Design innovations and baseline findings in a long-term Parkinson's trial: the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson's Disease Long-Term Study-1

Division of Biostatistics and Epidemiology, Medical University of South Carolina, 135 Cannon Street, Suite 303, P.O. Box 250835, Charleston, SC 29425, USA. .
Movement Disorders (Impact Factor: 5.68). 10/2012; 27(12):1513-1521. DOI: 10.1002/mds.25175
Source: PubMed


Based on the preclinical data and the results of a phase II futility study, creatine was selected for an efficacy trial in Parkinson's disease (PD). We present the design rationale and a description of the study cohort at baseline. A randomized, multicenter, double-blind, parallel-group, placebo-controlled phase III study of creatine (10 g daily) in participants with early, treated PD, the Long-term Study-1 (LS-1), is being conducted by the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson's Disease network. The study utilizes a global statistical test (GST) encompassing five clinical rating scales to provide a multidimensional assessment of disease progression. A total of 1,741 PD participants from 45 sites in the United States and Canada were randomized 1:1 to either 10 g of creatine/day or matching placebo. Participants are being evaluated for a minimum of 5 years. The LS-1 baseline cohort includes participants treated with dopaminergic therapy and generally mild PD. LS-1 represents the largest cohort of patients with early treated PD ever enrolled in a clinical trial. The GST approach should provide high power to test the hypothesis that daily administration of creatine (10 g/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5-year follow-up visit against the background of dopaminergic therapy and best PD care. © 2012 Movement Disorder Society.

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    • "In addition, markers associated with LID—prodynorphin and FosB/ΔFos180181182183—were reduced in the brains of mice fed a creatine-supplemented diet indicating that creatine supplementation had significant positive effects even after the development of pathology in this model[179]. On the basis of the animal and tissue culture studies, a number of clinical trials have examined the potential of creatine as a possible therapy for PD82838485868788184]. A randomized, double-blind futility trial was undertaken with 200 participants who received creatine (10 g d − 1 ), minocycline (200 mg d −1 ), or placebo. "
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    ABSTRACT: Creatine is widely used by both elite and recreational athletes as an ergogenic aid to enhance anaerobic exercise performance. Older individuals also use creatine to prevent sarcopenia and, accordingly, may have therapeutic benefits for muscle wasting diseases. Although the effect of creatine on the musculoskeletal system has been extensively studied, less attention has been paid to its potential effects on other physiological systems. Because there is a significant pool of creatine in the brain, the utility of creatine supplementation has been examined in vitro as well as in vivo in both animal models of neurological disorders and in humans. While the data are preliminary, there is evidence to suggest that individuals with certain neurological conditions may benefit from exogenous creatine supplementation if treatment protocols can be optimized. A small number of studies that have examined the impact of creatine on the immune system have shown an alteration in soluble mediator production and the expression of molecules involved in recognizing infections, specifically toll-like receptors. Future investigations evaluating the total impact of creatine supplementation are required to better understand the benefits and risks of creatine use, particularly since there is increasing evidence that creatine may have a regulatory impact on the immune system.
    No preview · Article · Jan 2016 · International immunopharmacology
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    • "The NET-PD (National Institute of Neurological Disorders and Stroke Exploratory Trials in PD) Long-term Study-1 (LS1, NCT00449865) was a multicenter, double-blind, randomized clinical trial of potential disease-modifying efficacy comparing creatine to placebo [5]. To be eligible, subjects were required to have the diagnosis of PD within 5 years and also to be taking dopaminergic therapy for more than 3 months but less than 2 years at study enrollment. "
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    ABSTRACT: The effects of dopaminergic therapy in parkinson's disease (PD) can vary depending on the class of medication selected. The aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD. A non-parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life. The outcomes measured at the beginning of the study showed lower disease burden for participants on initial DA monotherapy compared to those taking combined LD and DA therapy after controlling for age, education, taking cog-meds and amantadine. This observation suggests that clinicians treating early PD patients favor combined LD and DA therapy in patients with more disabling features over DA monotherapy. As such, studies of PD progression in treated PD patients may be affected by the class of symptomatic dopaminergic therapy. Published by Elsevier Ltd.
    Full-text · Article · Dec 2014 · Parkinsonism & Related Disorders
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    • "The combined effect of these processes is ultimately wheelchair-bound status [5]. The NIH Exploratory Trials in Parkinson Disease Long-Term Study 1 (LS-1) [6] was designed as a 5- year double blind, placebo controlled trial to examine the disease-modifying potential of creatine in PD. As a primary outcome measure it utilizes a composite measure that takes into account ambulatory capacity, activities of daily living, cognitive status, and global disability. "
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    ABSTRACT: Background: A construct calculated as the sum of items 13-15, 29, 30 of the Unified Parkinson's Disease Rating Scale (UPDRS) has been used as an "Ambulatory Capacity Measure" (ACM in Parkinson disease (PD). Its construct validity has never been examined. A similar construct, consisting of the mean value of the same UPDRS items has been used under the acronym PIGD as a measure of postural instability and gait disorder in PD. Objective: To examine the construct validity of the ACM and PIGD in PD. Methods: We analyzed data in an existing database of 340 PD patients, Hoehn and Yahr stages (HYS) 1-5 who participated in a study of falls. Number of falls (NOF) was recorded over 4 weeks, and UPDRS (mental, ADL, and motor subscales), HYS, Activities Based Confidence Scale (ABC), Freezing of Gait Questionnaire (FOG), Five Times Sit-to-Stand (FTSS), Timed Up-and Go (TUG), Gait Velocity (GV), and Berg Balance Scale (BBS) evaluations were performed. Internal consistency was assessed by Cronbach's alpha. Construct validity was assessed through correlations of the ACM and PIGD to these measures and to their summed-ranks. A coefficient of determination was calculated through linear regression. Results: Mean age was 71.4, mean age at diagnosis 61.4 years; 46% were women; mean UPDRS subscale scores were: Mental 3.7; ADL 15.7; motor: 27.1; mean ACM was 6.51, and mean PIGD 1.30. Cronbach's alpha was 0.78 for both ACM and PIGD. Spearman correlation coefficients between the ACM/PIGD and ABC, FOG, TUG, GV and BBS were 0.69, 0.72, 0.67, 0.58, and 0.70 respectively. Correlation between the ACM/PIGD and summed-ranks of HYS, NOF, ABC, FOG, FTSS, TUG, GV and BBS was high (Spearman r = 0.823, p < 0.0001); 68% of the variability in the summed-ranks was explained by ACM/PIGD. Conclusion: The ACM and the PIGD are valid global measures and accurately reflect the combined effects of the various components of ambulatory capacity in PD patients with HY stages 1-4.
    Full-text · Article · Oct 2014 · Journal of Parkinson's Disease
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