Issues in Design and Conduct of Clinical Trials for Cognitive-Enhancing Drugs

Schneider, Lon S.

doi:10.1016/b978-0-12-373861-5.00014-x

Cited by 15 publications

(24 citation statements)

References 64 publications

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“…N orth American and European Union regulatory criteria for marketing approval of putative symptomatic and disease-modifying therapeutic agents for Alzheimer disease (AD) are based on a demonstration of efficacy supported by improvements compared to placebo treatment on cognitive function, activities of daily living (ADL), and often evidence of overall clinical improvement or less overall decline, accompanied by adequate evidence of safety (Schneider 2008b). In practice this has led to rather standardized protocols by sponsors of experimental drugs.…”

Section: Regulatory Landscape and Clinical Trialsmentioning

confidence: 99%

“…Another Phase III trial, assessing the addition of dimebon to standard therapy for 1 year, continues. Lessons from the dimebon program include the role of serendipity, and the unpredictability and inconsistency in Phase II and smaller sample size AD trials learned from other programs (Schneider 2008b), as well as reasons specific to this drug (Jones 2010).…”

Section: Dimebon (Latrepirdine)mentioning

confidence: 99%

“…The trials are commonly 6-18 months in duration: 6 months for symptomatic and 12 -18 months for disease-modifying trials. There is a current trend to include more mild patients with AD, operationalized as MMSE greater than 20, amnestic mild cognitive impairment (MCI), or MCI due to AD, prodromal or early AD (supported by a positive cerebrospinal fluid [CSF] or imaging biomarker) (Schneider 2008b;Albert et al 2011).…”

Section: Regulatory Landscape and Clinical Trialsmentioning

confidence: 99%

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Symptomatic and Nonamyloid/Tau Based Pharmacologic Treatment for Alzheimer Disease

Aisen

Cummings

Schneider

2011

Cold Spring Harbor Perspectives in Medicine

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In this work we consider marketed drugs for Alzheimer disease (AD) including acetylcholinesterase inhibitors (AChE-Is) and antiglutamatergic treatment involving the N-methyl-D-aspartate (NMDA) receptor. We discuss medications and substances available for use as cognitive enhancers that are not approved for AD or cognitive impairment, and other neurotransmitter-related therapies in development or currently being researched. We also review putative therapies that aim to slow disease progression by mechanisms not directly related to amyloid or tau. REGULATORY LANDSCAPE AND CLINICAL TRIALS

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Section: Regulatory Landscape and Clinical Trialsmentioning

confidence: 99%

Section: Dimebon (Latrepirdine)mentioning

confidence: 99%

Section: Regulatory Landscape and Clinical Trialsmentioning

confidence: 99%

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Symptomatic and Nonamyloid/Tau Based Pharmacologic Treatment for Alzheimer Disease

Aisen

Cummings

Schneider

2011

Cold Spring Harbor Perspectives in Medicine

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“…Animal models of depression in drug discovery: a historical perspective. Pharmacology, biochemistry, and behaviour 84, 436-452. ments and change are also assessed psychometrically (Schneider, 2008).…”

Section: Introductionmentioning

confidence: 99%

Aligning physiology with psychology: Translational neuroscience in neuropsychiatric drug discovery

McArthur¹

2017

Neuroscience & Biobehavioral Reviews

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“…Specifically, AD trials that allow patients to enter with Mini-Mental State Examination (5) scores of 26 and below can include some patients with MCI; and MCI trials that allow patients to enter with MMSE scores of 24 and higher could include patients with mild AD. A practical effect for MCI trials is to enrich a sample for the development of probable AD over a 2 to 4 year period (2). Consequently, a group of amnestic MCI patients likely includes the subset 'pre-dementia AD,' prodromal AD, or early AD.…”

Section: Introductionmentioning

confidence: 99%

The potential and limits for clinical trials for early Alzheimer’s disease and some recommendations

Schneider

2010

J Nutr Health Aging

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Recommendations for clinical trials methods for 'pre-dementia,' 'prodromal,' or early Alzheimer's disease are discussed. Early AD can be considered as subsets of both 'amnestic MCI' and 'probable AD.' In principle, it can be operationalized using recently proposed, new research criteria for AD that specifically does not require impairment in non-memory cognitive function and activities of daily living, and consequently does not require the presence of dementia. The criteria also require patients to show abnormal putative biomarkers but require validation. Trials in early AD should be done when models of drug action and response suggest that the drug in development likely would be effective in early AD and clinical effects could be expected in a relatively short time.Biomarkers should be used as stratification or explanatory variables that may help to explain clinical outcomes from early AD trials rather than as inclusion/exclusion criteria in order to avoid pseudospecificity.Trials should be multicentered, double-blinded, randomized, placebo-controlled, generally with dose-ranging of two doses if indicated. Duration of trials should be based on expected onsets and durations of effects, and generally should be less than one year. Crossover trials should be considered when appropriate.Primary outcomes should specifically assess memory and include repeated assessments. Potential secondary outcomes could include self-and observer-rated health-related quality of life and global impressions of change in lieu of activities of daily living. Onset of dementia should not be an endpoint because many patients would be on the cusp of dementia and dementia onset is influenced by numerous biological and environmental factors. Inferences that can be made from trials results will likely involve the effects of the test drug on memory and self-rated global function. Disease modification is not likely to be inferred except in trials over two years in duration in which a change in a biomarker can be used as an adjunctive assessment. Models and simulations using existing clinical trials databases would be helpful in planning early AD trials.

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Issues in Design and Conduct of Clinical Trials for Cognitive-Enhancing Drugs

Cited by 15 publications

References 64 publications

Symptomatic and Nonamyloid/Tau Based Pharmacologic Treatment for Alzheimer Disease

Symptomatic and Nonamyloid/Tau Based Pharmacologic Treatment for Alzheimer Disease

Aligning physiology with psychology: Translational neuroscience in neuropsychiatric drug discovery

The potential and limits for clinical trials for early Alzheimer’s disease and some recommendations

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