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
-
Assessment and Treatment of Older People with Depression in a Secondary Mental Health Trust
Current Drug Therapy Telmisartan Promotes Potential Glucose Homeostasis in Stroke-Resistant Spontaneously Hypertensive Rats via Peroxisome Proliferator-Activated Receptor γ Activation
Current Neurovascular Research Pathophysiology of Blood-Spinal Cord Barrier in Traumatic Injury and Repair
Current Pharmaceutical Design Sigma-1 Receptor Agonists as Therapeutic Drugs for Cognitive Impairment in Neuropsychiatric Diseases
Current Pharmaceutical Design Effect of Nanotechnology Approaches on Anti-retroviral Molecule: Efavirenz
Current Organic Chemistry Hemolysis-Associated Pulmonary Hypertension in Sickle Cell Disease: Global Disruption of the Arginine-Nitric Oxide Pathway
Current Hypertension Reviews Lower Frequency of co-Morbid Medical Disorders Related to Poor Impulse Control in Parkinson’s than Alzheimer’s Disease
Current Aging Science Applying Knowledge of Enzyme Biochemistry to the Prediction of Functional Sites for Aiding Drug Discovery
Current Topics in Medicinal Chemistry Biological Evaluation of Halogenated Thioureas as Cholinesterases Inhibitors Against Alzheimer’s Disease & Molecular Modeling Studies
Letters in Drug Design & Discovery Obesity and Metabolic Syndrome Affect the Cholinergic Transmission a nd Cognitive Functions
CNS & Neurological Disorders - Drug Targets ABC Subfamily D Proteins and Very Long Chain Fatty Acid Metabolism as Novel Targets in Adrenoleukodystrophy
Current Drug Targets Estrogen Receptor Polymorphisms: Significance to Human Physiology, Disease and Therapy
Recent Patents on DNA & Gene Sequences Conformation as the Therapeutic Target for Neurodegenerative Diseases
Current Alzheimer Research COVID-19 Outbreak: Neurological Manifestations Beyond Cough and Fever
CNS & Neurological Disorders - Drug Targets Pathophysiology of the Vascular Wall and its Relevance for Cerebrovascular Disorders in Aged Rodents
Current Neurovascular Research Polydeoxyribonucleotide (PDRN): A Safe Approach to Induce Therapeutic Angiogenesis in Peripheral Artery Occlusive Disease and in Diabetic Foot Ulcers
Cardiovascular & Hematological Agents in Medicinal Chemistry A Role for TGF-β Signaling in Neurodegeneration: Evidence from Genetically Engineered Models
Current Alzheimer Research Effect of the Interaction Between Hypertension and Cerebral White Matter Changes on the Progression of Alzheimer Disease
Current Alzheimer Research The Role of Aβ Peptides in Alzheimers Disease
Protein & Peptide Letters Insulin-Like Growth Factor-1, a Potential Predicative Biomarker for Postoperative Delirium Among Elderly Patients with Open Abdominal Surgery
Current Pharmaceutical Design