Long-term safety of gantenerumab in participants with Alzheimer's disease: A phase III, open-label extension study (SCarlet RoAD).

Background: Gantenerumab is a fully human anti-amyloid-β (Aβ) immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in SCarlet RoAD (SR; NCT01224106), a Phase III, double-blind (DB), placebo-controlled study in participants with prodromal Alzheimer's disease. Following a pre-planned futility analysis, SR was converted into an open-label extension (OLE) study.

Long-Term Safety of Gantenerumab in Participants with Alzheimer's Disease: A Phase III, Double-Blind, and Open-Label Extension Study (Marguerite RoAD).

Background: Gantenerumab is an anti-amyloid-β immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in Marguerite RoAD (MR; NCT02051608), a Phase III, double-blind (DB), placebo-controlled study in participants with mild Alzheimer's disease (AD) dementia. Following a preplanned futility analysis of the SCarlet RoAD study (NCT01224106), MR was converted into an open-label extension (OLE).

Care partner-informed meaningful change thresholds for the Clinical Dementia Rating-Sum of Boxes for trials of early Alzheimer's disease.

Introduction: Consensus definitions of meaningful within-patient change (MWPC) on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) are needed. Existing estimates use clinician-rated anchors in clinically diagnosed Alzheimer's disease (AD) populations. Incorporating the care partner perspective offers important insights, and evaluating biomarker-confirmed cohorts aligns estimates with ongoing trials.

Rejoinder to the letter: "Standard and reference-based conditional mean imputation: Regulators and trial statisticians be aware!".

We appreciate Cro et al.'s efforts to bring wider attention to the debate surrounding variance estimation for reference-based imputation methods. However, we believe that the way this debate is presented as "multiple imputation" versus "conditional mean imputation" can be misleading.

Examining amyloid reduction as a surrogate endpoint through latent class analysis using clinical trial data for dominantly inherited Alzheimer's disease.

Introduction: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab.

Methods: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker.

Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer's Disease.

Background: Consensus is lacking on what constitutes a meaningful score change for individual patients on clinical outcome assessments (COAs) that are commonly used in clinical trials of Alzheimer's disease. Such thresholds are one important approach to help contextualize trial results and demonstrate meaningful treatment benefit.

Objectives: To estimate meaningful within-patient change thresholds for the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE) among participants with mild cognitive impairment (MCI).

Comparing ARIA-E severity scales and effects of treatment management thresholds.

Introduction: Amyloid-related imaging abnormalities-edema (ARIA-E) is associated with anti-amyloid beta monoclonal antibody treatment. ARIA-E severity may be assessed using the Barkhof Grand Total Scale (BGTS) or the 3- or 5-point Severity Scales of ARIA-E (SSAE-3/SSAE-5). We assessed inter- and intra-reader correlations between SSAE-3/5 and BGTS.

Evaluation of dose-dependent treatment effects after mid-trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect.

Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes.

In silico exploration of amyloid-related imaging abnormalities in the gantenerumab open-label extension trials using a semi-mechanistic model.

Introduction: Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) are commonly observed with anti-amyloid therapies in Alzheimer's disease. We developed a semi-mechanistic, in silico model to understand the time course of ARIA-E and its dose dependency.

Methods: Dynamic and statistical analyses of data from 112 individuals that experienced ARIA-E in the open-label extension of SCarlet RoAD (a study of gantenerumab in participants with prodromal Alzheimer's disease) and Marguerite RoAD (as study of Gantenerumab in participants with mild Alzheimer's disease) studies were used for model building.

Standard and reference-based conditional mean imputation.

Clinical trials with longitudinal outcomes typically include missing data due to missed assessments or structural missingness of outcomes after intercurrent events handled with a hypothetical strategy. Approaches based on Bayesian random multiple imputation and Rubin's rules for pooling results across multiple imputed data sets are increasingly used in order to align the analysis of these trials with the targeted estimand. We propose and justify deterministic conditional mean imputation combined with the jackknife for inference as an alternative approach.

Proportional constrained longitudinal data analysis models for clinical trials in sporadic Alzheimer's disease.

Introduction: Clinical trials for sporadic Alzheimer's disease generally use mixed models for repeated measures (MMRM) or, to a lesser degree, constrained longitudinal data analysis models (cLDA) as the analysis model with time since baseline as a categorical variable. Inferences using MMRM/cLDA focus on the between-group contrast at the pre-determined, end-of-study assessments, thus are less efficient (eg, less power).

Methods: The proportional cLDA (PcLDA) and proportional MMRM (pMMRM) with time as a categorical variable are proposed to use all the post-baseline data without the linearity assumption on disease progression.

Classification, Prediction, and Concordance of Cognitive and Functional Progression in Patients with Mild Cognitive Impairment in the United States: A Latent Class Analysis.

Background: Progression trajectories of patients with mild cognitive impairment (MCI) are currently not well understood.

Objective: To classify patients with incident MCI into different latent classes of progression and identify predictors of progression class.

Methods: Participants with incident MCI were identified from the US National Alzheimer's Coordinating Center Uniform Data Set (09/2005-02/2019).

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years.

Psychometric Properties of the Clinical Dementia Rating - Sum of Boxes and Other Cognitive and Functional Outcomes in a Prodromal Alzheimer's Disease Population.

Background: The Clinical Dementia Rating-Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population.

Objective: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD.

Thirty-Six-Month Amyloid Positron Emission Tomography Results Show Continued Reduction in Amyloid Burden with Subcutaneous Gantenerumab.

Previous findings from the positron emission tomography (PET) substudy of the SCarlet RoAD and Marguerite RoAD open-label extension (OLE) showed gantenerumab doses up to 1200 mg every 4 weeks administered subcutaneously resulted in robust beta-amyloid (Aβ) plaque removal over 24 months in people with prodromal-to-moderate Alzheimer's disease (AD). In this 36-month update, we demonstrate continued reduction, with mean (standard error) centiloid values at 36 months of -4.3 (7.

Initiation of symptomatic medication in Alzheimer's disease clinical trials: Hypothetical versus treatment policy approach.

In clinical trials in populations with mild cognitive impairment, it is common for participants to initiate concurrent symptomatic medications for Alzheimer's disease after randomization to the experimental therapy. One strategy for addressing this occurrence is to exclude any observations that occur after the concurrent medication is initiated. The rationale for this approach is that these observations might reflect a symptomatic benefit of the concurrent medication that would adversely bias efficacy estimates for an effective experimental therapy.

Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis.

Background: We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD).

Real-world anaplastic lymphoma kinase (ALK) rearrangement testing patterns, treatment sequences, and survival of ALK inhibitor-treated patients.

Background: The anaplastic lymphoma kinase (ALK) treatment landscape is crowded following recent ALK inhibitor approvals, and updated information on real-world treatment patterns in advanced non-small-cell lung cancer (aNSCLC) with ALK rearrangement (ALK+) is needed.

Methods: This retrospective US cohort study used Flatiron Health's longitudinal electronic health record (EHR)-derived database. Patients (≥ 18 years old) diagnosed with stage IIIB/IV aNSCLC, with documented ALK rearrangement and ≥2 visits after January 1, 2011 were followed until February 28, 2016.

Correction to: A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease.

Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows.

Comparative effectiveness from a single-arm trial and real-world data: alectinib versus ceritinib.

Aim: To compare the overall survival of anaplastic lymphoma kinase-positive non-small-cell lung cancer patients who received alectinib with those who received ceritinib.

Materials & Methods: Two treatment arms (alectinib [n = 183] and ceritinib [n = 67]) were extracted from clinical trials and an electronic health record database, respectively. Propensity scores were applied to balance baseline characteristics.

A novel cognitive disease progression model for clinical trials in autosomal-dominant Alzheimer's disease.

Clinical trial outcomes for Alzheimer's disease are typically analyzed by using the mixed model for repeated measures (MMRM) or similar models that compare an efficacy scale change from baseline between treatment arms with or without participants' disease stage as a covariate. The MMRM focuses on a single-point fixed follow-up duration regardless of the exposure for each participant. In contrast to these typical models, we have developed a novel semiparametric cognitive disease progression model (DPM) for autosomal dominant Alzheimer's disease based on the Dominantly Inherited Alzheimer Network (DIAN) observational study.

Use of a historical control group in a noninferiority trial assessing a new antibacterial treatment: A case study and discussion of practical implementation aspects.

When recruitment into a clinical trial is limited due to rarity of the disease of interest, or when recruitment to the control arm is limited due to ethical reasons (eg, pediatric studies or important unmet medical need), exploiting historical controls to augment the prospectively collected database can be an attractive option. Statistical methods for combining historical data with randomized data, while accounting for the incompatibility between the two, have been recently proposed and remain an active field of research. The current literature is lacking a rigorous comparison between methods but also guidelines about their use in practice.

A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL.

Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naïve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction.