Paul Shin

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

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.

AVP‐825 Breath‐Powered Intranasal Delivery System Containing 22 mg Sumatriptan Powder vs 100 mg Oral Sumatriptan in the Acute Treatment of Migraines (The COMPASS Study): A Comparative Randomized Clinical Trial Across Multiple Attacks

The objective of this study was to compare the efficacy, tolerability, and safety of AVP‐825, an investigational bi‐directional breath‐powered intranasal delivery system containing low‐dose (22 mg) sumatriptan powder, vs 100 mg oral sumatriptan for acute treatment of migraine in a double‐dummy, randomized comparative efficacy clinical trial allowing treatment across multiple migraine attacks.

Erratum to: PRISM II: An open-label study to assess effectiveness of dextromethorphan/quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury [BMC Neurol., 16 (2016) 89], DOI:10.1186/s12883-016-0609-0

Erratum After publication of the original article [1], the authors noticed that there were errors in the caption of Fig. 3, and the y-axis of Fig. 6 itself. The following statement should not have been included in the caption of Fig. 3: “CNS-LS scores were not normalized.” The CNS-LS is a rank-order scale, and is not normalized. This statement was included erroneously and the authors intended on removing it prior to resubmission, but this was unfortunately overlooked. Similarly, the y-axis within Fig. 6 was mislabelled. The CNS-LS scale ranges from 7 to 35, so the y-axis for Fig. 6 should start at a base score of 7 and not zero. The correct and updated version of Fig. 6, in which the data presented remain accurate and are unchanged, is published in this erratum.

Dextromethorphan/quinidine (AVP-923) phase 2 study for treatment of agitation in Alzheimer’s disease: Comparing the enrolled agitation sample with the international psychogeriatric association definition of agitation in cognitive disorders (NCT01584440)

PHASE 2 STUDY FOR TREATMENT OF AGITATION IN ALZHEIMER’S DISEASE: COMPARING THE ENROLLED AGITATION SAMPLE WITH THE INTERNATIONAL PSYCHOGERIATRIC ASSOCIATION DEFINITION OF AGITATION IN COGNITIVE DISORDERS (NCT01584440) Jeffrey L. Cummings, Constantine Lyketsos, Elaine R. Peskind, Anton P. Porsteinsson, Jacobo E. Mintzer, Douglas W. Scharre, Jos e E. De La G andara, Marc Agronin, Charles S. Davis, Uyen Nguyen, Paul Shin, Pierre N. Tariot, Joao Siffert, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA; Johns Hopkins University School of Medicine, Baltimore, MD, USA; VA Puget Sound Health Care System, Seattle, WA, USA; University of Washington, Seattle, WA, USA; University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Roper St. Francis Hospital, The Clinical Biotechnology Research Institute, Charleston, SC, USA; Ralph H. Johnson VA Medical Center, Charleston, SC, USA; Ohio State University, Columbus, OH, USA; Quantum Laboratories, Inc., West Palm Beach, FL, USA; Miami Jewish Health Systems, Miami, FL, USA; CSD Biostatistics, Inc., Tucson, AZ, USA; Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA; Banner Alzheimer’s Institute, Phoenix, AZ, USA. Contact e-mail: Anton_Porsteinsson@urmc.rochester.edu

PRISM II: AN OPEN-LABEL STUDY TO ASSESS THE SAFETY, TOLERABILITY, AND EFFECTIVENESS OF DEXTROMETHORPHAN 20 MG/QUINIDINE 10 MG (NUEDEXTA®) IN PSEUDOBULBAR AFFECT (PBA) SECONDARY TO DEMENTIA, STROKE, OR TRAUMATIC BRAIN INJURY (TBI)–EARLY RESULTS OF TRIAL

explanation for the paradoxical findings. Methods: Hyman and colleagues have demonstrated in the mouse taoupathy model that NFT formation does not lead rapidly to cell death (de Calignon, 2011). Rather, NFT-containing neurons appear to be long-lived and able to revert to a normal state (Polydoro, 2013). We have modeled the inferred biology and run simulations using Vensim PLE+, version 6.2Results: The rate of neuronal loss, which in this framework is directly related to the absolute size of the NFT-containing neuron pool, follows a distinctive pattern: an initial increase; a build to a near plateau due to reversion to normal neurons and establishment of an equilibrium between NFT formation and reversion; a decline after the peak, driven by decrease in the size of the pool of NFT-containing neurons due to neuronal death. Importantly, we maintained the same k ATR, representing neurodegenerative stress, over time. Thus this model accounts for an increase in the absolute number of neurons dying per unit time, and associated CSF-ptau, in the initial phases of disease followed by a decline despite constant neurodegenerative stress.The model further predicts that interventions that blocks neuronal loss from the NFT-containing neuron pool (i.e. prevented neurodegeneration) should lead to an acute decrease, rather than preventing an increase, in CSF-ptau. Conclusions: Reductions in CSF-ptau in advanced Alzheimer’s can be accounted for by a biological model in which the number of neurons dying per unit time is related to the size of the pool of long-lived NFT-containing neurons.