Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia a randomized clinical trial

Jeffrey L. Cummings, Constantine G. Lyketsos, Elaine R. Peskind, Anton P. Porsteinsson, Jacobo E. Mintzer, Douglas W. Scharre, Jose E. De La Gandara, Marc Agronin, Charles S. Davis, Uyen Nguyen, Paul Shin, Pierre N. Tariot, João Siffert

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Abstract

IMPORTANCE Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. OBJECTIVE To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. DESIGN, SETTING, AND PARTICIPANTS Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. INTERVENTIONS In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). MAIN OUTCOMES AND MEASURES The primary end pointwas change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). RESULTS Atotal of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders)showedsignificantlyreducedNPIAgitation/Aggressionscoresfordextromethorphanquinidinevsplacebo( ordinaryleastsquareszstatistic,-3.95;P < .001).Instage1,meanNPIAgitation/ Aggression scoreswere reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0to 5.3withplacebo.Between-grouptreatmentdifferencesweresignificantinstage1(leastsquaresmean, -1.5; 95%CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scoreswere reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatmentdifferenceswere also significant in stage2(leastsquaresmean,-1.6;95%CI,-2.9to-0.3; P=.02).Adverseevents included falls (8.6%fordextromethorphan-quinidine vs3.9%for placebo), diarrhea (5.9%vs 3.1%respectively), and urinary tract infection (5.3%vs 3.9%respectively). Serious adverse events occurred in 7.9%with dextromethorphan-quinidine vs 4.7%with placebo. Dextromethorphan-quinidinewas not associated with cognitiveimpairment, sedation, or clinically significantQTc prolongation. CONCLUSIONS AND RELEVANCE In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01584440

Original languageEnglish (US)
Pages (from-to)1242-1254
Number of pages13
JournalJAMA - Journal of the American Medical Association
Volume314
Issue number12
DOIs
StatePublished - Sep 22 2015

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ASJC Scopus subject areas

  • Medicine(all)

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Cummings, J. L., Lyketsos, C. G., Peskind, E. R., Porsteinsson, A. P., Mintzer, J. E., Scharre, D. W., De La Gandara, J. E., Agronin, M., Davis, C. S., Nguyen, U., Shin, P., Tariot, P. N., & Siffert, J. (2015). Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia a randomized clinical trial. JAMA - Journal of the American Medical Association, 314(12), 1242-1254. https://doi.org/10.1001/jama.2015.10214