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JAMA. 2015 Sep 22-29;314(12):1242-54. doi: 10.1001/jama.2015.10214.

Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial.

Author information

1
Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada.
2
Johns Hopkins Memory and Alzheimer's Treatment Center, Johns Hopkins Bayview, Baltimore, Maryland.
3
VA Puget Sound Health Care System, University of Washington School of Medicine, Seattle.
4
University of Rochester School of Medicine and Dentistry, Rochester, New York.
5
Clinical Biotechnology Research Institute, Roper St Francis Hospital, Charleston, South Carolina6Ralph H. Johnson VA Medical Center, Charleston, South Carolina.
6
Ohio State University, Columbus.
7
Quantum Laboratories Inc, West Palm Beach, Florida.
8
Miami Jewish Health Systems, Miami, Florida.
9
CSD Biostatistics Inc, Tucson, Arizona.
10
Avanir Pharmaceuticals Inc, Aliso Viejo, California.
11
Banner Alzheimer's Institute, Phoenix, Arizona.

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 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 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.

PMID:
26393847
DOI:
10.1001/jama.2015.10214
[Indexed for MEDLINE]

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