title: Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  The primary end point was 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
  A total 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) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% 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-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01584440.
authors.affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Cummings
authors.affiliation: Johns Hopkins Memory and Alzheimer's Treatment Center, Johns Hopkins Bayview, Baltimore, Maryland.
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Lyketsos
authors.affiliation: VA Puget Sound Health Care System, University of Washington School of Medicine, Seattle.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
authors.affiliation: University of Rochester School of Medicine and Dentistry, Rochester, New York.
authors.forename: Anton P
authors.initials: AP
authors.lastname: Porsteinsson
authors.affiliation: Clinical Biotechnology Research Institute, Roper St Francis Hospital, Charleston, South Carolina6Ralph H. Johnson VA Medical Center, Charleston, South Carolina.
authors.forename: Jacobo E
authors.initials: JE
authors.lastname: Mintzer
authors.affiliation: Ohio State University, Columbus.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Scharre
authors.affiliation: Quantum Laboratories Inc, West Palm Beach, Florida.
authors.forename: Jose E
authors.initials: JE
authors.lastname: De La Gandara
authors.affiliation: Miami Jewish Health Systems, Miami, Florida.
authors.forename: Marc
authors.initials: M
authors.lastname: Agronin
authors.affiliation: CSD Biostatistics Inc, Tucson, Arizona.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Davis
authors.affiliation: Avanir Pharmaceuticals Inc, Aliso Viejo, California.
authors.forename: Uyen
authors.initials: U
authors.lastname: Nguyen
authors.affiliation: Avanir Pharmaceuticals Inc, Aliso Viejo, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Shin
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Pierre N
authors.initials: PN
authors.lastname: Tariot
authors.affiliation: Avanir Pharmaceuticals Inc, Aliso Viejo, California.
authors.forename: João
authors.initials: J
authors.lastname: Siffert
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000374:Aggression / Q000187:drug effects; D000544:Alzheimer Disease / Q000150:complications*; D003915:Dextromethorphan / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D011595:Psychomotor Agitation / Q000188:drug therapy*; D011802:Quinidine / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; D010919:Placebos; C507057:dextromethorphan - quinidine combination; D003915:Dextromethorphan; D011802:Quinidine