scholarly journals INTEREST GROUP SESSION—ALZHEIMER'S DISEASE AND RELATED DIMENTIAS: OPPORTUNITIES AND CHALLENGES TO DEVELOPING AND TESTING PRAGMATIC ADRD INTERVENTIONS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S363-S363
Author(s):  
Abraham A Brody ◽  
Laura N Gitlin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Real World ◽  
Psychological Symptoms ◽  
Wide Spectrum ◽  
Pragmatic Trial ◽  
Intervention Development ◽  
Pragmatic Trials ◽  
Pragmatic Clinical Trials

Abstract Many clinical trials have been performed to develop the evidence for caring for persons with Alzheimer’s Disease and Related Disorders (ADRD) in tightly controlled settings. These trials have found efficacy of a wide spectrum of interventions to address issues from advanced care planning to behavioral and psychological symptoms of dementia (BPSD). However, few ADRD interventions have been tested in wide-scale pragmatic fashion in long term supportive settings (LTSS) such as nursing homes, primary care clinics, hospices, or community based organizations. This is due to a variety factors, principle amongst them are the difficulty in implementing pragmatic trials, and that many of the interventions developed in tightly controlled settings are not directly translatable to real-world settings. Without translating and testing interventions in real world settings, the evidence base remains largely inaccessible to the end user, the persons with ADRD and their caregivers. Moreover, effectiveness remains unclear. The lack of pragmatic trials in ADRD exists despite significant recent investment from the NIH Office of the Director in a health systems collaboratory to support pragmatic clinical trials. In 2018, NIA therefore released a call for 2-phase intervention development and pragmatic trial testing via an R61-R33 mechanism (PAR-18-585). Four proposals were funded in September 2018 from this PAR. This symposium will explore the opportunities and challenges present in developing and testing pragmatic interventions in ADRD in LTSS. The speakers will also share specific scientific methodological and implementation questions that need to be addressed in applying for pragmatic trial awards.

scholarly journals Exploring the Feasibility of Using Real-World Data from a Large Clinical Data Research Network to Simulate Clinical Trials of Alzheimer’s Disease

2020 ◽  
Author(s):  
Zhaoyi Chen ◽  
Hansi Zhang ◽  
Yi Guo ◽  
Thomas J George ◽  
Mattia Prosperi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Data ◽  
Real World ◽  
Large Scale ◽  
Research Network ◽  
Real World Data ◽  
World Data ◽  
Trial Simulation

AbstractClinical trials are essential but often have high financial costs and long execution time. Trial simulation using real world data (RWD) could potentially provide insights on a treatment’s efficacy and safety before running a large-scale trial. In this work, we explored the feasibility of using RWD from a large clinical data research network to simulate a randomized controlled trial of Alzheimer’s disease considering two different scenarios: an one-arm simulation of the standard-of-care control arm; and a two-arm simulation comparing treatment safety between the intervention and control arms with proper patient matching algorithms. We followed original trial’s design and addressed some key questions, including how to translate trial criteria to database queries and establish measures of safety (i.e., serious adverse events) from RWD. Our simulation generated results comparable to the original trial, but also exposed gaps in both trial simulation methodology and the generalizability issue of clinical trials.

scholarly journals Principles and procedures for data and safety monitoring in pragmatic clinical trials

Trials ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Gregory E. Simon ◽  
Susan M. Shortreed ◽  
Rebecca C. Rossom ◽  
Robert B. Penfold ◽  
Jo Ann M. Sperl-Hillen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Pragmatic Trial ◽  
Mental Health Research ◽  
Study Data ◽  
Research Network ◽  
Pragmatic Trials ◽  
Study Staff ◽  
Pragmatic Clinical Trials ◽  
Effective Delivery ◽  
Trial Monitoring

Abstract Background All clinical trial investigators have ethical and regulatory obligations to monitor participant safety and trial integrity. Specific procedures for meeting these obligations, however, may differ substantially between pragmatic trials and traditional explanatory clinical trials. Methods/Results Appropriate monitoring of clinical trials typically includes assessing rate of recruitment or enrollment; monitoring safe and effective delivery of study treatments; assuring that study staff act to minimize risks; monitoring quality and timeliness of study data; and considering interim analyses for early detection of benefit, harm, or futility. Each of these responsibilities applies to pragmatic clinical trials. Just as design of pragmatic trials typically involves specific and necessary departures from methods of explanatory clinical trials, appropriate monitoring of pragmatic trials typically requires specific departures from monitoring procedures used in explanatory clinical trials. We discuss how specific aspects of pragmatic trial design and operations influence selection of monitoring procedures and illustrate those choices using examples from three ongoing pragmatic trials conducted by the Mental Health Research Network. Conclusions Pragmatic trial investigators should not routinely adopt monitoring procedures used in explanatory clinical trials. Instead, investigators should consider core principles of trial monitoring and design monitoring procedures appropriate for each pragmatic trial.

scholarly journals Exploring the feasibility of using real-world data from a large clinical data research network to simulate clinical trials of Alzheimer’s disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Zhaoyi Chen ◽  
Hansi Zhang ◽  
Yi Guo ◽  
Thomas J. George ◽  
Mattia Prosperi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Real World ◽  
Comparative Effectiveness ◽  
Research Network ◽  
Real World Data ◽  
World Data ◽  
Trial Simulation ◽  
Simulation Scenario

AbstractIn this study, we explored the feasibility of using real-world data (RWD) from a large clinical research network to simulate real-world clinical trials of Alzheimer’s disease (AD). The target trial (i.e., NCT00478205) is a Phase III double-blind, parallel-group trial that compared the 23 mg donepezil sustained release with the 10 mg donepezil immediate release formulation in patients with moderate to severe AD. We followed the target trial’s study protocol to identify the study population, treatment regimen assignments and outcome assessments, and to set up a number of different simulation scenarios and parameters. We considered two main scenarios: (1) a one-arm simulation: simulating a standard-of-care (SOC) arm that can serve as an external control arm; and (2) a two-arm simulation: simulating both intervention and control arms with proper patient matching algorithms for comparative effectiveness analysis. In the two-arm simulation scenario, we used propensity score matching controlling for baseline characteristics to simulate the randomization process. In the two-arm simulation, higher serious adverse event (SAE) rates were observed in the simulated trials than the rates reported in original trial, and a higher SAE rate was observed in the 23 mg arm than in the 10 mg SOC arm. In the one-arm simulation scenario, similar estimates of SAE rates were observed when proportional sampling was used to control demographic variables. In conclusion, trial simulation using RWD is feasible in this example of AD trial in terms of safety evaluation. Trial simulation using RWD could be a valuable tool for post-market comparative effectiveness studies and for informing future trials’ design. Nevertheless, such an approach may be limited, for example, by the availability of RWD that matches the target trials of interest, and further investigations are warranted.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

2018 ◽  
Vol 15 (5) ◽  
pp. 429-442 ◽  
Author(s):  
Nishant Verma ◽  
S. Natasha Beretvas ◽  
Belen Pascual ◽  
Joseph C. Masdeu ◽  
Mia K. Markey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Latent Variable ◽  
Brain Regions ◽  
Disease Assessment ◽  
Latent Variable Analysis ◽  
The Relationship ◽  
Selection Of

Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer’s disease.

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

scholarly journals On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

2021 ◽  
pp. 174077452110344
Author(s):  
Michelle M Nuño ◽  
Joshua D Grill ◽  
Daniel L Gillen ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cerebrospinal Fluid ◽  
Phosphorylated Tau ◽  
Inclusion Criteria ◽  
Eligibility Criteria ◽  
Total Tau ◽  
Prodromal Alzheimer’S Disease ◽  
Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

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