Abstract
Objective: To determine the value of continued donepezil treatment in patients with Alzheimer’s disease for whom clinical benefit was initially judged to be uncertain.
Methods: The study consisted of three phases: (i) a 12- to 24-week, pre-randomisation, open-label donepezil-treatment phase; (ii) a 12-week, randomised, double-blind, placebo-controlled phase; and (iii) a 12-week, single-blind (i.e. patient-blind) donepezil-treatment phase. Patients with mild to moderate Alzheimer’s disease received open-label treatment with donepezil (5 mg/day for 4 weeks, then 10 mg/day for the remainder of the phase) for 12–24 weeks. Patients who exhibited a decline or no change from baseline on the Mini-Mental State Examination (MMSE) and whose physician was not sufficiently certain of clinical benefit to warrant continued treatment were randomised into the double-blind phase in which patients received 12 weeks of treatment with donepezil (10 mg/day) or placebo. At the end of the double-blind phase, donepezil-treated patients continued to receive donepezil, while placebo-treated patients were rechallenged with donepezil, in a 12-week single-blind phase. Patients were assessed at the start of the double-blind phase and at weeks 6 and 12 of this phase, and at the end of the single-blind phase.
Results: Six hundred and nineteen patients completed the open-label phase; 69% showed clear clinical benefit and 31% showed uncertain benefit. 202 patients were randomised to continued donepezil treatment (n = 99) or placebo (n = 103). Differences in favour of continued donepezil versus placebo were observed in cognition and behaviour. In addition, there was a non-significant trend favouring donepezil in activities of daily living (ADL) [week 12 observed case mean treatment differences: MMSE, 1.13 (p = 0.02); Alzheimer’s Disease Assessment Scale - cognitive subscale, 0.57 (p = 0.5); the Neuropsychiatric Inventory, −3.16 (p = 0.02); Disability Assessment for Dementia scale, 3.67 (p = 0.1)].
Conclusion: Most patients showed clear clinical benefit during initial donepezil treatment. Among patients for whom clinical benefit was uncertain, improvement in cognition and behaviour were observed for those who continued donepezil treatment compared with the group switched to placebo. Initial decline or stabilisation does not necessarily indicate a lack of efficacy in Alzheimer’s disease, and the decision to discontinue treatment should be based on an evaluation of all domains (cognition, behaviour and ADL) and performed at several timepoints.
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Acknowledgements
This study was funded by Pfizer Inc., New York, NY, USA, and Eisai Inc., Teaneck, NJ, USA.
Dr Johannsen has received honoraria from the study sponsors. Dr Hampel has received an investigator initiated research grant and honoraria from the study sponsors. Dr Salmon has received honoraria for participating in conferences organised by the study sponsors. Drs Xu and Schindler are employees of Pfizer Inc., and also hold equity in the company. Dr Qvitzau was an employee of Pfizer Denmark when the study was being conducted. Dr Richardson is an employee of Eisai Inc.
The authors acknowledge the assistance of Dr Elliot Schwam in the protocol design, data collection and analysis, and Dr Ponni Subbiah in the protocol design and implementation. In addition, the help of Nis Kumar and Lillian Bergendorff throughout the trial and the generation of this manuscript is gratefully acknowledged. The authors thank the AWARE Study Group for their work during the study, and Rebecca Sutch and Rebecca Mant from PPS International Communications (Worthing, UK) for assisting in the development of this manuscript.
The AWARE Study Group principal investigators were:
K. Abelskov, Psykiatrisk Hospital i Århus, Risskov, Denmark; A. Andersen, Amtssygehuset i Glostrup, Glostrup, Denmark; F. Andersen, Centralsygehuset I Holstebro, Holstebro, Denmark; B. Arias, Gulf Coast Education and Research Center, Port Charlotte, Florida, USA; M. Barcikowska, Klinika Neurologiczna, Warsaw, Poland; C. Bisgård, Vejle Sygehus, Vejle, Denmark; L. Boelaarts, Medisch Centrum Alkmaar, Alkmaar, The Netherlands; F. Boesen, Centralsygehuset i Slagelse, Slagelse, Denmark; H. Brændgaard, Århus Kommunehospital, Århus, Denmark; P. Calabrese, Bochum, Germany; L. Csekey, A Kenessey Hospital, Rákòczi, Hungary; P.L.J. Dautzenberg, Jeroen Bosch Ziekenhuis, Den Bosch, The Netherlands; K. Elleman, Amtssygehuset i Roskilde, Roskilde, Denmark; J. Elley, Vestergade, Lemvig, Denmark; J. Feilberg, Amtssygehuset i Gentofte, Hellerup, Denmark; R. Ferszt, Marienfelder Allee, Berlin, Germany; M. Fink, Stenvænget 1, Sommersted, Denmark; D.G. Folks, University of Nebraska Medical Center, Omaha, Nebraska, USA; L. Froelich, Klinikum der Johann Wolfgang Goethe-Universitaet, Frankfurt, Germany; M. Gastpar, Rheinische Klinik Essen, Essen, Germany; W. Gehlen, Neuropsychologische Universitaetsklinik Knappschafts-Krankenhaus, Bochum, Germany; H-J. Gertz, Universitaet Leipzig, Leipzig, Germany; G. Gorman, Lovelace Scientific Resources, Albuquerque, New Mexico, USA; H. Gutzmann, Krankenhaus Hedwigshoehe, Berlin, Germany; S. Hasselbalch, HS Rigshospitalet, København Ø, Denmark; A. Heick, Frederiksberg Hospital, Frederiksberg, Denmark; R.F. Holub, Neurological Association of Albany PC, Albany, New York, USA; R. Ihl, Rheinische Landes-u, Dusseldorf, Germany; G. Jakab, Uzsoki Street Hospital of Budapest Municipality, Budapest, Hungary; S. Jakobsen, Sygehus Fyn, Rudkøbing, Denmark; J. Jensen, Amtssygehuset I Esbjerg, Esbjerg, Denmark; C.J. Kalisvaart, Medisch Centrum Alkmaar, Alkmaar, The Netherlands; C. Karageorgiou, Peripheral General Hospital of Athens “G Gennimatas”, Athens, Greece; M.G. Kat, Medisch Centrum Alkmaar, Alkmaar, The Netherlands; L. Kirby, Pivotal Research Centers, Peoria, Arizona, USA; A. Kiejna, Katedra i Klinika Psychiatrii, Wroclaw, Poland; I. Kloszewska, I Klinika Psychiatryczna, Lódz, Poland; R. Klysner, Frederiksberg Hospital, Frederiksberg, Denmark; W. Kozubski, Klinika Neurologii, Poznan, Poland; Kragh-Sørensen, Center for Demens, Odense, Denmark; A. Kurz, Psychiatriche Klinik der TU Muenchen, Munich, Germany; M. Lambert, Dienst Geriatrie, Brussels, Belgium; L. Lauritzen, Hillerød Sygehus, Hillerød, Denmark; J.M. Lesser, University of Texas Medical School, Houston, Texas, USA; W Maier, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Bonn, Germany; J. McCarthy, 119 Cedar Street, Hyannis, MA, USA; T. Mets, Dienst Geriatrie, Brussels, Belgium; J.E. Mintzer, Medical University of South Carolina, North Charleston, South Carolina, USA; H.J. Moeller, Ludwig-Maximilians Universitaet, Munich, Germany; M. Nunez, CNS (Comprehensive Neuroscience, Inc.), St. Petersburg, Florida, USA; S. Ochudlo, Centralny Szpital Kliniczny, Katowice, Poland; P.K. Østergaard, Middelfart Midtpunkt, Middelfart, Denmark; G. Ostorharics-Horváth, A. Petz County Hospital, Györ, Hungary; P Sakka, 417 NIMTS, Terma Zaimi St Melissia, Greece; S. Sanders, Amager Hospital, København, Denmark; P.H. Scheltens, VU Medisch Centrum, Amsterdam, The Netherlands; E. Siebenga, Groene Hart Ziekenhuis, Gouda, The Netherlands; J. Snædal, Öldrunarlækingadeild SHR, Reykjavik, Iceland; H.A. Tilker, Four Rivers Clinical Research, Inc., Paducah, Kentucky, USA; E. Triau, Koning Leopold I, Leuven, Belgium; M. Trixler, University Medical School of PÈCS, Pécs, Hungary; M. Tsolaki, Peripheral General Hospital of Thessaloniki “Papanikolaou”, Thessaloniki, Greece; F. Túry, County Hospital of Borsod, Szentpéteri kapu, Hungary; J. Tybjerg, Horsens Sygehus, Horsens, Denmark; V. Vagenas, 1st IKA Hospital – “Papadimitriou”, Athens, Greece; F.R.J. Verhey, Academish Ziekenhuis Maastricht, Maastricht, The Netherlands; I.M. Wedebye, Sygehus Fyn, Ringe, Denmark; C.J. Wouters, Jeroen Bosch Ziekenhuis, Den Bosch, The Netherlands.
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Johannsen, P., Salmon, E., Hampel, H. et al. Assessing Therapeutic Efficacy in a Progressive Disease. CNS Drugs 20, 311–325 (2006). https://doi.org/10.2165/00023210-200620040-00005
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DOI: https://doi.org/10.2165/00023210-200620040-00005