WASHINGTON, DC—A drug that contains dextromethorphan and quinidine may reduce agitation in patients with Alzheimer’s disease, according to a study described at the 67th Annual Meeting of the American Academy of Neurology. The drug, known as AVP-923, has a “robust” effect size and does not affect quality of life or activities of daily living, said Jeffrey Cummings, MD, Director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas.
Jeffrey Cummings, MD
AVP-923 is approved for the treatment of pseudobulbar affect. Dr. Cummings and colleagues tested the drug’s effects on agitation related to Alzheimer’s disease in a randomized, placebo-controlled study with a sequential parallel comparison design (SPCD). The trial design had been used successfully in other settings and represents “an important new clinical trial strategy” for neurology, according to Dr. Cummings.
Placebo Nonresponders Were Rerandomized
The researchers enrolled 220 patients in the study. Participants were between ages 50 and 90 and had moderate to severe agitation, Clinical Global Impression (CGI) severity scores of at least 4, and a diagnosis of probable Alzheimer’s disease. The population’s Mini-Mental State Examination (MMSE) scores ranged from 8 to 28.
In Stage 1 of the trial, which lasted for five weeks, patients were randomized to placebo or AVP-923 titrated to 30/10 mg bid. In Stage 2, which lasted for an additional five weeks, the participants who did not respond to placebo in Stage 1 were rerandomized to AVP-923 or placebo. The patients randomized to AVP-923 in Stage 1 continued taking the same dose in Stage 2.
The study’s primary end point was change from baseline on the agitation or aggression domain of the Neuropsychiatric Inventory (NPI), using standard SPCD methodology. Secondary end points included change in total NPI, individual NPI domains, NPI Caregiver Distress, Clinical Global Impression of Change (CGIC), Patient Global Impression of Change, Caregiver Strain Index, MMSE, and Cornell Scale for Depression in Dementia.
The investigators randomized 220 patients and included all in the safety analysis. In all, 194 participants completed the trial. In the AVP-923 arm, 17 patients discontinued treatment, eight of them because of adverse events. Nine controls also discontinued treatment, five of them for adverse events. The primary analysis included 218 patients. The 10-week analysis included 159 patients who completed Stages 1 and 2.
The population’s mean age was 77.8, and 58% of participants were female. The mean agitation score was 4.5, mean NPI agitation score was 7, and total NPI scores were 38 for controls and 40 for the active group. Participants’ average MMSE score was approximately 17, and about 75% of patients were taking cholinesterase inhibitors.
Drug Showed Efficacy by Week 1
In Stage 1, NPI agitation or aggression scores declined by 3.3 points (47%) for patients receiving AVP-923 and by 1.7 points (22%) for controls. In Stage 2, scores declined by 2 (26%) for patients receiving AVP-923 and by 0.8 (6.7%) for controls. The primary end point was highly significant.
In the 10-week analysis, the researchers observed a statistically significant difference in NPI agitation or aggression scores between the treatment and placebo arms by week 1. The drug demonstrated consistent efficacy throughout the trial.
In the SPCD primary analysis, AVP-923’s effects on the NPI total, the NPI composite, the NPI distress, and the CGIC were statistically significant. The drug reduced depression, but had no effect on MMSE scores. This result is “important because in the antipsychotic trials and in the citalopram trials, the patient paid a price of at least one MMSE point for reduction in agitation,” said Dr. Cummings.
More patients in the treatment group had falls, compared with the placebo group; these patients also had more falls before randomization. Adverse events included diarrhea, urinary tract infection, and dizziness. Discontinuation rates for adverse events were 5.3% for the treatment arm and 3.1% for controls. No deaths occurred during the trial, and the investigators found no clinically significant difference between groups on ECG. Serious adverse events occurred in 7.9% of the active group and 4.7% of the placebo group.
—Erik Greb
