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PHILADELPHIA (FRONTLINE MEDICAL NEWS)A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

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