The Alzheimer’s Disease Assessment Scale’s cognitive subscale (ADAS-Cog) has been widely used as an outcome measure in Alzheimer’s Disease (AD) clinical trials. In its original form (ADAS-Cog11), the scale has been used successfully in mild-to-moderate AD dementia populations, but its use is more limited in the study of earlier disease (mild cognitive impairment [MCI] or mild dementia due to AD) owing to lack of appropriate sensitivity of some items. With recent focus on earlier treatment, efforts have focused on the development of more sensitive tools, including the Clinical Dementia Rating-Sum of Boxes (CDRSB), a global assessment tool to evaluate both cognition and function. The ability of the ADAS-Cog and CDR-SB to detect treatment group differences in the clinical trial environment has not been systematically studied. The aim of this analysis was to compare the utility of these tools in detecting treatment group differences, by reviewing study findings identified through advanced searches of clinicaltrials.gov and Ovid, and press releases and scientific presentations. Findings from placebo-controlled studies of ≥ 6m duration and enrolling >100 participants were included; reporting of both the ADAS-Cog and CDR-SB at endpoint was also a requirement. Of the >300 records identified, 34 studies fulfilled the criteria. There were significant placebo versus active drug group differences based on findings from at least one measure for 14 studies. The ADASCog detected treatment differences more frequently than the CDR-SB. Based on these and previously published findings, the ADAS-Cog appears more useful than the CDR-SB in detecting treatment group differences.
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Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984;141;1356–1364.
Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer’s Disease Assessment Scale that broaden its scope. Alzheimer Dis Assoc Disord. 1997;11;13–21.
Cano SJ, Posner HB, Moline ML, et al. The ADAS-cog in Alzheimer’s disease clinical trials: psychometric evaluation of the sum and its parts. Journal of Neurology, Neurosurgery & Psychiatry. 2010;81;1363–1368.
Hobart J, Cano S, Posner H, Selnes O, Stern Y, Thomas R. Alzheimer’s Disease Neuroimaging Initiative. Putting the Alzheimer’s cognitive test to the test I: traditional psychometric methods. Alzheimers Dement. 2013;9;S4–S9.
Raghavan N, Samtani MN, Farnum M, et al. The ADAS-Cog revisited: novel composite scales based on ADAS-Cog to improve efficiency in MCI and early AD trials. Alzheimers Dement. 2013;9;S21–S31.
Hughes CP, Berg L, Danziger WL, Coben LA, Martin R. A new clinical scale for the staging of dementia. BJPsych. 1982;140;566–572.
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993.
Coley N, Andrieu S, Jaros M, Weiner M, Cedarbaum J, Vellas B. Suitability of the Clinical Dementia Rating-Sum of Boxes as a single primary endpoint for Alzheimer’s disease trials. Alzheimers Dement. 2011;7;602–610. e602.
Cedarbaum JM, Jaros M, Hernandez C, et al. Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer’s disease clinical trials. Alzheimers Dement. 2013;9;S45–S55.
Wessels A, Siemers E, Yu P, et al. A combined measure of cognition and function for clinical trials: the integrated Alzheimer’s disease rating scale (iADRS). JPAD. 2015;2;227.
Williams MM, Storandt M, Roe CM, Morris JC. Progression of Alzheimer’s disease as measured by Clinical Dementia Rating Sum of Boxes scores. Alzheimers Dement. 2013;9;S39–S44.
Cedarbaum J, Crans G, Grundman M. Seeing with new eyes: finding a path to early intervention trials in Alzheimer’s disease. J Nutr Health Aging. 2010;14;306–309.
(CDER) USDoHaHSFaDACfDEaR. Guidance for Industry -Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease. 2013 [Available from: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338287.pdf]
Thal LJ, Calvani M, Amato A, Carta A. A 1-year controlled trial of acetyl-lcarnitine in early-onset AD. Neurology. 2000;55;805–810.
Schneeberger A, Hendrix S, Mandler M, et al. Results from a phase II study to assess the clinical and immunological activity of AFFITOPE® AD02 in patients with early Alzheimer’s disease. JPAD. 2016;2;103–114.
Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69;1430–1440.
Vandenberghe R, Rinne JO, Boada M, et al. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016;8;18.
Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73;2061–2070.
Quinn JF, Raman R, Thomas RG, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304;1903–1911.
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, doubleblind, 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 Trial1. Dement Geriatr Cogn Disord. 1999;10;237–244.
Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352;2379–2388.
Wang J, Logovinsky V, Hendrix SB, et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials. J Neurol Neurosurg Psychiatry. 2016;87;993–999.
Doody R, Ferris S, Salloway S, et al. Donepezil treatment of patients with MCI A 48-week randomized, placebo-controlled trial. Neurology. 2009;72;1555–1561.
Imbimbo BP, Troetel WM, Martelli P, Lucchelli F. A 6-month, double-blind, placebo-controlled trial of eptastigmine in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2000;11;17–24.
Hilt D, Gawryl M, Koenig G, Dgetluck N, Moebius H. EVP-6124, a selective alpha-7 partial agonist, has positive effects on cognition and clinical function in mild-to-moderate Alzheimer’s disease patients: Results of a six-month, double-blind, placebo controlled, dose ranging study. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2012;8;S746.
Winblad B, Gauthier S, Scinto L, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology. 2008;70;2024–2035.
Lasser R, Ostrowitzki S, Scheltens P. Efficacy and safety of gantenerumab from the phase 3 SCarlet RoAD trial, a study of ganenerumab in patients with prodromal AD. J Prev Alzheimer Dis. 2015;2;275–276.
Pasqualetti P, Bonomini C, Dal Forno G, et al. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease. Aging clinical and experimental research. 2009;21;102–110.
Investor Update -Roche announces phase II clinical results of crenezumab in Alzheimer’s disease. 2014 [Available from: http://www.roche.com/investors/updates/inv-update-2014-07-16.htm]
Sevigny J, Ryan J, Van Dyck C, et al. Growth hormone secretagogue MK-677 No clinical effect on AD progression in a randomized trial. Neurology. 2008;71;1702–1708.
Aisen PS, Schafer KA, Grundman M, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003;289;2819–2826.
Galasko D, Bell J, Mancuso JY, et al. Clinical trial of an inhibitor of RAGEAbeta interactions in Alzheimer disease. Neurology. 2014;82;1536–1542.
Harrington C, Sawchak S, Chiang C, et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer’s disease: two phase 3 studies. Curr Alzheimer Res. 2011;8;592–606.
Maher-Edwards G, Watson C, Ascher J, et al. Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer’s disease. TRCI. 2015;1;23–36.
Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369;341–350.
Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370;311–321.
Honig L, Aisen P, Carrillo M, Vellas B, Seimers E. Expedition 3: A Phase 3 Trial of Solanezumab in Mild Dementia Due to Alzheimer’s Disease. CTAD, 2016.
Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 2016;12;110–120.
Green R, Schneider L, Amato D, et al. Tarenflurbil Phase 3 Study Group: Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302;2557–2564.
Aisen PS, Gauthier S, Ferris SH, et al. Tramiprosate in mild-to-moderate Alzheimer’s disease–a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Archives of medical science: AMS. 2011;7;102.
Burstein AH, Grimes I, Galasko DR, Aisen PS, Sabbagh M, Mjalli AM. Effect of TTP488 in patients with mild to moderate Alzheimer’s disease. BMC Neurol. 2014;14;12.
Tariot PN, Schneider LS, Cummings J, et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry. 2011;68;853–861.
CTAD 2017 Highlights. [Available from: http://www.ctad-alzheimer.com/files/files/Highlights%20Nov%201%20and%20Nov%202.pdf]
Aisen PS, Schneider LS, Sano M, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300;1774–1783.
Khan A, Yavorsky C, DiClemente G, et al. Reliability of the Alzheimer’s disease assessment scale (ADAS-Cog) in longitudinal studies. Curr Alzheimer Res. 2013;10;952–963.
Burke WJ, Miller JP, Rubin EH, et al. Reliability of the Washington University clinical dementia rating. Arch Neurol. 1988;45;31–32.
McCulla MM, Coats M, Van Fleet N, Duchek J, Grant E, Morris JC. Reliability of clinical nurse specialists in the staging of dementia. Arch Neurol. 1989;46;1210–1211.
Rockwood K, Strang D, MacKnight C, Downer R, Morris JC. Interrater reliability of the Clinical Dementia Rating in a multicenter trial. J Am Geriatr Soc. 2000;48;558–559.
Tractenberg RE, Schafer K, Morris JC. Interobserver disagreements on clinical dementia rating assessment: interpretation and implications for training. Alzheimer Dis Assoc Disord. 2001;15;155–161.
Morris JC, Ernesto C, Schafer K, et al. Clinical Dementia Rating training and reliability in multicenter studies The Alzheimer’s Disease Cooperative Study experience. Neurology. 1997;48;1508–1510.
Cummings J, Reynders R, Zhong K. Globalization of Alzheimer’s disease clinical trials. Alzheimers Res Ther. 2011;3;24.
Chiu HF, Lam LC. Relevance of outcome measures in different cultural groups–does one size fit all? International psychogeriatrics. 2007;19;457–466.
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Wessels, A.M., Dowsett, S.A. & Sims, J.R. Detecting Treatment Group Differences in Alzheimer’s Disease Clinical Trials: A Comparison of Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) and the Clinical Dementia Rating - Sum of Boxes (CDR-SB). J Prev Alzheimers Dis 5, 15–20 (2018). https://doi.org/10.14283/jpad.2018.2