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Luigi Giorgi - One of the best experts on this subject based on the ideXlab platform.
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long term safety and efficacy of Zonisamide versus carbamazepine monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy results of a phase iii randomized double blind study
Epilepsia, 2014Co-Authors: Michel Baulac, Anna Patten, Luigi GiorgiAbstract:SummaryObjective To investigate the long-term safety and maintenance of efficacy of monotherapy with once-daily Zonisamide versus twice-daily controlled-release carbamazepine for partial seizures in adults with newly diagnosed epilepsy. Methods Long-term, double-blind, extension study, conducted in patients completing a phase III noninferiority trial comparing Zonisamide and carbamazepine monotherapy. Patients continued their randomized treatment, with dosing adjusted according to tolerability/response (Zonisamide 200–500 mg/day; carbamazepine 400–1,200 mg/day). Safety assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory parameters. Efficacy assessments included retention rate and the proportion of patients remaining seizure free for ≥24 months. Results Overall, 120 (87.6%) of 137 patients randomized to Zonisamide and 134 (84.8%) of 158 patients randomized to carbamazepine completed the study. More than three-fourths of patients were exposed to >24 months of treatment. For Zonisamide versus carbamazepine, incidences were similar for TEAEs (52.6% vs. 46.2%), serious treatment-related TEAEs (0.7% vs. 1.9%), and TEAEs leading to withdrawal (1.5% vs. 0.6%). The incidence of treatment-related TEAEs was 26.3% for Zonisamide compared with 19.6% for carbamazepine, and the most frequently reported treatment-related TEAEs were decreased weight (5.1% vs. 0%), decreased appetite (3.6% vs. 0%), memory impairment (2.9% vs. 3.2%), and decreased hemoglobin level (1.5% vs. 3.2%). Most TEAEs were of mild or moderate intensity. There were no reports of Stevens-Johnson syndrome or toxic epidermal necrolysis in either group. Zonisamide was associated with small-to-moderate decreases in bicarbonate levels from baseline (mean −3.4 mm). There were no reports of metabolic acidosis. Retention rates were generally similar between treatment groups at all time points throughout the extension study. The proportion of patients remaining seizure free for ≥24 months was also similar for Zonisamide (32.3%) and carbamazepine (35.2%). Significance Once-daily Zonisamide monotherapy demonstrated favorable long-term safety and maintenance of efficacy in treating partial seizures in adults with newly diagnosed epilepsy. No new or unexpected safety findings emerged.
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adjunctive Zonisamide therapy in the long term treatment of children with partial epilepsy results of an open label extension study of a phase iii randomized double blind placebo controlled trial
Epilepsia, 2014Co-Authors: Renzo Guerrini, Anna Rosati, Kate Bradshaw, Luigi GiorgiAbstract:Summary Objective To investigate the safety/tolerability and efficacy of long-term adjunctive Zonisamide and its impact on growth and development in children (6–18 years) with partial epilepsy. Methods Open-label extension of a phase III, placebo-controlled trial. Started with double-blind transition period (2–11 weeks), during which patients on Zonisamide continued at the same dose and those on placebo switched to Zonisamide 1 mg/kg/day, up-titrated to 8 mg/kg/day (maximum 500 mg/day). During the subsequent open-label period (45–57 weeks), Zonisamide dosing could be adjusted according to tolerability/response. Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters, and vital signs. Efficacy assessments included responder rate (primary assessment) and seizure freedom rate during the open-label period. Growth and development assessments comprised Tanner stages, hand x-rays, Child Behavior Checklist (CBCL 6/18), School Performance questionnaire, Physician and Parent/Guardian Global Impression of Change, and Controlled Oral Word Association Test (COWAT). Results One hundred forty-four children entered the study; 99 (68.8%) of 144 children completed it, and 108 (75.0%) of 144 received Zonisamide for ≥1 year. TEAEs occurred in 39 (27.1%) of 144 patients. There were low incidences of serious TEAEs (2.1%) and TEAEs leading to discontinuation (2.8%). Bicarbonate level decreases >3.5 mm occurred in 64 patients (44.4%), and 24 patients (16.7%) had a weight decrease of ≥10% from baseline. During the open-label period, 81 (56.3%) of 144 patients were responders and 16 (11.1%) of 144 achieved seizure freedom. Tanner staging and skeletal development were as expected for the study population. Changes were minimal for CBCL 6/18 and School Performance scores. Most patients were “much improved”/“very much improved” on Physician (73.8%) and Parent/Guardian (75.4%) Global Impressions of Change. Median changes in COWAT Category and Letter Fluency scores were 2.0 and 0.5, respectively. Significance Adjunctive Zonisamide was well tolerated and efficacious over a period of at least 1 year in children with partial epilepsy, with no unexpected safety concerns and no consistent detrimental effects on growth and development. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
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a randomized phase iii trial of adjunctive Zonisamide in pediatric patients with partial epilepsy
Epilepsia, 2013Co-Authors: Renzo Guerrini, Anna Rosati, Joanna Segieth, Simona Pellacani, Kate Bradshaw, Luigi GiorgiAbstract:Summary Purpose To assess the efficacy and safety/tolerability of adjunctive Zonisamide treatment in pediatric patients with partial epilepsy. Methods In this phase III, double-blind, randomized, placebo-controlled, multicenter trial, 207 patients (age 6–17 years) with partial epilepsy, receiving one or two antiepileptic drugs, were randomized to receive adjunctive Zonisamide or placebo. Zonisamide was initiated at 1 mg/kg/day, titrated to a target dose of 8 mg/kg/day over 8 weeks (one down-titration permitted), and maintained for 12 weeks. The primary efficacy end point was the proportion of responders (≥50% seizure frequency reduction from baseline) during the 12-week maintenance period. Safety/tolerability assessments included the incidence of treatment-emergent adverse events (TEAEs). Key Findings In total, 93 (86.9%) of 107 patients randomized to Zonisamide and 90 (90.0%) of 100 patients randomized to placebo completed the trial. Responder rates were 50% for Zonisamide versus 31% for placebo (p = 0.0044; intention-to-treat population, last observation carried forward). The overall incidence of TEAEs was similar for Zonisamide (55.1%) versus placebo (50.0%), with low rates of serious TEAEs with Zonisamide and placebo (3.7% vs. 2.0%) and TEAEs leading to withdrawal (0.9% vs. 3.0%). TEAEs reported more frequently with Zonisamide versus placebo were decreased appetite (6.5% vs. 4.0%), decreased weight (4.7% vs. 3.0%), somnolence (4.7% vs. 2.0%), vomiting (3.7% vs. 2.0%), and diarrhea (3.7% vs. 1.0%). Significance Adjunctive Zonisamide treatment was shown to be effective and well tolerated in pediatric patients with partial epilepsy. No new or unexpected safety findings emerged.
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efficacy and tolerability of Zonisamide versus controlled release carbamazepine for newly diagnosed partial epilepsy a phase 3 randomised double blind non inferiority trial
Lancet Neurology, 2012Co-Authors: Michel Baulac, Joanna Segieth, Anna Patten, Martin J Brodie, Luigi GiorgiAbstract:Summary Background Additional options are needed for monotherapy treatment of adults newly diagnosed with partial epilepsy. This trial compares the efficacy and tolerability of once-daily Zonisamide with twice-daily controlled-release carbamazepine monotherapy for such patients. Methods In this phase 3, randomised, double-blind, parallel-group, non-inferiority trial, adults from 120 centres in Asia, Australia, and Europe, aged 18–75 years and newly diagnosed with partial epilepsy, were randomly assigned (in a 1:1 ratio, done with a computer-generated pseudorandom code) to receive Zonisamide or carbamazepine. Patients, investigators, and sponsor personnel giving drugs, analysing outcomes, and interpreting data were masked to treatment allocation. After treatment initiation (Zonisamide 100 mg/day vs carbamazepine 200 mg/day [given in two doses]) and up-titration (to 300 mg/day vs 600 mg/day), patients entered a 26–78 weeks flexible-dosing period (200–500 mg/day vs 400–1200 mg/day, according to response and tolerance). Once patients were seizure-free for 26 weeks they entered a 26-week maintenance phase. The primary endpoint was the proportion of patients who achieved seizure freedom for 26 weeks or more in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00477295. Findings 583 patients were randomly assigned to treatment groups (282 Zonisamide, 301 carbamazepine), of whom 456 were analysed for the primary endpoint (per-protocol population: 223 Zonisamide, 233 carbamazepine). 177 of 223 (79·4%) patients in the Zonisamide group and 195 of 233 (83·7%) patients in the carbamazepine group were seizure-free for 26 weeks or more (adjusted absolute treatment difference −4·5%, 95% CI −12·2 to 3·1). The incidence of treatment-emergent adverse events was 170 (60%) in the Zonisamide group versus 185 (62%) in the carbamazepine group, of which 15 (5%) versus 17 (6%) were serious and 31 (11%) versus 35 (12%) led to withdrawal. Interpretation Zonisamide was non-inferior to controlled-release carbamazepine—according to International League Against Epilepsy guidelines—and could be useful as an initial monotherapy for patients newly diagnosed with partial epilepsy. Funding Eisai Ltd.
Miho Murata - One of the best experts on this subject based on the ideXlab platform.
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long term efficacy and safety of Zonisamide for treatment of parkinsonism in patients with dementia with lewy bodies an open label extension of a phase three randomized controlled trial
American Journal of Geriatric Psychiatry, 2021Co-Authors: Toshinari Odawara, Kazuko Hasegawa, Masaaki Tagawa, Kenji Kosaka, Ritsuko Kajiwara, Hisao Takeuchi, Miho MurataAbstract:Abstract Objectives To evaluate the long-term efficacy and safety of Zonisamide, an antiepileptic agent, in dementia with Lewy bodies (DLB). Design Phase 3 clinical trial with 12-week, randomized, placebo-controlled, double-blind, and subsequent 40-week, open-label, extension periods. Setting 109 centers in Japan between April 2015 and November 2017. Participants Outpatients diagnosed with probable DLB. Intervention Outpatients were randomly assigned to receive placebo (P) or Zonisamide 25 or 50 mg/day for 12 weeks. In the subsequent open-label 40-week period, all patients initially received Zonisamide 25 mg/day for at least 2 weeks followed by optional flexible dosing with Zonisamide 25 or 50 mg/day for the remaining period. Measurements The primary outcome was efficacy on motor symptoms, assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score, over the total 52-week trial period. Effects on behavioral and psychological symptoms of dementia and cognitive function, and safety were also evaluated. Results In total, 335 patients were included in the long-term analysis: 106, 117, and 112 in the P-, 25mg-, and 50mg-Flex groups, respectively. UPDRS-III score continued to improve for an additional 12–16 weeks in the open-label period (mean [standard deviation] change from baseline at Week 28: −5.1 [7.3] and −6.3 [8.2] in the 25mg- and 50mg-Flex groups) and remained almost constant thereafter. No unexpected neurological or psychiatric adverse events occurred, and no adverse events increased in incidence in the open-label period. Conclusions Long-term treatment with Zonisamide was well tolerated and yielded sustained improvement in motor symptoms. Trial registration JapicCTI-152839 (Registered on 9 March 2015) https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-152839
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effect of Zonisamide on parkinsonism in patients with dementia with lewy bodies a phase 3 randomized clinical trial
Parkinsonism & Related Disorders, 2020Co-Authors: Miho Murata, Kazuko Hasegawa, Toshinari Odawara, Masaaki Tagawa, Ritsuko Kajiwara, Hisao Takeuchi, Kenji KosakaAbstract:Abstract Introduction Zonisamide is approved in Japan for treating motor dysfunction in Parkinson's disease, and might also be effective for parkinsonism in patients with dementia with Lewy bodies (DLB). Our study evaluated the safety and efficacy of Zonisamide for treating parkinsonism in patients with DLB. Methods This multicenter, randomized, double-blind, phase 3 trial was conducted in Japan between April 2015 and November 2017. Following a 4-week run-in period, outpatients diagnosed with probable DLB who had developed parkinsonism were randomized to receive oral Zonisamide (25 or 50 mg/day) or placebo for 12 weeks, followed by a 40-week open-label extension. The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part III total score at Week 12. Results Of 351 patients randomized, 346 (mean age, 77.2 years; 188 males) were included in the modified intention-to-treat population. At Week 12, the group difference (least squares mean ± SEM) for changes from baseline (vs placebo) in UPDRS part III total score was −2.7 ± 0.9 (95% confidence interval [CI]: −4.4, −0.9, P = 0.005) in the Zonisamide 25-mg group and −2.6 ± 0.9 (95% CI: −4.4, −0.8, P = 0.005) in the Zonisamide 50-mg group. Adverse events were reported in 47.1%, 48.7%, and 54.5% of patients in the placebo and Zonisamide 25- and 50-mg groups, and led to treatment discontinuation in 5.0%, 4.3%, and 9.8% of patients, respectively. Conclusion Daily administration of 25- or 50-mg Zonisamide significantly improved motor function compared with placebo; both doses were safe and well tolerated in patients with DLB.
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genome wide association study identifies Zonisamide responsive gene in parkinson s disease patients
Journal of Human Genetics, 2020Co-Authors: Peichieng Cha, Miho Murata, Wataru Satake, Yuko Andokanagawa, Ken Yamamoto, Tatsushi TodaAbstract:Long-term treatment of Parkinson’s disease (PD) by levodopa leads to motor complication “wearing-off”. Zonisamide is a nondopaminergic antiparkinsonian drug that can improve “wearing-off” although response to the treatment varies between individuals. To clarify the genetic basis of Zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose “off” time decreased ≥1.5 h after 12 weeks of Zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and “off” time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced “off” time (PAdjusted = 4.85 × 10−9). Carriers of responsive genotype showed >7-fold decrease in mean “off” time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 × 10−7). In silico eQTL data indicated that Zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing “off” time, calcium and glutamate signaling have also been associated with anti-epileptic effect of Zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of “wearing-off” in PD by genotype-guided Zonisamide treatment.
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adjunct Zonisamide to levodopa for dlb parkinsonism a randomized double blind phase 2 study
Neurology, 2018Co-Authors: Miho Murata, Kazuko Hasegawa, Toshinari Odawara, Sayaka Iiyama, Masatoshi Nakamura, Masaaki Tagawa, Kenji KosakaAbstract:Objective To investigate the efficacy and safety of Zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with dementia with Lewy bodies (DLB). Methods This phase 2, placebo-controlled, randomized, double-blind study consisted of run-in (placebo, 4 weeks) and treatment (placebo or Zonisamide 25 or 50 mg once daily, 12 weeks) periods. Outpatients diagnosed with probable DLB were eligible for inclusion. The primary endpoint was the change from baseline in Unified Parkinson9s Disease Rating Scale (UPDRS) part 3 total score at week 12. Cognitive function, behavioral and psychological symptoms of dementia (BPSD), caregiver burden, other UPDRS parts as secondary endpoints, and safety were also assessed. Results Overall, 158 patients with DLB received the study drug; 21 discontinued during treatment and 137 completed treatment. Improvement in UPDRS part 3 total score at week 12 was significantly greater in the Zonisamide 50 mg group compared with placebo (between-group difference −4.1; 95% confidence interval −6.8 to −1.4; p = 0.003). Zonisamide did not worsen cognitive function, BPSD, or caregiver burden. The overall incidence of adverse events was higher in the Zonisamide 50 mg than the 25 mg and placebo groups (65.3%, 43.1%, and 50.0%, respectively); similar rates of serious adverse events were observed among all groups. Conclusion Zonisamide (adjunctive to levodopa) improved parkinsonism accompanying DLB without worsening cognitive function or psychiatric symptoms. Clinical trial registration JapicCTI-122040. Classification of evidence This study provides Class I evidence that Zonisamide (adjunctive to levodopa) improves parkinsonism and is well-tolerated in patients with DLB.
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randomized placebo controlled trial of Zonisamide in patients with parkinson s disease
Neurology and Clinical Neuroscience, 2016Co-Authors: Miho Murata, Kazuko Hasegawa, Ichiro Kanazawa, Kenji Kochi, Kenji Shirakura, Rieko ShimazuAbstract:Background We previously showed that Zonisamide significantly improved parkinsonian symptoms by a multicenter, double-blind clinical trial. Aim To confirm the efficacy of Zonisamide on Parkinson's disease, a phase 3, randomized, placebo-controlled, multicenter, double-blind trial was carried out in Japan. Methods Participants had advanced Parkinson's disease taking L-dopa with at least one other antiparkinson drug, but were developing a deterioration of response to L-dopa therapy. The trial consisted of a 2-week initial phase (single-blind, with administration of placebo) and a 12-week treatment phase (double-blind, with patients randomly assigned to either placebo, or Zonisamide 25 or 50 mg/day). Patients were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Results A total of 185 patients (mean age 64.8 years; mean duration 7.5 years) were included in the efficacy analysis (placebo, Zonisamide 25 mg, 50 mg; 63, 61, 61 patients, respectively). When compared with the placebo group, the UPDRS Part III total score at final assessment (the primary end-point for efficacy) significantly improved (P = 0.029) in the Zonisamide 25 mg group. After 12 weeks of therapy, the UPDRS Part III total score significantly improved in both the Zonisamide 25 mg (P = 0.038) and 50 mg groups (P = 0.049), compared with the placebo group. Neither the Zonisamide 25 mg nor 50 mg group differed significantly from the placebo group in the incidence of adverse events (P = 0.363 and P = 0.713, respectively). Conclusion These findings confirmed that Zonisamide is well tolerated and efficacious in the treatment of advanced Parkinson's disease.
Ilo E Leppik - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of adjunctive Zonisamide therapy for refractory partial seizures
Epilepsy Research, 2007Co-Authors: Michel Baulac, Ilo E LeppikAbstract:Summary An approach to the selection of appropriate antiepileptic drugs (AEDs) for inclusion in polytherapy is to take into account both the efficacy of a drug and also its mechanism of action and pharmacokinetic profile. The AED Zonisamide is licensed in Europe and the USA for use as adjunctive therapy in adult patients with partial onset epilepsy. Four pivotal clinical studies in patients with refractory partial seizures demonstrated that Zonisamide as an add-on was most effective at doses of ≥300 mg/day, with responder rates (≥50% reduction from baseline in seizure frequency) ranging from 28 to 47% for all seizures. In addition, Zonisamide has a unique combination of multiple mechanisms of action that are potentially complementary with concomitant AEDs. Zonisamide has no clinically relevant effects on the pharmacokinetics of other commonly used AEDs, however, co-administration with cytochrome P450 3A4 (CYP3A4) inducers or inhibitors may change Zonisamide's pharmacokinetic profile. Zonisamide is well tolerated with the majority of adverse events being mild-to-moderate and generally manageable. The tolerability of Zonisamide has also been shown to improve with slower drug titration and duration of drug treatment. These characteristics suggest that Zonisamide may be suitable as a key adjunct in rational polytherapy.
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practical prescribing and long term efficacy and safety of Zonisamide
Epilepsy Research, 2006Co-Authors: Ilo E LeppikAbstract:Abstract Long-term efficacy, tolerability and safety of antiepileptic drug (AED) therapy is essential given the chronic nature of epilepsy. Zonisamide (Zonegran ® ), a novel AED with a broad range of mechanisms of action contributing to its antiseizure efficacy, has been evaluated extensively for the long-term management of epilepsy. Open-label extension studies in the United States and Europe suggest continued efficacy of Zonisamide in long-term treatment without development of adverse events further to those seen in registration studies. Baseline seizure frequency is reduced by approximately 40–70% during long-term treatment for up to 2 years, and 30–50% of patients attain ≥50% reduction in seizure frequency across all categories of seizure and durations of treatment. Preliminary data indicate a progressive decline in seizure frequency with continued Zonisamide treatment. Zonisamide is well tolerated in long-term use, with a trend towards decreasing incidence of generally mild adverse events over time and a low rate of withdrawal during chronic use. Nephrolithiasis and other serious adverse events are infrequent, and can be minimised by appropriate management and patient education. This profile of maintained efficacy, tolerability and safety during sustained administration in combination with other AEDs supports Zonisamide as a valuable adjunctive agent in the long-term management of refractory partial epilepsy.
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Zonisamide chemistry mechanism of action and pharmacokinetics
Seizure-european Journal of Epilepsy, 2004Co-Authors: Ilo E LeppikAbstract:Zonisamide is a synthetic 1,2-benzisoxazole-3-methanesulfonamide with anticonvulsant properties. The sulfamoyl group on Zonisamide was expected to suppress seizures in a manner similar to another sulfonamide analogue, acetazolamide, through inhibition of carbonic anhydrase. However, this does not appear to be the primary mechanism of action since Zonisamide requires much higher doses than acetazolamide to achieve equivalent titration in vivo. Studies with cultured neurons indicate that Zonisamide blocks repetitive firing of voltage-sensitive sodium channels and reduces voltage-sensitive T-type calcium currents without affecting L-type calcium currents. Its dual mechanism of action may explain its efficacy in patients resistant to other antiepileptic drugs (AEDs). Zonisamide has a pharmacokinetic profile favorable for clinical use. It is rapidly and completely absorbed and has a long half-life (63-69h in healthy volunteers) which allows twice-daily, or even once-daily, dosing. Zonisamide is not highly bound to plasma proteins. Consequently, it does not affect protein binding of other highly protein-bound AEDs. Furthermore, Zonisamide does not induce its own metabolism and does not induce liver enzymes. However, since Zonisamide is metabolized by cytochrome P450, liver enzyme-inducing AEDs will increase Zonisamide clearance, and dosage adjustments may be necessary when it is used in combination with certain AEDs.
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randomized controlled trial of Zonisamide for the treatment of refractory partial onset seizures
Neurology, 2001Co-Authors: Edward Faught, R Ayala, G G Montouris, Ilo E LeppikAbstract:Background: Zonisamide is a sulfonamide antiepilepsy drug with sodium and calcium channel–blocking actions. Experience in Japan and a previous European double-blind study have demonstrated its efficacy against partial-onset seizures. Methods: A randomized, double-blind, placebo-controlled trial enrolling 203 patients was conducted at 20 United States sites to assess Zonisamide efficacy and dose response as adjunctive therapy for refractory partial-onset seizures. Zonisamide dosages were elevated by 100 mg/d each week. The study design allowed parallel comparisons with placebo for three dosages and a final crossover to 400 mg/d of Zonisamide for all patients. The primary efficacy comparison was change in seizure frequency from a 4-week placebo baseline to weeks 8 through 12 on blinded therapy. Results: At 400 mg/d, Zonisamide reduced the median frequency of all seizures by 40.5% from baseline, compared with a 9% reduction ( p = 0.0009) with placebo treatment, and produced a ≥50% seizure reduction (responder rate) in 42% of patients. A dosage of 100 mg/d produced a 20.5% reduction in median seizure frequency ( p = 0.038 compared with placebo) and a dosage of 200 mg/d produced a 24.7% reduction in median seizure frequency ( p = 0.004 compared with placebo). Dropouts from adverse events (10%) did not differ from placebo (8.2%, NS). The only adverse event differing significantly from placebo was weight loss, though somnolence, anorexia, and ataxia were slightly more common with Zonisamide treatment. Serum Zonisamide concentrations rose with increasing dose. Conclusion: Zonisamide is effective and well tolerated as an adjunctive agent for refractory partial-onset seizures. The minimal effective dosage was 100 mg/d, but 400 mg/d was the most effective dosage.
Michel Baulac - One of the best experts on this subject based on the ideXlab platform.
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long term safety and efficacy of Zonisamide versus carbamazepine monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy results of a phase iii randomized double blind study
Epilepsia, 2014Co-Authors: Michel Baulac, Anna Patten, Luigi GiorgiAbstract:SummaryObjective To investigate the long-term safety and maintenance of efficacy of monotherapy with once-daily Zonisamide versus twice-daily controlled-release carbamazepine for partial seizures in adults with newly diagnosed epilepsy. Methods Long-term, double-blind, extension study, conducted in patients completing a phase III noninferiority trial comparing Zonisamide and carbamazepine monotherapy. Patients continued their randomized treatment, with dosing adjusted according to tolerability/response (Zonisamide 200–500 mg/day; carbamazepine 400–1,200 mg/day). Safety assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory parameters. Efficacy assessments included retention rate and the proportion of patients remaining seizure free for ≥24 months. Results Overall, 120 (87.6%) of 137 patients randomized to Zonisamide and 134 (84.8%) of 158 patients randomized to carbamazepine completed the study. More than three-fourths of patients were exposed to >24 months of treatment. For Zonisamide versus carbamazepine, incidences were similar for TEAEs (52.6% vs. 46.2%), serious treatment-related TEAEs (0.7% vs. 1.9%), and TEAEs leading to withdrawal (1.5% vs. 0.6%). The incidence of treatment-related TEAEs was 26.3% for Zonisamide compared with 19.6% for carbamazepine, and the most frequently reported treatment-related TEAEs were decreased weight (5.1% vs. 0%), decreased appetite (3.6% vs. 0%), memory impairment (2.9% vs. 3.2%), and decreased hemoglobin level (1.5% vs. 3.2%). Most TEAEs were of mild or moderate intensity. There were no reports of Stevens-Johnson syndrome or toxic epidermal necrolysis in either group. Zonisamide was associated with small-to-moderate decreases in bicarbonate levels from baseline (mean −3.4 mm). There were no reports of metabolic acidosis. Retention rates were generally similar between treatment groups at all time points throughout the extension study. The proportion of patients remaining seizure free for ≥24 months was also similar for Zonisamide (32.3%) and carbamazepine (35.2%). Significance Once-daily Zonisamide monotherapy demonstrated favorable long-term safety and maintenance of efficacy in treating partial seizures in adults with newly diagnosed epilepsy. No new or unexpected safety findings emerged.
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efficacy and tolerability of Zonisamide versus controlled release carbamazepine for newly diagnosed partial epilepsy a phase 3 randomised double blind non inferiority trial
Lancet Neurology, 2012Co-Authors: Michel Baulac, Joanna Segieth, Anna Patten, Martin J Brodie, Luigi GiorgiAbstract:Summary Background Additional options are needed for monotherapy treatment of adults newly diagnosed with partial epilepsy. This trial compares the efficacy and tolerability of once-daily Zonisamide with twice-daily controlled-release carbamazepine monotherapy for such patients. Methods In this phase 3, randomised, double-blind, parallel-group, non-inferiority trial, adults from 120 centres in Asia, Australia, and Europe, aged 18–75 years and newly diagnosed with partial epilepsy, were randomly assigned (in a 1:1 ratio, done with a computer-generated pseudorandom code) to receive Zonisamide or carbamazepine. Patients, investigators, and sponsor personnel giving drugs, analysing outcomes, and interpreting data were masked to treatment allocation. After treatment initiation (Zonisamide 100 mg/day vs carbamazepine 200 mg/day [given in two doses]) and up-titration (to 300 mg/day vs 600 mg/day), patients entered a 26–78 weeks flexible-dosing period (200–500 mg/day vs 400–1200 mg/day, according to response and tolerance). Once patients were seizure-free for 26 weeks they entered a 26-week maintenance phase. The primary endpoint was the proportion of patients who achieved seizure freedom for 26 weeks or more in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00477295. Findings 583 patients were randomly assigned to treatment groups (282 Zonisamide, 301 carbamazepine), of whom 456 were analysed for the primary endpoint (per-protocol population: 223 Zonisamide, 233 carbamazepine). 177 of 223 (79·4%) patients in the Zonisamide group and 195 of 233 (83·7%) patients in the carbamazepine group were seizure-free for 26 weeks or more (adjusted absolute treatment difference −4·5%, 95% CI −12·2 to 3·1). The incidence of treatment-emergent adverse events was 170 (60%) in the Zonisamide group versus 185 (62%) in the carbamazepine group, of which 15 (5%) versus 17 (6%) were serious and 31 (11%) versus 35 (12%) led to withdrawal. Interpretation Zonisamide was non-inferior to controlled-release carbamazepine—according to International League Against Epilepsy guidelines—and could be useful as an initial monotherapy for patients newly diagnosed with partial epilepsy. Funding Eisai Ltd.
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efficacy and safety of adjunctive Zonisamide therapy for refractory partial seizures
Epilepsy Research, 2007Co-Authors: Michel Baulac, Ilo E LeppikAbstract:Summary An approach to the selection of appropriate antiepileptic drugs (AEDs) for inclusion in polytherapy is to take into account both the efficacy of a drug and also its mechanism of action and pharmacokinetic profile. The AED Zonisamide is licensed in Europe and the USA for use as adjunctive therapy in adult patients with partial onset epilepsy. Four pivotal clinical studies in patients with refractory partial seizures demonstrated that Zonisamide as an add-on was most effective at doses of ≥300 mg/day, with responder rates (≥50% reduction from baseline in seizure frequency) ranging from 28 to 47% for all seizures. In addition, Zonisamide has a unique combination of multiple mechanisms of action that are potentially complementary with concomitant AEDs. Zonisamide has no clinically relevant effects on the pharmacokinetics of other commonly used AEDs, however, co-administration with cytochrome P450 3A4 (CYP3A4) inducers or inhibitors may change Zonisamide's pharmacokinetic profile. Zonisamide is well tolerated with the majority of adverse events being mild-to-moderate and generally manageable. The tolerability of Zonisamide has also been shown to improve with slower drug titration and duration of drug treatment. These characteristics suggest that Zonisamide may be suitable as a key adjunct in rational polytherapy.
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introduction to Zonisamide
Epilepsy Research, 2006Co-Authors: Michel BaulacAbstract:Abstract Zonisamide (Zonegran ® ), a novel antiepileptic drug (AED) approved recently in Europe as adjunctive therapy for refractory partial seizures in adults, has been used extensively in Japan and the United States. A substantial body of clinical experience has accumulated over a 14-year period, allowing the properties and pharmacologic/clinical profiles of Zonisamide to be clearly defined. Zonisamide is structurally distinct from other AEDs and has multiple and complementary mechanisms of action, which likely contribute to its efficacy across a broad range of epilepsy types. Zonisamide has a long T 1/2 enabling once-daily dosing, linear pharmacokinetics and minimal interaction with other drugs; plasma levels of commonly administered AEDs and oral contraceptives are unaffected by concomitant Zonisamide. Effective control of partial seizures (up to 51% decrease in seizure frequency) is attained at doses of ≥300mg/day, and optimal titration and maintenance dosing schedules have been established. The adverse event profile is well defined; in common with most AEDs, most adverse events are central nervous system-related (e.g. somnolence, dizziness, tiredness). Adverse events may be minimised with appropriate patient management. Zonisamide therefore has many characteristics considered desirable in an AED and represents a valuable addition to the therapeutic options for treating epilepsy in Europe.
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long term efficacy and safety of Zonisamide for treatment of parkinsonism in patients with dementia with lewy bodies an open label extension of a phase three randomized controlled trial
American Journal of Geriatric Psychiatry, 2021Co-Authors: Toshinari Odawara, Kazuko Hasegawa, Masaaki Tagawa, Kenji Kosaka, Ritsuko Kajiwara, Hisao Takeuchi, Miho MurataAbstract:Abstract Objectives To evaluate the long-term efficacy and safety of Zonisamide, an antiepileptic agent, in dementia with Lewy bodies (DLB). Design Phase 3 clinical trial with 12-week, randomized, placebo-controlled, double-blind, and subsequent 40-week, open-label, extension periods. Setting 109 centers in Japan between April 2015 and November 2017. Participants Outpatients diagnosed with probable DLB. Intervention Outpatients were randomly assigned to receive placebo (P) or Zonisamide 25 or 50 mg/day for 12 weeks. In the subsequent open-label 40-week period, all patients initially received Zonisamide 25 mg/day for at least 2 weeks followed by optional flexible dosing with Zonisamide 25 or 50 mg/day for the remaining period. Measurements The primary outcome was efficacy on motor symptoms, assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score, over the total 52-week trial period. Effects on behavioral and psychological symptoms of dementia and cognitive function, and safety were also evaluated. Results In total, 335 patients were included in the long-term analysis: 106, 117, and 112 in the P-, 25mg-, and 50mg-Flex groups, respectively. UPDRS-III score continued to improve for an additional 12–16 weeks in the open-label period (mean [standard deviation] change from baseline at Week 28: −5.1 [7.3] and −6.3 [8.2] in the 25mg- and 50mg-Flex groups) and remained almost constant thereafter. No unexpected neurological or psychiatric adverse events occurred, and no adverse events increased in incidence in the open-label period. Conclusions Long-term treatment with Zonisamide was well tolerated and yielded sustained improvement in motor symptoms. Trial registration JapicCTI-152839 (Registered on 9 March 2015) https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-152839
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effect of Zonisamide on parkinsonism in patients with dementia with lewy bodies a phase 3 randomized clinical trial
Parkinsonism & Related Disorders, 2020Co-Authors: Miho Murata, Kazuko Hasegawa, Toshinari Odawara, Masaaki Tagawa, Ritsuko Kajiwara, Hisao Takeuchi, Kenji KosakaAbstract:Abstract Introduction Zonisamide is approved in Japan for treating motor dysfunction in Parkinson's disease, and might also be effective for parkinsonism in patients with dementia with Lewy bodies (DLB). Our study evaluated the safety and efficacy of Zonisamide for treating parkinsonism in patients with DLB. Methods This multicenter, randomized, double-blind, phase 3 trial was conducted in Japan between April 2015 and November 2017. Following a 4-week run-in period, outpatients diagnosed with probable DLB who had developed parkinsonism were randomized to receive oral Zonisamide (25 or 50 mg/day) or placebo for 12 weeks, followed by a 40-week open-label extension. The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part III total score at Week 12. Results Of 351 patients randomized, 346 (mean age, 77.2 years; 188 males) were included in the modified intention-to-treat population. At Week 12, the group difference (least squares mean ± SEM) for changes from baseline (vs placebo) in UPDRS part III total score was −2.7 ± 0.9 (95% confidence interval [CI]: −4.4, −0.9, P = 0.005) in the Zonisamide 25-mg group and −2.6 ± 0.9 (95% CI: −4.4, −0.8, P = 0.005) in the Zonisamide 50-mg group. Adverse events were reported in 47.1%, 48.7%, and 54.5% of patients in the placebo and Zonisamide 25- and 50-mg groups, and led to treatment discontinuation in 5.0%, 4.3%, and 9.8% of patients, respectively. Conclusion Daily administration of 25- or 50-mg Zonisamide significantly improved motor function compared with placebo; both doses were safe and well tolerated in patients with DLB.
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adjunct Zonisamide to levodopa for dlb parkinsonism a randomized double blind phase 2 study
Neurology, 2018Co-Authors: Miho Murata, Kazuko Hasegawa, Toshinari Odawara, Sayaka Iiyama, Masatoshi Nakamura, Masaaki Tagawa, Kenji KosakaAbstract:Objective To investigate the efficacy and safety of Zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with dementia with Lewy bodies (DLB). Methods This phase 2, placebo-controlled, randomized, double-blind study consisted of run-in (placebo, 4 weeks) and treatment (placebo or Zonisamide 25 or 50 mg once daily, 12 weeks) periods. Outpatients diagnosed with probable DLB were eligible for inclusion. The primary endpoint was the change from baseline in Unified Parkinson9s Disease Rating Scale (UPDRS) part 3 total score at week 12. Cognitive function, behavioral and psychological symptoms of dementia (BPSD), caregiver burden, other UPDRS parts as secondary endpoints, and safety were also assessed. Results Overall, 158 patients with DLB received the study drug; 21 discontinued during treatment and 137 completed treatment. Improvement in UPDRS part 3 total score at week 12 was significantly greater in the Zonisamide 50 mg group compared with placebo (between-group difference −4.1; 95% confidence interval −6.8 to −1.4; p = 0.003). Zonisamide did not worsen cognitive function, BPSD, or caregiver burden. The overall incidence of adverse events was higher in the Zonisamide 50 mg than the 25 mg and placebo groups (65.3%, 43.1%, and 50.0%, respectively); similar rates of serious adverse events were observed among all groups. Conclusion Zonisamide (adjunctive to levodopa) improved parkinsonism accompanying DLB without worsening cognitive function or psychiatric symptoms. Clinical trial registration JapicCTI-122040. Classification of evidence This study provides Class I evidence that Zonisamide (adjunctive to levodopa) improves parkinsonism and is well-tolerated in patients with DLB.
