PRISM II: an open-label study to assess effectiveness of dextromethorphan/quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury.

William Sauve,Rachelle S. Doody,David N. Alexander,Flora M. Hammond,Paul Shin,Charles Yonan,Richard D. Zorowitz,Andrew J. Cutler,Andrea E. Formella,Joao Siffert,Fred Ledon,Charles S. Davis,Stephen D’Amico

doi:10.1186/s12883-016-0609-0

Abstract

BackgroundPhase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI).MethodsParticipants in this open-label, multicenter, 90-day trial received DM/Q 20/10 mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C).ResultsThe study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, −7.7 [6.1]; P < .001, 95 % CI: −8.4, −7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95 % CI] change from baseline, −8.2 [−9.4, −7.0]) and numerically exceeds the improvement seen with placebo in that study (−5.7 [−6.8, −4.7]). Reduction in PBA episode count was 72.3 % at Day 90/Final Visit compared with baseline (P < .001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4 % of participants, respectively, were “much” or ”very much” improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4 %), headache (4.1 %), urinary tract infection (2.7 %), and dizziness (2.5 %); 9.8 % had AEs that led to discontinuation. Serious AEs were reported in 6.3 %; however, none were considered treatment related.ConclusionsDM/Q was shown to be an effective and well-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q.Trial registrationClinicaltrials.gov, NCT01799941, registered on 25 February 2013Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0609-0) contains supplementary material, which is available to authorized users.

Highlights

Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS)
Prevalence estimates vary by rigor of diagnostic requirements, screening methodology, and causative neurological disorder; a registry sample of 5,290 clinic patients with 1 of 6 neurologic conditions known to be associated with PBA—Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), stroke, and traumatic brain injury (TBI)— found 36.7 % had a Center for Neurologic Study-Lability Scale (CNS-LS) score ≥13, a score that predicted neurologist diagnosis of PBA in validation studies for 82 % of patients with ALS and 78 % with MS; 9.3 % of this registry sample had a CNS-LS ≥21 [5]
Study findings showed that DM/Q 20/10 mg administered twice daily in non-blinded fashion over 12 weeks to participants with PBA secondary to dementia, stroke, or TBI was generally well tolerated and was associated with improvements in CNS-LS scores and reductions in PBA episodes

Summary

Introduction

Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI). Prevalence estimates vary by rigor of diagnostic requirements, screening methodology, and causative neurological disorder; a registry sample of 5,290 clinic patients with 1 of 6 neurologic conditions known to be associated with PBA—Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), stroke, and traumatic brain injury (TBI)— found 36.7 % had a Center for Neurologic Study-Lability Scale (CNS-LS) score ≥13, a score that predicted neurologist diagnosis of PBA in validation studies for 82 % of patients with ALS and 78 % with MS; 9.3 % of this registry sample had a CNS-LS ≥21 [5]. Various drugs have been studied as treatments for PBA, including tricyclic antidepressants and selective serotonin reuptake inhibitors, though no agents in these drug classes have been approved for this use [15]

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