energy mishandling, excitotoxicity, activation of cell death pathways and inflammation likely all contribute to neurodegeneration in ALS. Past trials may have been negative in part because they tested single agents, usually influencing only one mechanism of neurodegeneration. Combinations of agents that affect different and multiple mechanisms of cell death may be necessary to reach meaningful outcomes in trials of ALS. This trial has several unique features. •     The trial compares the neuroprotective potential of two combinations of agents that impact multiple mechanisms of cell death. The combinations of minocycline/creatine and celecoxib/creatine are the only agents to date that have had additive effects in the mouse model of ALS, reducing neurodegeneration and prolonging survival more than individual agents alone. •     It uses an important new phase II selection trial design to determine which combination is superior. Not only does this trial test combination therapy, but there is no placebo, so that everyone who enrolls in the trial will receive active treatment. The trial investigators will measure changes in function, using the ALS Functional Rating Scale, and measures of pulmonary function, coordination and quality of life. Each participant will have monthly evaluations and analysis of laboratory and adverse events for 6 months. Participants will be allowed to take riluzole, but not other investigational agents during the trial. Those with kidney disease, liver disease, or lupus will be excluded. Despite advances in understanding the pathogenesis, ALS remains an incurable disease. Given the myriad mechanisms of neurodegeneration, it is likely that combinations of agents, targeting different processes, will be necessary for a meaningful effect. The large therapeutic benefit of the combinations of agents in this trial on survival in transgenic mice provides evidence that using combined therapies may be the currently most expedient means to improve the course of human ALS. Each of the drugs individually has been shown to have meaningful neuroprotective effects in models of neurodegeneration. When given together, they have additive effects. This is one of the first times that the selection trial paradigm will be used to select a superior combinaion in ALS. If successful, this trial will lead directly to the design and implentation of a phase III placebo-controlled trial of the selected combination, and to future large scale phase II trials testing medications simultaneously, thereby improving the speed and efficiency of drug screening in ALS. For more information about the trial contact: Carolyn Doorish, Project Coordinator Eleanor and Lou Gehrig MDA/ALS Research Center Columbia Presbyterian Medical Center Department of Neurology 710 West 168th Street, 9th Floor,New York, NY 10032 Phone: (212) 305-2027 E-mail: cd2141@columbia.edu