A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease

Salloway, Stephen; Sperling, Reisa A.; Keren, Ron; Porsteinsson, Anton P.; Dyck, C H van; Tariot, Pierre N.; Gilman, Sid; Arnold, Douglas L.; Abushakra, Susan; Hernandez, Chito; Crans, Gerald; Liang, Earvin; Quinn, Grainne; Bairu, Menghis; Pastrak, Aleksandra; Cedarbaum, Jesse M.

doi:10.1212/wnl.0b013e3182309fa5

Cited by 236 publications

(171 citation statements)

References 42 publications

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“…The majority of trials (n = 94) used at least one cognitive outcome, 25,27-29, 51,52,55,57,64,66,68,75,78,[86][87][88][89][90][91][92][93]97,104,106,107,110,112,115,118,119,121,123,125,126,130,131,133,134,[137][138][139][140]143,145,146 with a variety of 16 measures used. ADLs were measured in 55 trials, using 12 measures.…”

Section: Published Trialsmentioning

confidence: 99%

“…ADLs were measured in 55 trials, using 12 measures. 27,28,33,37,41,45,46,49,51,52,54,55,57,59,61,63,64,66,68,77,78,81,[85][86][87][88][89][90]92,97,104,[106][107][108][110][111][112]114,115,118,119,[121][122][123][124][125]128,134,135,137,138,[142][143][144][145] Biological markers were measured in 51 trials using a variety of nine biological t...…”

Section: Published Trialsmentioning

confidence: 99%

See 1 more Smart Citation

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Webster

Groskreutz

Grinbergs-Saull

et al. 2017

Health Technol Assess

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Background: There is currently no disease-modifying treatment available to halt or delay the progression of the disease pathology in dementia. An agreed core set of the best-available and most appropriate outcomes for disease modification would facilitate the design of trials and ensure consistency across disease modification trials, as well as making results comparable and meta-analysable in future trials. Objectives: To agree a set of core outcomes for disease modification trials for mild to moderate dementia with the UK dementia research community and patient and public involvement (PPI). Data sources: We included disease modification trials with quantitative outcomes of efficacy from (1) references from related systematic reviews in workstream 1; (2) searches of the Cochrane Dementia and Cognitive Improvement Group study register, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Latin American and Caribbean Health Sciences Literature and PsycINFO on 11 December 2015, and clinical trial registries [International Standard Randomised Controlled Trial Number (ISRCTN) and clinicaltrials.gov] on 22 and 29 January 2016; and (3) hand-searches of reference lists of relevant systematic reviews from database searches. Review methods: The project consisted of four workstreams. (1) We obtained related core outcome sets and work from co-applicants. (2) We systematically reviewed published and ongoing disease modification trials to identify the outcomes used in different domains. We extracted outcomes used in each trial, recording how many used each outcome and with how many participants. We divided outcomes into the domains measured and searched for validation data. (3) We consulted with PPI participants about recommended outcomes. (4) We presented all the synthesised information at a conference attended by the wider body of National Institute for Health Research (NIHR) dementia researchers to reach consensus on a core set of outcomes. Results: We included 149 papers from the 22,918 papers screened, referring to 125 individual trials. Eighty-one outcomes were used across trials, including 72 scales [31 cognitive, 12 activities of daily living (ADLs), 10 global, 16 neuropsychiatric and three quality of life] and nine biological techniques. We consulted with 18 people for PPI. The conference decided that only cognition and biological markers are core measures of disease modification. Cognition should be measured by the Mini Mental State Examination (MMSE) or the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog), and brain changes through structural magnetic resonance imaging (MRI) in a subset of participants. All other domains are important but not core. We recommend using the Neuropsychiatric Inventory for neuropsychiatric symptoms: the Disability Assessment for Dementia for ADLs, the Dementia Quality of Life Measure for quality of life and the Clinical Dementia Rating scale to measure dementia globally. Limitations: Most of the trials inclu...

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Section: Published Trialsmentioning

confidence: 99%

Section: Published Trialsmentioning

confidence: 99%

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Webster

Groskreutz

Grinbergs-Saull

et al. 2017

Health Technol Assess

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“…But clinical efficiency outcomes in a phase two clinical trial of AD patients using 250 mg Scyllo-inositol were not significantly different from placebo, and higher dose studies were discontinued due to increased infections and mortalities (Salloway et al, 2011). …”

Section: Potential Therapies For Hchwa-dmentioning

confidence: 99%

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Kamp

Moursel²,

Haan³

et al. 2014

Reviews in the Neurosciences

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Hereditary cerebral hemorrhage with amyloidosis – Dutch type is an autosomal dominant hereditary disease caused by a point mutation in the amyloid precursor protein gene on chromosome 21. The mutation causes an amino acid substitution at codon 693 (E22Q), the ‘Dutch mutation’. Amyloid β, the product after cleavage of the amyloid precursor protein, is secreted into the extracellular space. The Dutch mutation leads to altered amyloid β cleavage and secretion, enhanced aggregation properties, higher proteolysis resistance, lowered brain efflux transporter affinity, and enhanced cell surfaces binding. All these result in amyloid β accumulation in cerebral vessel walls, causing cell death and vessel wall integrity loss, making cerebral vessel walls in hereditary cerebral hemorrhage with amyloidosis-Dutch type more prone to rupture and obstruction, leading to hemorrhages and infarcts. Studying the effects of altered amyloid β metabolism due to mutations like the ‘Dutch’ provides us with a better understanding of amyloid β toxicity, also in other amyloid β diseases like sporadic cerebral amyloid angiopathy and Alzheimer’s disease.

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“…[67] A phase 2 clinical trial of scyllo-inositol established a twice daily dose of 250mg as being safe, but the sample size was too small to establish efficacy. [68] scyllo-Inositol inhibits the aggregation of Aβ in Alzheimer's disease and also inhibits the neuronal aggregation of α-synuclein, a pathological hallmark of Parkinson's disease. [69] Likewise, scyllo-inositol reduces the number of neuronal aggregates and inclusions containing polyglutamine-expanded huntingtin protein in Huntington disease and does this by reducing the amount of mutant protein produced.…”

Section: Scyllo-inositol and Neurological Disordersmentioning

confidence: 99%

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

2015

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Cell signalling via inositol phosphates, eg the second messenger myo-inositol 1,4,5-trisphosphate, and phosphoinositides comprises a huge field of biology. Of nine 1,2,3,4,5,6-cyclohexanehexol isomers, myo-inositol is pre-eminent, with "other" inositols (cis-, epi-, allo-, muco-, neo-, L-chiro-, D-chiro-and scyllo-) and derivatives rarer or thought not to exist in nature. However, recently, neoand D-chiro-inositol hexakisphosphates were revealed in both terrestrial and aquatic ecosystems, highlighting the paucity of knowledge of the origins and potential biological functions of such stereoisomers, a prevalent group of environmental organic phosphates, and their parent inositols. Some "other" inositols are medically relevant, e.g. scyllo-inositol (neurodegenerative diseases), and D-chiro-inositol (diabetes). It is timely to consider exploration of roles and applications of "other" isomers and their derivatives, likely by exploiting techniques now well developed for the myo-series.

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A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease

Cited by 236 publications

References 42 publications

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

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