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Randomized Controlled Trial
. 2015 Feb 10;313(6):584-93.
doi: 10.1001/jama.2015.120.

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  1 , Barbara C Tilley  2 , Jordan J Elm  3 , Debra Babcock  4 , Robert Hauser  5 , G Webster Ross  6 , Alicia H Augustine  1 , Erika U Augustine  1 , Michael J Aminoff  7 , Ivan G Bodis-Wollner  8 , James Boyd  9 , Franca Cambi  10 , Kelvin Chou  11 , Chadwick W Christine  7 , Michelle Cines  12 , Nabila Dahodwala  13 , Lorelei Derwent  14 , Richard B Dewey Jr  15 , Katherine Hawthorne  16 , David J Houghton  17 , Cornelia Kamp  1 , Maureen Leehey  18 , Mark F Lew  16 , Grace S Lin Liang  19 , Sheng T Luo  2 , Zoltan Mari  20 , John C Morgan  21 , Sotirios Parashos  22 , Adriana Pérez  2 , Helen Petrovitch  6 , Suja Rajan  2 , Sue Reichwein  13 , Jessie Tatsuno Roth  7 , Jay S Schneider  23 , Kathleen M Shannon  24 , David K Simon  25 , Tanya Simuni  26 , Carlos Singer  27 , Lewis Sudarsky  28 , Caroline M Tanner  19 , Chizoba C Umeh  28 , Karen Williams  26 , Anne-Marie Wills  28
Collaborators, Affiliations
Randomized Controlled Trial

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 et al. JAMA. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kieburtz reported serving as a consultant for National Institutes of Health (NIH) (National Institute of Neurological Disorders and Stroke [NINDS]), the US Food and Drug Administration (FDA), the US Veterans Administration, Acorda, Astellas Pharma, AstraZeneca, Auspex, Biotie, Britannia, Cangene, CHDI Foundation, Civitas, Clintrex, Cynapsus, INC Research, Intec, Isis, Lilly, Lundbeck, Medavante, Medivation, Melior Discovery, Neuroderm, Omeros, Otsuka, Pharm2B, Prothena/Neotope/Elan Pharmaceutical, Roche/Genentech, Sage Bionetworks, Serina, Stealth Peptides, Synagile, Teikoku Pharma, Titan, Upsher-Smith, US WorldMeds, Vaccinex, Voyager, and Weston Brain Institute; and receiving grants or research support from the NIH (National Eye Institute, NINDS, National Institute on Aging [NIA], Eunice Kennedy Shriver National Institute of Child Health and Human Development), the Michael J. Fox Foundation, and Teva. Dr Tilley reported receiving grant support from NINDS and receiving travel funding from the CHDI Foundation. Dr Elm reported receiving research grant support from NINDS and serving as a consultant for Teva. Dr Hauser reported receiving honoraria or payments for consulting AbbVie, Allergan, AstraZeneca, Biotie Therapeutics, Ceregene, Chelsea Therapeutics, Cleveland Clinic, Eli Lilly, GE Healthcare, Impax Laboratories, Neurocrine, Indus, Ipsen Biopharmaceuticals, Lundbeck, Merck/MSD, Noven Pharmaceuticals, Pfizer, Straken Pharmaceuticals, Targacept, Teva Pharmaceuticals Industries Ltd, Teva Neuroscience, Upsher-Smith Laboratories, GLG, UCB Pharma SA, University of Houston, US WorldMeds, Xenoport, Zambon Company, SpA, Pricespective LLC, HealthLogix, and Gerson Lehrman Group Inc. Dr Ross reported receiving funding support from NINDS. Dr E. U. Augustine reported receiving funding from NINDS. Dr Aminoff reported receiving research support from NINDS (U10 NS044460; AAV-hAADC-2-003 [site principal investigator]) and the National Parkinson Foundation (NPF). Dr Boyd reported receiving personal fees from Lundbeck and Auspex and receiving grants from Auspex, the Michael J. Fox Foundation, Parkinson Disease Foundation, AbbVie, CHDI Foundation, and NINDS. Dr Chou reported receiving research support from the NIH (NS44504-08) and serving as a consultant to Medtronic. Dr Dahodwala reported receiving grants from NINDS, NIA, Teva, and the Parkinson Council. Dr Dewey reported serving as a consultant for Teva Pharmaceuticals, US WorldMeds, Lundbeck, Acadia, Merz, Xenoport, and GE Healthcare and receiving speakers fees from Teva Pharmaceuticals, US WorldMeds, and UCB. Ms Kamp reported receiving a grant from the University of Rochester. Dr Leehey reported receiving a grant from the NIH and receiving personal fees from Guidepoint Global, Gerson Lehman Group, MEDAcorp, and the Health Practices Institute. Dr Lew reported serving as a consultant for Teva Neurosciences, Baxter, Auspex, UCB, Impax, US WorldMeds, and Ipsen. Dr Liang reported receiving a grant from NINDS to the Parkinson’s Institute; receiving research support from Impax Pharmaceuticals, Teva Neuroscience, the Michael J. Fox Foundation, Novartis, NPF, Merck-Serono, Merck, Adamas, Kyowa, Chelsea Therapeutics, Berg Pharma, and Acadia; receiving an honorarium from Teva Neuroscience; and that she is currently employed by, and holds stock options in, Neurocrine Biosciences. Dr Luo reported receiving grants from the NIH, the Movement Disorder Society, and the CHDI Foundation. Dr Mari reported that his institution has received grant support from the NIH, NPF, Michael J. Fox Foundation, AVID, and AbbVie. Dr Morgan receiving grant support from the NIH and NPF; receiving speaking fees from NPF and Teva; and serving as a consultant for Teva, Impax Labs, Veloxis, Lundbeck, UCB, and Noven. Dr Morgan reported receiving grants from the NIH and the NPF and receiving speaking and consulting fees from Teva. Dr Pérez reported receiving grant support from the NIH. Dr Petrovich reported receiving grant support from NINDS. Dr Simon reported receiving grant support from NINDS. Dr Simuni reported receiving research support from NPF, Teva, Impax, Synosia, Auspex, Serono, Phytopharm, NIH, Michael J. Fox Foundation, the Dixon Foundation, and the Parkinson Associated Risk Study; receiving consulting fees from Acadia, AbbVie, Allergan, Boehringer Ingelheim, GE Medical, Eli Lilly, Harbor, Ibsen, Impax, Lundbeck, Merz, NPF, Navidea, Teva, UCB, and US WorldMeds; receiving honoraria from Allergan, GE Medical, Ibsen, Teva, and UCB; and receiving educational grant support from GE Medical and Teva. Dr Sudarsky reported receiving a grant from the NIH. Dr Tanner reported receiving grant support from NINDS and serving as a consultant for Adamas (fees paid to institution), Impax (fees paid to institution), and Pfizer. No other authors reported disclosures.

Figures

Figure
Figure. CONSORT Diagram of Long-term Study 1 Trial Enrollment Status From Initiation of Screening to the Time of the Interim Analysis on July 17, 2013
aTaking exclusionary medications (n = 67), not taking dopaminergic therapy (n = 34), diagnosis uncertain (n = 24), medical condition (n = 22), Parkinson disease too advanced (n = 22), enrolled in another study (n = 4), inability to consent (n = 2), non–English-speaking (n = 2), or failure to meet other inclusion criteria (n = 11). bNine additional deaths occurred after participants withdrew consent (creatine monohydrate, n = 4; placebo, n = 5). cCohort (cohort 1) used in the interim efficacy analyses.
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