Alzheimer's disease progression model using disability assessment for dementia scores from bapineuzumab trials
Steven X Xu, Mahesh N Samtani, Alberto Russu, Omoniyi J Adedokun, Ming Lu, Kaori Ito, Brian Corrigan, Sangeeta Raje, H Robert Brashear, Scot Styren, Chuanpu Hu, Steven X Xu, Mahesh N Samtani, Alberto Russu, Omoniyi J Adedokun, Ming Lu, Kaori Ito, Brian Corrigan, Sangeeta Raje, H Robert Brashear, Scot Styren, Chuanpu Hu
Abstract
Objective: Disability assessment for dementia (DAD) measurements from two phase-3 studies of bapineuzumab in APOE ε4 noncarrier and carrier Alzheimer's disease (AD) patients were integrated to develop a disease progression model.
Methods: We evaluated longitudinal changes in DAD scores, baseline factors affecting disease progression, and bapineuzumab effect on disease progression.
Results: A beta regression model best described DAD disease progression. The estimated treatment effect of bapineuzumab was not significant, consistent with lack of clinical efficacy observed in the primary analysis. The model suggested that progression of DAD tended to decrease with increase in bapineuzumab exposure. The exposure-response relationship was similar regardless of APOE ε4 status but more pronounced in patients with mild AD. Baseline disease status, age, memantine use, and years since onset (YSO) had significant effects on baseline DAD scores. AD concomitant medication use, baseline disease status, and YSO had significant effects on disease progression rate, measured by DAD score.
Conclusions: The beta regression model is a sensible modeling approach to characterize functional decline in AD patients. This analysis suggested a possible effect of bapineuzumab exposure on DAD progression. Further evaluation may be warranted in future studies.
Trial registration: ClinicalTrials.gov identifier: NCT00575055 and NCT00574132.
Keywords: Alzheimer's disease; Bapineuzumab; Disability assessment for dementia; Disease progression model.
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References
- Dubois B., Feldman H.H., Jacova C., Cummings J.L., DeKosky S.T., Barberger-Gateau P. Revising the definition of Alzheimer's disease: A new lexicon. Lancet Neurol. 2010;9:1118–1127.
- Knapp M.J., Knopman D.S., Solomon P.R., Pendlebury W.W., Davis C.S., Gracon S.I. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA. 1994;271:985–991.
- Rogers S.L., Farlow M.R., Doody R.S., Mohs R., Friedhoff L.T. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology. 1998;50:136–145.
- Trinh N.H., Hoblyn J., Mohanty S., Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: A meta-analysis. JAMA. 2003;289:210–216.
- Ito K., Ahadieh S., Corrigan B., French J., Fullerton T., Tensfeldt T. Disease progression meta-analysis model in Alzheimer's disease. Alzheimers Dement. 2010;6:39–53.
- Ito K., Corrigan B., Zhao Q., French J., Miller R., Soares H. Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database. Alzheimers Dement. 2011;7:151–160.
- Samtani M.N., Farnum M., Lobanov V., Yang E., Raghavan N., DiBernardo A. An improved model for disease progression in patients from the Alzheimer's disease neuroimaging initiative. J Clin Pharmacol. 2012;52:629–644.
- Samtani M.N., Raghavan N., Novak G., Nandy P., Narayan V.A. Disease progression model for clinical dementia rating-sum of boxes in mild cognitive impairment and Alzheimer's subjects from the Alzheimer's Disease Neuroimaging Initiative. Neuropsychiatr Dis Treat. 2014;10:929–952.
- Samtani M.N., Raghavan N., Shi Y., Novak G., Farnum M., Lobanov V. Disease progression model in subjects with mild cognitive impairment from the Alzheimer's disease neuroimaging initiative: CSF biomarkers predict population subtypes. Br J Clin Pharmacol. 2013;75:146–161.
- Gelinas I., Gauthier L., McIntyre M., Gauthier S. Development of a functional measure for persons with Alzheimer's disease: The disability assessment for dementia. Am J Occup Ther. 1999;53:471–481.
- Salloway S., Sperling R., Fox N.C., Blennow K., Klunk W., Raskind M. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370:322–333.
- William-Faltaos D., Chen Y., Wang Y., Gobburu J., Zhu H. Quantification of disease progression and dropout for Alzheimer's disease. Int J Clin Pharmacol Ther. 2013;51:120–131.
- Tsoularis A., Wallace J. Analysis of logistic growth models. Math Biosci. 2002;179:21–55.
- Yang E., Farnum M., Lobanov V., Schultz T., Raghavan Nandini, Samtani M.N. Quantifying the pathophysiological timeline of Alzheimer's disease. J Alzheimers Dis. 2011;26:745–753.
- Ospina R., Ferrari S.L.P. A general class of zero-or-one inflated beta regression models. Comput Stat Data Anal. 2012;56:1609–1623.
- Verkuilen J., Smithson M. Mixed and mixture regression models for continuous bounded responses using the beta distribution. J Educ Behav Stat. 2012;37:82–113.
- Molas M., Lesaffre E. A comparison of three random effects approaches to analyze repeated bounded outcome scores with an application in a stroke revalidation study. Stat Med. 2008;27:6612–6633.
- Holford N.H., Peace K.E. Results and validation of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci U S A. 1992;89:11471–11475.
- Holford N.H., Peace K.E. Methodologic aspects of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci U S A. 1992;89:11466–11470.
- Wahlby U., Jonsson E.N., Karlsson M.O. Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis. AAPS PharmSci. 2002;4:E27.
- Adedokun O LM, Ito K, Raje S, Samtani MN, Xu S, Corrigan B, Hu C. Confirmatory population pharmacokinetic analysis of bapineuzumab in subjects with mild to moderate Alzheimer's disease in two phase 3 studies (ELN115727–301 and ELN115727-302) in American Conference on Pharmacometrics. Fort Lauderdale 2013.
- Hedeker D., Gibbons R.D. John Wiley & Sons; New York: 2006. Longitudinal data analysis.
- Kleinbaum D.G. Springer; New York, NY: 1996. Survival analysis: A self-learning text.
- Karlsson M.O., Holford N., editors. A tutorial on visual predictive checks. 2008.
- Suh G.H., Ju Y.S., Yeon B.K., Shah A. A longitudinal study of Alzheimer's disease: Rates of cognitive and functional decline. Int J Geriatr Psychiatry. 2004;19:817–824.
- Salloway S., Sperling R., Gilman S., Fox N.C., Blennow K., Raskind M. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061–2070.
- Ito K., Hutmacher M.M., Corrigan B.W. Modeling of functional assessment questionnaire (FAQ) as continuous bounded data from the ADNI database. J Pharmacokinet Pharmacodyn. 2012;39:601–618.
- EMA . Qualification opinion of a novel data driven model of disease progression and trial evaluation in mild and moderate Alzheimer's disease. In: Agency E.M., editor. European Medicines Agency; London: 2013.
- Romero K., Stephenson D., Rogers J., Polhamus D., Ito K., Qiu R. Advancement of a drug-disease trial model for Alzheimer's disease through a regulatory science path: The CAMD experience. Alzheimers Dement. 2012;8:P587–P588.
- Xu X.S., Samtani M., Yuan M., Nandy P. Modeling of bounded outcome scores with data on the boundaries: Application to disability assessment for dementia scores in Alzheimer's disease. AAPS J. 2014;16:1271–1281.
- Xu X.S., Samtani M.N., Dunne A., Nandy P., Vermeulen A., De Ridder F. Mixed-effects beta regression for modeling continuous bounded outcome scores using NONMEM when data are not on the boundaries. J Pharmacokinet Pharmacodyn. 2013;40:537–544.
Source: PubMed