Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.
Writing Group for the NINDS Exploratory Trials in Parkinson Disease (NET-PD) Investigators, Karl Kieburtz, Barbara C Tilley, Jordan J Elm, Debra Babcock, Robert Hauser, G Webster Ross, Alicia H Augustine, Erika U Augustine, Michael J Aminoff, Ivan G Bodis-Wollner, James Boyd, Franca Cambi, Kelvin Chou, Chadwick W Christine, Michelle Cines, Nabila Dahodwala, Lorelei Derwent, Richard B Dewey, Katherine Hawthorne, David J Houghton, Cornelia Kamp, Maureen Leehey, Mark F Lew, Grace S Lin Liang, Sheng T Luo, Zoltan Mari, John C Morgan, Sotirios Parashos, Adriana Pérez, Helen Petrovitch, Suja Rajan, Sue Reichwein, Jessie Tatsuno Roth, Jay S Schneider, Kathleen M Shannon, David K Simon, Tanya Simuni, Carlos Singer, Lewis Sudarsky, Caroline M Tanner, Chizoba C Umeh, Karen Williams, Anne-Marie Wills
Author Information
Karl Kieburtz: University of Rochester, Rochester, New York.
Barbara C Tilley: University of Texas Health Science Center at Houston.
Jordan J Elm: Medical University of South Carolina, Charleston.
Debra Babcock: National Institutes of Health, Bethesda, Maryland.
Robert Hauser: University of South Florida, Tampa.
G Webster Ross: Pacific Health Research and Education Institute, Honolulu, Hawaii.
Alicia H Augustine: University of Rochester, Rochester, New York.
Erika U Augustine: University of Rochester, Rochester, New York.
Michael J Aminoff: University of California, San Francisco.
Ivan G Bodis-Wollner: State University of New York Downstate Medical Center, Brooklyn.
James Boyd: University of Vermont, Burlington.
Franca Cambi: University of Kentucky, Lexington.
Kelvin Chou: University of Michigan, Ann Arbor.
Chadwick W Christine: University of California, San Francisco.
Michelle Cines: University of Maryland School of Medicine, Baltimore.
Nabila Dahodwala: University of Pennsylvania, Philadelphia.
Lorelei Derwent: University of Calgary, Calgary, Alberta, Canada.
Richard B Dewey: University of Texas Southwestern Medical Center, Dallas.
Katherine Hawthorne: University of Southern California, Los Angeles.
David J Houghton: Ochsner Medical Center, New Orleans, Louisiana.
Cornelia Kamp: University of Rochester, Rochester, New York.
Maureen Leehey: University of Colorado Denver, Aurora.
Mark F Lew: University of Southern California, Los Angeles.
Grace S Lin Liang: The Parkinson's Institute and Clinical Center, Sunnyvale, California.
Sheng T Luo: University of Texas Health Science Center at Houston.
IMPORTANCE: There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE: To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS: The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS: Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES: The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. RESULTS: The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE: Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00449865.
