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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    • "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.
    Parkinsonism & Related Disorders 12/2014; 21(3). DOI:10.1016/j.parkreldis.2014.10.016 · 3.97 Impact Factor
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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.
    Journal of Parkinson's Disease 10/2014; 5(1). DOI:10.3233/JPD-140405 · 1.91 Impact Factor
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    ABSTRACT: Substantial evidence from both genetic and toxin induced animal and cellular models and postmortem human brain tissue indicate that mitochondrial dysfunction plays a central role in pathophysiology of the neurodegenerative disorders including Parkinson's disease (PD), and Huntington's disease (HD). This review discusses the emerging understanding of the role of mitochondrial dysfunction including bioenergetics defects, mitochondrial DNA mutations, familial nuclear DNA mutations, altered mitochondrial fusion/fission and morphology, mitochondrial transport/trafficking, altered transcription and increased interaction of pathogenic proteins with mitochondria in the pathogenesis of PD and HD. This review recapitulates some of the key therapeutic strategies applied to surmount mitochondrial dysfunction in these debilitating disorders. We discuss the therapeutic role of mitochondrial bioenergetic agents such as creatine, Coenzyme-Q10, mitochondrial targeted antioxidants and peptides, the SIRT1 activator resveratrol, and the pan-PPAR agonist bezafibrate in toxin and genetic cellular and animal models of PD and HD. We also summarize the phase II-III clinical trials conducted using some of these agents. Lastly, we discuss PGC-1α, TORC and Sirtuins as potential therapeutic targets for mitochondrial dysfunction in neurodegenerative disorders.
    Molecular and Cellular Neuroscience 12/2012; 55. DOI:10.1016/j.mcn.2012.11.011 · 3.84 Impact Factor
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