Alzheimer's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Alzheimer's Disease, including details on diagnosis, memory loss, heredity, treatment, medication. | ||||||
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Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: a case study based on documents from rofecoxib litigation.Psaty BM, Kronmal RA Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington and Center for Health Studies, Group Health, Seattle, WA 98101, USA. psaty@u.washington.edu Sponsors have a marketing interest to represent their products in the best light. This approach conflicts with scientific standards that require the symmetric and comparable reporting of safety and efficacy data. Selective reporting of the results of clinical trials can misrepresent the risk-benefit profile of drugs. We summarize how the sponsor represented mortality findings associated with rofecoxib in clinical trials of patients with Alzheimer disease or cognitive impairment. We reviewed documents that became available during litigation related to rofecoxib involving Merck & Co, including internal company analyses and information provided by the sponsor to the FDA. We also evaluated information in 2 published articles that reported results of these trials. In one article (reporting results of protocol 091) published in 2004, 11 "non-drug related deaths" were reported (9 deaths among 346 rofecoxib patients and 2 deaths among 346 placebo patients). In another article (reporting results of protocol 078) published in 2005, 39 deaths were reported among patients taking study treatment or within 14 days of the last dose (24 among 725 rofecoxib patients and 15 among 732 placebo patients) and an additional 22 deaths in the off-drug period (17 in rofecoxib patients and 5 in placebo patients). However, these articles did not include analyses or statistical tests of the mortality data, and the 2 articles concluded that regarding safety, rofecoxib is "well tolerated." In contrast, in April 2001, the company's internal intention-to-treat analyses of pooled data from these 2 trials identified a significant increase in total mortality (hazard ratio [HR], 4.43; 95% CI, 1.26-15.53 for protocol 091, and HR, 2.55; 95% CI, 1.17-5.56 for protocol 078), with overall mortality of 34 deaths among 1069 rofecoxib patients and 12 deaths among 1078 placebo patients (HR, 2.99; 95% CI, 1.55-5.77). These mortality analyses were neither provided to the FDA nor made public in a timely fashion. The data submitted by the sponsor to the FDA in a Safety Update Report in July 2001 used on-treatment analysis methods and reported 29 deaths (2.7%) among 1067 rofecoxib patients and 17 deaths (1.6%) among 1075 placebo patients. This on-treatment approach to reporting minimized the appearance of any mortality risk. In December 2001, when the FDA raised safety questions about the submitted safety data, the sponsor did not bring these issues to an institutional review board for review and revealed that there was no data and safety monitoring board for the protocol 078 study. The findings from this case study suggest that additional protections for human research participants, including new approaches for the conduct, oversight, and reporting of industry-sponsored trials, are necessary. Published 16 April 2008 in JAMA, 299(15): 1813-7. Articles on Alzheimer's Disease published 10 April 2008: The use of advanced tracking technologies for the analysis of mobility in Alzheimer's disease and related cognitive diseases. BMC Geriatr, 8: 7. BACKGROUND: One of the more common behavioral manifestations of dementia-related disorders is severe problems with out-of-home mobility. Various efforts have been attempted to attain a better understanding of mobility behavior, but most studies are based on institutionalized patients and the assessment usually relies on reports of caregivers and institutional staff, using observational approaches, activity monitoring, or behavioral checklists. The current manuscript describes the research ... [Abstract] [Full-text] Articles on Alzheimer's Disease published 8 April 2008: Change in depressive symptoms during the prodromal phase of Alzheimer disease. Arch Gen Psychiatry, 65(4): 439-45. CONTEXT: Prospective studies have established an association between depressive symptoms and risk of dementia, but how depressive symptoms change during the evolution of dementia is uncertain. OBJECTIVE: To test the hypothesis that depressive symptoms increase during the prodromal phase of Alzheimer disease (AD). DESIGN: Prospective cohort study. PARTICIPANTS AND SETTING: For up to 13 years, 917 older Catholic nuns, priests, and monks without dementia at study onset completed annual clinical ... [Abstract] [Full-text] Articles on Alzheimer's Disease published 2 April 2008: Stabilization of a beta-hairpin in monomeric Alzheimer's amyloid-beta peptide inhibits amyloid formation. Proc Natl Acad Sci U S A, 105(13): 5099-104. According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-beta (Abeta) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Abeta assemblies is accompanied by a conformational change toward a high content of beta-structure. Here, we report the solution structure of Abeta(1-40) in complex with the phage-display selected affibody protein Z(Abeta3), a binding protein of ... [Abstract] [Full-text] Apolipoprotein E epsilon4, Alzheimer's disease, and cognitive performance in elderly Mexican Mestizos. J Am Geriatr Soc, 56(4): 677-82. OBJECTIVES: To determine the relationship between apolipoprotein E (APOE) epsilon4 and Alzheimer's disease (AD) in the Mexican Mestizo population, as well as its effects on the cognitive profile of AD and elderly Mestizos without dementia. DESIGN: Cross-sectional analysis of a cohort study. SETTING: Evaluations were conducted at the geriatrics clinic of an academic medical hospital in Mexico City. PARTICIPANTS: Forty-nine elderly subjects with AD and 141 controls selected from a representative ... [Abstract] [Full-text] Alpha7 nicotinic acetylcholine receptor gene and reduced risk of Alzheimer's disease. J Med Genet, 45(4): 244-8. BACKGROUND: Sporadic Alzheimer's disease (AD) is a common disabling disease of complex aetiology for which there are limited therapeutic options. We sought to investigate the role of the alpha7 nicotinic acetylcholine receptor gene (CHRNA7) in influencing risk of AD in a large population. CHRNA7 is a strong candidate gene for AD for several reasons: (1) its expression is altered differentially in the AD brain; (2) it interacts directly with beta amyloid peptide (Abeta(42)); and (3) agonist ... [Abstract] [Full-text] Articles on Alzheimer's Disease published 1 April 2008: A longitudinal study of drivers with Alzheimer disease. Neurology, 70(14): 1171-8. OBJECTIVE: The goal of this study was to define the natural progression of driving impairment in persons who initially have very mild to mild dementia. METHODS: We studied 128 older drivers, including 84 with early Alzheimer disease (AD) and 44 age-matched control subjects without cognitive impairment. Subjects underwent repeated assessments of their cognitive, neurologic, visual, and physical function over 3 years. Self-reports of driving accidents and traffic violations were supplemented by ... [Abstract] [Full-text] Race/ethnic differences in AD survival in US Alzheimer's Disease Centers. Neurology, 70(14): 1163-70. OBJECTIVE: Survival after Alzheimer disease (AD) is poorly understood for patients of diverse race/ethnic groups. We examined whether nonwhite AD patients (African American, Latino, Asian, American Indian) had different rates of survival compared with white AD patients. METHODS: The National Alzheimer's Coordinating Center (NACC) cataloged data from more than 30 Alzheimer's Disease Centers in the United States from 1984 to 2005. Patients aged 65 years or older with a diagnosis of ... [Abstract] [Full-text] Articles on Alzheimer's Disease published 28 March 2008: Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice. J Neurochem, 105(1): 262-71. Neurodegeneration in Alzheimer's disease (AD) has been linked to intracellular accumulation of misfolded proteins and dysregulation of intracellular Ca2+. In the current work, we determined the contribution of specific Ca2+ pathways to an alteration in Ca2+ homeostasis in primary cortical neurons from an adult triple transgenic (3xTg-AD) mouse model of AD that exhibits intraneuronal accumulation of beta-amyloid proteins. Resting free Ca2+ concentration ([Ca2+](i)), as measured with ... [Abstract] [Full-text] © 2004-2008 Alzheimer's Disease Research Today. All Rights Reserved. |
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