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

Abstract

Background: 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).

Methods: Participants 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).

Results: The 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.

Conclusions: DM/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 registration: Clinicaltrials.gov, NCT01799941, registered on 25 February 2013.

Keywords: Brain injuries; Center for neurologic study-lability scale; Dementia; Dextromethorphan; Neuropsychiatric symptoms; Pseudobulbar affect; Quinidine; Stroke.

Figures

Fig. 1

Schedule of study assessments. Caregivers completed ratings as proxies for patients who were unable (except for the MMSE). AE = adverse event; CGI-C = Clinical Global Impression of Change; CNS-LS = Center for Neurologic Study–Lability Scale; MMSE = Mini-Mental State Exam; NFI = Neurobehavioral Functioning Inventory; PBA = pseudobulbar affect; PGI-C = patient/caregiver Global Impression of Change; PHQ-9 = 9-item Patient Health Questionnaire; QOL-VAS = quality-of-life visual analog scale; SIS = Stroke Impact Scale

Fig. 2

Consort diagram for PRISM II cohort. CNS-LS = center for neurologic study–lability scale

Fig. 3

Mean (SD) CNS-LS Score at Baseline, Day 30, and Day 90 (Effectiveness Analysis Set). CNS-LS scores range from 7 to 35, with higher scores indicating increased frequency and severity of PBA episodes. P values are based on the one sample t-test and represent comparison with baseline. *P < .001 vs. baseline. †The CNS-LS is a patient-reported quantitative measure of the perceived frequency and severity of PBA episodes; CNS-LS scores were not normalized. CNS-LS = Center for Neurologic Study–Lability Scale; PBA = pseudobulbar affect; SD = standard deviation

Fig. 4

Distribution of PBA Episodes (occurring in the past 7 days) by Visit. Solid bars illustrate the percentage of patients experiencing the given number of episodes shown within the range provided on the x axis. The solid curved line represents the number of PBA episodes that would be predicted based on each patient’s values for the parameters (age, gender and time [Day 30, Day 90]; fixed effects) and baseline rate (random effects) in the mixed-effects Poisson regression model. Patients or daytime caregivers were asked to identify, count, and recall the total episodes of exaggerated or uncontrollable laughing and/or crying over the previous 7 days (prior to visit) at baseline, Day 30, and Day 90. Estimated percent change from baseline for PBA episode count was evaluated via a mixed-effects Poisson regression model for the effectiveness analysis set. *P < .001 vs. baseline

Fig. 5

90-Day Clinical and Patient Global Impression of Change (Effectiveness Analysis Set). CGI-C is a 7-point investigator-rated scale that assessed overall treatment response (with respect to PBA) from baseline to Day 90/Final Visit, rated as very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse. PGI-C is a 7-point patient/patient’s caregiver rated scale that assessed overall treatment response (with respect to PBA) from baseline to Day 90/Final Visit, rated as very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse. CGI-C = Clinical Global Impression of Change; PGI-C = Patient/Caregiver Global Impression of Change

Fig. 6

Mean CNS-LS Scores Across DM/Q Studies for PBA Secondary to Diverse Neurologic Conditions. *DM/Q 30/30 mg twice daily; †DM/Q 20/10 mg twice daily. ‡Improvement from baseline in mean CNS-LS (SE). 99-AVR-102 (4 week study comparing DM/Q to DM or Q monotherapy): End of study is the mean of the CNS-LS scores for Days 15 and 29; P = 0.001 vs. dextromethorphan comparator and P < 0.001 vs quinidine comparator. 02-AVR-106 (12 week DBPC study): End of study is the mean of the CNS-LS scores on Days 15, 29, 57, and 85; P < 0.0001 vs. placebo. 07-AVR-123 (12 week DBPC study): End of study is at Week 12 intent to treat; P < 0.05 vs. placebo. PRISM II: End of study is at Day 90/Final Visit; P < 0.001 vs. baseline in all 3 cohorts. ALS = amyotrophic lateral sclerosis; CNS-LS = Center for Neurologic Study–Lability Scale; DM/Q = dextromethorphan/quinidine; MS = multiple sclerosis; PBA = pseudobulbar affect; TBI = traumatic brain injury; SE = standard error