Integrated Alzheimer's Disease Rating Scale: Clinically meaningful change estimates

Abstract Introduction The Integrated Alzheimer's Disease Rating Scale (iADRS) has been used to detect differences in disease progression in early Alzheimer's disease (AD). The objectives of this study were to enhance understanding of iADRS point changes within the context of clinical trials, and to establish a minimal clinically important difference (MCID) on the iADRS. Methods Data from AMARANTH and EXPEDITION3 were analyzed using various approaches, including anchor‐based, distribution‐based, regression analyses, and cumulative distribution function (CDF) plots. Three potential anchors were examined, including the Clinical Dementia Rating—Sum of Boxes, Mini‐Mental State Examination, and Functional Activities Questionnaire. Triangulation of all results was used to determine the MCID for participants with mild cognitive impairment (MCI) due to AD and AD with mild dementia. Results All three anchors met criteria for “sufficiently associated” (|r| = 0.4–0.7). Cumulatively, results from anchor‐based and distribution‐based results converged to suggest an iADRS MCID of 5 points for MCI due to AD and 9 points for AD with mild dementia. Regression analyses and CDF plots supported these values. Discussion These findings suggest the iADRS can be used in clinical trials to detect a clinically meaningful outcome of AD progression

Microvascular disease in type 1 diabetes alters brain activation: A functional magnetic resonance imaging study

Individuals with type 1 diabetes have mild performance deficits on a range of neuropsychological tests compared with nondiabetic control subjects. The mechanisms underlying this cognitive deterioration are still poorly understood, but chronic hyperglycemia is now emerging as a potential determinant, possibly through microvascular changes in the brain. In 24 type 1 diabetic patients, we tested at euglycemia and at acute hypoglycemia whether the presence of proliferative diabetic retinopathy, as a marker of microvascular disease, adversely affects the ability of the brain to respond to standardized hypoglycemia, using functional magnetic resonance imaging with a cognitive task. Patients with retinopathy, compared with patients without, showed less deactivation (hence, an increased response) in the anterior cingulate and the orbital frontal gyrus during hypoglycemia compared with euglycemia (P < 0.05). Task performance and reaction time were not significantly different for either group. We conclude that microvascular damage in the brain of patients with retinopathy caused this increased brain response to compensate for functional loss

Statistical properties of continuous composite scales and implications for drug development

<p>Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite. We demonstrated that the treatment effect size of a composite is greater than the minimum treatment effect size of its components and that above certain thresholds of correlations of components and ratios of component effect sizes, the composite may outperform its components. Examples from Alzheimer’s disease (AD) clinical studies of solanezumab and donepezil using the composite Integrated AD Rating Scale (iADRS) and its components, the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living inventory, instrumental items (ADCS-iADL) were consistent with the theoretical statistical properties. The understanding of the quantitative relationships between continuous composites and their components will be useful in clinical trial design and the development of new scales and composites across therapeutic areas.</p

Adherence to escitalopram treatment in depression: a study of electronically compiled dosing histories in the 'Depression: the search for phenotypes' study.

Poor adherence to depression treatment is common. Understanding determinants of poor adherence to therapy is crucial to ensure optimal clinical outcomes. The aim of this study was to describe characteristics of dosing history in participants with depression receiving once daily escitalopram. Participants were randomly assigned to interpersonal psychotherapy (IPT) or pharmacotherapy. Participants assigned to IPT who did not evidence a response or remission had escitalopram added to their treatment. Adherence to pharmacotherapy was assessed using an electronically monitored pill cap (MEMS). Fifty-four participants on escitalopram alone and 32 on escitalopram+IPT were monitored. After 200 days, 71.7% of the participants in the escitalopram group and 54.8% of those in the escitalopram+IPT group were still engaged with the dosing regimen. Of those engaged in the dosing regimen, 17.9% (average over 210 days) of the participants did not take their medication (nonexecution). In 69% of the days participants took the correct dosage required. On average, participants had three drug holidays and the mean length of a holiday was 7 days per patient. No difference in adherence patterns was observed between patients receiving escitalopram alone vs. IPT+escitalopram. Early discontinuation of treatment and suboptimal daily execution of the prescribed regimen are the most common facets of poor adherence in this study population

Adherence to escitalopram treatment in depression

Poor adherence to depression treatment is common. Understanding determinants of poor adherence to therapy is crucial to ensure optimal clinical outcomes. The aim of this study was to describe characteristics of dosing history in participants with depression receiving once daily escitalopram. Participants were randomly assigned to interpersonal psychotherapy (IPT) or pharmacotherapy. Participants assigned to IPT who did not evidence a response or remission had escitalopram added to their treatment. Adherence to pharmacotherapy was assessed using an electronically monitored pill cap (MEMS). Fifty-four participants on escitalopram alone and 32 on escitalopram + IPT were monitored. After 200 days, 71.7% of the participants in the escitalopram group and 54.8% of those in the escitalopram + IPT group were still engaged with the dosing regimen. Of those engaged in the dosing regimen, 17.9% (average over 210 days) of the participants did not take their medication (nonexecution). In 69% of the days participants took the correct dosage required. On average, participants had three drug holidays and the mean length of a holiday was 7 days per patient. No difference in adherence patterns was observed between patients receiving escitalopram alone vs. IPT+ escitalopram. Early discontinuation of treatment and suboptimal daily execution of the prescribed regimen are the most common facets of poor adherence in this study population

Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials

Importance Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1/beta-secretase), was developed to modify the clinical course of AD by slowing disease progression. Objective To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. Design, Setting, and Participants AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging-Alzheimer's Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study. Interventions Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo. Main Outcomes and Measures The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale-cognitive subscale. Secondary outcomes included Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population. Results Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo. Conclusions and Relevance Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]