Abstract
Introduction: Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety. Methods: In these two double-blind, placebo-controlled studies, subjects with mild-to-moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE 4- positive, APOE 4-negative) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 weeks (REFLECT-2, N=1,496; REFLECT-3, N=1,485). Co-primary efficacy endpoints were change from baseline in Alzheimers Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4-negative, all subjects except APOE 4 homozygotes, and the full intent- to-treat population. Results: No statistically or clinically relevant differences between treatment groups were observed on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, respectively, at 8 mg RSG XR). Conclusions: No evidence of statistically or clinically significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone.
Keywords: Acetylcholine esterase inhibitors, adjunctive therapy, Alzheimer's disease, apolipoprotein E allele 4, cognition, phase 3, REFLECT, rosiglitazone, Stroke-Alzheimer's Disease, depressive disorder, hepatic disorders
Current Alzheimer Research
Title: Rosiglitazone Does Not Improve Cognition or Global Function when Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies
Volume: 8 Issue: 5
Author(s): C. Harrington, S. Sawchak, C. Chiang, J. Davies, C. Donovan, A. M. Saunders, M. Irizarry, B. Jeter, M Zvartau-Hind, C. H. van Dyck and M. Gold
Affiliation:
Keywords: Acetylcholine esterase inhibitors, adjunctive therapy, Alzheimer's disease, apolipoprotein E allele 4, cognition, phase 3, REFLECT, rosiglitazone, Stroke-Alzheimer's Disease, depressive disorder, hepatic disorders
Abstract: Introduction: Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety. Methods: In these two double-blind, placebo-controlled studies, subjects with mild-to-moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE 4- positive, APOE 4-negative) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 weeks (REFLECT-2, N=1,496; REFLECT-3, N=1,485). Co-primary efficacy endpoints were change from baseline in Alzheimers Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4-negative, all subjects except APOE 4 homozygotes, and the full intent- to-treat population. Results: No statistically or clinically relevant differences between treatment groups were observed on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, respectively, at 8 mg RSG XR). Conclusions: No evidence of statistically or clinically significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone.
Export Options
About this article
Cite this article as:
Harrington C., Sawchak S., Chiang C., Davies J., Donovan C., M. Saunders A., Irizarry M., Jeter B., Zvartau-Hind M, H. van Dyck C. and Gold M., Rosiglitazone Does Not Improve Cognition or Global Function when Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies, Current Alzheimer Research 2011; 8 (5) . https://dx.doi.org/10.2174/156720511796391935
DOI https://dx.doi.org/10.2174/156720511796391935 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Inflammation in Neurodegenerative Disorders: Friend or Foe?
Current Aging Science Molecular Insights into Mechanisms of the Cell Death Program:Role in the Progression of Neurodegenerative Disorders
Current Alzheimer Research Nanoparticles as Alternative Strategies for Drug Delivery to the Alzheimer Brain: Electron Microscopy Ultrastructural Analysis
CNS & Neurological Disorders - Drug Targets Analytical Procedures for Secondary Metabolites Determination: Recent Trends and Future Perspectives
Letters in Drug Design & Discovery Association of Red Blood Cell Indices with Mild Cognitive Impairment in Chinese Elderly Individuals: A Matched Case-control Study
Current Alzheimer Research Role of Amylin and its Receptors in Neurodegeneration
Current Protein & Peptide Science Hallucinations Associated with Topiramate Therapy: A Case Report and Review of the Literature
Current Drug Safety Connection between JAK/STAT and PPARγ Signaling During the Progression of Multiple Sclerosis: Insights into the Modulation of T-Cells and Immune Responses in the Brain
Current Molecular Pharmacology Secondary Prevention of Atherothrombotic Cerebrovascular Events
Current Vascular Pharmacology Blurred Edges: Evolving Concepts of Autism Spectrum Disorders and Schizophrenia
Adolescent Psychiatry Novel AβIsoforms in Alzheimer's Disease - Their Role in Diagnosis and Treatment
Current Pharmaceutical Design Adeno-associated Viral Vectors for Correction of Inborn Errors of Metabolism: Progressing Towards Clinical Application
Current Pharmaceutical Design Innate Inflammatory Responses in Stroke: Mechanisms and Potential Therapeutic Targets
Current Medicinal Chemistry Ras Family Small GTPase-Mediated Neuroprotective Signaling in Stroke
Central Nervous System Agents in Medicinal Chemistry Anemia and Chronic Kidney Disease: Making Sense of the Recent Trials
Reviews on Recent Clinical Trials The Effect of <i>Stachy sieboldii</i> MIQ. Supplementation on Modulating Gut Microflora and Cytokine Expression in Mice
Combinatorial Chemistry & High Throughput Screening Etiology of Neuroinflammatory Pathologies in Neurodegenerative Diseases: A Treatise
Current Psychopharmacology The Genetics of Frontotemporal Dementia and Related Disorders
Current Genomics On the Paradigm Shift Towards Multitarget Selective Drug Design
Current Computer-Aided Drug Design Easy Screening for Mild Alzheimer's Disease and Mild Cognitive Impairment from Elderly Speech
Current Alzheimer Research