Determining the minimum clinically important differences for outcomes in the DOMINO trial

Howard, Robert; Phillips, Patrick P. J.; Johnson, Tony; O’Brien, John T.; Sheehan, Bart; Lindesay, James; Bentham, Peter; Burns, Alistair; Ballard, Clive; Holmes, Clive; McKeith, Ian G.; Barber, Robert; Dening, Tom; Ritchie, Craig W.; Jones, Rob; Baldwin, Ashley; Passmore, Peter; Findlay, D.J.S.; Hughes, Alan; Macharouthu, Ajay; Banerjee, Sube; Jones, Roy; Knapp, Martín; Brown, Richard G.; Jacoby, Robin; Adams, Jessica R.; Griffin, Mary; Gray, Richard

doi:10.1002/gps.2607

Cited by 139 publications

(142 citation statements)

References 28 publications

(28 reference statements)

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“…Whereas the psychometric changes in the placebo arm are in keeping with observed changes reported elsewhere in similar populations, 28,29 the change in ADAS-cog was double than anticipated. 4 While every attempt was made to improve internal validity by ensuring raters received the same psychometric rating training and, wherever possible, not change between visits, small numbers in the study cannot rule out the random allocation of a more rapidly declining group to the placebo arm and differences between groups should be viewed with caution.…”

Section: (1) 4 (3)supporting

confidence: 71%

Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial

2015

Neurology

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Objectives: To determine whether the tumor necrosis factor a inhibitor etanercept is well tolerated and obtain preliminary data on its safety in Alzheimer disease dementia. Methods:In a double-blind study, patients with mild to moderate Alzheimer disease dementia were randomized (1:1) to subcutaneous etanercept (50 mg) once weekly or identical placebo over a 24-week period. Tolerability and safety of this medication was recorded including secondary outcomes of cognition, global function, behavior, and systemic cytokine levels at baseline, 12 weeks, 24 weeks, and following a 4-week washout period. This trial is registered with EudraCT (2009-013400-31) and ClinicalTrials.gov (NCT01068353).Results: Forty-one participants (mean age 72.4 years; 61% men) were randomized to etanercept (n 5 20) or placebo (n 5 21). Etanercept was well tolerated; 90% of participants (18/20) completed the study compared with 71% (15/21) in the placebo group. Although infections were more common in the etanercept group, there were no serious adverse events or new safety concerns. While there were some interesting trends that favored etanercept, there were no statistically significant changes in cognition, behavior, or global function.Conclusions: This study showed that subcutaneous etanercept (50 mg/wk) was well tolerated in this small group of patients with Alzheimer disease dementia, but a larger more heterogeneous group needs to be tested before recommending its use for broader groups of patients. Classification of evidence:This study shows Class I evidence that weekly subcutaneous etanercept is well tolerated in Alzheimer disease dementia. Neurology ® 2015;84:2161-2168 GLOSSARY AD 5 Alzheimer disease; ADAS-cog 5 Alzheimer's Disease Assessment Scale-cognitive; BADLS 5 Bristol Activities of Daily Living Scale; CGI-I 5 Clinical Global Impression-Improvement; CI 5 confidence interval; CRP 5 C-reactive protein; IL 5 interleukin; IQR 5 interquartile range; ITT-LOCF 5 intention to treat-last observation carried forward; NPI 5 Neuropsychiatric Inventory; RPCT 5 randomized placebo-controlled trial; sMMSE 5 standardized Mini-Mental State Examination; TNFa 5 tumor necrosis factor a.Acute and chronic systemic inflammation is characterized by the production of proinflammatory cytokines including tumor necrosis factor a (TNF-a) from immune cells. TNF-a has a role in systemic immune-to-brain communication by activating the central immune response.1 In humans, low levels of chronic systemic inflammation are associated with evidence of microglial activation.2 In animals, experimentally induced acute systemic inflammation results in an exaggerated central immune response leading to exacerbated neurodegeneration. 3 In participants with Alzheimer disease (AD) dementia, we have shown that modestly increased serum TNF-a levels are associated with an increased rate of cognitive decline 4 and an exaggeration of neuropsychiatric symptoms. Peer-reviewed published data on the use of the TNF-a inhibitor etanercept in AD dementia is limited to small open-l...

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Section: (1) 4 (3)supporting

confidence: 71%

Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial

2015

Neurology

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“…At least for the area of quality of life, there is empirical evidence of the suitability of such an MID [35]. In the recent DOMINO trial in moderate to severe AD, however, MIDs were suggested for cognition (MMSE) and function (Bristol ADLs Scale) based on 0.4 of the SD, since this produced values which aligned the closest with the opinion of the investigators [36,37]. In the literature, various methods have been used to estimate MIDs for patient-reported outcome instruments (for a review, see [34]) - from consideration of the statistical distribution of scores, to anchor-based methods in which the MID is determined by comparing the scale to real-life criteria.…”

Section: Discussionmentioning

confidence: 99%

Memantine in Patients with Moderate to Severe Alzheimer's Disease: Meta-Analyses Using Realistic Definitions of Response

Wilkinson

Wirth²,

Goebel

2013

Dement Geriatr Cogn Disord

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Background/Aims: We aimed to develop realistic definitions of clinical worsening in advanced Alzheimer's disease (AD) and to use them in a post hoc responder analysis of memantine. Methods: 2,340 patients with moderate to severe AD (Mini-Mental State Examination <20) were included from 9 multicentre, 16- to 28-week, randomised, double-blind, placebo-controlled studies of memantine 20 mg/day versus placebo. Responder meta-analyses were performed, with definitions of response based on minimally important differences (MIDs) on cognitive, functional, and global assessment scales. Validated or established MIDs were used where available; otherwise, MIDs were estimated by a data-driven approach, using data from our moderate to severe AD population. Results: Patients with moderate to severe AD treated with memantine had a lower incidence of worsening from baseline to endpoint than patients treated with placebo, in cognition [24.4 vs. 35.0%; odds ratio (OR) = 0.60; p < 0.001], function (38.1 vs. 43.4%; OR = 0.81; p = 0.01), global status (39.8 vs. 48.6%; OR = 0.70; p < 0.001), and in a combined ‘triple' worsening measure (9.4 vs. 16.1%; OR = 0.54; p < 0.001). Conclusions: New definitions of clinical worsening based on MIDs represent a more realistic functional decline in advanced stages of AD. Results of this new analysis show that memantine reduces the incidence of clinical worsening in key symptomatic domains in moderate to severe AD.

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“…Although there was no significant intergroup difference on the MMSE, the cost-effectiveness analyses suggest that MCST would be a cost-effective addition to usual care at low willingness-to-pay thresholds. Howard et al 19 suggested that a difference of 1.4 on MMSE is clinically significant; the mean cost of achieving this difference through MCST is £781.…”

Section: Cost-effectiveness (At 6 Months)mentioning

confidence: 99%

Maintenance Cognitive Stimulation Therapy: An Economic Evaluation Within a Randomized Controlled Trial

D’Amico

Rehill

Knapp

et al. 2015

Journal of the American Medical Directors Association

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Determining the minimum clinically important differences for outcomes in the DOMINO trial

Abstract: Reference to MCIDs is important for the full interpretation of the results of dementia trials and those conducting such trials should be open about the way in which they have determined and chosen their values for the MCIDs.

Cited by 139 publications

References 28 publications

Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial

Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial

Memantine in Patients with Moderate to Severe Alzheimer's Disease: Meta-Analyses Using Realistic Definitions of Response

Maintenance Cognitive Stimulation Therapy: An Economic Evaluation Within a Randomized Controlled Trial

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