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14 publications

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  1. 2022 · Stat Med

    Using principal stratification in analysis of clinical trials

    Mallinckrodt, Craig

    Abstract

    The ICH E9(R1) addendum (2019) proposed principal stratification (PS) as one of five strategies for dealing with intercurrent events. Therefore, understanding the strengths, limitations, and assumptions of PS is important for the broad community of clinical trialists. Many approaches have been developed under the general framework of PS in different areas of research, including experimental and observational studies. These diverse applications have utilized a diverse set of tools and assumptions. Thus, need exists to present these approaches in a unifying manner. The goal of this tutorial is threefold. First, we provide a coherent and unifying description of PS. Second, we emphasize that estimation of effects within PS relies on strong assumptions and we thoroughly examine the consequences of these assumptions to understand in which situations certain assumptions are reasonable. Finally, we provide an overview of a variety of key methods for PS analysis and use a real clinical trial example to illustrate them. Examples of code for implementation of some of these approaches are given in Supplemental Materials.

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  2. 2022 · Neurology

    Safety of a Fixed-Dose Coformulation of Sodium Phenylbutyrate and Taurursodiol in Amyotrophic Lateral Sclerosis and Alzheimer's Disease: Integrated Clinical Trials Experience (S11. 005)

    Hendrix, Suzanne · Nicodemus-Johnson, Jessie · Dickson, Samuel · Knowlton, Newman

    Abstract

    Objective: Safety and tolerability of an oral, fixed-dose sodium phenylbutyrate/taurursodiol (PB/TURSO) coformulation were assessed in phase 2 trials in amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). Background: PB/TURSO was designed to reduce neurodegeneration by targeting endoplasmic reticulum and mitochondrial stress, both implicated in the pathophysiology of ALS and AD. Design/Methods: In the AMX-3500 Study (CENTAUR) in ALS, participants (PB/TURSO, n=89; placebo, n=48) completing the 24-week randomized phase (NCT03127514) were eligible to enroll in an open-label extension (OLE) phase (NCT03488524) and receive PB/TURSO (≤132 weeks, week 24 reported). Study AMX-8000 (PEGASUS; NCT03533257) was a 24-week randomized trial in adults with AD or mild cognitive impairment (PB/TURSO, n=51; placebo, n=44). PB/TURSO safety and tolerability was the primary objective of both trials. Results: Mean (SD) ages were 57.7 (9.6) and 70.7 (7.5) years in CENTAUR and PEGASUS, respectively. Treatment-emergent adverse event (TEAE) incidence was similar between groups in the CENTAUR randomized phase (PB/TURSO, 97%; placebo, 96%); 77% reported ≥1 TEAEs in the OLE phase. In PEGASUS, TEAEs occurred in 67% and 59% of the PB/TURSO and placebo groups, respectively. Gastrointestinal TEAEs were more frequent during initial PB/TURSO exposure (week ≤3) in CENTAUR and accounted for the predominance of PB/TURSO-related TEAEs in PEGASUS. Incidence of cardiac events with PB/TURSO was low (CENTAUR, 8%; PEGASUS, 4%), and in both studies, electrocardiographic findings were similar between groups at baseline, with no clinically meaningful changes observed over the course of treatment. Conclusions: These findings support the PB/TURSO safety profile in ALS and AD. TEAE incidence was generally similar between PB/TURSO and placebo in both trials. PB/TURSO-associated TEAEs were mostly gastrointestinal, consistent with the known profiles for PB and TURSO. Findings in AD further elucidate the PB/TURSO safety profile, as TEAEs in CENTAUR appear to have been largely disease driven. An updated safety analysis (pooled and OLE data) will be presented.

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  3. 2022 · Neurology

    Feasibility, Safety, and Efficacy of Gamma Sensory Stimulation as a Novel Therapeutic Intervention for Alzheimer's Disease (N1. 001)

    Nicodemus-Johnson, Jessie · Hendrix, Suzanne

    Abstract

    Objective: To evaluate the safety, tolerability, adherence, and efficacy of 40Hz sensory stimulation therapy in subjects with Alzheimer’s disease (AD). Background: 40Hz gamma sensory stimulation diminishes AD pathology, neurodegeneration, and brain atrophy, synaptic and learning dysfunctions in transgenic mice carrying AD-related human pathological genes (Adaikkan & Tsai, 2020). These results initiated the development and validation of non-invasive, gamma sensory stimulation as a potential therapeutic for AD treatment. Design/Methods: Participants on AD spectrum were randomized to receive daily, one-hour, EEG-calibrated, noninvasive audio-visual stimulation, or sham stimulation in a 6-month clinical trial (Overture trial; NCT03556280) using Cognito Therapeutics medical device. Both safety (MRI, physical and neurological exams), and efficacy (AD cognitive and functional instruments, volumetric MRI) were assessed. Results: A total of 135 subjects were screened, 74 were randomized, and 53 completed the trial. The rate of AEs during the trial were roughly equivalent between groups. There were no unexpected serious treatment adverse events. Over the 6-month treatment period, changes in ADCS-ADL scores were significantly better in the treatment group compared to sham, indicating a 78% slowing in functional decline (P<0.0003). Similarly, the treatment group demonstrated a statistically significant 83% (p<0.013) reduction in cognitive decline, shown by changes in MMSE scores. The outcomes of MADCOMs, ADAS-cog14 and CDR-sb were not statistically different between groups. Quantitative MRI analysis revealed that whole brain volume loss in the treatment group demonstrated a significant, 72% reduction in brain atrophy (p<0.01) compared to sham group. Reduced lateral ventricle enlargement and diminished loss in cortical thickness in the occipital cortex have been also observed. MRI data demonstrated absence of ARIA in all subjects. Conclusions: Long-term, daily, self-administered, home-use of gamma sensory stimulation is both safe and well tolerated in AD subjects. Patients given gamma stimulation therapy maintained cognitive and functional abilities. Gamma sensory stimulation reduced brain atrophy, indicating potential disease-modifying effects in AD.

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  11. 2022 · The Journal of Prevention of Alzheimer's Disease

    Aducanumab: appropriate use recommendations update

    Hendrix, Suzanne

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  14. 2022 · Alzheimer's Disease Drug Development: Research and Development Ecosystem

    Statistical Considerations in the Design and Analysis of Alzheimer's Disease Clinical Trials

    Hendrix, Suzanne · Nicodemus-Johnson, Jessie · Knowlton, Newman · Hennessey, Sean · Dickson, Samuel

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