Disease progression model using the integrated Alzheimer's Disease Rating Scale

Gueorguieva, Ivelina; Chua, Lynette J.; Willis, Brian A.; Sims, John R.; Wessels, Alette M.

doi:10.1002/alz.12876

Cited by 7 publications

(8 citation statements)

References 33 publications

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“…The iADRS is an integrated assessment of cognition and daily function from the 13-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog 13 ) and Alzheimer Disease Cooperative Study—Instrumental Activities of Daily Living (ADCS-iADL), measuring global disease severity across the Alzheimer disease continuum as a single summary score. The iADRS is validated and captures clinical progression from MCI due to Alzheimer disease through moderate dementia due to Alzheimer disease, and treatment effects have been demonstrated across MCI and Alzheimer disease with mild dementia . The possible scores on the iADRS range from 0 to 144 (lower scores indicate greater impairment), and the meaningful within-patient change (MWPC) is a change of 5 points for those with Alzheimer disease with MCI and 9 points for those with Alzheimer disease with mild dementia.…”

Section: Methodsmentioning

confidence: 99%

Donanemab in Early Symptomatic Alzheimer Disease

Sims

Zimmer

Evans

et al. 2023

JAMA

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803

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ImportanceThere are limited efficacious treatments for Alzheimer disease.ObjectiveTo assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.Design, Setting, and ParticipantsMulticenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).InterventionsParticipants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.Main Outcomes and MeasuresThe primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.ResultsAmong 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P &lt; .001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P &lt; .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P &lt; .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P &lt; .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.Conclusions and RelevanceAmong participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.Trial RegistrationClinicalTrials.gov Identifier: NCT04437511

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Section: Methodsmentioning

confidence: 99%

Donanemab in Early Symptomatic Alzheimer Disease

Sims

Zimmer

Evans

et al. 2023

JAMA

Self Cite

803

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“…Two disease‐progression models were developed with TRAILBLZAER‐ALZ data for CDR‐SB and iADRS using an identical approach. Richard's logistic model was used to describe the non‐linear disease progression 13 . Beta regression was used to account for decreasing variance in residual error as data approached the boundaries (0–144 for iADRS and 0–18 for CDR‐SB) 13–15 .…”

Section: Methodsmentioning

confidence: 99%

Donanemab exposure and efficacy relationship using modeling in Alzheimer's disease

Gueorguieva

Willis

Chua

et al. 2023

A&D Transl Res & Clin Interv

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INTRODUCTION:Donanemab is an amyloid-targeting therapy that specifically targets brain amyloid plaques. The objective of these analyses was to characterize the relationship of donanemab exposure with plasma biomarkers and clinical efficacy through modeling.METHODS: Data for the analyses were from participants with Alzheimer's disease from the phase 1 and TRAILBLAZER-ALZ studies. Indirect-response models were used to fit plasma phosphorylated tau 217 (p-tau217) and plasma glial fibrillated acidic protein (GFAP) data over time. Disease-progression models were developed using pharmacokinetic/pharmacodynamic modeling. RESULTS:The plasma p-tau217 and plasma GFAP models adequately predicted the change over time, with donanemab resulting in decreased plasma p-tau217 and plasma GFAP concentrations. The disease-progression models confirmed that donanemab significantly reduced the rate of clinical decline. Simulations revealed that donanemab slowed disease progression irrespective of baseline tau positron emission tomography (PET) level within the evaluated population. DISCUSSION:The disease-progression models show a clear treatment effect of donanemab on clinical efficacy regardless of baseline disease severity.

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“…It provides a single measure of global AD severity rather than separate measures of cognition and function and captures more items identified as meaningful to patients and caregivers than other commonly used assessment tools. 12,[16][17][18][19][20][21] In April 2022, the Centers for Medicare & Medicaid Services (CMS) established a class-based National Coverage Determination (NCD) that covers US Food and Drug Administration (FDA)-approved mAbs directed against amyloid for the treatment of AD (i.e., amyloidtargeting therapies). 22,23 CMS determined that for patients who have depend on the characteristics of patients, treating clinicians, and settings?…”

Section: Introductionmentioning

confidence: 99%

“…The iADRS is a validated integrated measure of cognition and function that captures clinically meaningful changes in early symptomatic AD. It provides a single measure of global AD severity rather than separate measures of cognition and function and captures more items identified as meaningful to patients and caregivers than other commonly used assessment tools 12,16–21 …”

Section: Introductionmentioning

confidence: 99%

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How donanemab data address the coverage with evidence development questions

Klein,

Schroeder,

Wessels

et al. 2024

Alzheimer's & Dementia

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The Centers for Medicare & Medicaid Services (CMS) established a class‐based National Coverage Determination (NCD) for monoclonal antibodies directed against amyloid for Alzheimer's disease (AD) with patient access through Coverage with Evidence Development (CED) based on three questions. This review, focused on donanemab, answers each of these CED questions with quality evidence. TRAILBLAZER‐ALZ registration trials are presented with supporting literature and real‐world data to answer CED questions for donanemab. TRAILBLAZER‐ALZ registration trials demonstrated that donanemab significantly slowed cognitive and functional decline in amyloid‐positive early symptomatic AD participants, and lowered their risk of disease progression while key safety risks occurred primarily within the first 6 months and then declined. Donanemab meaningfully improved health outcomes with a manageable safety profile in an early symptomatic AD population, representative of Medicare populations across diverse practice settings. The donanemab data provide the necessary level of evidence for CMS to open a reconsideration of their NCD.Highlights Donanemab meaningfully improved outcomes in trial participants with early symptomatic Alzheimer's disease. Comorbidities in trial participants were consistent with the Medicare population. Co‐medications in trial participants were consistent with the Medicare population. Risks associated with treatment tended to occur in the first 6 months. Risks of amyloid‐related imaging abnormalities were managed with careful observation and magnetic resonance imaging monitoring.

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Disease progression model using the integrated Alzheimer's Disease Rating Scale

Cited by 7 publications

References 33 publications

Donanemab in Early Symptomatic Alzheimer Disease

Donanemab in Early Symptomatic Alzheimer Disease

Donanemab exposure and efficacy relationship using modeling in Alzheimer's disease

How donanemab data address the coverage with evidence development questions

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