The anticonvulsant zonisamide combined with levodopa improves motor symptoms in patients with dementia with Lewy bodies (DLB), without exacerbating cognitive decline or psychiatric symptoms, new research shows.
Japanese researchers compared two different dosages of adjunctive zonisamide to placebo in patients with DLB and found the drug improved parkinsonism without worsening cognitive function or psychiatric symptoms.
“In DLB, hallucinations and delusions tend to appear easily with dopaminergic agents, so until now it has not been possible to adequately treat these motor symptoms,” lead author, Miho Murata, MD, PhD, director general, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan, told Medscape Medical News.
“We found that 50 mg of zonisamide vs placebo, in combination with levodopa, achieved a statistically significant improvement in the Unified Parkinson’s Disease Rating Scale Part 3 total score without worsening cognitive function, behavioral and psychological symptoms of dementia, and burden on caregivers,” he said.
The study was published online January 24 in Neurology.
Hallucinations, Delusions
“Patients with DLB frequently complain of common symptoms, including hallucinations and parkinsonism,” the authors write.
Although treatment with levodopa is “beneficial” for symptoms of parkinsonism accompanying DLB, conventional anti-Parkinson drugs, including levodopa, “should be prescribed with care because they can induce psychiatric symptoms, such as hallucinations and delusions.”
Zonisamide has been used adjunctively in Japan with levodopa to treat Parkinson’s disease motor symptoms and has shown a low incidence of motor complications and psychiatric symptoms.
Similarly, a previous study of three patients with DLB and two case studies, each with one patient, showed the drug improved motor symptoms without increasing hallucinations.
The current phase 2 placebo-controlled, double-blind study was designed to expand these findings.
The researchers studied 158 outpatients with DLB (aged 56 to 84 years) who were required to have a Unified Parkinson’s’ Disease Rating Scale (UPDRS) part 3 total score of 10 or greater, a Mini Mental State Examination (MMSE) total score of 10 to 26, and administration of levodopa/decarboxylase inhibitor (DCI) for at least 12 weeks before the run-in period.
The study consisted of a 4-week run-in period and a 12-week treatment period. During the run-in period, participants received daily orally administered placebo under single-blind conditions.
Participants were allowed to be taking antidementia and anti-Parkinson drugs other than levodopa/DCI; antihypertensives; drugs to address the cardiovascular, gastrointestinal, or central nervous systems; or Yokukansan (a traditional Japanese herbal medicine). These agents had to have been administered unchanged for at least 2 weeks before the run-in period.
Patients were randomly assigned to receive zonisamide 25 mg (n = 51), zonisamide 50 mg (n = 49), or placebo (n = 58) on a once-daily basis.
The primary endpoint was change from baseline in UPDRS part 3 total score at week 12, while secondary endpoints were changes from baseline in total scores of UPDRS, each UPDRS part, and changes from baseline in total MMSE scores, Neuropsychiatric Inventory-10 (NPI-10), and Zarit Burden Interview (ZBI).
Laboratory test values, vital signs, and body weight were measured at each visit, and 12-lead resting electrocardiography was measured at screening, baseline, and weeks 4 and 12.
The researchers used analysis of covariance (ANCOVA) to determine the superiority of zonisamide over placebo, and changes from baseline were calculated as least-squares mean ± standard error of the mean.
Approximately 60% of the modified intention-to-treat (mITT) population (n = 152) were male, and the mean age of participants was 75.1 years. Patients had been diagnosed with DLB a mean of 1.5 years before the study, and the mean durations of motor symptoms and dementia were 3.6 and 3.8 years respectively.
In addition, about 70% of patients experienced fluctuating cognition and visual hallucinations. Motor dysfunction was present in all patients. All three groups had roughly similar baseline disease-related variables.
“Clinically Safe, Useful”
At week 12, UPDRS part 3 total scores were decreased in all groups, compared with baseline, “indicating improved parkinsonism,” the authors report.
However, there were fewer changes in the placebo group than in the zonisamide 25- and 50-mg groups (least-squares mean values were −2.1 ± 0.9, −4.4 ± 1.0, and −6.2 ± 1.0, respectively).
The zonisamide 50- and 20-mg groups showed significantly greater change in UPDRS part 3 total score (between-group difference, −4.1 [95% confidence interval (CI), −6.8 to −1.4; P = .003] and −2.3 [95% CI, −5.0 to 0.4; P = .099], respectively) compared with placebo.
When ANCOVA of the per protocol population was conducted, significant changes in UPDRS part 3 total scores were observed between zonisamide 50 mg and placebo (between-group difference, −4.4; 95% CI, −7.2 to −1.5; P = .003).
Findings were similar on the mixed-effect model repeated-measures analysis of the mITT population (between-group difference, −4.7; 95% CI, −7.5 to −1.9; P = .001).
All three groups showed a decrease in the UPDRS part 3 total score from baseline at week 4. However, the score remained constant up to week 12 for placebo, in contrast with further decreases in the zonisamide groups.
The score was significantly lower at week 8 in the zonisamide 50-mg group (between-group difference, −2.8; 95% CI, −5.3 to −0.4; P = .022) and at week 12 (between-group difference, −5.1; 95% CI, −8.0 to −2.2; P < .001) compared with placebo.
The total scores for MMSE, NPI-10, and ZBI did not change significantly from baseline in any group, “suggesting administration of zonisamide did not worsen cognitive function, [behavioral and psychological symptoms of dementia], or caregiver burden,” the researchers reported.
Although the overall incidence of adverse events was similar between zonisamide 25 mg and placebo, it was higher for zonisamide 50 mg.
Discontinuation rates were higher in the zonisamide 25- and 50-mg groups than with placebo (five patients [six events], six patients [six events], and two patients [two events]).
Except for decreased appetite, other serious adverse events were not considered to be causally related to the study drug.
Notably, the incidences of adverse events related to neurologic and psychiatric disorders, such as hallucinations and visual hallucinations, were similar between zonisamide and placebo.
There were no clinically significant changes in laboratory test values, vital signs, body weight, or electrocardiographic findings in any group.
The authors note the findings “suggest zonisamide is clinically safe and useful for treatment of parkinsonism in DLB.”
“The study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well-tolerated in patients with DLB, according to the classification scheme requirements for therapeutic questions,” the authors write.
Dr Murata believes the findings are relevant to practicing clinicians, noting that application for approval of zonisamide is underway.
Impetus for Larger Studies
Commenting on the study for Medscape Medical News, Linda A. Hershey, MD, PhD, professor of neurology, University of Oklahoma Health Sciences Center, Oklahoma City, who was not involved with the study, said that it “was very exciting that this drug improved the motor function without making hallucinations worse.”
The coauthor of an accompanying editorial, Dr Hershey noted that the drug is not yet US Food and Drug Administration (FDA) approved for use in DLB.
“This was a phase II trial with a relatively small group of patients and for safety reasons, we usually like to wait until a phase III trial is conducted with larger groups before it goes to prime time.”
A clinician who does choose to prescribe the drug to a patient with severe parkinsonism and levodopa-induced hallucinations “should caution patients and caregivers that it is not FDA-approved for this indication, has been tested only in a small number of patients, and is being used off-label.”
The study “should be an impetus for larger studies where we can have more confidence in the safety and efficacy of the use of this drug,” she said.
The authors agree that although their findings “suggest that zonisamide is clinically safe and useful in patients with DLB,” the sample size was small.
“Further studies are needed to investigate the efficacy of zonisamide in a large number of participants,” they note.
Dr Murata added that he would also “like to study the mechanism of how zonisamide improved parkinsonism without exacerbating hallucinations and dyskinesia.”
The study was supported by Sumitomo Dainippon Pharma.
Dr Murata received honoraria for consulting and/or lecturing from Sumitomo Dainippon Pharma, Otsuka Pharmaceutical, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Nihon Medi-Physics, FUJIFILM Pharma, Hisamitsu Pharmaceutical, and AbbVie GK. Dr Murata received grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Japan Agency for Medical Research and Development; and the Ministry of Health, Labour and Welfare of Japan. The other authors’ disclosures are listed on the original paper. Dr Hershey was the site principal investigator for two studies sponsored by Forum Pharmaceuticals. She was a coinvestigator for an Alzheimer’s Association grant. She has received honoraria for educational presentations and online publications. Her coauthor’s disclosures are listed on the original editorial.
Neurology. Published online January 24, 2018. Abstract, Editorial
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