April 13, 2010 (Toronto, Ontario) — Results of an open-label extension study examining the effect of a combination of dextromethorphan and quinidine (Zenvia, Avanir Pharmaceuticals) confirm continued efficacy of this still investigational combination in the treatment of pseudobulbar affect (PBA).
"There's a continued incremental improvement over the 12-week period in this open-label phase," Erik P. Pioro, MD, PhD, director of the Section for ALS and Related Disorders at the Cleveland Clinic in Ohio, told a press conference here.
|Dr. Erik P. Pioro|
The Safety, Tolerability and Efficacy Results of AVP-923 in PBA (STAR) trial was funded by Avanir Pharmaceuticals.
Results were presented here at the American Academy of Neurology 62nd Annual Meeting. Top-line results of the randomized phase of the STAR trial were released in August 2009 and presented soon after at the annual meeting of the American Neurological Association in Baltimore, Maryland, by coauthor Benjamin Brooks, MD, from Carolinas Medical Center in Charlotte, North Carolina.
The STAR trial was undertaken to address previous concerns of the US Food and Drug Administration (FDA) about safety issues with a formulation of the compound that used a higher dose of quinidine, concerns outlined in an earlier approvable letter issued in 2006. Dr. Pioro said the company plans to file a submission to the FDA soon on this new formulation and hopes to have a decision at some point in the fourth quarter of this year.
PBA is a neurologic disorder secondary to a variety of other neurologic conditions, including traumatic brain injury, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and dementias such as Alzheimer's disease, Parkinson's disease, and stroke and is characterized by sudden, inappropriate, and unpredictable outbursts of crying, laughing, or anger and irritability that have little to do with how the patient is actually feeling. It is disturbing for patients and families and causes problems in social and occupational settings, making patients who already have neurologic disorders become more withdrawn, noted Dr. Pioro.
The new drug is a combination of 2 well-known compounds: dextromethorphan, the active treatment, and quinidine, an enzyme inhibitor that increases the bioavailability of dextromethorphan. The previous combination of these drugs had used a 30-mg dose of quinidine, raising concern about the potential for proarrhythmia, Dr. Pioro said.
The STAR trial was an international multicenter study that randomly assigned 326 patients with ALS and MS and signs and symptoms of PBA to 1 of 2 doses of the combination therapy, 30/10 mg twice daily or 20/10 mg twice daily, or placebo. The double-blind phase lasted 3 months, at which point patients were eligible for a 3-month, open-label extension.
The primary efficacy outcome was changes in crying or laughing episode rates recorded in patient diaries, expressed as episodes per day, with the 30/10-mg dose vs placebo. Secondary endpoints included the Center for Neurologic Study–Lability Scale (CNS-LS) score, the Neuropsychiatric Inventory Questionnaire, the 36-item Short Form Health Survey, the Beck Depression Inventory, and the Pain Rating Scale score (in MS patients only).
Results showed that the 30/10-mg dose was associated with a 47.2% reduction in episode rates vs placebo (P < .0001). The 20/10-mg dose was also associated with a significant reduction in crying or laughing episodes vs placebo.
The CNS-LS score, a measure of PBA frequency and severity, was also reduced significantly with the 30/10-mg dose from 20 to 21 at the outset of the double-blind phase to below 13, the threshold for clinically detectable PBA.
Lower scores on this scale are better; the highest score possible is 35, and the score of someone without PBA is 7. Patients had to have a score of 13 or higher to be included in the double-blind trial, Dr. Pioro noted.
Of 283 patients who completed the randomized trial, 253 entered the open-label extension study. CNS-LS scores had rebounded to about 14 at the outset of the open-label extension. All were then treated during the 12-week extension study with the 30/10-mg dose of dextromethorphan and quinidine, regardless of whether they were in the active or placebo-treated arms during the randomized trial.
Investigators used the CNS-LS as the outcome of interest for the extension study. The study's original primary outcome, the number of laughing or crying episodes, was not assessed during the extension.
Asked about this decision, Dr. Pioro pointed out that the CNS-LS had been primary endpoint in 2 previous trials of this drug combination. "It was changed to a secondary endpoint really based on the FDA's request to make episode count be the primary endpoint," he explained. Although these 2 endpoints don't always match up, he added, "on the whole they typically do."
The investigators report that the mean CNS-LS score decreased significantly from 13.8 at baseline of the extension assessment to 11.2 at week 12. The mean change from the new baseline at the time of the open-label assessment was a reduction of 2.7 points, which was highly significant, he noted (P < .0001).
Not unexpectedly, the biggest mean change from the start of the extension study was a reduction of 3.1 points among patients previously treated with placebo (P < .0001). "Interestingly, the ones who had been in the DM 20 [20 mg of dextromethorphan] group also had improvement," Dr. Pioro said. As expected, those already treated with the 30/10-mg dose did not show any improvement, "but overall there was a statistically significant reduction of the overall CNS-LS score."
Safety data from the open-label extension will be presented here on Thursday in separate poster presentations, one looking at safety and tolerability (P06.128) and the other at any cardiac toxicity (P06.119) seen during the STAR trial.
Significantly Socially Disabling
Asked for comment on these findings, Lily Jung, MD, a neurologist at the Swedish Neuroscience Institute in Seattle, Washington, pointed out that PBA commonly occurs with neurodegenerative conditions such as ALS and MS and can cause patients to withdraw from social contact. "It's very embarrassing and hard for family members and others to comprehend," she told Medscape Neurology.
Currently, there is no FDA-approved treatment specifically for PBA, although antidepressants are used off label. Unfortunately, Dr. Jung said, antidepressants cause adverse effects and are in general not very effective in this setting.
Although dextromethorphan has been around for a long time and has been used for years in cough syrup, it is metabolized quickly and stable levels are hard to maintain. The addition of low doses of quinidine appears to reduce the metabolism of dextromethorphan, she noted.
In the STAR extension trial, the effect of the drug combination was studied using the CNS-LS self-reported test, and treatment was associated with significantly reductions. "This is exciting because pseudobulbar affect can be so significantly socially disabling," Dr. Jung said.
"This is a small study which suggests that 2 common drugs may potentially improve the symptoms seen in pseudobulbar affect," she added. "Obviously, more studies need to be done in larger groups of patients, and testing for benefit should be done with other validated measures, such as PLACS [Pathological Laughing and Crying Scale], which is an observer-rated measure, or the Emotion Lability Questionnaire, which rates symptoms both by patients and signs documented by their healthcare providers."
The study was supported by Avanir Pharmaceuticals. Dr. Pioro reports he has received personal compensation for activities with Avanir Pharmaceuticals Inc as a scientific advisory board member and consultant. Disclosures for the other coauthors are reported in the published abstract. Dr. Jung has disclosed no relevant financial relationships.
American Academy of Neurology (AAN) 62nd Annual Meeting: Abstract P02.295. Presented April 13, 2010.
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Cite this: Continued Efficacy for Dextromethorphan/Quinidine Combination for Pseudobulbar Affect - Medscape - Apr 13, 2010.