Dataset Information

A call for clinical trial globalization in Alzheimer's disease and related dementia.

ABSTRACT:

Background

The burden of Alzheimer's disease and related dementia (ADRD) is projected to disproportionally impact low-middle-income countries (LMICs). However, there is a systematic under-representation of LMICs in ADRD clinical trial platforms.

Methods

We aimed to determine the global distribution of ADRD clinical trials and identify existing barriers for conducting clinical trials in LMICs. Primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and the International Trials Registry Platform. An additional systematic review and expert consensus interviews were conducted to identify barriers for conducting clinical trials in LMICs.

Findings

Among 1237 disease-modifying therapies tested in ADRD clinical trials, only 11.6% have been or are conducted in emerging economies (upper-middle income [9.6%] and low-middle income [2.0%]). We identified several limitations for trial implementation including a lack of financial resources, low industry presence, regulatory obstacles, and operational barriers INTERPRETATION: Although LMICs bear the greatest burden of ADRD globally, substantial development of clinical trial platforms to address this inequity and health disparity is lacking.

SUBMITTER: Llibre-Guerra JJ

PROVIDER: S-EPMC10450094 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

A call for clinical trial globalization in Alzheimer's disease and related dementia.

Llibre-Guerra Jorge J JJ Heavener Anika A Brucki Sonia Maria Dozzi SMD Marante Juan Pablo Díaz JPD Pintado-Caipa Maritza M Chen Yaohua Y Behrens María Isabel MI Hardi Angela A Admirall-Sanchez Arianna A Akinyemi Rufus R Alladi Suvarna S Dorsman Karen A KA Rodriguez-Salgado Ana M AM Solorzano Joel J Babulal Ganesh M GM

Alzheimer's & dementia : the journal of the Alzheimer's Association 20230225 7

<h4>Background</h4>The burden of Alzheimer's disease and related dementia (ADRD) is projected to disproportionally impact low-middle-income countries (LMICs). However, there is a systematic under-representation of LMICs in ADRD clinical trial platforms.<h4>Methods</h4>We aimed to determine the global distribution of ADRD clinical trials and identify existing barriers for conducting clinical trials in LMICs. Primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov ...[more]

PMID: 36840622

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Project description:BackgroundAlzheimer's disease and related dementia (ADRD) are characterized by multiple and progressive anatomo-clinical changes including accumulation of abnormal proteins in the brain, brain atrophy and severe cognitive impairment. Understanding the sequence and timing of these changes is of primary importance to gain insight into the disease natural history and ultimately allow earlier diagnosis. Yet, modeling changes over disease course from cohort data is challenging as the usual timescales (time since inclusion, chronological age) are inappropriate and time-to-clinical diagnosis is available on small subsamples of participants with short follow-up durations prior to diagnosis. One solution to circumvent this challenge is to define the disease time as a latent variable.MethodsWe developed a multivariate mixed model approach that realigns individual trajectories into the latent disease time to describe disease progression. In contrast with the existing literature, our methodology exploits the clinical diagnosis information as a partially observed and approximate reference to guide the estimation of the latent disease time. The model estimation was carried out in the Bayesian Framework using Stan. We applied the methodology to the MEMENTO study, a French multicentric clinic-based cohort of 2186 participants with 5-year intensive follow-up. Repeated measures of 12 ADRD markers stemmed from cerebrospinal fluid (CSF), brain imaging and cognitive tests were analyzed.ResultsThe estimated latent disease time spanned over twenty years before the clinical diagnosis. Considering the profile of a woman aged 70 with a high level of education and APOE4 carrier (the main genetic risk factor for ADRD), CSF markers of tau proteins accumulation preceded markers of brain atrophy by 5 years and cognitive decline by 10 years. However we observed that individual characteristics could substantially modify the sequence and timing of these changes, in particular for CSF level of A[Formula: see text].ConclusionBy leveraging the available clinical diagnosis timing information, our disease progression model does not only realign trajectories into the most homogeneous way. It accounts for the inherent residual inter-individual variability in dementia progression to describe the long-term anatomo-clinical degradations according to the years preceding clinical diagnosis, and to provide clinically meaningful information on the sequence of events.Trial registrationclinicaltrials.gov, NCT01926249. Registered on 16 August 2013.

Project description:BackgroundGlobalization of clinical trials has important consequences for trial planning and interpretation. This study investigated heterogeneity in patient characteristics and outcomes among world regions in the global idalopirdine Phase 3 clinical program.MethodsData were pooled from three 24-week randomized controlled trials in patients aged ≥ 50 years with mild-to-moderate Alzheimer's disease (AD) (n = 2506). Patients received idalopirdine (10, 30, or 60 mg/day) or placebo, added to cholinesterase inhibitor treatment. Patients were categorized into the following regions: Eastern Europe/Turkey (n = 759), Western Europe/Israel (n = 709), USA/Canada (n = 444), South America/Mexico (n = 361), Asia (n = 134), and Australia/South Africa (n = 99). For each region, operational characteristics, baseline demographic and clinical characteristics, adverse events, and mean change from baseline to week 24 in clinical rating scale scores (placebo group only) were summarized using descriptive statistics.ResultsCompletion rates were 0.86-0.90 in all regions. Heterogeneity among global regions was evident. Protocol deviations were twice as common in South America/Mexico as in USA/Canada (2.64 vs 1.35 per patient screened). Educational level ranged from 9.2 years in South America/Mexico to 13.4 years in USA/Canada. APOE ε4 carriage was 80.6% in Australia/South Africa, 63.1% in Western Europe/Israel, and < 60% in other regions. Screening Mini-Mental State Examination scores were higher in Eastern Europe/Turkey (18.0) and USA/Canada (17.5) than in other regions (16.9-17.1). Baseline AD Assessment Scale-Cognitive subscale (ADAS-Cog) scores ranged from 24.3 in USA/Canada to 27.2 in South America/Mexico. Baseline AD Cooperative Study-Activities of Daily Living, 23-item version (ADCS-ADL23) scores ranged from 58.5 in USA/Canada to 53.5 in Eastern Europe/Turkey. In the placebo group, adverse events were 1.6-1.7 times more common in Western Europe/Israel, USA/Canada, and Australia/South Africa than in Eastern Europe/Turkey. On the ADAS-Cog, Australia/South Africa and Western Europe/Israel showed the most worsening among patients receiving placebo (1.56 and 1.40 points, respectively), whereas South America/Mexico showed an improvement (-0.71 points). All regions worsened on the ADCS-ADL23, from -3.21 points in Western Europe/Israel to -0.59 points in Eastern Europe/Turkey.ConclusionsRegional heterogeneity-in terms of study conduct, patient characteristics, and outcomes-exists, and should be accounted for, when planning and conducting multinational AD clinical trials.Trial registrationClinicalTrials.gov, NCT01955161 . Registered on 27 September 2013. ClinicalTrials.gov, NCT02006641 . Registered on 5 December 2013. ClinicalTrials.gov, NCT02006654 . Registered on 5 December 2013.

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Dataset Information

A call for clinical trial globalization in Alzheimer's disease and related dementia.

Background

Methods

Findings

Publications

A call for clinical trial globalization in Alzheimer's disease and related dementia.

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