TY - JOUR
T1 - Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia a randomized clinical trial
AU - Cummings, Jeffrey L.
AU - Lyketsos, Constantine G.
AU - Peskind, Elaine R.
AU - Porsteinsson, Anton P.
AU - Mintzer, Jacobo E.
AU - Scharre, Douglas W.
AU - De La Gandara, Jose E.
AU - Agronin, Marc
AU - Davis, Charles S.
AU - Nguyen, Uyen
AU - Shin, Paul
AU - Tariot, Pierre N.
AU - Siffert, João
N1 - Publisher Copyright:
Copyright 2015 American Medical Association. All rights reserved.
PY - 2015/9/22
Y1 - 2015/9/22
N2 - 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
AB - 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
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U2 - 10.1001/jama.2015.10214
DO - 10.1001/jama.2015.10214
M3 - Article
C2 - 26393847
AN - SCOPUS:84942241583
SN - 0098-7484
VL - 314
SP - 1242
EP - 1254
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 12
ER -