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


BACKGROUND
Clinicaltrials.gov, NCT01799941, registered on 25 February 2013.
Physical Medicine and Rehabilitation, Indiana University School of Medicine, Rehabilitation Hospital of Indiana, 4141 Shore Drive, Indianapolis, IN, 46254, USA. Flora.hammond@rhin.com.
Flora M
FM
Hammond
University of California, Los Angeles, CA, USA.
David N
DN
Alexander
Florida Clinical Research Center, LLC, Bradenton, FL, USA.
Andrew J
AJ
Cutler
Cornerstone Medical Group, Franklin, TN, USA.
Stephen
S
D'Amico
Baylor College of Medicine, Houston, TX, USA.
Rachelle S
RS
Doody
TMS NeuroHealth Centers, Richmond, VA, USA.
William
W
Sauve
MedStar National Rehabilitation Network, Washington, DC, USA.
Richard D
RD
Zorowitz
CSD Biostatistics, Inc., Tucson, AZ, USA.
Charles S
CS
Davis
Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA.
Paul
P
Shin
Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA.
Fred
F
Ledon
Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA.
Charles
C
Yonan
Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA.
Andrea E
AE
Formella
Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA.
Joao
J
Siffert
D000368:Aged; D000070642:Brain Injuries, Traumatic / Q000150:complications; D003704:Dementia / Q000150:complications; D003915:Dextromethorphan / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020828:Pseudobulbar Palsy / Q000150:complications / Q000188:drug therapy*; D011802:Quinidine / Q000008:administration & dosage / Q000627:therapeutic use*; D012720:Severity of Illness Index; D020521:Stroke / Q000150:complications; D016896:Treatment Outcome
D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; C507057:dextromethorphan - quinidine combination; D003915:Dextromethorphan; D011802:Quinidine
Brain injuries; Center for neurologic study-lability scale; Dementia; Dextromethorphan; Neuropsychiatric symptoms; Pseudobulbar affect; Quinidine; Stroke