Avoid or Embrace? Practice Effects in Alzheimer's Disease Prevention Trials

Demonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer’s disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed “practice effects”). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies

Amyloid-related imaging abnormalities in the DIAN-TU-001 trial of gantenerumab and solanezumab: lessons from a trial in dominantly inherited Alzheimer disease

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n=52), solanezumab IV (n=50), or placebo (n=40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (OR=9.1, CI[1.2, 412.3]; p=0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR=5.0, CI[1.0, 30.4]; p=0.055), as were individuals with microhemorrhage at baseline (OR=13.7, CI[1.2, 163.2]; p=0.039). No ARIA-E was observed at the initial 225mg/month gantenerumab dose, and most cases were observed at doses >675mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR>0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. This article is protected by copyright. All rights reserved

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

<div><p>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.</p></div

Delayed start analysis of ADAS-Cog14 scores in patients mild AD from the EXPEDITION, EXPEDITION2, and EXPEDITION-EXT studies of solanezumab.

<p>Abbreviations: ADAS-Cog₁₄ = 14-item Alzheimer’s Disease Assessment Scale—Cognitive subscale; Q4W = every 4 weeks. Note: All p-values shown for values <.05 and endpoint. Error bars represent standard error. Dashed line indicates end of EXPEDITION and EXPEDITION-2 (feeder studies) and beginning of EXPEDITION-EXT.</p

Candidate test procedures for noninferiority test.

<p>Note: For each procedure, the lower bound of the 1-sided 90% confidence interval must be greater than the specified threshold (right column).</p><p>Candidate test procedures for noninferiority test.</p

Delayed-start design under conditions of (a) a disease-modifying treatment effect and (b) a symptomatic treatment effect.

<p>Δ₁ represents the initial treatment effect at the end of the placebo-controlled period (T₁) and Δ₂ represents the treatment effect at the end of the delayed-start period (T₂). The hypothetical results for a symptomatic treatment (b) assume that the time to peak treatment effect is equal to the duration of the delayed-start period.</p

Power curves for underlying treatment scenarios for method 4 (Δ_2–0.5 Δ₁ > 0) for 25% patient dropout (left) and 40% patient dropout (right).

<p>Power curves for underlying treatment scenarios for method 4 (Δ_2–0.5 Δ₁ > 0) for 25% patient dropout (left) and 40% patient dropout (right).</p

95% confidence intervals for conditional bias.

<p>25: 25% discontinuation rate; 40: 40% discontinuation rate; All: all data from all randomized patients in both study periods; DS: delayed-start period data only; MAR: missing at random; MCAR: missing completely at random; MNAR: missing not at random; S1: scenario 1, disease-modifying treatment effect scenario; S2: scenario 2, symptomatic treatment effect scenario; T1: time 1, end of placebo-controlled period; T2: time 2, end of delayed-start period. Each line segment represents the 95% confidence interval for the conditional bias estimated across various missingness mechanisms, conditions of underlying drug effect, discontinuation rates, and modeling approaches.</p

Magnetic resonance imaging measures of brain volumes across the EXPEDITION trials in mild and moderate Alzheimer's disease dementia

Abstract Introduction Solanezumab is a monoclonal antibody that preferentially binds soluble amyloid beta and promotes its clearance from the brain. The aim of this post hoc analysis was to assess the effect of low‐dose solanezumab (400 mg) on global brain volume measures in patients with mild or moderate Alzheimer's disease (AD) dementia quantified using volumetric magnetic resonance imaging (vMRI) data from the EXPEDITION clinical trial program. Methods Patients with mild or moderate AD (EXPEDITION and EXPEDITION2) and mild AD (EXPEDITION3), were treated with either placebo or solanezumab (400 mg) every 4 weeks (Q4W) for 76 weeks. vMRI scans were acquired at baseline and at 80 weeks from 427 MRI facilities using a standardized imaging protocol. Whole brain volume (WBV) and ventricle volume (VV) changes were estimated at 80 weeks using either boundary shift integral (EXPEDITION and EXPEDITION2) or tensor‐based morphometry (EXPEDITION3). Results The pooled cohort used for this study consisted of participants with vMRI at baseline and week 80 across the three trials. Analyzed patient subgroups comprised full patient cohort (N = 2933), apolipoprotein E (APOE) ε4+ carriers (N = 1835), and patients with mild (N = 2497) or moderate AD dementia (N = 428). No significant effect (all P‐values ≥.05) of treatment was observed in the pooled sample, individual trials, or subgroups of patients with mild or moderate AD or APOE ε4 carriers, in either WBV or VV change. Discussion Analysis of patients with mild or moderate AD dementia from baseline to 80 weeks using vMRI measures of WBV and VV changes suggested that low‐dose solanezumab was not linked to changes in volumes at 80 weeks. Analysis of the pooled cohort did not demonstrate an effect on brain volumes with treatment. Evaluation of a higher dose of solanezumab in the preclinical stage of AD is currently being undertaken

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