A double-blind, controlled trial of circadian effective light therapy in patients with Parkinson's disease.

Despite current medical therapy for Parkinson's Disease (PD), many experience persistent motor symptoms and significant unmanaged non-motor issues. Previous studies suggest that light therapy (LT) provides benefits for motor and non-motor features of PD. This study evaluated Circadian Effective LT (CELT) with a spectral band between 460 and 545 ​nm for the motor and non-motor features of PD.

Development and Validation of PARCOMS Composite Scales for Assessing Disease Progression and Treatment Effects in Parkinson's Disease.

Introduction: Measures designed to comprehensively assess Parkinson's disease (PD) irrespective of disease stage and treatment status may be unable to capture nuances in disease progression, particularly in early-stage PD. The objective of this paper is to develop PARkinson's COMposite Scales (PARCOMS) with increased responsiveness to clinical decline using items of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) for three discrete cohorts of patients.

Methods: Patients with confirmed PD from the Parkinson's Progression Markers Initiative (PPMI) data were assigned to three cohorts based on use of dopaminergic treatment, stage of disease, and presence of motor complication.

Time saved in activities of daily living and whole-brain volume: Post hoc analysis of a randomized feasibility trial of gamma oscillation treatment in participants with mild or moderate Alzheimer's disease.

Introduction: Gamma oscillations in the brain are necessary for normal cognitive function, sensory processing, and memory consolidation, and are reduced in Alzheimer's disease (AD). In a 6 month, randomized, feasibility trial in participants with mild-to-moderate AD (OVERTURE [NCT03556280],  = 76), a non-invasive method for sensory-evoked brain gamma oscillations outperformed sham on the secondary outcomes of slowing decline on the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) functional scale, magnetic resonance imaging measures of whole brain volume and the Mini-Mental State Examination (MMSE) cognitive outcome, despite not showing statistical significance on the primary outcome (Mild and Moderate Alzheimer's Disease Composite [MADCOMS]), a composite cognitive-functional score. In this post hoc analysis of OVERTURE, we evaluated the effects of investigational sensory-evoked gamma oscillation treatment in terms of time saved, as an estimate of slowing in disease progression, on ADCS-ADL, MMSE, and whole-brain volume.

Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease.

Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer's disease (AD). Clinical trials focused on cellular senescence are in early stages and have yet to establish reliable outcome measures reflecting senescent cell burden or response to senolytics, therapeutics that clear senescent cells. Results from the first open-label trial of senolytics, dasatinib plus quercetin (D ​+ ​Q), in older adults (N ​= ​5) with early AD demonstrated central nervous system penetration of dasatinib and favorable safety and tolerability.

Cohen-mansfield agitation inventory total score as a measure of agitation and aggression in Alzheimer's disease: A factor analysis.

Background: Alzheimer's disease (AD) is often associated with agitation and aggression, which may impair function, impede care, and be a major source of stress for caregivers. The Cohen-Mansfield Agitation Inventory (CMAI) is often used to assess agitation and aggression. In its original, nursing-home version, it is a 29-item, caregiver-informed, clinician-administered 7-point scale that assesses the frequency of various agitation or aggressive behaviors.

Key considerations for combination therapy in Alzheimer's clinical trials: Perspectives from an expert advisory board convened by the Alzheimer's drug discovery foundation.

There is growing consensus in the Alzheimer's community that combination therapy will be needed to maximize therapeutic benefits through the course of the disease. However, combination therapy raises complex questions and decisions for study sponsors, from preclinical research through clinical trial design to regulatory, statistical, and operational considerations. In January 2024, the Alzheimer's Drug Discovery Foundation convened an expert advisory board to discuss the key considerations in each of these areas.

Development of a General Composite Scale (GENCOMS) for Progressive Neurodegenerative Diseases and Implications for the Assessment of Disease-Modifying Therapies.

Introduction: The reliable assessment of treatment outcomes for disease-modifying therapies (DMT) in neurodegenerative disease is challenging. The objective of this paper is to describe a generalized framework for developing composite scales that can be applied in diverse, degenerative conditions, termed "GENCOMS." Composite scales optimize the sensitivity for detecting clinically meaningful effects that slow disease progression.

Fluid biomarkers in the context of amyloid-targeting disease-modifying treatments in Alzheimer's disease.

Clinical management and therapeutics development for Alzheimer's disease (AD) have entered a new era, with recent approvals of monoclonal antibody therapies targeting the underlying pathophysiology of the disease and modifying its trajectory. Imaging and fluid biomarkers are becoming increasingly important in the clinical development of AD therapeutics. This review focuses on the evidence of fluid biomarkers from recent amyloid-β-targeting clinical trials, summarizing biomarker data across 12 trials.

Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease.

Introduction: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology.

Methods: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging).

Development and Validation of SCACOMS, a Composite Scale for Assessing Disease Progression and Treatment Effects in Spinocerebellar Ataxia.

Spinocerebellar ataxias (SCA) are rare inherited neurodegenerative disorders characterized by a progressive impairment of gait, balance, limb coordination, and speech. There is currently no composite scale that includes multiple aspects of the SCA experience to assess disease progression and treatment effects. Applying the method of partial least squares (PLS) regression, we developed the Spinocerebellar Ataxia Composite Scale (SCACOMS) from two SCA natural history datasets (NCT01060371, NCT02440763).

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation.

Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 2a study.

Background: Anti-amyloid vaccines may offer a convenient, affordable, and accessible means of preventing and treating Alzheimer's disease. UB-311 is an anti-amyloid-β active immunotherapeutic vaccine shown to be well-tolerated and to have a durable antibody response in a phase 1 trial. This phase 2a study assessed the safety, immunogenicity, and preliminary efficacy of UB-311 in participants with mild Alzheimer's disease.

Avoiding future controversies in the Alzheimer's disease space through understanding the aducanumab data and FDA review.

Key points of disagreement between the aducanumab FDA statistical review, which had primarily negative conclusions, and the clinical review, which had primarily positive conclusions, were investigated. Results from secondary endpoints in positive Study 302 were significant and these endpoints provided meaningful additional information. Findings indicate the statistical review of the aducanumab data was incorrect in a number of key areas.

Why a clinical trial is as good as its outcome measure: A framework for the selection and use of cognitive outcome measures for clinical trials of Alzheimer's disease.

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials.

Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes.

Introduction/aims: Trials incorporating placebo-to-active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank-preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo-controlled and open-label extension (OLE) phases.

Methods: Intent-to-treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date.

Repeated intravenous cardiosphere-derived cell therapy in late-stage Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

Background: Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy.

Methods: In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial.

Background: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer's disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss.

Objective: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton.

Methods: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects.

GenoRisk: A polygenic risk score for Alzheimer's disease.

Introduction: Recent clinical trials are considering inclusion of more than just apolipoprotein E () ε4 genotype as a way of reducing variability in analysis of outcomes.

Methods: Case-control data were used to compare the capacity of age, sex, and 58 Alzheimer's disease (AD)-associated single nucleotide polymorphisms (SNPs) to predict AD status using several statistical models. Model performance was assessed with Brier scores and tenfold cross-validation.

Potential Virus Involvement in Alzheimer's Disease: Results from a Phase IIa Trial Evaluating Apovir, an Antiviral Drug Combination.

Background: Accumulating data suggest infectious agents are involved in Alzheimer's disease (AD). The two primary aims of this trial were to assess safety and efficacy of an antiviral drug combination on AD progression.

Objective: The trial evaluated whether Apovir, a combination of two antiviral agents, pleconaril (active on enteroviruses) and ribavirin (active on several viruses), could slow AD progression.

Perspectives on statistical strategies for the regulatory biomarker qualification process.

Qualification of a biomarker for use in a medical product development program requires a statistical strategy that aligns available evidence with the proposed context of use (COU), identifies any data gaps to be filled and plans any additional research required to support the qualification. Accumulating, interpreting and analyzing available data is outlined, step-by-step, illustrated by a qualified enrichment biomarker example and a safety biomarker in the process of qualification. The detailed steps aid requestors seeking qualification of biomarkers, allowing them to organize the available evidence and identify potential gaps.

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study.

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25.