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Long-Term Creatine Therapy Fails to Improve Parkinson's Outcomes

February 13, 2015

By Larry Hand

NEW YORK - Adding creatine monohydrate to dopaminergic therapy for early Parkinson's disease doesn't slow its course, a new study finds.

"The most likely explanation is that the drug is not effective," Dr. Karl Kieburtz, of the University of Rochester, New York, told Reuters Health by email on behalf of the National Institute of Neurological Disorders and Stroke (NINDS) Exploratory Trials in Parkinson Disease (NET-PD) Investigators.

At 45 sites in the U.S. and Canada, the researchers randomly assigned 1741 patients to receive creatine monohydrate (10 g/d) or placebo for five years. Participants were all within five years of diagnosis and had received treatment with dopaminergic therapy; they were allowed to continue their other prescribed Parkinson's disease therapy.

The trial was terminated early, however, when a planned interim analysis of 955 patients showed no improvement with creatine, with a median follow-up of four years of treatment.

Creatine was the only one of four compounds to be tested after earlier futility trials by the NET-PD group eliminated three others from further testing.

"Creatine was initially considered because of evidence that it plays an important role in cellular energy production, which may be impaired in Parkinson disease," the authors explain.

The group compared clinical decline between treatment groups using a global statistical test (GST) to analyze five measures of PD progression: function, activities of daily living, ambulation, cognition, and quality of life.

"There was no detected benefit or harm attributable to creatine at the time of . . . termination," the researchers reported online February 10 in JAMA. The GST score was higher for creatine than for placebo, with a higher score meaning worse outcomes.

Nevertheless, Dr. Kieburtz told Reuters Health, "I think that the results of the study do not alter future research in a major way. The study demonstrated a series of new things, however, including that it is possible to recruit and follow PD subjects treated with dopaminergic drugs and monitor disease progression, and that you can measure multiple outcomes at once and analyze these outcomes using a global statistical test."

He continued, "Part of our study conduct was to have at least annual conference calls directly with participants (yes, conference calls with hundreds of participants), which allowed participants to speak directly with study leaders and get their questions answered. We think this helped maintain interest on the part of the participants. We also shared with them directly the need to stop the study, and they again appreciated the direct contact and, despite the outcome, their enthusiasm for having participated in the trial."

"We proceeded directly to a clinical approach (futility studies) because the mechanisms and molecular targets in Parkinson disease remain unclear," the researchers wrote. "Until such targets are well established, the screening of compounds with futility studies without prior mechanistic studies is useful to identify clearly futile compounds."

Dr. Kieburtz concluded, "I think futility studies still play a role. We studied four possible drugs, all of which could have gone to subsequent efficacy testing, and we found that it would not be useful to advance three. The fourth we did advance was not successful, but the futility analysis does not assure success; it only excludes drugs highly likely to fail."

The National Institute of Neurological Disorders and Stroke funded this research.


JAMA 2015.


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