FOREWORD: AD DRUG DEVELOPMENT IS NOT BROKEN: CLINICAL TRIALS IN ALZHEIMER’S DISEASE 2014 CONFERENCE, PHILADELPHIA

2014 ◽  
pp. 1-2
Author(s):  
J. Touchon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Drug Development

IS ALZHEIMER’S DISEASE DRUG DEVELOPMENT BROKEN? WHAT MUST BE IMPROVED

2014 ◽  
pp. 1-6
Author(s):  
P.-J. Ousset ◽  
J. Cummings ◽  
J. Delrieu ◽  
V. Legrand ◽  
N. Prins ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Drug Development ◽  
Drop Out ◽  
New Drugs ◽  
Trial Duration ◽  
Surrogate Outcomes ◽  
Technical Requirements ◽  
Number Of Patients

During the decade from 2002 to 2012, 99.6% of the 244 agents tested for efficacy in slowing the progression of Alzheimer’s’ disease (AD) failed to achieve their primary endpoints. At a CTAD symposium on November 14, 2013, in San Diego, USA, an international group of AD researchers met to discuss the evolution of trials over the past 10 years and proposed a number of changes intended to streamline and enhance the efficiency of clinical trials. Approximately 1,031 AD trials were conducted between 2000 and 2012. The number of patients per trial site tended to decrease over time necessitating a larger number of sites. The use of biomarkers for enrichment purposes, or as measures of target engagement or surrogate outcomes, results in higher screen failure and drop-out rates, adding to trial duration and/or costs. Present disease modifying AD trials ask for increasing logistical and technical requirements, necessitating the creation of highly specialized trial facilities and limiting the participation of smaller sites. Due to heavy administrative and regulatory task, only about 13% of the team's time is used for the essential recruitment. Proposals and perspectives: Strategies suggested to improve the efficiency of recruitment include establishing “ready to go cohorts” in advance of trials using biomarkers and clinical measures. Simplification and harmonization of administrative procedures, including harmonization of certification procedures, are urgently needed. Alternative approaches, such as using the Internet to screen volunteers for possible inclusion needs to be evaluated. The AD drug development enterprise from discovery through clinical trials requires re-examination and re-organization if new drugs are to be delivered to patients in a timely way.

scholarly journals THE CASE FOR USING ACTIGRAPHY GENERATED SLEEP AND ACTIVITY ENDPOINTS IN ALZHEIMER’S DISEASE CLINICAL TRIALS

2016 ◽  
pp. 1-4
Author(s):  
M. Mc Carthy ◽  
W. Muehlhausen ◽  
P. Schüler
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Drug Development ◽  
Outcome Measures ◽  
Patient Population ◽  
Daily Activities ◽  
Site Staff ◽  
Consumer Devices ◽  
Relevant Outcome

More and more people in the industrialised world use wearables and smartphones to monitor their health and fitness. These devices are often used in combination with special apps to monitor and document daily activities and sleep. It would appear to be a logical step to assess the relevance of these devices in drug development trials. In contrast to the consumer devices, the technology used in clinical trials needs to be validated and compliant with the relevant regulations. Even under these complex requirements, wearables offer a number of new opportunities to objectively capture clinically relevant outcome measures –potentially with lower burden for patients and site staff. As an example, we describe the use in Alzheimer’s disease drug development studies. This is an indication where there have been a number of failures, in part due to the difficulties this patient population has in reliably completing existing tools. In addition rater scales add complexity due to inter- and intra-rater variability.

Alzheimer's disease: clinical trials and drug development

2010 ◽  
Vol 9 (7) ◽  
pp. 702-716 ◽  
Author(s):  
Francesca Mangialasche ◽  
Alina Solomon ◽  
Bengt Winblad ◽  
Patrizia Mecocci ◽  
Miia Kivipelto
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Drug Development

scholarly journals Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014

2014 ◽  
Vol 275 (3) ◽  
pp. 251-283 ◽  
Author(s):  
L. S. Schneider ◽  
F. Mangialasche ◽  
N. Andreasen ◽  
H. Feldman ◽  
E. Giacobini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Drug Development ◽  
Late Stage

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.

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Tanay Dalvi ◽  
Bhaskar Dewangan ◽  
Rudradip Das ◽  
Jyoti Rani ◽  
Suchita Dattatray Shinde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Phase Iii ◽  
Complex Nature ◽  
New Drug ◽  
Development Pipeline ◽  
Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

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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