Avanir Pharmaceuticals, Inc. has announced top-line data from the PRISM II study showing that treatment with NUEDEXTA® was associated with a statistically significant reduction in symptoms of pseudobulbar affect (PBA) in patients with traumatic brain injury (TBI) or stroke. PBA is a distressing condition characterized by sudden and uncontrollable outbursts of laughing and/or crying resulting from certain neurologic diseases or brain injury. PRISM II is a phase IV study evaluating the safety and effectiveness of NUEDEXTA in treating PBA in patients with dementia/Alzheimer's disease, stroke and TBI. Data from patients with PBA secondary to TBI were presented Monday, June 29th at the 33rd Annual Symposium of the National Neurotrauma Society in Santa Fe, New Mexico. Data from patients with PBA secondary to dementia/Alzheimer's disease were presented at last year's American Neurological Association Meeting, and full results from the stroke cohort will be presented at a future date.

"The improvement in PBA symptoms that we saw in the TBI and stroke cohorts of this study are consistent with what we saw in the pivotal phase III study of PBA in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), as well as that seen for PBA patients with dementia also enrolled in PRISM II. The data show that physicians, patients and caregivers see treatment benefit, providing further evidence that NUEDEXTA can offer relief from the disruptive and debilitating effects of PBA," said Joao Siffert, M.D., executive vice president, R&D, and chief medical officer at Avanir. "We have now studied NUEDEXTA in over 1,000 patients of different ages, including many above 70 years of age, who had PBA resulting from a wide variety of neurological disorders. In all groups, we have seen consistent levels of effectiveness and safety."

Enrollment in PRISM II is complete with 134 patients with PBA in the dementia/Alzheimer's disease cohort, 120 patients with PBA in the TBI cohort, and 113 patients with PBA in the stroke cohort. The average age of patients in this study was 72 for dementia/Alzheimer's disease, 61 for stroke and 46 for TBI. The effectiveness endpoints included a PBA symptom rating scale called the Center for Neurologic Study-Lability Scale (CNS-LS; scored from 7 = no symptoms to 35 = maximum symptoms), the number of weekly PBA episodes, the degree to which PBA symptoms affected overall quality of life (QOL; 0 = "Not at all" and 10 = "Significantly"), and Clinician and Patient Global Impression of Change with respect to PBA (CGI-C; PGI-C). Standard safety measures were recorded throughout the study.

TBI Cohort Top-Line Results

  • At baseline, patients had a mean CNS-LS score of 20.5 and were suffering from a median of 10 PBA episodes per week.
  • At the end of the study period, mean CNS-LS improved to 11.9 (P<0.001 compared with baseline) and the median number of PBA episodes decreased to one per week, with an overall 78.5% reduction in episode count compared to baseline (P<0.001).
  • Consistent improvement was observed in other effectiveness endpoints.
    • 73.0% of patients or caregivers rated themselves/the patient as being much/very improved on the PGI-C (P<0.001).
    • Clinicians rated 78.0% of patients to be much/very much improved on the CGI-C (P<0.001).
  • Adverse events (AE) were reported by 43 patients (35.8%) with 23 (19.2%) having an AE deemed to be treatment-related. The most commonly reported AE was diarrhea (8.3%). A total of four patients had serious AEs (none of which were deemed to be treatment-related), and 14 patients discontinued the study due to AEs. The AE profile was generally consistent with that observed in other trials of NUEDEXTA.

Stroke Cohort Top-Line Results

  • At baseline, patients had a mean CNS-LS score of 20.8 and were suffering from a median of 10 PBA episodes per week.
  • At the end of the study period, mean CNS-LS improved to 13.1 (P<0.001 compared with baseline) and the median number of PBA episodes decreased to two per week with an overall 75.5% reduction in episode count compared to baseline (P<0.001).
  • Consistent improvement was observed in other effectiveness endpoints.
    • 68.0% of patients or caregivers rated themselves/the patient as being much/very improved on the PGI-C (P<0.001).
    • Clinicians rated 75.0% of patients to be much/very much improved on the CGI-C (P<0.001).
  • AEs were reported by 40 patients (35.4%) with 16 (14.2%) having an AE deemed to be treatment-related. The most commonly reported AEs were diarrhea (4.4%), headache (3.5%) and constipation (2.7%). A total of seven patients had serious AEs (none of which were deemed to be treatment-related), and six patients discontinued the study due to AEs. This AE profile was generally consistent with that observed in other trials of NUEDEXTA.

About PRISM II

The objectives of the study were to evaluate the safety, tolerability and effectiveness of NUEDEXTA capsules containing 20 mg dextromethorphan hydrobromide (DM) and 10 mg quinidine sulfate (Q) for treatment of PBA in patients with Alzheimer's disease and other dementias, stroke and traumatic brain injury.

PRISM II is a nationwide, open-label, multicenter, study that enrolled 367 patients at approximately 100 study centers. Eligible patients were age ≥18 years with a clinical diagnosis of PBA and baseline score ≥13 on the CNS-LS. Patients with TBI due to a penetrating head injury were excluded. Patients were treated with NUEDEXTA twice daily for 12 weeks. The primary endpoint was change from baseline in PBA symptoms as measured by the CNS-LS, an instrument originally validated as a measure of PBA episode frequency and severity in patients with ALS and MS. Determination of effectiveness was based on a comparison of CNS-LS change in PRISM II with that seen for NUEDEXTA and placebo in a previous pivotal phase III study. Additional outcomes measures included number of weekly PBA episodes (laughing and/or crying); Mini-Mental State Examination; PBA impact on quality of life; CGIC; PGIC; patients' satisfaction with treatment; Patient Health Questionnaire (PHQ-9) (to evaluate mood symptoms), and a functional measure consisting of the Neurobehavioral Functioning Inventory for patients with TBI and Stroke Impact Scale for patients with stroke. Safety measures included monitoring of adverse events, concomitant medication usage, and vital signs.

The CNS-LS has been validated in ALS and MS patients.

Poster Presentation Details:
Title: Safety, Tolerability, and Effectiveness of Dextromethorphan/Quinidine for Pseudobulbar Affect in Traumatic Brain Injury: PRISM II
Poster Number: A2-01
Poster Session: A2 Poster Session I - Group A: Secondary Injury, Monday, June 29th