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Abstract
Objective: To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD).
Methods: Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD and Mini-Mental State Examination score 14–26 were randomized to PF-04494700 60 mg/day × 6 days, then 20 mg daily (high dose); 15 mg/day × 6 days, then 5 mg daily (low dose); or placebo, for 18 months. Clinical and laboratory measures were used to evaluate safety and tolerability. The primary efficacy measure was the Alzheimer's Disease Assessment Scale–cognitive (ADAS-cog). Secondary measures assessed clinical stage, function, behavior, MRI, and CSF biomarkers.
Results: A total of 399 subjects were randomized. In a prespecified interim analysis, when 50% of subjects had completed the 6-month visit, the high dose was associated with confusion, falls, and greater ADAS-cog decline and was discontinued. A second prespecified analysis compared low-dose and placebo groups for futility and safety approximately 12 months after all subjects were randomized. This analysis met criteria for futility, and treatment was discontinued. There were no safety concerns in the low-dose group. Analyses including post-futility data showed decreased decline on the ADAS-cog in the low-dose group at month 18. Other clinical and biomarker measures showed no differences between low-dose treatment and placebo.
Conclusions: PF-04494700 at 20 mg/d was associated with increased adverse events and cognitive decline. At 5 mg/d, PF-04494700 had a good safety profile. A potential benefit for this low dose on the ADAS-cog is not conclusive, because of high dropout and discontinuation rates subsequent to the interim analyses.
Classification of evidence: This study provides Class I evidence that in patients with AD high-dose PF-04494700 increased cognitive decline at 6 months and Class IV evidence that low-dose PF-04494700 slowed cognitive decline at 18 months.
GLOSSARY
- Aβ=
- amyloid β protein;
- AD=
- Alzheimer disease;
- ADAS-cog=
- Alzheimer's Disease Assessment Scale–cognitive;
- ADCS=
- Alzheimer's Disease Cooperative Study;
- ADCS-ADL=
- Alzheimer's Disease Cooperative Study Activities of Daily Living Scale;
- ANCOVA=
- analysis of covariance;
- ARIA=
- amyloid-related imaging abnormalities;
- CDR-sb=
- Clinical Dementia Rating–sum of boxes;
- DSMB=
- data and safety monitoring board;
- MMSE=
- Mini-Mental State Examination;
- NPI=
- Neuropsychiatric Inventory;
- RAGE=
- receptor for advanced glycation end products;
- SAE=
- serious adverse events;
- SAP=
- statistical analysis plan
Footnotes
Coinvestigators are listed on the Neurology® Web site at Neurology.org.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received October 10, 2013.
- Accepted in final form January 15, 2014.
- © 2014 American Academy of Neurology
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