Creatine Safety and Efficacy in HD: Coordination and Statistical Center

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DESCRIPTION (provided by applicant): This application is a competing renewal, entitled "Creatine Safety and Efficacy in HD: Coordination and Statistical Center", and is a companion application to that of Steven Hersch, M.D., PhD. from Massachusetts General Hospital (MGH), entitled "Creatine Safety, Tolerability and Efficacy in Huntington's Disease: CREST- E". The primary aim of the study is to investigate the efficacy and long-term safety of chronic creatine monohydrate treatment in Huntington's disease (HD). The competitive renewal is necessary to complete the study that is now 64% accrued. HD is a dominantly inherited, fatal, neurodegenerative disorder for which there is no effective treatment. HD is characterized by the cellular expression of the mutant huntingtin protein, which leads to aberrant protein/protein interactions and a net effect of altered cellular functioning including impaired energy production, oxidative damage, and altered transcriptional regulation. HD manifests clinically with chorea, dystonia, personality changes, and cognitive impairment leading to the loss of independence and eventually death. Approximately 30,000 people in the United States have symptomatic HD, and an additional 150,000 healthy people are at genetic risk of developing HD. The disease burden to patients and their family is severe and is combined with an estimated economical cost to society of about two billion dollars per year. Preclinical and clinical data suggest that creatne may play a disease modifying role in HD. In HD transgenic and knock-in mice, creatine delays the onset and slows the progression of the pathologic phenotype in a dose dependent manner, extends survival, reduces neuropathology and reverses cerebral ATP deficiency. In our initial controlled study, creatine 8 g/d daily increased serum and brain levels of creatine and reduced a plasma marker of oxidative injury to DNA (8OH2'dG) that is otherwise elevated 3-4 fold in symptomatic HD. Our most recent work in HD suggests that creatine may slow brain atrophy, as measured by magnetic resonance morphometry. Based on the above preclinical and clinical data, the primary hypothesis of the study is that 40 grams daily of creatine or highest tolerated dose will slow the functional decline associated with HD. The specific aim of this proposal is to test this hypothesis in a longitudinal, randomized, double-blind, placebo-controlled clinical trial that is designed to achieve 84% power to detect a 25% or greater slowing of disease progression. The primary outcome is the annualized rate of change in total functional capacity. To achieve this goal, 650 subjects will be enrolled in this multicenter, international study and followed for a minimum of 12 months and a maximum of 48 months. The strong rationale and the lack of any therapeutic agent able to slow the progression of this devastating neurodegenerative disease justify the completion of this phase III clinical trial. Should the resuls of the trial show efficacy, the readily available and inexpensive manufacturing of creatine will no only decrease the burden of the disease but do so at very low cost.