Karen C. Holdridge

Delayed-start analysis: Mild Alzheimer's disease patients in solanezumab trials, 3.5 years

Solanezumab is an anti‐amyloid monoclonal antibody in clinical testing for treatment of Alzheimers disease (AD). Its mechanism suggests the possibility of slowing the progression of AD.

A Novel Approach to Delayed-Start Analyses for Demonstrating Disease-Modifying Effects in Alzheimer’s Disease

One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period. We conducted simulations to identify the optimal noninferiority testing procedure to ensure the method was robust across scenarios and assumptions, and to evaluate the appropriate modeling approach for analyzing the delayed-start period. We then applied this methodology to Phase 3 solanezumab clinical trial data for mild Alzheimer’s disease patients. Simulation results showed a testing procedure using a proportional noninferiority margin was robust for detecting disease-modifying effects; conditions of high and moderate discontinuations; and with various missing data mechanisms. Using all data from all randomized patients in a single model over both the placebo-controlled and delayed-start study periods demonstrated good statistical performance. In analysis of solanezumab data using this methodology, the noninferiority criterion was met, indicating the treatment difference at the end of the placebo-controlled studies was preserved at the end of the delayed-start period within a pre-defined margin. The proposed noninferiority method for delayed-start analysis controls Type I error rate well and addresses many challenges posed by previous approaches. Delayed-start studies employing the proposed analysis approach could be used to provide evidence of a disease-modifying effect. This method has been communicated with FDA and has been successfully applied to actual clinical trial data accrued from the Phase 3 clinical trials of solanezumab.

Delayed-start analyses of up to 3.5 years in the phase 3 solanezumab expedition program in mild Alzheimer's disease

effect’). Methods:The ADAGIO study of rasagiline represented an example of a delayed start study design in Parkinson’s disease. Results: Two dose groups (low and high dose rasagiline) showed benefit after the initial 36 week period. Persistent benefit (according to the complex, pre-specified analysis plan) in the low dose group after the placebo subjects started active low-dose therapy was interpreted by study investigators to possibly suggest a disease modifying effect at this dose, although no such effect was seen at the higher dose. However, ultimately an FDA advisory committee advised against regulatory acceptance of this interpretation. The complexity of the required analyses, assumptions required and unexpected differences in the high and low dose group results, likely contributed to this determination. However, the recent FDA draft guidance on early stage trials in AD reiterated the utility of this type of trial to establish disease-modification, while also indicating the potential value of biomarker data for this purpose. Conclusions: Consideration of these alternative strategies remains important in the drug development process in chronic, progressive neurologic disease.

Function and clinical meaningfulness of treatments for mild Alzheimer's disease.

Effectiveness of Alzheimers disease (AD) treatments is commonly evaluated with coprimary outcomes; cognition with function to ensure clinical meaningfulness of a cognitive effect.

DELAYED-START ANALYSES OF SOLANEZUMAB PHASE 3 EXPEDITION STUDIES IN MILD ALZHEIMER'S DISEASE

institutionalization, and high costs. Exercise studies in AD are just emerging and have produced conflicting findings on cognitive outcomes, largely due to low levels of exercise, poor delivery of aerobic exercise, and lack of controls. Methods: This randomized controlled trial (RCT) will investigate the effects of a novel 6-month, individualized, moderate-intensity stationarycycling intervention on cognition and hippocampal volume in communitydwelling older adults with mild-to-moderate AD. Ninety subjects will be randomized to the 6-month cycling intervention or attention control (sham exercise) groups using permuted blocks of 3 and 6 subjects randomly and a 2:1 allocation ratio, and followed for another 6months (see Figure 1). A combined heart rate reserve and perceived exertionmethod shown to be feasible and reliable in our preliminary studies will be used to prescribemoderate intensity exercise. Cognition will be measured by the AD Assessment Scale-Cognition (ADAS-Cog) at baseline, 3, 6, 9, and 12 months. Hippocampal volume will be measured by magnetic resonance imaging (MRI) at baseline, 6, and 12 months. The sample size will give us 80% power to detect at least a 2.5-point difference in within-group changes in ADAS-Cog at 6 months for the intervention group. Results: This study is funded by the National Institutes of Health’s National Institute on Aging (NIA) from 8/1/2013 to 7/31/2018, and is currently enrolling. Findings from the study will determine the immediate and long-term effects of the cycling intervention on cognition and hippocampal volume in AD over 1 year. Conclusions: This study is testing a rigorously-designed and delivered moderate-intensity of aerobic exercise intervention in a clinical AD population. Findings will provide important data to address the critical gap in knowledge of the therapeutic effects of aerobic exercise in AD and offer a potentially effective treatment for AD.

Delayed-start analyses in the phase 3 solanezumab expedition3 study in mild alzheimer’s disease

ObjectiveA delayed-start design has been proposed to assess a potential disease-modifying effect in investigational drugs for Alzheimer’s disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3.MethodsEXPEDITION3 was a Phase 3, double-blind study with participants randomized to solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a statistically significant treatment difference established during the placebo-controlled period is maintained (at predefined level) during the delayed-start period, which would suggest the active drug has a disease-modifying effect. The delayed-start analysis was assessed across multiple efficacy measures, and includes data from baseline in the placebo-controlled period and up to 9 months in the delayed-start period.ResultsNo significant difference was observed between the placebo and solanezumab treatment groups at the end of the placebo-controlled period for the Alzheimer’s Disease Assessment Scale-Cognitive 14-item subscale. A significant treatment difference was observed at the end of the placebo-controlled period for the Alzheimer’s Disease Cooperative Study-Activities of Daily Living instrumental items, an effect also seen at 6 months in the delayed-start period, and the noninferiority criterion was met. No other efficacy measures met these criteria.ConclusionsDelayed-start statistical methodology was used to understand the longitudinal outcomes in EXPEDITION3 and its extension. The small treatment differences observed at the end of the placebo-controlled phase prevented adequate assessment of any putative disease modifying effect.

TAU PET IN A4: PRELIMINARY REPORT

ASHS volume measurements (mm), standard deviation in parentheses Number of subjects 178 90 139 103 116 Anterior hippocampus 1722.0 (223.6) 1707.4 (205.3) 1662.7 (236.9) 1517.2 (260.0) 1414.7 (207.7) % Diff 0.8 3.4 11.9 17.8 t value <2 2.3 6.9 11.8 p value >0.1 0.023 2.4e-11 1.1e-26 Posterior hippocampus 1652.3 (159.8) 1664.3 (163.1) 1575.6 (180.3) 1400.4 (205.9) 1336.1 (179.3) % Diff -0.7 4.6 15.2 19.1 t value <2 4.0 10.7 15.8 p value >0.1 7.6e-5 8.1e-21 4.6e-41 Whole hippocampus 3374.4 (300.2) 3371.6 (302.9) 3238.3 (353.6) 2917.6 (414.1) 2750.8 (337.4) % Diff 0.1 4.0 13.5 18.5 t value <2 3.6 9.8 16.6 p value >0.1 3.4e-4 3.7e-18 6.4e-44 Entorhinal cortex 593.9 (76.2) 585.4 (69.5) 575.4 (82.1) 518.4 (93.0) 462.1 (84.1) % Diff 1.4 3.1 12.7 22.2 t value <2 2.1 7.0 13.9 p value >0.1 0.039 5.2e-11 4.2e-34 Brodmann area 35 617.8 (82.6) 608.9 (82.8) 586.4 (94.9) 542.0 (98.4) 483.3 (89.1) % Diff 1.4 5.1 12.3 21.8 t value <2 3.1 6.9 13.2 p value >0.1 1.8e-3 3.5e-11 1.2e-31 Brodmann area 36 1824.9 (254.2) 1844.1 (245.7) 1789.4 (219.8) 1683.0 (257.3) 1551.5 (234.9) % Diff -1.1 1.9 7.8 15.0 t value <2 <2 4.5 9.3 p value >0.1 >0.1 l.le-5 3.8e-18 Parahippocampal cortex 869.6 (120.9) 893.3 (125.0) 885.4 (145.9) 831.5 (129.4) 773.3 (121.9) % Diff -2.7 -1.8 4.4 11.1 t value <2 <2 2.5 6.7 p value >0.1 >0.1 0.014 1.4e-10

Statistical properties of continuous composite scales and implications for drug development

ABSTRACT 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.

SOLANEZUMAB CENTRAL TARGET ENGAGEMENT AND PHARMACODYNAMIC ACTIVITY IN THE EXPEDITION 3 TRIAL OF PATIENTS WITH MILD AD: COMPARISON TO EXPEDITION/EXPEDITION 2

Background: Vasogenic edema and sulcal effusions, resulting from leakage of proteinaceous fluid in the brain parenchyma and leptomeningeal spaces, became a topic of interest several years ago when it became apparent that it was a somewhat common adverse event (AE) in amyloid-lowering therapies, where it was later hypothesized to be caused by the removal of amyloid plaque within the brain. It was even given a dedicated name, ARIA-E [Sperling, Lancet Neurol 2012], and began to be systematically monitored in all such subsequent clinical trials. While those findings can be subtle and require thorough training to be detected, one also needs to standardize the way their severity is reported, since those may lead to suspension/withdrawal from treatment depending on severity and potential clinical symptoms. This work assessed the robustness of two variations of a simple scale, which would be easy to implement while still providing enough granularity for proper AE management. Methods:MRI scans (baseline and follow-up FLAIR data) from 39 subjects with no, mild, moderate or severe ARIA-E were reviewed twice each, at 5-month intervals, by 6 blinded neuroradiologists with experience in ARIA-E monitoring. A 3-point severity scale was defined by assessing the extent of ARIA-E findings, e.g. parenchymal and/or sulcal hyperintensities with or without gyral swelling and sulcal effacement, affecting an area of <5 cm (single=mild, multiple=moderate), 5-10 cm (moderate) or >10 cm (severe) in single greatest dimension. 2 sub-levels, mild+ and moderateþ, were added by scoring whether findings were monoor multi-focal (see Table 1). Intraand inter-reader agreements were calculated using ICC, and Cohen’s/Fleiss’ Kappa respectively. Results: A high overall inter-reader agreement was observed both for the 3-level (ICC1⁄40.94, 95%CI [0.91,0.96]) and 5-level (0.94 [0.92,0.97]) scales. Intra-reader agreement was equally high. Kappa statistics confirmed substantial/almost perfect agreement. See Table 2 for detailed results. Conclusions: Both proposed scales provide a simple severity rating, based on a single overall assessment of ARIA-E extent, with a high degree of agreement among readers. Such rating is sufficient for proper treatment management in subjects experiencing ARIA-E. Those scales are clinically relevant, reliable, valid and easy to use, which are key aspects for future applications.

DELAYED-START ANALYSES IN THE PHASE 3 SOLANEZUMAB EXPEDITION3 STUDY IN MILD ALZHEIMER’S DISEASE

Background: Information about the sensitivity of cognitive tests to frontotemporal dementia (FTD) natural progression is limited and highly variable since neuropsychological assessments in FTD natural history studies are typically performed yearly, using tests optimized for clinical description and diagnosis (Knopman DS, et al. Brain 2008;131(Pt 11):2957-68; Ranasinghe KG, et al. Neurology 2016;86(7):600-10). This study goal is to identify cognitive measures predictive of behavioral variant FTD (bvFTD) progression over 12 months or less, to estimate this effect size and its clinical meaningfulness by examining their relationship with changes in behavioral, functional, quality of life (QOL), and caregiver burden measures. Methods:70 subjects (40 with early-stages, symptomatic bvFTD with their caregivers and 30 healthy volunteers, matched by age and education) will be enrolled in this observational study conducted at 10 FTD centers within United States. Subjects will undergo cognitive tests during 13 monthly visits (quarterly at site, otherwise at home). Tests were selected for their previously demonstrated sensitivity to change over short intervals, relative lack of learning and cultural effect, breadth of cognitive domains relevant to bvFTD. Frequent assessments should increase sensitivity to decline (relative to annual assessments) by improving slope estimates. BvFTD subjects and caregivers will also complete behavioral, functional, QOL and caregiver burden assessments, where relationships with cognitive measures will be investigated. Measures requiring expert clinicians (Modified Clinical Dementia Rating, Neuropsychiatric Inventory, Clinical Global Impression of Change) will only be conducted at quarterly site visits. Contributing blood samples for DNA/RNA and biomarker explorations is voluntary. The minimal “standardized effect size” that can be detected in this study (considering 20% dropout) is 0.76 standard deviation units with 80% power and 0.05 significance level. For each cognitive outcome measure and composite measure, mixed-effects regression will be used to model both subject-specific and grouplevel slopes and estimate their withinand between-subject variance components. Results: The study is currently in the start-up phase. Results will be presented at study completion. Conclusions: Identification of cognitive measures that are clinically meaningful, brief, sensitive to change, and predictive of bvFTD progression over short time would greatly benefit bvFTD drug development.