A clinical trial of creatine in ALS

Shefner, Jeremy M.; Cudkowicz, Merit; Schoenfeld, David; Conrad, Thomas; Taft, J; Chilton, Mark; Urbinelli, Leo; Qureshi, Muddasir; Zhang, H.; Pestronk, Alan; Caress, James B.; Donofrio, Peter D.; Sorenson, Eric J.; Bradley, Walter G.; Lomen‐Hoerth, Catherine; Pioro, Erik P.; Rezania, Kourosh; Ross, Mark A.; Pascuzzi, Robert M.; Heiman‐Patterson, Terry; Tandan, Rup; Mitsumoto, Hiroshi; Rothstein, Jeffery D.; Smith‐Palmer, Truis; MacDonald, Daniel J.; Burke, Darren

doi:10.1212/01.wnl.0000142992.81995.f0

Cited by 267 publications

(123 citation statements)

References 36 publications

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“…A case in point is creatine, which is proposed to increase energy storage capacity and could be used to generate ATP under high-energy demands. However, creatine failed in clinical trials and in some cases even caused negative effects [86,87].…”

Section: Mitochondrial Bioenergetics As a Therapeutic Targetmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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Section: Mitochondrial Bioenergetics As a Therapeutic Targetmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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“…However, in clinical studies in which creatine was supplemented in the diet, patients were found not to derive any benefit (51,123,124). Coenzyme Q10, a cofactor in the electron transfer chain, is also a scavenger of free radicals in lipid and mitochondrial membranes, and is thought to improve energy production by the mitochondrial membrane and the cell.…”

Section: Therapeutic Approaches To Alsmentioning

confidence: 99%

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Carter

Anklesaria

Choi

et al. 2009

Antioxidants & Redox Signaling

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Enhanced redox-stress caused by neuroinflammation, mitochondria, and NADPH oxidases has been hypothesized to play critical roles in disease progression of amyotrophic lateral sclerosis (ALS). However, distinguishing whether the redox-stress observed in ALS is due to a primary defect in cellular reactive oxygen species metabolism=catabolism, or is a secondary consequence of neuroinflammation, has been difficult and the issue remains a matter of debate. Emerging evidence suggests that defects in genes that regulate NADPH oxidases may account for at least some forms of ALS. NADPH oxidases are key signaling complexes that influence cellular responses to growth factors and cytokines. In this context, NADPH oxidase-derived reactive oxygen species exert spatial control over the redox-dependent activation of certain pro-inflammatory receptors. Understanding the biology of how NADPH oxidases control cell signaling may help to clarify how genetic determinants of ALS lead to dysregulated pro-inflammatory signaling. This review provides a framework for understanding endosomal signaling through NADPH oxidases and potential mechanisms whereby gene defects in various forms of ALS may influence this cellular process and lead to motor neuron degeneration. Lastly, this review discusses past and current efforts to treat ALS using antioxidant therapies, as well as the limitations and advantages of each of these approaches. Antioxid. Redox Signal. 11, 1569-1586.

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“…While recent trials have failed to demonstrate benefit of a variety of therapeutic interventions, including celecoxib, topiramate, creatine (Cudkowicz et al, 2003;Shefner et al, 2004;Cudkowicz et al, 2006), advances in basic science are leading to a proliferation of new agents that will require clinical evaluation. A significant problem in clinical trial design is that large numbers of patients must be studied for long time periods for modest therapeutic benefit to be appreciated, making the design of phase II proof-of-concept trials challenging.…”

Section: Introductionmentioning

confidence: 99%

Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials

Rutkove

Zhang

Schoenfeld

et al. 2007

Clinical Neurophysiology

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Objective-Standard outcome measures used for amyotrophic lateral sclerosis (ALS) clinical trials, including the ALS Functional Rating Scale-revised (ALSFRS-R), maximal voluntary isometric contraction testing (MVICT), and manual muscle testing (MMT) are limited in their ability to detect subtle disease progression. Electrical impedance myography (EIM) is a new non-invasive technique that provides quantitative data on muscle health by measuring localized tissue impedance. This study investigates whether EIM could provide a new outcome measure for use in ALS clinical trials work.Methods-Fifteen ALS patients underwent repeated EIM measurements of one or more muscles over a period of up to 18 months and the primary outcome variable, θ z-max , measured. The θ z-max megascore was then calculated using the same approach as has been applied in the past for MVICT. This and the MMT data were then used to assess each measure's statistical power to detect a given effect on disease progression in a hypothetical planned clinical therapeutic trial.Results-θ z-max showed a mean decline of about 21% for the test period, averaged across all patients and all tested muscles. The θ z-max megascore had a power of 73% to detect a 10% treatment effect in our planned hypothetical trial, as compared to a 28% power for MMT. These results also compared favorably to historical data for ALSFRS-R and MVICT arm megascore from the trial of celecoxib in ALS, where both measures had only a 23% power to detect the same 10% treatment effect.Conclusions-The θ z-max megascore may provide a powerful new outcome measure for ALS clinical trials.Significance-The application of EIM to future ALS trials may allow for smaller, faster studies with an improved ability to detect subtle treatment effects.

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A clinical trial of creatine in ALS

Cited by 267 publications

References 36 publications

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials

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