- Rosiglitazone, extended release
- Alzheimer’s disease
- Peroxisome proliferator-activated receptor-γ
- ApolipoproteinE allele ε4
- Health outcomes
Background/Aims: A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer’s disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR. Methods: This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-positive, ε4-negative), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC+). Results: At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%). Conclusion: No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.
Copyright © 2010 S. Karger AG, Basel
- Cummings JL: Alzheimer’s disease. N Engl J Med 2004;351:56–67.
- Watson GS, Craft S: The role of insulin resistance in the pathogenesis of Alzheimer’s disease: implications for treatment. CNS Drugs 2003;17:27–45.
- Craft S: Insulin resistance and Alzheimer’s disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res 2007;4:147–152.
- Craft S: The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 2009;66:300–305.
- Profenno LA, Porsteinsson AP, Faraone SV: Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 2010;67:505–512.
- Solfrizzi V, Scafato E, Capurso C, et al: Metabolic syndrome, mild cognitive impairment, and progression to dementia: the Italian Longitudinal Study on Aging. Neurobiol Aging 2009, E-pub ahead of print.
- Forti P, Pisacane N, Rietti E, et al: Metabolic syndrome and risk of dementia in older adults. J Am Geriatr Soc 2010;58:487–492.
- Geroldi C, Frisoni GB, Paolisso G, et al: Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol 2005;62:1067–1072.
- Bourdel-Marchasson I, Lapre E, Laksir H, Puget E: Insulin resistance, diabetes and cognitive function: consequences for preventative strategies. Diabetes Metab 2010;36:173–181.
- Rasgon NL, Kenna HA, Wroolie TE, et al: Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol Aging 2009, E-pub ahead of print.
- de Felice FG, Vieira MN, Bomfim TR, et al: Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Aβ oligomers. Proc Natl Acad Sci USA 2009;106:1971–1976.
- Park CR, Seeley RJ, Craft S, Woods SC: Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 2000;68:509–514.
- Craft S, Asthana S, Cook DG, et al: Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 2003;28:809–822.
- Reger MA, Watson GS, Green PS, et al: Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008;70:440–448.
- Balfour JA, Plosker GL: Rosiglitazone. Drugs 1999;57:921–930.
- Strum JC, Shehee R, Virley D, et al: Rosiglitazone induces mitochondrial biogenesis in mouse brain. J Alzheimers Dis 2007;11:45–51.
- Straus DS, Glass CK: Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol 2007;28:551–558.
- Ghisletti S, Huang W, Ogawa S, et al: Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPAR-γ. Mol Cell 2007;25:57–70.
- Nicolakakis N, Aboulkassim T, Ongali B, et al: Complete rescue of cerebrovascular function in aged Alzheimer’s disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor-γ agonist. J Neurosci 2008;28:9287–9296.
- Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR: Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 2006;199:265–273.
- Toledo EM, Inestrosa NC: Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer’s disease. Mol Psychiatry 2010;15:272–285, 228.
- Watson GS, Cholerton BA, Reger MA, et al: Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 2005;13:950–958.
- Risner ME, Saunders AM, Altman JF, et al: Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J 2006;6:246–254.
- McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944.
- Folstein MF, Folstein SE, McHugh PR: ‘Mini-Mental State’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
- Román GC, Tatemichi TK, Erkinjuntti T, et al: Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop. Neurology 1993;43:250–260.
- Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.
- Schneider LS, Olin JT, Doody RS, et al: Validity and reliability of the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change: the Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11(suppl 2):S22–S32.
- Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308–2314.
- Gélinas 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.
- GlaxoSmithKline: AVANDIA® prescribing information. Research Triangle Park, GlaxoSmithKline.
- Doward LC: The development of the Alzheimer’s Carers’ Quality of Life Instrument (ACQLI). Qual Life Res 1997;6:639.
- Wimo A, Wetterholm AL, Mastey V, Winblad B: Evaluation of the healthcare resource utilization and caregiver time in anti-dementia drug trials: a quantitative battery; in Wimo A, Karlsson G, Jonsson B, Winblad B (eds): The Health Economics of Dementia. London, John Wiley & Sons, 1998, pp 465–499.
- EuroQol Group: EuroQol: a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208.
- Lane P: Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches. Pharm Stat 2008;7:93–106.
- Gold M: Study design factors and patient demographics and their effect on the decline of placebo-treated subjects in randomized clinical trials in Alzheimer’s disease. J Clin Psychiatry 2007;68:430–438.
- Kreider M, Heise M: Rosiglitazone in the management of older patients with type 2 diabetes mellitus. Int J Clin Pract 2002;56:538–541.
- Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT: A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 1998;50:136–145.
- Burns A, Rossor M, Hecker J, et al: The effects of donepezil in Alzheimer’s disease: results from a multinational trial. Dement Geriatr Cogn Disord 1999;10:237–244.
- Farlow M, Anand R, Messina J Jr, Hartman R, Veach J: A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol 2000;44:236–241.
- Raskind MA, Peskind ER, Wessel T, Yuan W: Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000;54:2261–2268.
- Wilcock GK, Lilienfeld S, Gaens E: Efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ 2000;321:1445–1449.
- Hoyt BD, Massman PJ, Schatschneider C, Cooke N, Doody RS: Individual growth curve analysis of APOE ε4-associated cognitive decline in Alzheimer disease. Arch Neurol 2005;62:454–459.
- Frisoni GB, Govoni S, Geroldi C, et al: Gene dose of the ε4 allele of apolipoprotein E and disease progression in sporadic late-onset Alzheimer’s disease. Ann Neurol 1995;37:596–604.
- Stern Y, Brandt J, Albert M, et al: The absence of an apolipoprotein ε4 allele is associated with a more aggressive form of Alzheimer’s disease. Ann Neurol 1997;41:615–620.
- Irizarry MC, Webb DJ, Bains C, et al: Predictors of placebo group decline in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) in 24-week clinical trials of Alzheimer’s disease. J Alzheimers Dis 2008;14:301–311.
- Doraiswamy PM, Krishnan KR, Anand R, et al: Long-term effects of rivastigmine in moderately severe Alzheimer’s disease: does early initiation of therapy offer sustained benefits? Prog Neuropsychopharmacol Biol Psychiatry 2002;26:705–712.
- Kurz A, Farlow M, Quarg P, Spiegel R: Disease stage in Alzheimer disease and treatment effects of rivastigmine. Alzheimer Dis Assoc Disord 2004;18:123–128.
- Maher-Edwards G, Zvartau-Hind M, Hunter AJ, et al: Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer’s disease. Curr Alzheimer Res 2009, E-pub ahead of print.
- Cukierman-Yaffee T: The relationship between dysglycemia and cognitive dysfunction. Curr Opin Investig Drugs 2009;10:70–74.
- Craft S, Dagogo-Jack SE, Wiethop BV, et al: Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type: a longitudinal study. Behav Neurosci 1993;107:926–940.
- Domínguez RO, Marschoff ER, Guareschi EM, et al: Insulin, glucose and glycated hemoglobin in Alzheimer’s and vascular dementia with and without superimposed type II diabetes mellitus condition. J Neural Transm 2008;115:77–84.
- Zhang H, Zhang A, Kohan DE, Nelson RD, Gonzalez FJ, Yang T: Collecting duct-specific deletion of peroxisome proliferator-activated receptor-γ blocks thiazolidinedione-induced fluid retention. Proc Natl Acad Sci USA 2005;102:9406–9411.
- Yang T, Soodvilai S: Renal and vascular mechanisms of thiazolidinedione-induced fluid retention. PPAR Res 2008;2008:943614.
- Karalliedde J, Buckingham RE: Thiazolidinediones and their fluid-related adverse effects: facts, fiction and putative management strategies. Drug Saf 2007;30:741–753.
- Cortes F, Nourhashémi F, Guérin O, et al: Prognosis of Alzheimer’s disease today: a two-year prospective study in 686 patients from the REAL-FR Study. Alzheimers Dement 2008;4:22–29.
- Schneider LS, Sano M: Current Alzheimer’s disease clinical trials: methods and placebo outcomes. Alzheimers Dement 2009;5:388–397.
- Gendelman HE: Biomarkers, laboratory, and animal models for the design and development of adjunctive therapies for HIV-1 dementia and other neuroinflammatory disorders. J Neuroimmune Pharmacol 2007;2:8–13.
- Bauer B, Hartz AM, Miller DS: Tumor necrosis factor-α and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier. Mol Pharmacol 2007;71:667–675.
- Yu C, Argyropoulos G, Zhang Y, Kastin AJ, Hsuchou H, Pan W: Neuroinflammation activates Mdr1b efflux transport through NF-ĸB: promoter analysis in BBB endothelia. Cell Physiol Biochem 2008;22:745–756.
Michael Gold, MS, MD
Neurosciences Medicine Development Center
Research Triangle Park, NC (USA)
Tel. +1 919 483 8119, Fax +1 919 315 4687, E-Mail email@example.com
Accepted: June 21, 2010
Published online: August 21, 2010
Number of Print Pages : 16
Number of Figures : 4, Number of Tables : 7, Number of References : 60
Dementia and Geriatric Cognitive Disorders
Vol. 30, No. 2, Year 2010 (Cover Date: September 2010)
Journal Editor: Chan-Palay V. (New York, N.Y.)
ISSN: 1420-8008 (Print), eISSN: 1421-9824 (Online)
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